This review, broadcast from the Amgen campus in Thousand Oaks, California.
Hello, everyone, and thank you for joining us. We'll be talking to you mostly today about the future of our business, and in particular, what we expect to deliver through 2030. As we think about what's next, we're encouraged by our past accomplishments, and we're ready and looking forward to delivering on the future for patients and shareholders. As the industry's response to the pandemic has shown, this is an extraordinary time for biotechnology. Science and technology are converging in ways that are accelerating the cadence of innovation in our field. Though our industry is not without its challenges, we believe the fundamentals remain very attractive for global companies that are able to innovate at speed. We expect to be one of those companies. We've been a leader in biotechnology for the past 40 years, and we think we're well-positioned to maintain that leadership for decades to come.
Our goal today is to share with you the reasons why we're excited about the future. As we talk to you today, our comments will be governed by these elements of our safe harbor statement. Now, here's what we'll cover. I'll provide an overview of our business through 2030. Peter Griffith will then review our 2021 financial results and provide guidance for 2022 and guidance through the end of the decade, including our perspectives on capital allocation. Murdo Gordon and Susan Sweeney will review our key growth products, and the reasons why they're confident in the outlook for our brands through 2030.
David Reese will discuss the dozen or so potential first-in-class medicines that are advancing through our late and mid-stage pipeline, medicines that have the potential to help many patients and accelerate growth in 2025 and beyond. Dave will then be joined by two additional leaders from our R&D organization, Raymond Deshaies and Alan Russell, to discuss the capabilities we've recently added to our research organization, positioning us for long-term success in the discovery field. While the bulk of our time today will be focused on the future, I thought it might be instructive to take a few minutes to reflect on the past. Let me remind you what we said we were gonna do in the past. First, if you look back over the past decade, we said we were gonna launch a wave of new innovative medicines, and that's what we did.
Since 2012, we've launched 10 novel medicines directed at cancer, heart disease, osteoporosis, and other serious illnesses, building a broad base for our business. We said we would roughly double the number of countries in which we do business around the world, and we did that, too, creating a global platform for our innovation without diluting returns or drawing on significant shareholder capital to do it. We said we would leverage our installed capabilities and build an industry-leading biosimilars business that would be accretive to earnings and shareholder value, and we've done that, launching five biosimilars around the world on time and on budget that collectively generated $2 billion or more than $2 billion of revenues last year. We have six more molecules to come.
We said we would launch our ecologically and economically efficient manufacturing of the future, and we've done that, too, in Singapore and soon in Rhode Island as well, enabling us to uphold our record of serving every patient every time, even during a pandemic that has wreaked havoc on global supply chains. We said we would do all this, launch new products, expand into new countries, invest in manufacturing, and still increase our operating margins, and we did that, too. From 38% in 2012, we now consistently deliver industry-leading operating margins north of 50%, driven by productivity efforts that are embedded in every aspect of our business. As for capital allocation, we said we would look to strengthen our company through business development, and that's what we've done.
Over the past decade, we've invested more than $30 billion in nearly three dozen significant deals, including three already announced this year. We said we would return capital to shareholders, and we've done that, returning some $75 billion to shareholders since 2012 through our share repurchases and a dividend that's risen six-fold since inception. Finally, a decade ago, we were often asked if we could grow through patent expiration. We thought we could, and as you know, we did. Revenues grew by 5% per year, EPS grew by 2.5-fold, and shareholder value more than tripled. Even if the past is not prologue, I hope that quick look back has given you a sense that when we talk about what we're planning to do next, we're building on a foundation of solid execution.
Looking back, I hope you can also see an important fundamental of our business, which is that we're heavily weighted to biologics, and we have skill in managing them throughout the whole of their life cycle, a capability which we expect to serve us well in the future as it has in the past. Cash flows from biologic products don't disappear overnight following loss of exclusivity, as is the case with small molecules. A decade ago, about 40% of our revenues, largely biologic, were exposed to loss of exclusivity. Those biologic products today still account for about 10% of our revenues. If you're measuring our business for quarterly performance, the slow erosion is a drag.
If you're measuring our business for long-term cash flows, those residual biologics margins are clearly an asset to be managed thoughtfully. Those residual biologics margins enabled us a decade ago to invest in efforts like our international expansion, our biosimilars development, new manufacturing technologies, and there's no question that we will reap the benefit of those investments over the coming decade. Though we don't have any biologics patent expiries still for several years, we'll approach them in the future as we did in the past and seek to repeat our success. Now let's look forward.
Similar to what we achieved over the past decade, when we look at the products and opportunities that we have in hand and take into account the likely competition and industry pressures that we see, we believe we can deliver mid-single-digit revenue growth and more than double our EPS through the end of the decade. Now, this is an organic outlook, so any growth from business development would be additive to these numbers. How will we do it? Well, that'll be the focus of our presentations today. We don't think we're taking a great leap of faith in giving this outlook. We think we're banking on our ability to execute against known opportunities. Our future doesn't hinge on one product or one clinical trial or in one country. Amgen has a broad portfolio of 25 products across three major therapeutic categories.
Many of these products have the momentum of their established efficacy and safety profiles and are clearly poised for continued growth. We do business now in 100 countries around the world, and many of these are also poised for considerable growth during the decade. Our pipeline is robust at all stages, and our balance sheet is strategically strong. We think we have the pieces in place that we need to succeed, and no single piece will disproportionately tell the tale. It's our job now to execute across the board. While the success factors for Amgen moving forward may be familiar, we recognize that the world that we live in has changed, and we've worked hard to anticipate many of these changes, trying to stay ahead of the curve. I'll just give you two examples.
First, we all know there's intense price pressure on prescription drugs, and the impact of the pandemic on economies around the world will only increase this. Irrespective of what may or may not come out of Washington, the direction of travel is clear. Prices will continue to come down, and our business is built around that assumption. How have we positioned ourselves to succeed in this environment? Well, we've focused on being first and best and having first and best in class medicines that deliver significant benefits in areas of high unmet need and that demonstrate clear value to patients and the healthcare system. We've also positioned our portfolio to feature medicines that can grow through volume, not just through price increases. Our fully integrated biosimilars business saves money for the healthcare system, thereby freeing up funds for our innovative offerings.
Second, we recognize there's tremendous life cycle compression in our industry. Growing competition, narrowing landscapes for intellectual property, and technological leapfrogging all have the same effect, fewer years to earn a return on innovation, and that puts a premium on speed. We've taken steps to significantly reduce our cycle times across the business, and especially in R&D, where on average, we've been able to eliminate three years out of the life cycle of the development of a new medicine. With Lumakras, we delivered one of the fastest cycle times in industry history. While many companies are pursuing their own KRAS inhibitors, Lumakras remains the only one approved anywhere in the world. Nearly 40 countries now and still counting. Lumakras is far from our only first. We have a history of them. Prolia and Xgeva, they were the first antibodies against RANKL ligand in bone health.
Repatha was the first PCSK9 inhibitor for high cholesterol. Aimovig was the first CGRP inhibitor for migraine. BLINCYTO, the first approved bispecific T-cell engager for cancer. Of course, Tezspire, the first approved TSLP inhibitor for severe asthma. To succeed in our industry, you're going to have to be fast, and we're confident that we are that, and we're confident that there are many more firsts still to come at precisely the time when being first matters most. While the world has certainly challenged or changed rather in ways that are challenging, other changes represent extraordinary opportunities. Take demographics. The world's growing older, right? That's the future that is certain. There are already 700 million people worldwide over the age of 65 coping with diseases of the aging process like cancer, heart disease, and osteoporosis.
These individuals consume 3x as much health care as those under the age of 65. By 2030, another 150 million people will have joined the over-65 club. If you do the math, there'll be huge demand for what we do through 2030 and beyond. Innovation is another. There's never been a better moment for innovating than now. The protein folding problem, for example, was considered to be one of the grandest challenges in biology for 50 years, and the solution to the problem was reported on July 22nd last year. There's no question that this will increase the speed and success of biologics discovery.
Closer to home with Lumakras, we achieved something that had eluded cancer researchers for more than 40 years, offering new hope to patients with KRAS G12C mutated cancers. It's not a coincidence that we're seeing these decades-old challenges being solved at this particular moment in time. As I said at the outset, we're entering an extraordinary new era in biotechnology, a moment where both the need for innovation and our ability to innovate are expanding exponentially. That's good news for Amgen. We intend to ride this wave of opportunity and not watch it pass us by. You see our strategy here, and we've made some adjustments to it over time, but the fundamentals remain in place and will guide our focus to 2030. At the heart of our strategy are innovative medicines that make a significant difference for patients around the world suffering from serious diseases.
You look at our portfolio and all the firsts I just mentioned, for example, or you look at the pipeline that Dave Reese is gonna review with you, every molecule that we speak to you about today from the pipeline is a potential first-in-class medicine, and the world needs more innovation, and we're bringing it. At a time of extraordinary scientific progress, we recognize that great ideas are happening everywhere, not just at Amgen, and we want the best innovation we can get our hands on, whether internally or externally generated. Historically, roughly half of Amgen's revenues have come from products discovered internally, while the other half has come from products that we've acquired or licensed. We'll continue to be active deal makers moving forward in our stated areas of interest.
I would note that any growth coming from external sources will be additive to the financial outlook we're sharing with you today. It's not lost on us that the recent decline in valuations for many biotech assets could create more compelling opportunities for us, and we have the financial strength and the flexibility to consider a wide range of possibilities. Where are we looking to innovate? You can expect us to remain focused in inflammation, oncology, and general medicine. These are categories where innovative medicines have already demonstrated tremendous value to patients and the healthcare system. To give just one example, the death rate for cancer in the United States peaked in 1991 and has been steadily declining ever since, falling by more than a quarter.
Fully half of this decline is attributed to the growing number of innovative cancer medicines that have become available to patients. Despite this progress, there are still categories, or these are still categories where we see millions of patients in need. We know the pandemic has overshadowed other health concerns for the past two years, and that's understandable. The pandemic will eventually recede. When it does, we expect society to turn its attention to solving some of the massive health challenges that we know haven't gone away, and we're ready. You'll hear more shortly about that from Murdo, Susan, and Dave Reese, who will share with you their perspectives on the growth opportunities that we see in each of our focus areas through the end of the decade. Another key element of our strategy is to capitalize on the investments we made to expand our geographic presence.
We're especially excited about our growth prospects in the Asia-Pacific region, where for many years we did business largely through partners. In Japan, for example, we only took full ownership of our business in 2020, and our portfolio of products there is particularly well suited to the needs of what is the world's oldest population. In China, our oncology collaboration with BeiGene is going very well, even as we continue to independently grow our general medicines business through products like Repatha and Prolia. Overall, we expect sales outside the U.S. to account for roughly 35% of our total sales by 2030, up from less than 30% today. Now I'd like to spend a moment on discovery research, our engine for growth beyond 2030. We've been actively building differentiated research capabilities in three particular areas that are rapidly emerging in our industry.
These are human data, multi-specific drugs, and generative biology. We've been active internally and externally in these areas, and we think they'll each play a prominent role in our future. We thought it was appropriate today to share some of the thinking behind our strategy with you. Our established leadership in human genetics is paving the way for us to build a competitive advantage in personalized medicine and the broader use of human data for target discovery and drug development. With our multi-specific drug capabilities, we're no longer willing to accept that 85% of the targets in humans are undruggable. Already two-thirds of our preclinical molecules are multi-specifics. With our decades of leadership in large molecules, we're already quickly capitalizing on machine learning and automation in the new field of generative biology.
You'll hear more about all of these areas from Dave, Ray, and Alan shortly. Underpinning and enabling everything we do is our commitment to being a responsible corporate citizen. The past few years have certainly raised the bar in terms of what's expected for corporations, and that's a welcome development here at Amgen. We've long embraced our responsibility to be a good corporate citizen. Let me just give you a few examples. More than 30 years ago, we created the Amgen Foundation to inspire the next generation of scientists. This year, the foundation's science education programs will reach nearly 24 million students worldwide.
More than 20 years ago, we created the Amgen Safety Net Foundation to help patients in financial need gain access to our medicines at no cost, including $6 billion worth of medicines in just the past five years. 15 years ago, we began implementing a series of projects to reduce our impact on the environment. Now we're aiming even higher with plans to achieve carbon neutrality by 2027. We're grateful for the recognitions we've achieved from a number of external organizations, and we're eager to do more. We'll be publishing our next environmental, social, and governance report in April, and ESG is an element of our corporate goals for 2022, as it was last year. As I wrap up, I hope you've gotten a clear sense from me that I'm excited about Amgen's future and the value I think we can create for patients and shareholders.
I think you'll see that excitement is shared by the rest of the team, too. Our people believe in Amgen's mission to serve patients, and they understand the role they play in advancing that mission. They've executed exceptionally well under very challenging circumstances these past two years. The commitment they've shown to patients, to our business, and to each other during these difficult times has been nothing short of extraordinary. I'm very grateful to all of them. You know, of the thousands of companies that were founded during the biotech revolution of the 1980s, only two of note remain independent to this day, and one of them is Amgen. That's not by chance. We wake up every morning knowing that in our business, we innovate or we disappear. We've had great people delivering great innovation throughout our history.
I'm convinced that we have the right people and we have the right focus to remain a leader through the end of this decade and beyond. Now, I'll turn things over to Peter Griffith in a moment, but before I do, let me just say that we understand we earn the right to compete over the long term by delivering in the near term. We delivered our targets in 2021, and clearly, 2022 is a year that will still be where we'll still be affected by the pandemic and by pricing pressures from competitive products. But we see this as a year that will set the stage for the long-term growth that I've just described. The fundamentals of our growth story are in place, as Peter will describe to you in some detail. Now let's turn to Peter.
Thank you, Bob. Before turning to 2021, let me also reiterate Amgen's strong record of accomplishment and execution, and that we are extremely excited about the future value we believe we can deliver for patients, shareholders, and staff. Since 2012, we have realized revenue and non-GAAP EPS growth of 5% and 11%, respectively. We are well-positioned to deliver long-term growth. From now through 2030, we expect mid-single-digit revenue and high single-digit to low double-digit non-GAAP EPS growth, respectively. Recall in 2014, we committed to margin improvement, and we have since consistently delivered on a 50% non-GAAP operating margin with focus efforts in productivity and efficiency, including our next-generation manufacturing capability that saves time, space, and money, that adds flexibility, and that contributes significantly to meeting the environmental goals that are part of our ESG efforts.
From 2021, cost of sales was about 1.3 percentage points lower by moving to this technology versus utilizing the traditional fed-batch manufacturing approach. Process improvement, simplification, and digitalization are indisputably important to deliver results for patients, shareholders, and staff. With revenue growth, efficiency, and a strong biologics portfolio, we have driven stable and consistent cash flows, enabling both internal and external innovation, as well as attractive shareholder payouts. Free cash flow was $85 billion from 2012- 2021, growing from $5.2 billion in 2012 to $8.4 billion in 2021. We expect our cash flows to continue to be strong through 2030.
We had a shareholder payout ratio of well over 70% over the 2012- 2021 period, comprising about $28 billion of dividends and $48 billion of share repurchases. Recall that the higher level of share repurchases in 2018 and 2019 were primarily a function of U.S. tax reform. When we normalized the payout ratio in this period, it was roughly 70%. Let's turn now to our full year 2021 financial results. You've had the opportunity to review the press release, so I will focus on the fiscal year highlights. Total revenue grew 2% on a year-over-year basis. Within that, product sales were flat with strong volume growth of 7%, offset by decreases in net selling prices of 7%.
Foreign exchange had a -1% impact on growth, which was more than offset by about $400 million of favorable changes to estimated sales deductions. Volume growth continued to be negatively impacted by the cumulative effect of COVID on diagnoses and treatment rates since the onset of the pandemic. Total revenue benefited from about $400 million in other revenue from our partnership with Lilly in manufacturing COVID-19 antibodies.
Strong expense discipline resulted in a 51% operating margin, while we continued to invest in both internal and external innovation. In addition to the $3.2 billion in upfront payments we paid for external innovation that we excluded from our non-GAAP results, we did layer in about $300 million in our non-GAAP operating expenses related to the acquisitions of Five Prime , Teneobio, and Rodeo Therapeutics Corporation, as well as the licensing transactions with Kyowa Kirin, Generate Biomedicines, and Arrakis Therapeutics. Full-year non-GAAP EPS grew 6% year-over-year to a record $17.10. We generated $8.4 billion in free cash flow for the year. Total dividend payments in 2021 were about $4 billion as we grew the dividend by 10% from 2020, and we grew it an additional 10% from Q4 2021 to Q1 2022.
Total share repurchases were about $5 billion in 2021. With our strategy established and our execution during COVID strong, we are confident about the long-term growth prospects for the company. Let's turn to our long-term outlook. We prepared many years ago for the evolving pricing environment, particularly that related to the United States. As a result, we increased our focus on embedding productivity initiatives across the company, in addition to increasing our focus on innovative products that also drive volume growth. As anticipated, we and the industry have experienced net selling price pressure since 2018 and expect to continue to operate in a declining net price environment going forward. Recall net selling prices had risen for the previous four decades, but we saw the pricing pressure coming and have adjusted while keeping our fundamentals intact.
Our long-range plan projects meaningful volume growth that will more than offset projected price declines and will result in strong revenue growth. In a declining price environment, we have also accelerated digitalization, automation, and process simplification efforts, which are keys to success in declining price industries. Finally, speed is required to make sure revenue growth leads expense growth. We are working faster and faster. You've heard about our Lumakras development program from first-in-human to FDA filing in 28 months. In manufacturing, we made our first COVID antibody shipment to Lilly about six months after signing the agreement. Commercially, the first Tezspire patient obtained their medicine within three days of approval. As Bob stated, we expect mid-single-digit revenue growth and high single-digit to low double-digit EPS growth from 2022- 2030.
Between our marketed products, upcoming biosimilar launches, innovative and longer-range biosimilar pipeline, and with sales from new products more than offsetting the impact of future competition for Denosumab, Otezla, and Enbrel, we are confident in our long-term growth through the end of the decade. We plan our quality of execution high and we will achieve an operating margin as a percent of sales of roughly 50% despite a declining net price environment. We project a payout ratio of greater than 60% of non-GAAP net income on average through 2030. I'll come back and provide more details on our long-range guidance after reviewing our 2022 guidance. For 2022, we are expecting revenue of $25.4 billion-$26.5 billion, an EPS of $17-$18.
The revenue range is a bit wider than recent history, and the top end of it is predicated on the possibility of additional COVID antibody manufacturing revenue, which I'll discuss later in my remarks. On a portfolio basis, we expect net selling prices to decline in the mid- to high-single digits, driven primarily by Neulasta and our biosimilar portfolio. Let me start with Neulasta, which continues to be the most preferred long-acting filgrastim product for patients and physicians. Neulasta exited Q4 2021 with 61% U.S. volume share, and the Onpro kit still represents nearly half of the volume of the total long-acting filgrastim segment. However, we expect the declining pricing trends for Neulasta to continue into 2022. Average selling price in the U.S. declined 32% in 2021 versus 2020, following a 15% decline from 2019.
Given our projection of this continuing trend, we expect 2022 worldwide Neulasta sales to be between $900 million and $1 billion. Regarding biosimilars, we see that portfolio growing to more than double by 2030. With no new significant biosimilar launches in 2022, we expect biosimilars to decline in 2022 before returning to growth in 2023 on the U.S. launch of Amjevita in January of next year. Enbrel is our largest brand. With its strong track record of safety and efficacy, it has a very important role for rheumatology and dermatology patients and providers. We note that the pace of volume decline for Enbrel has been slowing over the last three quarters. In fact, in Q4 2021, we delivered 2% sequential volume growth. Recall that Enbrel benefited from about $250 million of accounting adjustments in 2022 that may not repeat in 2022.
Excuse me, of accounting adjustments in 2021 that may not repeat in 2022. Foreign exchange had an adverse impact on our fourth quarter 2021 sales, and based on current rates, is expected to create a roughly $200 million year-over-year headwind to product sales in 2022. Recall, however, that we have an effective hedging program that partially mitigates the foreign exchange impact on our net income on a full-year basis. In total, our 2022 non-GAAP EPS guidance includes a negative impact from foreign exchange of approximately 1%. Switching to our view on the effects of COVID generally and the recent Omicron surge, we continue to anticipate some uncertainty and quarter-to-quarter variability in revenue and earnings in the first half of 2022. I previously mentioned that we had about $400 million of other revenue from our Lilly partnership.
COVID-related manufacturing partnership opportunities remain dynamic, and we look to utilize our world-class manufacturing capabilities to help in the fight against the pandemic. Therefore, we are guiding to a range of $1.4 billion-$1.7 billion for other revenue in 2022. We expect non-GAAP cost of sales as a percent of product sales will be in the range of 15.5%-16.5%. Non-GAAP research and development is expected to increase between 3%-5% year-over-year as we continue to invest in internal innovation across all the stages of R&D. Non-GAAP SG&A will be roughly flat to 2021, with productivity gains fueling investment in launches and geographic expansion. Within SG&A, we are continuously reallocating capital away from our lower opportunity brands to the highest opportunity growth brands, including Repatha and Otezla. All of this results in our non-GAAP operating margin guidance of approximately 50%.
For other income and expense, we had about a $285 million benefit from our share of BeiGene due to a combination of, first, a gain from dilution of our ownership stake when they raised capital on the Shanghai STAR Exchange in December, and second, their recognition of a large upfront license payment from a partner that we recorded in the second quarter of 2021. For 2022, we are guiding other income and expense to a range of $1.4-$1.6 billion of expense. We expect a non-GAAP tax rate in the range of 13%-14%. We expect capital expenditures of approximately $950 million, primarily increasing due to construction around our new facilities in Ohio and North Carolina, in which we also will further strengthen our leadership in environmental imperatives.
Just to wrap up on 2022, recall that the first quarter is historically our lowest revenue quarter due primarily to the effect of insurance reverifications, co-pays, and deductibles for patients, which is most pronounced for Otezla and Enbrel. Thus, we expect to see their historical patterns of lower sales in the first quarter. In addition, we expect to see the effects from the Omicron surge also impact our first quarter results. Overall, we expect total revenues in the first quarter to be approximately flat when compared to the first quarter of 2021. Let us now come back to long-term guidance. We expect to generate strong financial results through the end of the decade, and we see accelerating growth in 2023. We expect this accelerating growth to come from the U.S.
launch of Amjevita, from continuing post-launch momentum from Tezspire and Lumakras, and in addition to continued growth from key brands, including Repatha, Otezla, Prolia, and Evenity. Let me remind you that we expect our biosimilar sales to more than double from 2021 levels by 2030, and that our biosimilars are not dilutive to our overall operating margin. This growth reflects layering in six new products on top of our existing five. While individual products may peak quickly and even turn down, in the aggregate, the portfolio will grow to a profile similar to one super blockbuster, yet with a lower risk profile versus just one innovative asset. Overall, our product portfolio is attractive given its diversity, both geographically and therapeutically, as well as its durability. Our portfolio effectively transitions through loss of exclusivities and competition and doesn't hinge on a single product.
This revenue profile, combined with our efficient operating model, is projected to deliver high single-digit to low double-digit EPS growth with an approximately 50% operating margin that effectively prioritizes investing in innovation wherever the best innovation is found, internal or external. Cost of sales will increase with the mix of products and also due to royalties and profit share payments. We expect our manufacturing cost per unit to decrease over the period. Research and development expense will increase to greater than $6 billion by 2030, of which we expect to allocate approximately $1 billion of the $6 billion or about 15% of our R&D budget to our research engine, which will fuel growth from 2030 and beyond. SG&A expense through 2030 will continue to benefit from our ongoing productivity efforts and digitalization, which will result in it being flat to declining as a percentage of product sales.
Our commercial group continues to dynamically reallocate resources towards the brands with the greatest potential to serve patients and generate after-tax cash flows for our shareholders. We are not including any potential tax reform in our estimates through 2030. Now let's turn to our capital allocation hierarchy. Our capital allocation hierarchy remains unchanged and uninterrupted. It starts with internal and external innovation focused on our core therapeutic areas wherever the best innovation for patients is found. Our internal innovation starts with research and development investments, which we expect to grow through 2030. Our external innovation sits right alongside internal innovation. We have a strong track record of value-generating deals across the commercialization spectrum and ones where we are confident that we will deliver returns to our shareholders, not just the shareholders of the sellers.
Our capital allocation goes to capital expenditures, primarily to maintain our industry-leading protein engineering and manufacturing capabilities. Our next-generation drug substance plant in Rhode Island was licensed in January, right on schedule and on budget, and meets our high level of standards for sustainability. We evaluate each of our projects for the impact on our ESG goals and work to assure that lines up with our commitment to be a leader in our industry on ESG achievements. I just wanna note that we expect to return to our historical levels of capital expenditures after we complete our Ohio and North Carolina facilities. After capital expenditures, we return capital to shareholders through growing dividends and then through opportunistic share repurchases. The foundation of our capital allocation hierarchy is an efficient capital structure that results in an optimal weighted average cost of capital.
We seek the best innovation, whether it's internally or externally generated. We've been active this year. We've been active in years past. As Bob mentioned, we've completed over $30 billion in deals over the last decade. These deals span the commercialization spectrum, from platform and technology-related deals that Ray and Alan will speak of shortly, to deals for marketed products like Otezla, and in every stage in between. We patiently evaluate external opportunities that clear our hurdle rate and are consistent with our core therapeutic areas. Although the plan we are presenting today is based on programs in hand, it's organic, we do expect external innovation to continue to contribute to our portfolio and pipeline going forward.
Let me also note that we have not assumed any additional COVID antibody revenue beyond 2022, and if COVID becomes endemic and continues to mutate, we will assess whether there's a role for our world-class antibody manufacturing capabilities going forward. We will continue to return capital to shareholders at attractive levels. In 2021, we paid dividends of $1.76 per share per quarter, which resulted in about $4 billion and repurchased approximately $5 billion in stock. We've grown the dividend meaningfully each year since we started it in 2011. We plan for continued dividend growth over the long term.
We're planning to buy back up to $6 billion in the first quarter, and over the balance of the decade, we plan on a competitive payout ratio and expect to return greater than 60% of our non-GAAP net income to our shareholders on average through a combination of dividends and share repurchases each year. Let me wrap up here before turning it over to Murdo and Susan. We're excited and confident in our future. We covered what we set out to cover with you this morning. We said what we would do and what we've accomplished. We reviewed 2021, which was highlighted by the early approvals of Lumakras and Tezspire, along with seven important transactions to get external innovation for patients. We shared our excitement around the rest of the decade and our long-term financial outlook.
We gave you our outlook for 2022 and our confidence in accelerating growth into 2023. We expect mid-single-digit compound annual revenue growth through the end of the decade, along with high single-digit to low double-digit growth in EPS. We are confident in our high quality of execution and will continue to create capacity for investment in both internal and external innovation for patients. Finally, we are excited to continue to deliver long-term value to patients, shareholders, and staff. Murdo?
Thanks, Peter. Over the next 30 minutes or so, Susan and I will share our excitement about how we'll capitalize on our growth opportunities now through 2030. For over four decades, Amgen has discovered and commercialized innovative first-in-class medicines, transforming the natural course of many diseases and positively impacting the lives of millions of people. Over the last decade, we've accelerated our ability to help even more patients across more disease areas. By launching 10 products since 2012, we have grown to 25 marketed brands and $26 billion in revenue in 2021. We've also delivered substantial value to healthcare systems around the world by launching 5 biosimilar products since 2018, generating over $2 billion in revenues in 2021.
This fully integrated biosimilar portfolio is supported by our outstanding development and manufacturing operations capabilities, and they ensure that we have first wave launches and resilient supply for patients globally. Amgen now operates in approximately 100 countries, doubling the geographic footprint we had in 2012, and revenues in our Asia-Pacific region surpassed $1 billion and will drive strong long-term revenue growth for the company. This portfolio transformation and global expansion required significant effort in order to allocate our resources to the highest growth opportunities in disease areas of significant unmet need that address tens of millions of patients worldwide. While managing our legacy portfolio and slowing the erosion from recent biosimilar competition, we've been looking ahead at the key opportunities we have for growth and have been building differentiated capabilities that Amgen needs to compete.
We invested in several critical areas to advance the way in which diseases like psoriasis, severe asthma, cancer, osteoporosis, and heart disease are treated. Given the increasing prevalence and burden of these conditions, it's imperative that in addition to improving screening and diagnosis efforts, we need to accelerate the adoption of novel treatments that can reduce morbidity and mortality and improve patient outcomes. As a leader in biotherapeutic innovation, we see it as our mission to serve as many patients as we can who are battling these diseases. We're focused on building our portfolio and critical capabilities to enable this mission, and these include our global reach in more than 100 countries, our broad and diverse portfolio of innovative and biosimilar products across six therapeutic areas. We've designed a global, locally deployed digital customer engagement model, and it'll allow us to reach customers despite COVID challenges.
These digital capabilities, along with our advanced customer data and analytics, also helps us optimize investment and predict customer response to field and remote engagement. We've significantly optimized our media spend, improving overall investment return. We've established very sophisticated value and access capabilities, particularly for growth in launch products, and this has allowed us to have access established in closer proximity to regulatory approval, and this was the case recently with Lumakras in the United Kingdom. We've also simplified and enhanced our patient reimbursement support on both innovative and biosimilar products, and this ensures lower abandonment and much improved persistency. When combined, these capabilities increase our competitiveness and our agility to meet and anticipate the needs of customers and patients, and that supports mid-single-digit revenue growth over the decade. This growth will largely be driven by our innovative in-line portfolio, recently approved launch brands, and soon-to-be-launched biosimilar products.
This means much of our future growth is secured, it has regulatory approval, is reimbursed, and is now in the hands of our highly effective medical and commercial teams to execute and drive demand by increasing physician adoption and supporting care. We're very pleased, despite the COVID pandemic challenges, with the early launch progress of two first-in-class products, Lumakras and Tezspire. Our biosimilar portfolio growth accelerates with the launch in early 2023 of Amjevita, our biosimilar to Humira in the U.S. We're currently the adalimumab market leader with Amjevita in Europe and have launched this product in more than 55 countries around the world. The U.S. Amgen launch will be complemented by subsequent launches of biosimilars to Stelara, EYLEA, and Soliris. Lastly, we expect additional launches in the decade from our deep R&D pipeline in inflammation, oncology, general medicine, along with additional biosimilar product development.
Given the challenges we face in the market today and the broad set of growth opportunities we have, it's essential that global brand strategies are clear and that we build global capabilities followed by outstanding local execution. Now, Susan Sweeney leads the Global Marketing, Access, and Customer Capabilities organization at Amgen. She has over a decade of experience in the inflammation therapeutic area and has launched multiple brands across our therapeutic areas, including inflammatory diseases. It's great to have Susan with us today, and she'll cover our inflammation portfolio in more detail. Susan?
Thank you, Murdo. Amgen Inflammation has been serving patients with autoimmune diseases for more than 20 years. Our diverse portfolio of innovative and biosimilar medicines and a highly efficient operating model enables strong execution and growth. We have broad coverage across the main areas of autoimmune disease, including gastroenterology, dermatology, rheumatology, and respiratory. One in 10 patients who receive a systemic therapy by a rheumatologist or a dermatologist in the U.S. is prescribed an Amgen product. Our nimble medical, sales, and access teams of more than 2,000 people globally give us a strong share of voice across all four of our core specialties. Ensuring patients and physicians get access to our products is critical. With the consolidation and vertical integration of payers and PBMs and increased competition, barriers prescribers experience related to treatment choice and patient affordability continue to be a challenge.
With our well-established presence, integrated biosimilar, and innovative brands, we are in a position of strength to sustain and gain access. When we launch a new product, whether it's a biosimilar like Amjevita, an innovative therapy like Tezspire, or an expanded indication, as in the case for Otezla, we can quickly leverage our experience and portfolio to speed access uptake. We serve millions of patients. We have proven success as the number one market leader in dermatology in the U.S., number two market leader in rheumatology in the U.S., and have the number one adalimumab biosimilar, Amjevita, in Europe. We expect to continue to achieve leading shares through effective launch of future biosimilars and by capitalizing on the strength of our partnership with AstraZeneca for Tezspire. In development, we have a robust inflammation pipeline and are expecting launches in these disease areas over this decade.
David Reese will discuss more about those potential products in detail. I've spent my career as a marketer working on many brands. Having a unique product like Otezla is a privilege because of its benefit for patients with psoriasis. Psoriasis is a visible and burdensome disease, the effects of which go well beyond the skin. Even mild disease can be unsightly, uncomfortable, and difficult to treat with topicals. For a complicated disease, the first and only oral systemic treatment for patients with mild, moderate, and severe psoriasis is now available with Otezla. Otezla is the oral standard of care and is well-positioned for growth. It is differentiated from both current and future competitors. It has been in the market for almost eight years, and over 700,000 patients have been treated. As we've seen with the JAK class, safety is important for patients and physicians.
Otezla's safety profile is well known by the healthcare community. The convenience of oral dosing and no requirements for pre-screening or lab tests is a benefit for starting patients on therapy. By leveraging our vast inflammation portfolio and negotiations with PBMs, in the U.S., we have over 90% first-line coverage. Now we've secured broad access to our expanded label without a step change in net price. Otezla has been broadly studied. It currently has three indications, and we are pursuing additional expansion of use into genital psoriasis, palmoplantar pustulosis, pediatric psoriasis, and once-daily treatment. With this strong profile, access position, and best-in-class team, we are well prepared for future competition. The psoriasis market is crowded. There are now 14 systemic brands to treat moderate to severe psoriasis. Otezla has maintained a leadership in this very competitive market.
As you can see from the graph on the left, there has been consistent growth in the use of systemic therapies to treat psoriasis. This growth trend has been steady, except for a slowing of new patient growth at the beginning of the pandemic. New patients initiating therapy for the first time flattened in 2020, but got back on track in 2021 as it progressed. We should see with the return of patients to their dermatologist, continued growth. As you can see from the graph on the right, we are and have been the number one therapy for patients initiating their first systemic. Because we are the only oral systemic, our growth is dependent on new patients seeking treatment. For Otezla, the pandemic initially had a disproportionate impact, with less patients being able to visit their dermatologists.
Now that the market is growing again, we will not only expect to keep our leading share position, but also expect to see an improvement in our growth rate. The expansion of our label in the U.S. provides an option for more patients and is a catalyst for growth. In 2021, Otezla grew 8% on a volume basis, offset by pricing pressures. We believe had it not been for the pandemic impacting the new to systemic therapy market in 2020, there was a high likelihood that the volume growth in 2021 would have been notably higher. The expansion of our label to all forms of psoriasis is off to a good start. Physician awareness is increasing. We're hearing stories from our field team of physicians prescribing Otezla to milder patients. We are also seeing an inflection in our dermatology new patient share.
As we look to 2022 and beyond, we feel confident in our ability to deliver low double-digit average annual sales growth until U.S. loss of exclusivity. Another major expansion in our inflammation franchise is the launch of Tezspire for patients with uncontrolled severe asthma. Launching Tezspire, a new mechanism that can help more patients, is something everyone at Amgen is proud of. We've seen tremendous anticipation and support from the asthma community and physicians for a new medicine that has the potential to treat severe patients regardless of their asthma type. 1 million people in the U.S. and 2.5 million people globally live with severe asthma that is uncontrolled or biologic-eligible. Serious exacerbations require 1.6 million emergency room visits and 180,000 hospitalizations per year, and that's just in the U.S. alone.
The number of Americans with asthma is anticipated to grow 10% by 2039. We feel we can change the way this disease is treated. There are many physicians who want a simpler approach given the complexity of the biomarker testing and phenotyping. Tezspire can be that simple approach. We were very pleased by the FDA's earlier approval of Tezspire and have been working to make the drug available to patients as quickly as possible. Tezspire is the first and only biologic for severe asthma to be approved without phenotypic or biomarker limitations. It has the opportunity to change the treatment paradigm. For a complex condition, Tezspire can streamline physician choice and access for more patients. In terms of where Tezspire will ultimately be used, there is a significant market opportunity given that 85% of eligible people with severe asthma are not currently receiving a biologic.
With the introduction of Tezspire in the U.S., the biologic-eligible patient population expanded by approximately 20%. Over time, we expect the U.S. biologic penetration to continue to increase. The Tezspire launch is very early, but we feel we're off to a strong start. In conversations with our teams and physicians, Tezspire is being received extremely well, and there's a lot of excitement. Patient initiations are starting. As a new mechanism, educating physicians is important. Through our field medical teams and disease education, we have high unaided awareness of TSLP, the mechanism for Tezspire. There have been almost 2,000 samples distributed since launch and over 1,000 patients enrolled in Tezspire Together, our patient support program. We submitted the application for coverage and medical benefit. The early approval and early launch allowed us to pursue a permanent reimbursement J-code.
Just a few weeks into launch, physician intent to prescribe is high, with 80% interested in prescribing Tezspire. Our winning position in severe asthma biologics comes from the strength of our partnership with AstraZeneca. Pairing their strong legacy in respiratory and pulmonology with our unmatched leadership in inflammation and our world-class commercial teams, we are confident in our opportunity and ability to deliver. Lastly, we have a broad lifecycle plan and are pursuing a number of indications that Dave Reese will review. As we round out this discussion on inflammation, we'll shift our focus to the U.S. launch of Amjevita, which is fully integrated into the inflammation portfolio. The model, integrative innovative products and biosimilars, positions us to address areas of greatest importance to payers, providers, and patients when a new biosimilar is introduced.
When we talk to stakeholders about what's the most important consideration for biosimilars, they have different needs. Proven safety and efficacy is table stakes for all, and a reliable product supply is often assumed but is critical. For providers, ongoing support from the manufacturer is needed to support the switch to biosimilars, and even when with a biosimilar, continued education is needed. Patients require efficacy, safety, and supply, but also have special needs for support. Patient support on device usage and copay assistance are required to ensure continuity of care. Amjevita's launch will meet the needs of our customers. Our unique integrated biosimilar and innovative product portfolio and experience in growing Amjevita to the number one biologic for adalimumab in Europe sets us up for success.
Amgen has treated more than 250,000 patients worldwide, and safety and efficacy is well understood thanks to our large real-world evidence dataset. This track record of efficacy and safety is important for all customer types. Amgen has a world-class supply chain, and as one of the first biologic manufacturers, a deep and long history in ensuring that we serve every patient every time. Our integrated medical field and access teams will launch Amjevita and provide the same support our customers have become accustomed to. We are a company with a rich history in development of devices and support for patients. We will leverage our current patient support systems to ensure seamless transitions with copays and other support services. We are well-positioned for a successful launch of Amjevita.
As Peter said, we will grow our biosimilar revenues beyond Amjevita by layering six additional sequential product launches throughout the decade, which fuel the steady growth. Given that biosimilar lifecycles are somewhat compressed, having a sequential set of biosimilars to launch allows us to sustain growth over time. We expect overall biosimilar revenues to be more than two times 2021 revenues by 2030. We have a very strong inflammation portfolio currently serving millions of patients. Our first-in-class inflammation product line has produced a leading market position, and the unique integration of biosimilars and innovative business will continue to drive impact over the next decade. I'll turn the discussion back to Murdo to talk about our exciting oncology portfolio.
Thanks, Susan. Amgen's been pursuing breakthroughs for cancer patients for over 40 years now. We have a deep, diverse portfolio and pipeline of cutting-edge therapeutic approaches that aim to improve patient outcomes. Now, in the United States, one in five cancer patients receives an Amgen medicine. This legacy and incumbent strength in the market builds an extremely strong global foundation to help more patients and generate growth. Our diverse portfolio of promoted oncology brands generated $5.7 billion in sales in 2021 and has grown 8% from 2018- 2021. This growth was driven by Xgeva and Kyprolis, as well as Lumakras, Nplate, Vectibix, BLINCYTO, and IMLYGIC, which will deliver durable growth throughout the decade. Our strong presence in oncology has been further augmented by the addition of our biosimilar products MVASI and KANJINTI, which generated $1.7 billion in sales last year.
It's expected that biosimilar competition will lead to declining price and revenue trends on these two biosimilar products. In addition to our legacy and incumbent strength, 2021 was exciting for us. We grew our portfolio of innovative oncology therapies in 2021 with the launch of Lumakras, the first KRAS G12C inhibitor for advanced non-small cell lung cancer patients with the KRAS G12C mutation. While this is one of the most prevalent biomarkers in lung cancer, treatment has remained elusive for these patients. Now they have hope, and we're really excited to be able to bring that to them. After 40 years of attempting to intervene in this driver mutation pathway, Amgen research and development teams moved at record pace to bring this transformative treatment option to patients.
Now we're exploring the potential safety and efficacy of Lumakras across a number of tumor types and lines of therapy. Lung cancer is, of course, the largest tumor type, and it's estimated that approximately 75,000 patients with advanced metastatic non-small cell lung cancer worldwide have KRAS G12C mutation, with 27,000 of these patients progressing to second-line. Beyond lung cancer, we're also exploring the efficacy of sotorasib in monotherapy and in combination in colorectal and pancreatic cancer. Our extensive and well-established customer presence in academic cancer centers and community oncology practices is supporting a strong launch of Lumakras, with over 1,000 physicians having prescribed the medicine so far. We generated $45 million in sales in Q4, with the majority coming from the U.S. We now have approvals in more than 35 countries, including United States, the U.K., Canada, E.U., and Japan.
We continue to drive biomarker testing efforts to ensure that every non-small cell lung cancer patient is tested for their KRAS G12C status. We're pleased that in the U.S., the majority of testing labs are now listing KRAS G12C as an actionable mutation, and this helps to prompt oncologists to provide Lumakras as an option for their patients. Let me transition now to our general medicines portfolio, which consists of products that have the ability to impact large populations that are highly underserved. We'll start first with osteoporosis, where we have the potential to positively impact the lives of millions of patients. Osteoporosis is a growing, significantly underdiagnosed and undertreated disease. It affects more than 200 million people worldwide.
The Bone Health and Osteoporosis Foundation estimates that osteoporotic fractures will increase by 68% by the year 2040, with associated Medicare costs exceeding $95 billion in the U.S. In summary, fractures related to osteoporosis are common, they're costly, and thanks to innovative medicines like Prolia and Evenity, preventable. Having two potential ways of intervening in this disease has never been more important. Prolia and Evenity really are stronger together. For post-menopausal patients with osteoporosis, treatment with Prolia over several years can significantly reduce the risk of fracture. If a patient has a fracture, that increases the risk of another osteoporosis-related fracture by 86%. For these high-risk patients, Evenity offers an opportunity to rapidly build bone strength and reduce spine fracture risk in 12 months.
For well over a decade, Amgen has partnered with governments, payers, healthcare systems, advocates, providers, and patients to improve the quality of care for women and men with osteoporosis. Many of these partnerships have created strategies that are extremely effective. Governments providing funding for increased screening and diagnosis, fracture liaison services within healthcare systems to provide better fracture care and prevention treatment, and of course, physician education to ensure appropriate therapy is initiated pre and post-fracture. As a result, care is improving and our bone health business is growing. There are many more patients who still need help, and we at Amgen are committed to working alongside the many stakeholders that can change the course of this disease and help prevent more unnecessary fractures. Given the large patient population and growing interest in providing better care, we expect continued growth in Prolia through our anticipated LOE.
As Peter mentioned, the more gradual biosimilar erosion curve that occurs post-LOE will allow us to continue to invest in bone health and to grow Evenity in the low double digits on average from 2021 through 2030. Now, turning to cardiovascular disease, aligning stakeholders to improve quality of care has never been more important. It remains the world's number one killer. Responsible for one out of three deaths globally. 85% of cardiovascular deaths are due to heart attacks and strokes and are on the rise. Many risk factors like LDL-C are modifiable. However, only two out of 10 patients treated with conventional statin therapy are at their LDL-C goal. Cholesterol is one of the most important modifiable risk factors to help prevent heart disease and stroke.
Despite overwhelming evidence that aggressively lowering LDL-C can reduce cardiovascular event risk, there are many barriers to accessing high-quality cardiovascular care. This means millions of patients around the world do not receive the care they need. Now, with Repatha, Amgen was the first company to demonstrate that by inhibiting PCSK9 receptors in combination with statins, more patients can get to goal, and you can further reduce cardiovascular risk in a population of CVD patients, regardless of their baseline LDL-C levels. Since then, we've accelerated growth by securing broad access and reimbursement at an affordable out-of-pocket cost for commercial and Medicare patients. We continue to work with payers and pharmacy benefit managers to make it easier for healthcare professionals to complete prior authorizations and ensure that a prescription written is a prescription filled.
Many patients, despite being on lipid-lowering therapy, have coronary events, and they end up in an acute care setting. Today, many healthcare systems overlook the importance of aggressive lipid management in these high-risk ASCVD patients. We've deployed a team of cardiovascular account managers to work with integrated health delivery systems to build standardized care pathways and quality programs to ensure more cardiovascular patients receive a lipid panel and the subsequent treatment to get to goal and lower their risk of a cardiovascular event. To date, over 120 health systems around the United States have established programs and are now more likely to discharge CVD patients on optimized lipid therapy, including Repatha. We're now the PCSK9 class leader globally, and we've treated more than 1 million patients with convenient self-administered Repatha.
Most recently, we were able to have Repatha listed on the National Reimbursement Drug List in China, ensuring that this truly global brand can help many, many more patients around the world in 2022 and beyond. We continue to invest in new data with hundreds of investigator-sponsored trials, and we also intend to expand our use through additional randomized trials with our VESALIUS study that David Reese will expand on. We're proud to be actively helping cardiovascular patients and changing the course of this disease that takes so many lives. We remain focused on ensuring that every high-risk ASCVD patient is given a choice to lower their risk by having access to Repatha. These actions have unlocked many of the barriers to Repatha growth, and we anticipate that Repatha will become a multi-billion-dollar franchise growing through the end of the decade.
This is truly an exciting time for Amgen. Our mission to serve patients has never been more clear. Amgen medicines have impacted tens of millions of patients over the last four decades. The potential for our integrated portfolio of innovative and biosimilar products will help transform the lives of even more patients across more disease areas around the world over the next decade. We have in hand what we need to be successful. We have the components of growth to deliver for patients and shareholders, and we have a team of resilient, dedicated professionals around the world who are driving execution to achieve this growth. Just in summary, Repatha will become a multi-billion-dollar franchise growing through 2030. Annual Otezla low double-digit growth on average until the U.S. LOE. 2030 biosimilars revenue to more than double our 2021 revenue.
Annual Evenity sales growth in the low double digits% on average from 2021- 2030. Of course, ensure we deliver launch excellence for Lumakras, Tezspire, and our new biosimilars. We're layering in the plans to prepare for many additional pipeline launches later in the decade. To review that extensive pipeline, I'll hand it over to our Head of Research and Development, David Reese.
Thanks, Murdo, and good morning, everyone. In the research and development part of our presentations, we'll focus on the near and intermediate pipeline, as well as give you a glimpse of the future. We believe we're in an era of profound transformation driven by technological change, and we'd like to highlight some of the strategic choices that we've made. Everything we do in research and development is innovated by our strategic vision. We wanna benefit patients and societies through transformative medicines. We bring that to life for our staff by organizing their activities around three strategic priorities: increasing success rates, reducing cycle times, and enabling access and use throughout the drug discovery and development continuum. Today, we'll focus on improving success rates and reducing cycle times through my presentations and what you'll hear from Ray and Alan.
Now, as Bob noted, in research, we really focus on three key therapeutic areas: inflammation, oncology, and general medicine, in particular, cardiovascular disease. Our goal is to develop first-in-class medicines that produce a large effect size in diseases where there remains residual high unmet medical need. In short, we want to change the practice of medicine. Now, before I launch into a description of the near-term pipeline, our exciting pipeline, I want to introduce some concepts and themes that you'll hear over the course of the next hour or so. First, we believe it is the era of human data. In the last decade, enormous amounts of human data have accumulated. More are coming every day. We believe those data will power drug discovery and drug development for the decades to come. Now, collecting human data isn't the end game, but rather a means to develop new transformative medicines.
Ray will talk about our plans in multispecificity. We believe multispecific molecules will be just as important in the coming decades as monoclonal antibodies have been in the past few decades. Alan Russell will then talk about a suite of capabilities we've developed called Biologics NExT that enables us to molecularly engineer the right molecule for a target in much reduced cycle times and with a much higher success rate. Well, first, let me start with a view of the portfolio. Here are some of the key molecules that I'll discuss over the course of the day, included here for your reference. I'll start with the inflammation portfolio. All of the molecules that I'll discuss in our inflammation portfolio are first-in-class agents. We organize our activities in inflammation across these four broad areas.
Dermatologic diseases, historically, of course, rich experience in psoriasis, now focusing on atopic dermatitis, respiratory medicine, in particular asthma, gastrointestinal disorders, including inflammatory bowel disease, and rheumatology. Of course, we have a long history in rheumatoid arthritis and psoriatic arthritis. Now we're focused on systemic lupus erythematosus as an additional disease. Well, let me start with Tezspire, our recently launched drug for severe asthma. Shown on the left here to remind you is Tezspire's mechanism of action. Tezspire inhibits TSLP, an upstream epithelial-derived initiator of the inflammatory cascade that is the pathogenic driver in asthma. As you can see on the right in the phase III NAVIGATOR study, regardless of eosinophilic subtype, high eosinophils or low eosinophils, Tezspire had a profound effect on the annualized asthma exacerbation rate. It is the first and only biologic, regardless of eosinophilic phenotype, to have this sort of effect.
I've had a chance to talk to a number of patients and physicians since the launch of the medicine. They couldn't be more thrilled to have this treatment option. I think this drug is going to have a profoundly important role to play in the treatment of asthma in the coming years. Now, asthma may not be the end of the story for Tezspire. We have a rich lifecycle management program. There's a phase III program ongoing in chronic rhinosinusitis with nasal polyps. We're planning phase III in eosinophilic esophagitis, and we've got ongoing phase II studies in chronic spontaneous urticaria and COPD. Shown here is a subset analysis from the NAVIGATOR phase III trial in asthma. These are patients with concomitant chronic rhinosinusitis and nasal polyps.
You can see on the left that these patients had a substantial 86% reduction in the asthma exacerbation rate over the course of the study. Importantly, Tezspire also led to a clinically meaningful reduction of 22% in clinical symptoms using one of the common scales employed in this disorder. This gives us confidence in the ongoing phase III study, and if that is positive, I think we can play a real role here in changing the natural history of the disease in patients where impaired quality of life is quite common. Well, another molecule that can also, I think, change the natural history of the disease and substantially improve quality of life is AMG 451 that targets the OX40 signaling pathway in atopic dermatitis. Atopic dermatitis is an increasingly recognized disorder now diagnosed in more than 30 million people around the world.
It's commonly called eczema, but this is not just an itchy rash. It is an autoimmune disorder, sometimes a severe autoimmune disorder driven by aberrantly activated T cells. AMG 451 has a putative dual mechanism of action, inhibiting the OX40 signaling pathway, also partially depleting activated T cells that are some of the bad actors in this disorder. This latter mechanism may account for the prolonged duration of effect that we've observed in clinical studies to date and may afford longer dosing intervals as the program progresses. Well, shown on this slide are data that were presented last fall at the EADV conference from a phase II-B study showing that across dose levels, patients with advanced refractory atopic dermatitis had substantial improvements in skin outcome upon receipt of AMG 451.
The placebo group at the bottom in gray and then black were patients who were treated with placebo for 18 weeks, then allowed to transition to AMG 451. You can see after that transition, a substantial improvement in skin outcomes in that group as well. Based on these data, and after very productive discussions with regulatory authorities, we're launching a broad-based phase III program called ROCKET. This is intended to establish safety and efficacy in a broad patient population, those who are naive to biologics, those who have received a prior biologic or JAK inhibitor, patients with a range of ethnicities, and patients across various age ranges, including adolescents. In addition, the program will investigate different treatment strategies, monotherapy, combination therapy, as well as different dosing and scheduling regimens. All of this is really designed to investigate the optimal way to improve patient outcomes in this disorder.
We expect that this suite of phase III studies will launch in the middle of 2022. Another first-in-class molecule is Efavaleukin alfa, or AMG 592, an interleukin-2 mutein that's being studied in patients with different autoimmune disorders. The fundamental hypothesis here is that in many autoimmune diseases, there is a dysregulation of the balance naturally achieved in the immune system. There's enhanced activity of effector T cells, those are the ones that cause tissue destruction, cell killing, and a concomitant decrease in activity of T regulatory cells, which are a natural brake on the immune system. AMG 592 is designed to increase the number and function of T regulatory cells and restore this immune balance. It's now in phase II-B studies in systemic lupus erythematosus and a just-launched trial in ulcerative colitis.
I should point out that the lupus trial was included as part of the FDA's Complex Innovative Design Pilot Program, which is really intended to allow rapid transition from phase II into potentially registration-enabling trials if promising data are observed in phase II. We'll provide more guidance as this program proceeds. What gives us confidence in AMG 592? These are data presented a few months ago at the American College of Rheumatology meeting showing that the molecule did what it was intended to do. In a dose-responsive fashion, there was an increase in the number of T regulatory cells. In fact, the expansion of T regulatory cells observed here was very consistent with our preclinical modeling. This tells us that we have the right tool in hand to explore the hypothesis that expanding the number and function of T regulatory cells can restore immune balance in autoimmune diseases.
Now, another aspect of the biology of lupus is that it's not just a B cell-driven disorder. In fact, there is a complex interplay between the T cell and B cell compartments. AMG 570 or Rozibafusp alfa is a first-in-class multispecific that is designed to target a T cell signaling pathway, the ICOS ligand pathway, and a B cell pathway, BAFF. As you can see on the next slide, in a phase I trial, we were able to demonstrate receptor occupancy and inhibition of signaling for both the ICOS pathway as well as the B cell compartment. Again, this gives us the right tool to explore the hypothesis that lupus is not just a disorder of aberrant B cell signaling and autoantibody production, but is both a B cell and T cell disorder. Well, let me transition to our oncology portfolio.
Of course, Amgen has a long history in supportive care, and we're now making a real transition into therapeutics. Shown here is our portfolio, mostly first-in-class medicines, and today I want to focus in particular on the solid tumor portfolio, lung cancer, prostate cancer, and gastrointestinal malignancy programs. Well, let me start with Lumakras. I know, of course, you have intense interest in the Lumakras program. We continue to investigate both monotherapy and combination therapy across a range of malignancies, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, and other tumors bearing the G12C mutation. In lung cancer, in the monotherapy program, both the dose comparison and the phase III head-to-head trials against docetaxel are on track.
Based on current event rate monitoring, we expect we'll have data in hand from those studies, top-line data, in the third quarter of this year. Now, as you know, there are also a number of combination programs in lung cancer that move forward, including combinations with checkpoint inhibitors and SHP2 molecules. We expect the initial data from those combinations in the middle of this year. There are other combinations under investigation in lung cancer that will potentially afford the opportunity to move into earlier lines of therapy. We expect data across these suite of studies to be available over the course of this year and into 2023. Now in gastrointestinal malignancies with Lumakras, we're moving forward in colorectal cancer and pancreatic cancer.
We've previously presented data shown on the left here demonstrating that combining Lumakras with Vectibix roughly tripled the response rate compared to Lumakras monotherapy alone in colorectal cancers with the G12C mutation. Based on those data, we've launched a phase III trial that's up and enrolling patients, and I'll provide guidance as time goes on as to when we can expect data availability from that event-driven trial. We've also generated what I think are very intriguing data, encouraging data in pancreatic cancer. A week from today, these data will be presented from a phase I-II study at the monthly ASCO plenary session. I'd urge you to tune in to that presentation to really take a look at data we've generated in pancreatic cancer. That program is moving forward.
In addition, we have combination programs moving forward in pancreatic cancer and colorectal cancer, in addition to those that I've already described. I think there's real promise for Lumakras in both of these indications. Now, another molecule that has real promise is tarlatamab, or AMG 757, that targets DLL3 in small cell lung cancer. Small cell lung cancer is a deadly disease. Survival rates haven't changed much in decades, and in fact, the same drugs are used for induction therapy now that were used when I was a newly minted fellow stepping onto the medical oncology wards nearly three decades ago. Checkpoint inhibitors have had a measurable but very modest impact on outcomes, and it's clear new therapies are required.
Well, shown here is a waterfall plot that we shared with you at ASCO last year, demonstrating that a number of patients in the ongoing first-in-human study across a range of doses experienced responses. I'm happy to report that as of today, three patients have transitioned to complete remissions and current preliminary estimates of the median duration of response now exceed one year. That's exceptional in patients with second-, third-line, and beyond small cell lung cancer where response rates are often in the single digits and last a matter of weeks or a few months. We're enrolling a potentially registrational phase II monotherapy study in third-line small cell lung cancer, and we're now investigating both combination therapy and sequential approaches that will allow us, hopefully, to move into earlier lines of therapy in this disease where there's really, I think, the possibility of having a big impact.
Now, another disease where we have a chance to make a big impact is gastric cancer with Bemarituzumab. Bemarituzumab targets the FGFR2b receptor that's overexpressed in about 30% of gastric cancers. Gastric cancer is a public health burden around the world, particularly in East Asia, but in many other countries as well. Treatment standards here also have not changed dramatically in the past decades. Checkpoint inhibitors have a measurable effect in improving outcome, but I think there's a long way to go here. Bemarituzumab, a biomarker-driven program, is one about which we're quite keen. These are data on the left that many of you have seen before from a phase II FIGHT trial showing an improvement in median overall survival when adding Bemarituzumab in first-line disease to standard backbone chemotherapy.
Based on these data, we've now launched and are enrolling two phase III trials in the first line. One is a combination with standard backbone chemotherapy. The other is a combination with standard backbone chemotherapy plus a checkpoint inhibitor. This accounts for different standards of care in the treatment of this disease around the world. Now, gastric cancer may not be the only solid tumor where FGFR2b is a driver alteration. In particular, squamous cell carcinoma of the lung, a fraction of those tumors will have overexpression of this receptor. In the coming weeks, we're launching a signal-seeking trial in that indication in combination with standard chemotherapy.
In addition, we'll be launching a basket trial in the second quarter of this year that will allow patients with other solid tumors that have FGFR2b overexpression to enroll to see if we can have an impact between gastric cancer and potentially squamous cell carcinoma of the lung. Let me move to our prostate cancer programs. This is an area I'd also like you to pay close attention. Let me start on the right here with tarlatamab. You just heard about that in small cell lung cancer. Well, it may also have utility in prostate cancer. A fraction of prostate tumors, as they evolve, will dedifferentiate to what's called a neuroendocrine phenotype. When that occurs, they almost uniformly express DLL3, the target of tarlatamab. So we've now got a trial up and running to explore the utility of tarlatamab in neuroendocrine prostate cancer.
The bulk of our efforts is focused around the PSMA and STEAP1 programs. I've talked previously about Acapatamab, previously known as AMG 160. We've completed enrollment in a dose expansion cohort and should have informative data by the middle of this year. AMG 340, formerly TNB-585, which came to us from the Teneobio acquisition, is marching through dose escalation. We're seeing promising preliminary data, and we also expect to have informative data by the middle of this year from that program. By the middle of the year then, I think we'll be able to outline for you what the development pathway looks like for Acapatamab, AMG 340, one or the other or both. Let me end this segment by talking about AMG 509, which targets STEAP1. STEAP1 is widely expressed in advanced prostate cancer.
AMG 509 is an XmAb being developed in collaboration with our partners at Xencor and shown here are preliminary data, a PSA waterfall plot from an ongoing dose escalation trial. As you can see, a substantial fraction of these patients had significant declines in PSA levels, 70%, 80%, and in many cases, exceeding 90%. Our investigators are very excited about these data. We're very excited about these data, and this is a program we plan to accelerate. I'll have more to say about this in the coming months. You can expect full data from the first-in-human study to be presented perhaps later this year or early next year at the ASCO GU meeting, but this is one to keep an eye on. Let me finish the pipeline review with an update on a couple of our cardiovascular and obesity medicines.
Let me start with Repatha and the Vesalius CV phase III study. Vesalius targets patients who are very high risk based on clinical criteria and laboratory criteria of having an event, often in a matter of a year or two. They haven't yet had a cardiovascular event, a myocardial infarction or a stroke, for example. Vesalius is designed to see if Repatha can prevent those first events from happening. It's also designed in a way that I think we can capture the benefit of this therapy, perhaps even in a year or two, because these patients are at such high risk. We've completed enrollment in this phase III trial, over 12,000 patients. As you see here, we anticipate data roughly in 2025 with a potential label update to follow that. Now, as the event rate accrues, we'll provide further guidance about when we will have...
LDL isn't the only factor that drives atherosclerosis. In fact, LDL probably accounts for 50% or 60% of the cases of atherosclerotic cardiovascular disease. There are other important factors, importantly, lipoprotein(a) or Lp(a), obesity, and inflammation, systemic drivers that contribute to atherosclerosis. We've got programs targeting a couple of these. Let me start with the Lp(a) program. Lp(a) is a lipoprotein, as the name implies. About 20% of patients will have elevated lipoprotein(a) levels. Now, this isn't a bell curve, but rather a skewed distribution. Roughly 80% of people will have relatively low and so-called normal levels, and then a tail of the population can have elevated levels, sometimes markedly elevated levels. There's overwhelming epidemiologic and genetic evidence that links elevated Lp(a) to atherosclerotic cardiovascular disease.
Importantly, lifestyle changes such as alterations in diet or exercise don't affect Lp(a) levels. The levels appear to be genetically fixed. In addition, currently available medicines have very minor or no effects on Lp(a) levels. It's clear that new therapies are required. Shown on the left of this slide is the cover from Nature Medicine. This was published just a couple of weeks ago, and it's a paper of ours that documents the preclinical and ongoing phase I data from Olpasiran, a small interfering RNA designed to lower Lp(a) levels. You can see here the mechanism of action. Olpasiran, an siRNA, is designed to affect the production of Lp(a) in a profound fashion in target liver cells.
On the right, you see data from an ongoing first-in-human study that actually showed that a single dose of Olpasiran induces profound reductions in Lp(a) on the order of 80% or 90% or more. Importantly, the duration of this effect can be quite long, suggesting that the dosing interval for Olpasiran can be relatively infrequent. We've completed enrollment in a phase II-B trial. We'll have top-line data from that in hand by the middle of this year, and we're actively planning the phase III program so that we can quickly transition into a registrational phase of the Olpasiran development program if the phase II-B data look good. Let me finish the pipeline update by talking about AMG 133, another multispecific that targets two key metabolic pathways that control weight and regulate metabolism. These are the GLP-1 and GIPR pathways. GLP-1 you're familiar with.
GLP-1 agonists have been used for the control of diabetes, and one arm of AMG 133 is designed as a GLP-1 agonist. Now, the GIPR pathway is one you may be a little less familiar with. There have been a series of genetic studies, we contributed substantially to two of these, in the past years that suggest conclusively that decreased expression of GIPR leads to lower body mass index, lower weight. That, I think, gives us a clear clinical hypothesis that inhibition of GIPR is the correct approach for weight reduction and restoring some of this imbalanced metabolism that occurs as a consequence of obesity. Shown here are data from an ongoing phase I trial of AMG 133, single dose generating weight loss of on the order of 10-20 pounds. No dose titration is required, and the side effect profile has been quite tolerable to date.
This trial is ongoing, but of course, weight reduction is not the end game here. Rather, it's weight reduction as a cardiovascular medicine and approach to the treatment of cardiovascular disease. As these data unfold, we'll have more to say in the coming months and few years. Let me finish my remarks by talking about our beliefs about human data and the fact that the human data era is now upon us. From in silico protein structures to computational biology to multi-omics, I'll show you an integrated multi-omics platform in a minute, to deep clinical trials data, to an absolute tsunami of real-world evidence and real-world data, this is the era of human data. That human data will generate insights that really power drug discovery and drug development in the years and decades to come. Now, human data isn't the end game here.
We want to use those insights to develop new molecules, in this case, multispecifics. Ray is going to talk to you about that. We need to engineer those molecules, and Alan will talk to you about the Biologics NExT platform. Well, let me start with human data. We saw this era coming, and for a decade now, we've been putting in place the pieces that will allow us to capitalize on the ability to amass and analyze large amounts of human data. You can see some of the acquisitions and partnerships that we've put in place to generate human data. What does that mean realistically? Well, here you can see the sorts of human data that we now have available. In 2012, we acquired deCODE genetics. At that time, we had about 100,000 genotypes and about 2,000 whole genome sequences.
Now we have 2.5 million genotypes and 350,000 whole genome sequences. Seven years ago, we talked about the fact that we had upgraded our capabilities to industry-leading and the ability to generate 24,000 new whole genomes each year. Now we have the capability to do more than 15,000 new whole genomes each month. In addition, we've got transcriptomic and proteomic data on tens of thousands of individuals. And crucially, all of this is tied to phenotypic data. Now, 10,000 traits, deep phenotyping across 2.5 million individuals. Every discovery program at Amgen now goes through a comprehensive, integrated multi-omic analysis that allows us to deeply interrogate a target and a pathway. We're also now infusing these data into clinical development. That's the future. That's where precision medicine will arise.
All told, we now have more than 100 PB of human data and accumulating month on month. Now, human data, again, is not the end. It's a means to an end. What do we think human data can do for us? Right target, the right patient, and enhanced benefit, meaning a large effect size that is transformative for patients and also benefits healthcare systems. This is true pre-precision medicine. I feel great about where we're positioned to have a real impact here and our ability to lead into the precision medicine era. Now, to do that, you need, you need molecules. Ray will next talk to you about our plans to develop multispecific molecules.
Multispecifics, we think, are going to play an important role, just as an important role in the next decade and two decades that monoclonal antibodies have played in the last few decades in this industry and in human medicine. With that, I'd like to turn things over to Ray, who'll talk to you about multispecifics, followed by Alan, who'll talk to you about Biologics NExT. Ray.
Thank you, Dave. Good morning, everyone. I'm thrilled to be here with you today to have an opportunity to tell you about who we are and what we're doing in Amgen research. Amgen has a rich history of discovery research that has led to important insights into fundamental biological processes that underlie diseases like osteoporosis and atherosclerosis. We've also overcome massive technical challenges that have bedeviled the industry for over four decades, as evidenced by our discovery of the KRAS inhibitor Lumakras. Today, I'm going to tell you how we are building on that rich legacy. We are at a hinge moment in the history of our industry, defined by a wave of transformation that's sweeping over biotech as we pivot towards a future of multispecific drugs.
Amgen is a leading innovator in the discovery and development of multispecific medicines, and today I will share with you how we plan to extend our leadership position and be a powerful engine for the discovery of the multispecific medicines of the future. Now, I'm going to start just by touching on and emphasizing three of the themes that came up during Dave Reese's talk. A key is that we use human genetics and data for almost everything we do, but of particular importance for the identification of targets. Now, that has a couple of very important consequences. The first is that the human genetics will often serve up targets that don't match a drug developer's view of what an easy target is. That requires agility on our part in picking the right modality to attack a given target.
We refer to that as biology first. The second is that the human data also tells us about what impact modulating the target has on a disease process, and that enables us to pick the targets that will have the greatest effect so that we can develop the most impactful medicines. Now, our industry goes back about 120 years. A couple of years ago, I wrote a review in Nature that summarized my view of sort of the technological history of our industry. I posited that there have really been three transformative waves of innovation, the most recent being the biotechnology revolution, of which Amgen was one of the leaders. We now find ourselves at the beginning of this incipient fourth wave of transformative innovation, and that wave is the wave of multispecific medicines.
Now, it's early in that wave, but already two-thirds of Amgen's discovery and early clinical portfolio is comprised of multispecific molecules. These molecules offer the potential for quantum leaps in efficacy and tolerability and the potential to deliver unprecedented value to patients. In this talk, I'm going to describe for you how Amgen intends to surf the leading edge of this fourth wave, just like we led the biotechnology revolution. Now, some of you are sitting there and probably asking yourself, why is this fourth wave of innovation happening now? I think the answer lies in part on this slide. If you look on the left, that's sort of where the biotech industry was about 30 years ago. We had invented these technologies for making recombinant protein drugs, and that allowed us to go after a whole new suite of targets that were never previously accessible.
You could think of this like the apple tree there, where there's all these apples, all these targets, low-hanging fruit that you could go and pick without too much difficulty. Well, the industry got really good at that, and that led to spectacular success over the past few decades, and the industry has collectively delivered enormous value, not just to patients, but also to society at large. Now in the 2020s, we find ourselves in a situation kind of like on the right there, where there's still a lot of valuable fruit in that tree. There's still a lot of great targets to go after. The easier targets, they've all been harvested. Now we are going to need technological prowess. We're gonna need technological ladders, if you will, as shown in the drawing there, to reach those remaining targets, that high fruit.
What I'm gonna do in this talk is I'm gonna tell you how we at Amgen plan on doing that. I mentioned, you know, you have these challenging targets up high in the tree. What are the challenges? Why are they challenging? Well, I believe that the challenges facing us can be broken down into three categories. The first is biological redundancy. This sounds like a complicated idea, but it's actually quite simple. If you wanna go from New York to Boston, you have two different major highway systems for getting there. You could take I-95, or you can take 684, which goes to 84 and then 90. If there's a block on I-95, you're looking on Google Maps, you could always take that second highway and still get to your destination on time. Now, in cells, it's very much the same.
Signals impinging on cells flow down different molecular pathways to get to their final destination. To interdict a signal, you need to be able to block multiple pathways at the same time, and that's why you see so many combination therapies. Now, the other challenge is therapeutic index. Again, this is a very simple idea. In chemotherapy of cancer, there are many drugs that are effective at killing rapidly growing tumor cells, but the problem is they also kill rapidly dividing normal cells, and that leads to many of the side effects associated with traditional chemotherapy. The third challenge is undruggability, that there are many proteins in the genome that they don't have crevices or handles that a drug can grab onto to block the activity of the target.
Now, you know, the encouraging news I'm gonna share with you today is that multispecifics can help solve all three of these challenges. David Reese already gave you some examples from the left-hand column where Rozibafusp alfa, which is AMG 570, targets two pathways in parallel to overcome redundancy. He also gave you an example of a targeted drug like Olpasiran. I'm gonna give you an example of a case where we have a target that's difficult to drug, but using principles of multispecificity, we can drug it and overcome challenges of therapeutic index. You know, in the remainder of my talk, well, actually the next three slides, I'm gonna talk about multispecificity, in particular, a particular form of multispecificity, and I'll highlight the internal capabilities that we've been building. However, we haven't just been resting on our own laurels.
We've gone out and we've scoured the globe looking for partners who have invented path-breaking new technologies that are complementary to our own and that enable us to build the most powerful possible engine for discovery of small molecule and biologic multispecific medicines. As I go along, I'll point out some of the companies listed below here on this slide and how they're helping us. Now, the classic approach to finding drugs is that you have a target and you have a drug that grabs onto that target and modulates it. The problem is, while that works sometimes, it often doesn't work, because as shown on the right, about 85% of targets are not classically druggable. Many of the targets you get from human genetics won't be classically druggable. Cells, on the other hand, they have no problem controlling their own proteins.
They've evolved powerful mechanisms that enable them to control proteins with a great degree of precision. Our approach here is to piggyback on these cellular mechanisms. To do so requires a very special kind of molecule. Instead of a molecule just having one hand like a conventional drug, these molecules need to have two hands, one hand that binds the target and one hand that binds the cellular mechanism. By bringing these two into proximity, the cellular mechanism can act upon the target. Now, our current focus is to use this approach to commandeer the mechanisms that the cell has for destroying proteins by bringing that mechanism adjacent to proteins so it can trigger their destruction and elimination. However, this idea is not restricted to protein degradation. It's highly generalizable. I'm really excited by this partnership that we just formed with Arrakis that was announced a few weeks ago.
Arrakis has developed a technology for isolating molecules that bind with great specificity and potency to RNA. Meanwhile, we've isolated molecules that bind to cellular machinery that destroys RNA. What we seek to do with Arrakis is take their molecules and take our molecules and join them together to make a multispecific that we can use to eliminate specific RNA molecules from a cell. Think about this as a form of siRNA, but with three very important differences. Number one, we can do this with small molecules. Number two, these are potentially can be used as oral delivery molecules. Number three, these molecules could potentially work anywhere in the body, just like a standard small molecule drug.
This affords us the possibility, instead of going after the protein by going after its RNA, of targeting any protein independent of its structure, independent of its function, or even independent of its location in the body. This really has potential to open up a new chapter in drug discovery for our entire industry. Now, how are we gonna get these fancy multi-specific molecules of the future? Well, in the old days, well, it's still currently actually the conventional way we seek drugs, is we build libraries of, say, 1 million or 2 million molecules, and they're arrayed out one by one, and we screen them one by one to find ones that have an effect on our target.
Now, that works for these conventional molecules that grab onto a single target, but now we seek a molecule with two hands, and screening 1 million is probably just not gonna be enough to get those special kind of molecules. We need to screen billions. How are we gonna do that? Well, that's where our acquisition of Nuevolution, now Amgen Research Copenhagen, about 2.5 years ago, comes into play. Nuevolution had developed, about 20 years ago, methods that I'll refer to as DNA-encoded or DEL technology. What this is when you build the library of molecules, you attach little snippets of DNA to the molecule, and that snippet of DNA is unique to the molecule it's attached to, so it serves as a barcode.
Because each molecule is barcoded, you could then mix them all together in a single tube, as shown in the second panel. Now to find the molecule you desire, as shown in the third panel, you take your protein, you stick it in that tube, and then you fish it back out, and you identify the molecules that stuck to it by reading out the DNA barcode, as shown in the fourth panel. This powerful new technology, or this powerful technology, allows you now to screen billions upon billions of molecules to find those special molecules that'll induce proximity and thereby bring about modulation of your target.
Now, I'm gonna walk you through on this slide an example of how we've applied DEL technology and the concept of induced proximity to tackle a target that posed one of these three challenges I outlined earlier, in this case, the challenge of therapeutic index. The target is this molecule, this protein PRMT5. This is a very high-value target in oncology. We believe this, and pretty much everybody else in our business believes this too. Companies have pursued this, they've made molecules that inhibit PRMT5, they've put them in the clinic, and those molecules have failed. Why? Because PRMT5 is also in normal cells, and they require PRMT5. When you inhibit PRMT5, it's toxic to those cells.
You know, we reasoned that there might be a way to get around this because about 10%-20% of the most common solid tumors carry a specific mutation that can serve as an Achilles' heel. That mutation causes accumulation of a metabolite known as MTA. MTA binds PRMT5, but only very weakly and doesn't really appreciably affect it. We reasoned that if we could find a molecule that bound PRMT5 but only when MTA was present, that could selectively inhibit PRMT5 in cancer cells. We sought such a molecule using the conventional methodology, but we failed. We turned to our colleagues in Copenhagen, and they applied DEL technology and found the molecule that's shown on the left there in blue. That molecule, like MTA, binds PRMT5 on its own, but only very, very weakly.
However, when both MTA and the blue molecule are present, they reinforce each other's binding by forming a handshake in the middle there that stabilizes their contact with PRMT5. Now when both are present, we can achieve strong inhibition. You see that in the middle panel here, where we're looking at killing of cancer cells that either do not accumulate MTA, that's the blue curve, or that accumulate MTA, that's the red curve. What you can see is our candidate therapeutic is about a hundredfold more potent at killing the cells that accumulate MTA, the red curve. We can achieve a significant degree of cancer selectivity using this approach. Now, I'm really excited about this for three different reasons.
First of all, it shows how we can bring a powerful technology plus this concept of induced proximity to bear to solve one of these three major challenges that faces us for future drug development. Second, this highlights that Amgen is a leading innovative force and that we can move very fast because other companies have come up with a similar idea and are trying to do similar things, but we were the first to come up with a molecule and bring it into the clinic where we are currently enrolling patients. Like we did with Lumakras, we got off the blocks very quickly here and are leading the industry in this powerful approach.
Third, you know, this opens up a broad potential because as I mentioned earlier, about 10%-20% of the most common solid tumors have this mutation that leads to accumulation of MTA. This could potentially open up many doors for us in the future. Now, on this last slide, I plan to take you through an example of what we can do with multi-specific biologics and how technology we acquired just this past summer will help. Now, Dave Rees described to you BiTE molecules and how powerful those can be for selectively killing cancer cells when you have a protein on the surface of cancer cells that's unique to the tumor. He showed you examples for STEAP1, for PSMA, and for DLL3. The problem is the number of unique cancer cell surface targets is limited.
We asked ourselves in research a question, what if? What if we could design a molecule that would bind a particular combination of unique of antigens that are unique to the surface of a cancer cell? The simplest such manifestation would be a cancer cell that carries a unique combination of two proteins. In the example shown on the left here, we have a blue protein also found on blue cells, a red protein also found on red cells, but only the cancer cells have both the blue and the red protein. We called these molecules, by analogy to logic gates in computers, AND-gate BiTEs.
We've actually been able to make such a molecule, and a schematic of that molecule, which is now a preclinical molecule that we hope enters the clinic in 2022. Schematic is shown in the middle panel. What you could see to make this molecule, we had to combine together five different pieces of antibody molecules. Now, the difficulty here is easy to explain. Imagine I gave you a quarter, and I asked you to flip it five times. Well, the chance that you'd flip five tails in a row is about 3%-4%. Likewise, when we take native antibodies, and we engineer them to combine them into a complex structure like shown in the middle panel, the chance that any one of them works is maybe about 50/50.
There's a correspondingly small chance that all of them will work to give the molecule with the desired properties. This involves a lot of empirical effort to arrive at a molecule like the one shown. However, that's where Teneobio comes in. They had developed a technology where they made an animal, a rat, that expresses human antibodies, but these are different in two important ways. Number one, they've been shrunk down, so they're smaller. Number two, they only have a single chain. Now, these single chain compact antibodies are stable, they're manufacturable, and they're highly modular, which enables us to construct these complex, you know, multi-domain proteins as shown in the middle panel much more quickly and efficiently.
Our aspiration for the future is to construct molecules like the one shown in the right panel there, where, you know, we can put together molecules of increasing structural and functional complexity to solve the biggest biological challenges that remain ahead of us. Now, as I said at the outset, we're at a hinge moment in the history of our industry. 20 years ago, when Craig Crews and I first conceived and demonstrated proof of concept for targeted protein degradation using PROTAC molecules, the idea of making multi-specific medicines was, well, it was a dream. 20 years later, the convergence of powerful technologies like DNA-encoded libraries and others that I haven't had a chance to go into, like artificial intelligence, is helping to make that dream a reality. This is a big part of why I left Caltech five years ago to come to Amgen.
My goal was to help Amgen drive a revolution in drug discovery that will fuel the future growth of the biotech industry. Amgen led the first biotech revolution 40 years ago. We are exceptionally well-positioned to lead again in this fourth wave of transformative innovation, the multi-specific era. We've assembled the key technologies as I went through in this presentation, but more important to me, and I'll admit I may be biased here, is I believe we have the most dedicated, the most innovative, and the most daring scientists on the planet. For me, it's a privilege to come into work every day and have a front-row seat and watch them as they pursue their craft. I, for one, am looking forward to the powerful new medicines that they can invent for our future patients. With that, I'm going to hand off to my colleague, Alan Russell.
His group has put together an exciting new program called Biologics NExT, which is going to help drive the production of the powerful multi-specific biological medicines of our future. With that, Alan, please take it away.
Well, thank you so much, Ray. You know, two years ago, when Ray first explained Amgen's vision for building multi-specifics to reach the highest fruit in the tree, I was so inspired that I leapt out of my comfy chair at Carnegie Mellon University and joined the team at Amgen to lead a transformation of our biologics discovery organization. It's worth spending a few moments to think about why we needed to transform. You know, the consequence of some of the grandest challenges in biologics and multi-specifics discovery is the harsh reality that it just takes too long. Even with all that time that we take, too many molecules with unpredicted liabilities advance into development. This is an industry-wide dilemma, not just an Amgen challenge.
For multi-specifics in particular, these challenges are more accentuated because the drugs we seek to discover are no longer simple variants of human proteins. For decades, we've built remarkable in vivo platforms that identify hopeful molecules that we then optimize by repetitive cycles of protein engineering. At Amgen, we then feed those molecules into perhaps the leading biologics manufacturing processes in the industry. That cycle process takes time, a lot of time, 2-4 years for many multi-specific drugs of the kind that Amgen's vision is calling for. To add insult to injury, more than 50% of those molecules may not behave as we'd hoped. There's no question that to discover the transformative biologics of tomorrow, we will need new science, and a science that builds on 40 years of leadership in the industry.
Today, I'm going to reveal the implementation of a strategy that's cutting our antibody discovery timelines in half, more than doubling the speed of our protein engineering optimization, and critically, doubling the success rate of the first molecules emerging from our new biologics discovery platform. The strategy was developed in 2021, and we call it Biologics NExT. We know better than anyone that finding a protein does not a priori mean that we can turn that protein into a therapeutic. With multi-specifics, that's especially the case. Predicting manufacturability and clinical behavior during the earliest phases of drug discovery is, of course, a holy grail for the whole industry, but one that's evaded us. At Amgen, we believe that a unique conversion of scientific advances across biology, data science, and automation presents an opportunity, assuming we have the right foundation.
That opportunity will move us from protein engineering that relies on iterative cycles where we make and test prototype after prototype to a future where we design the right molecule quickly and effectively. We call this fusion of biology, data science, and ultra-miniaturization generative biology. Biologics NExT does not stop there. As you listened to Ray, you will have heard that we need to learn how to build complex biologics from their parts, assembling therapeutics using building blocks that we discover through generative biology, turning proteins into drugs, fusing together biology, chemistry, and design. Our strategy did not just consider manufacturability and clinical behavior. We also thought carefully about the form in which we should deliver biologics.
RNA therapeutics clearly have a key place in our industry today, and Amgen's ideally placed to understand how to induce and when to induce a patient's cells to manufacture a protein versus a bioreactor. Investing in generative biology and molecular assembly will act as our guide to our targeted expansion of RNA therapeutic discovery and development. How do we move from the protein engineering era that takes years to find manufacturable biologics to the generative biology era that takes months? To answer that, we have to consider the limitations that we have today. Remember that the protein engineering era has been iterative, built on cycles. Why? Because for all the effort and creativity of the last 30 years, we still haven't extracted generalized principles that connect a protein sequence to its structure and its function.
If new science can pull back the curtain and reveal those hidden truths, then every time we work on one protein, we'll be able to improve our chances to hit the target with the next without the need for endless prototypes. For a decade, we've built a protein engineering foundation of exquisite biology, analytics, and automation, and we built that foundation in the knowledge that eventually it would be turbocharged by new science, enabling us to launch a generative loop. Decisions that we made a decade ago made us the ideal partner for companies looking to put our hand in their glove. The new science that creates that generative loop is artificial intelligence, machine learning, sequence to structure prediction, and a molecular discovery platform that was created for sequence-based discovery. Iterative becomes generative, slow becomes fast, unpredictable becomes predictable.
Amgen's business development work over the last year has inspired our biologics team, whether it's the partnership with Generate Biomedicines, the collaboration with the Institute for Protein Design at the University of Washington, or our exciting acquisition of Teneobio. We're building a digital biologics discovery platform and driving the generative biology era. We're surfing the wave of science that's going to transform our industry, and we are already at the leading edge of unveiling those generalized principles, connecting sequence to structure to function. You know, on July 22nd last year, our world changed. When DeepMind published incredible advances that used AI and machine learning to predict the structure of every human protein, we knew that those tools would become exponentially more effective as time went by, and that they would touch every part of our industry.
I could talk for hours about how AI and machine learning can provide the jet fuel for our work, but data speaks louder than words. Within just a few weeks of DeepMind publishing those algorithms that could predict structure from sequence, we were building on the foundation that we'd built for the prior decade. One example was a tool reagent protein that we'd been trying to make for years, E3 ligase, a specific E3 ligase. It's a complex protein, and no matter how hard we tried to manufacture it, we just couldn't do it. For two years we tried. 6 different, completely different attempts and approaches, nothing. Zero for six over two years.
Within weeks of AlphaFold being published and accessible, we predicted the structure of the protein, we identified the area of liabilities, we engineered those areas out, and one for one, in two months, we produced the protein, enabling a new line of discovery for our scientists. Zero for six over two years to one for one in two months. You know, this science may not solve all of our problems, and we're far from naive when it comes to the humbling realities that come with unpicking the lock of human biology, but it's a certainty that this new science will bear rich fruit. Why are we convinced that Biologics NExT will work?
Because over the last year, since we've implemented the strategy, we've seen the impact that generative biology is having in how fast and how effectively we can find and advance the multi-specific molecules that our patients need. With multiple targets, we've cut our antibody discovery timeline in half, we've doubled our protein engineering success rates, and we've reduced our protein engineering and optimization timelines by more than 70%. You know, Amgen was at the forefront of the biotech revolution. Indeed, Amgen was that revolution. Just as that revolution transformed patients' lives, this next wave of drug development will allow us to create the molecules that we've been dreaming of, so we can transform again the lives of our patients. At Amgen Research, we believe that the generative biology era is here to stay. This isn't just the dawn of a new era.
It's 9:00 A.M. in the morning, and the sun is shining. We're inspired, we're excited, and we're committed, and the fire that burns in the belly of our scientists is fueled by the knowledge that tomorrow will be better than today. With that, I hand the stage back to Bob. Thank you.
Okay. Thank you, Alan, and thank all of our presenters for their work this morning. I hope by now you have a clear sense of our enthusiasm for the opportunities that we have in hand in the existing portfolio, as well as the pipeline opportunities that we think will enable us to drive growth through the end of the decade. Of course, those opportunities are supplemented or complemented with our strong balance sheet and the focus we have and the determination we bring to growing this business with innovative medicines that can make a big difference for patients. With that, let's open up the floor to questions. I think, Ashley, if you could remind our callers of the process that they need to follow to register a question, we can begin the Q&A.
Ladies and gentlemen, if you would like to ask a question, press star one on your telephone and wait for your name to be announced. Again, that is star one. If you wish to cancel your request, press the pound or hash key. Your first question is from Evan Seigerman of BMO Capital Markets.
Hi, guys. Thank you so much for taking my question and for all the detail today. You know, on Lumakras, I have two questions. On Lumakras, can you talk about more on the ongoing dynamics you're seeing in the market? What's the uptake? I know you mentioned about 2,000 patients, but how do you expect that to change over the next year or so? On biosimilars, how do you see pricing dynamics evolving?
Okay, thanks, Evan. I think those are two good questions. Why don't we ask you, Murdo, to take the lead in answering both?
Yeah. Thanks, Evan. We're very pleased with the Lumakras launch. As you rightly stated, roughly 2,000 patients to date now secured approvals in over 35 countries. Majority of our revenue is obviously still coming from the U.S., and we're seeing really strong uptake in both academic cancer centers as well as community oncology centers. We're still ramping up the testing rate appearing as a queue in the electronic medical record, specifically for the oncologist as they're evaluating a frontline non-small cell lung cancer or KRAS G12C patient who is progressing beyond that frontline therapy, so that information is right there at point of care so that they can consider Lumakras as a treatment option for that patient. It's going really well.
Many of the national and regional networks have already updated their electronic medical record systems, as have academic cancer centers, but we're still working on a few more. We're seeing nice new patient start data and, you know, we're really excited about what we've been able to do. We're also seeing some recovery. We had a little bit of softness end of December into January, and we're seeing some recovery being able to reach our customers either live or through remote digital settings. I think you also asked about biosimilar pricing.
Yep. Yep.
You know, I think I mentioned in my prepared remarks that on our U.S. oncology biosimilars, MVASI and KANJINTI, we expect some price pressure in 2022, given that we've got the majority share of those biosimilars and are now competing to hold on to that share. There'll be some price pressure on those brands and businesses. A little more stable outside of the U.S., in our European business.
Okay. Thank you, Murdo.
Thank you.
Why don't we take our next question. Ashley, if you could bring in the next caller.
Your next question is from Umer Raffat of Evercore ISI.
Morning, Umer.
Hi, guys. Thanks so much for taking my question. I have a couple here, if I may. First, maybe just to clarify on KRAS then, do you guys expect the Lumakras to be similar to or bigger than the Tezspire in terms of peak sales in your estimate? Then also, as we think about the 2030 estimates, Street is obviously materially lower, and I think it's in part because Street believes there's a biosimilar on the bone franchise, and you guys may not think that. But there's additional stuff on the pipeline as well. So could you walk us through perhaps beyond Tezspire and beyond KRAS, how much contribution from pipeline could you possibly expect in 2030? Thank you very much.
Okay, thanks, Umer. We'll try and break that down, I guess, into a number of different parts. We're not gonna break out specific guidance for you between Lumakras and Tezspire. As you know, we think both of those have the potential to be important drugs, one for cancer patients, obviously the other for patients with severe asthma. Happy to ask Murdo if he'd like to elaborate further on the dynamics of growth for those two products. We think both of them will be successful products in their respective areas. While we expect we will face competition in our portfolio for sure, Umer, I think what we're trying to remind you is that the nature of biologic competition is different from what happens when small molecules go off patent.
I think that's partly reflected in our remarks this morning. In addition to the specific innovative pipeline questions that you asked about, Umer, we also again tried to help provide for you some clarity about how we see the portfolio of 11 biosimilars aggregating to provide significant growth through the end of the decade for us as well. Murdo, I'll invite you to add any additional thoughts if you have any, and then perhaps, Peter, if you wanna add anything as well, feel free to jump in.
Well, I think you covered the biosimilar comment really clearly. I think on Lumakras, we've you know, we're really just at the beginning of the launch, and it's very early days. I'm also excited about the potential for Lumakras to have additional indications. I think on Tezspire, you know, we've got very early data on the first few weeks of launch, but on Tezspire we really have a nice lifecycle program. We also expect Tezspire to add more addressable patients to the biologics pool in severe asthma, so we actually grow the addressable patient population there by about 20%. Then over time, we expect the current penetration of biologics in severe asthma to more than double by the end of the decade. Clearly an exciting growth opportunity for us.
I might just add.
Your next-
Sorry, Ashley, just.
Thank you, Ashley.
Go ahead. Yep.
Yeah, I'm Peter here, I'm just gonna jump in. Umer, I would just add, in my comments this morning, I reflected on the diversity of our portfolio as it builds to 2030, both therapeutically and geographically, and in addition to that, the durability of it. You know, we really look at that as the company moves forward through the end of the decade, and we're very pleased with that, and we think it builds a very strong portfolio and pipeline position. Thank you.
Your next question's from Salveen Richter of Goldman Sachs.
Good morning. Thanks for taking my questions. Another follow-up on KRAS. Could you just talk about what may have impacted 3Q versus 4Q trends? Was there a bolus of patients in 3Q, or you know, ramp up in patient identification. Then secondly, with regard to the interchangeability study you're running against Humira, how critical is that for uptake in that market?
Yeah, thank you, Salveen. I think both of those questions probably can be well addressed by Murdo. If you wanna fire away, Murdo.
Yeah, thanks, Salveen. On the KRAS trends Q3, Q4, again, let me just stress, very early days for our launch here. We did benefit initially from some of the patients converting from our early access program into commercial drug supply. So there was some pool of patients that came in very quickly. That being said, we're really pleased with the run rate we're getting on our new patient acquisition and adoption in the U.S., and we'll start to see other markets now come online given the broad array of approvals we have. So overall, you know, I'm quite pleased with the trends we're experiencing. As I said, little bit of softness late December, early January, we attribute to the spike in Omicron infections.
In the last few days and weeks, we're seeing good return to being able to reach our customers. When we look at our interchangeability status on Amjevita, we've been out talking to pharmacy benefit managers and providers, and I think I would say that this is a nice to have, not a need to have. We think it's important given our biologics and biosimilars experience globally, that we try to make sure that our biosimilars have all of the attributes that our customers would like. I think this one falls further down the list of priorities, but we still felt it was important to add. We initiated an interchangeability study to make sure that we've got a comprehensive set of attributes that differentiate our biosimilars.
I think more importantly, as we talk to these customers, they're looking to make sure that whoever they select as their biosimilar of choice has the ability, A, to supply, B, to help providers and patients with the transition from a branded product to a biosimilar. The way we run our biosimilars business is fully integrated with our innovative teams. The same people who have been out talking to rheumatologists and dermatologists for decades on our proprietary or branded inflammation portfolio are the people who are going to be representing Amjevita at launch. They'll be able to explain the quality of our safety and efficacy data, the quality of our manufacturing supply, our device, and all the rest of it, and patient programs for support and reimbursement.
They'll be able to do that, and then those same patient programs and reimbursement support are the programs that we've developed over the years for our innovative portfolio. That ranks a little higher in the attribution set that the PBMs are choosing from.
Great. Thank you.
Your next question is from Geoff Meacham of Bank of America.
Good morning, Geoff.
Morning. Hey, Bob. Thanks so much for the question and the event today. Just looking longer term, how much of a disruption do you expect the Denosumab LOE to be, and would you expect an inflection in Lumakras, Tezspire, or some of the early cycle products by then, or is that too early to expect? Thank you.
Well, again, Geoff, we recognize that we're likely to face competition for a variety of products in our portfolio between now and the end of the decade. One of those may well be Denosumab. That's something that, again, we are determined to manage effectively the product throughout its life cycle. I think we demonstrated pretty effectively in the past our ability to manage those products even in the face of biologics, even in the face of competition, and we're determined to do that again. We think we have a very strong bone health franchise. We think Evenity and Prolia together offer a very strong combination for patients that are at risk of fracture due to osteoporosis. and so we expect to continue to be a force in bone health throughout the course of the decade.
As to the inflections from Tezspire and Lumakras, Murdo, I don't know whether you wanna add anything further, but.
No, I think what I would say is obviously we're very bullish on our ability, as I was talking about Lumakras and Tezspire earlier, that being as unique as they are and being first to market in their categories, that represents a huge opportunity for us to grow them, and we have life cycle opportunities for new indications, which will further catalyze that growth. There's also the addition of other biosimilar launches in this timeframe. We are looking at, you know, not just Amjevita, but we're also looking at Stelara, Eylea, and Soliris, which have meaningful growth, generation during the timeframe we're talking about.
Thanks, guys.
Your next question is from Ronny Gal of Bernstein.
Hi. Good morning, and thank you for taking my question. A couple of them, I may. First, it seems that you are highlighting Repatha as a significant element between now and 2030. I'm just looking at your slide, looks at least 5x where it is today. Can you talk a little bit about the PCSK9 competition landscape? How do you see—how do you think about Leqvio? How do you think about the possibility of an oral PCSK9 coming to the market? This seems to be a big number, if you can just give us a bit more on that. And second, about Amjevita and biosimilar adalimumab. A couple of points there. It you know, from the discussion so far, it seems to be more of a 2024 than a 2023 transition.
Can you tell me if you're actually expecting this to be a material contributor in the early year of launch? When you look at the number of people doing interchangeability trials, about five or six of them, I kind of wonder if we're not going to get in a situation where the ultimate price of that molecule will decline kinda like five- to tenfold from where it is today. Is this in your model? Are you assuming this will have some sort of a stable ongoing pricing point, or are you modeling significant decline over the year? Thank you.
Okay, thanks. There are quite a few questions there, Murdo. Did you catch those?
Yeah, I think I've got them. Yeah.
Okay.
Yeah, it's a lot to unpack there. Let's start with the PCSK9 market. We're obviously very interested in making sure that the PCSK9 category of products, and in particular Repatha, and continue to impact the lives of many of these ASCVD patients, you know, who have severe disease, who are not optimally managed in their cholesterol, and we're making good progress. I mean, the last few years have really been about removing barriers for prescribers, healthcare systems, and patients in terms of identifying the right patient and treating their LDL-C aggressively. You know, there's roughly 50 million patients in the U.S., 25 million of those patients are really good target patient population for the PCSK9 treatment for Repatha to treat. We are barely penetrating that market.
We're roughly about 5% of the patients that are under the care of a cardiologist will actually see a PCSK9 today. There's a huge potential pool of patients for Repatha and any other PCSK9 mechanism that may come along. Our goal is to, as the market leader, continue to rapidly penetrate that patient population. I would also say geographically, the product's performing nicely around the world, and the recent National Reimbursement Drug List in China also helps catalyze some growth for that product. We have modeled in oral competitors later in the decade, and we've obviously modeled in competition from the likes of Leqvio, but Repatha remains convenient, self-administered product. It remains very affordable with the lowest list price in the category versus the inclisiran product.
Of course, we continue to provide strong commercial support, competitive share of voice, and we're driving penetration in that category. Now, if we go back to your other question, which is around what have we modeled in for Amjevita? We're not gonna get into very specific information here, but I do think we'll see some uptake in 2023 of Amjevita biosimilars. I think it'll accelerate in 2024 and beyond, as you rightly point out.
I also think first mover here is really important, and it's our responsibility to make sure that for PBMs and for providers and for patients, that they are confident in our ability to supply a high-quality biosimilar with resilience, with, you know, continuous supply, which our global manufacturing operations team have been able to do on all our other biosimilars where many others have struggled, quite frankly. And to be able to reassure them that with the integrated model we run, that we can help providers and patients have confidence on switching from that branded product to a biosimilar. We think we can accelerate adoption versus, say, analogs that have gone before, particularly in the pharmacy benefit side of the equation.
You know, I remember getting questions about what's your uptake gonna be like in oncology with biosimilars, and a lot of people felt that maybe oncologists weren't ready to adopt biosimilars. Of course, we now know that that was proven to be untrue, and we're the market leader in oncology with our biosimilars, Amjevita, KANJINTI and MVASI. I think yet to be seen what the rate of change will be on Part D, but we're confident that we can improve on it versus historical analogs. I think you asked about price. We're not gonna guide on price in the category.
Obviously, you know, we know the landscape in inflammation, we know the landscape in RA, and we know how that works, and we've got very talented country execs and contract managers, and we'll make sure that we're competitive.
Thank you.
Okay. Thank you, Ronny, for the question.
Your next question.
Go ahead. Sorry
... is from Michael Yee of Jefferies.
Okay. Morning, Michael.
Hey, good morning. Yeah. Hey, good morning. Thanks, guys, for this. Appreciate it. Maybe two questions for David Reese. On the probability-adjusted pipeline in the green bar chart you list in your revenue growth through 2030, you might laugh when you say I tried to eyeball that. It looks like $7 billion. Without breaking all of that out, maybe you could just comment on which three or four have the highest probability in your pipeline, or which ones are you most focused on that being likely in that green bar? That'd be helpful, David. Then as it relates to KRAS, which is a part of that, you know, of course, there's a lot of focus on the combos. You did mention PD-1 and SHP2. I know there's been a lot of focus on that.
Maybe just comment where you stand on your expectations for that this year on KRAS? Thank you.
Well, I'll give you a head start on the answer to that question, Dave, by just saying that, of course, that piece of the mountain includes Lumakras and Tezspire. Those we feel highly confident will be growing through this period. Dave, feel free to jump in and add your perspective on the others.
Yeah, thanks. You know, in addition to Lumakras and Tezspire, obviously, Lumakras combinations, as you mentioned, we think will contribute there. In addition, in the oncology portfolio, Bemarituzumab, and then the solid tumor BiTEs, that I spoke about today, on which we're quite bullish, we believe will make a contribution. Outside of oncology, Olpasiran in cardiovascular medicine a little later, in the decade, and then of course AMG 451, in the inflammation portfolio targeting atopic dermatitis. So really many of the molecules, that I covered today, you know, they've been partially de-risked, in most cases through the trials data generated to date, and we expect those to contribute meaningfully to that green portion of the curve that you saw.
Your next question's from Matthew Harrison of Morgan Stanley.
Great. Good morning. Thanks for hosting this. I guess two from me. One just on the 2030 numbers. You commented on internationals, a percentage of total sales at around 35%. You know, as you know, this has been something you've been growing, but your peers tend to have a much higher percentage of sales outside the U.S. I know historically this has been driven by a structural issue where you didn't have rights to many of your existing products, but that's shifting. I guess the question is, why isn't that higher? You know, is there potential upside to that number as you think about a contribution from international?
Then second on Lp(a), obviously the size of the patient population here is potentially quite large, maybe on par with the LDL population. How big a contributor do you think this drug can be, especially compared to what you've learned about how to launch Repatha? Thanks.
Okay, Matthew, why don't we take that in two parts? I'll address your international sales question and then invite Murdo and Dave to share thoughts on Lp(a). You're right. As a percentage of total revenues, our business outside the U.S. is smaller than some of our comparably sized peers. You're also right that that reflects our history, where for many years we relied on partnerships, in particular in Japan and China and Asia more generally. As I said in my remarks, in 2020, we took back the rights to our products and our future in Japan. We have the same in China, same opportunity in China.
We think we have a portfolio that's very well suited to those markets, osteoporosis, cardiovascular disease, cancer, issues that are particularly challenging in that part of the world. We look forward to growing our revenues throughout the balance of the decade. Those will be amongst our fastest-growing markets. We think that in aggregate we'll achieve that 35%. You know, if those markets perform better than we hope, then yes, we may end up exiting the decade with a balance that looks more like what you see from our peers.
We're very pleased with the progress and the growth that we've been able to achieve in those markets, and I'm sure it's not lost on you that over the coming decade, the margin for us in those markets will improve as our absorption of the infrastructure becomes more consistent with what the steady state should be for those of us. With that, let me turn Murdo to you or David on Lp(a), and I guess David, you wanna take the start?
Yeah, maybe I'll start on Lp(a), and then Murdo can jump in. You know, as you mentioned, Matt, there is a very large pool of patients here. Probably 30% of cases of atherosclerotic cardiovascular disease, not driven primarily by LDL cholesterol, are due to Lp(a). This is disease that's often showing up in younger patients, someone who has an event unexpectedly in their mid-forties, for example, in the face of normal cholesterols, almost always that will be Lp(a) driven. This is a pool of population that's undoubtedly many tens of millions of patients around the world, and it's clear that you need profound pharmacologic intervention. We're actively planning the phase III program predicated on the belief that we'll see nice phase II data over the course of this year.
That's actually where our Multiomic program is being used to really select patients at the highest risk levels where we can demonstrate what we hope is an unequivocally large effect size. Building on that and what we've learned from Repatha, I think really gives us a path forward with the Olpasiran program. I'll let Murdo talk a bit more about what we've learned from Repatha and how we're thinking about the Olpasiran program in light of that experience.
Yeah. Thanks, Dave. We're really pleased that we've got another lipid-lowering agent to follow Repatha, and Repatha is one of the products where we have global rights around the world, so it's a truly global footprint representing that product. As Dave mentioned, there's an urgency to treat Lp because it's not modifiable by diet and exercise. We think that by running programs prior to launch and helping patients understand what their Lp levels are and so that they can self-identify as having elevated Lp should allow for fairly rapid adoption of Olpasiran upon approval. We also clearly know all of the cardiologists and lipidologists globally, given our history in the lipid-lowering market, so a really nice product to add to the portfolio of our cardiovascular business.
Okay. Ashley, can we take the next caller?
Your next question's from Chris Raymond of Piper Sandler.
Okay, great. Morning, Chris.
Hey, good morning, and thanks for doing this call. You know, just a strategic question for you, Bob. I know you guys have the resources to execute on multiple fronts, but I'm getting a few questions from investors around the buyback announcement. You know, Bob, at the beginning of your talk, you acknowledged that valuations have come down nicely for some potential targets around the biotech space in general. Maybe just square the decision to execute the buyback sort of near term with these valuations. Is it your view that these valuations will be compressed for some time? Maybe just any color on how to think about these two dynamics. And then maybe sort of a related question.
You know, just looking at the revenue mix by therapeutics, you know, eyeballing, you know, the mix into 2030, you know, it looks like you guys are projecting inflammation as a share of the total to shrink to, you know, a little bit less than 25%, versus about a third now. You know, I know, you know, this is exclusive of any M&A, but-
Inflammation has a ton, you know, of innovation going on now outside of Amgen. Just talk about. You guys, I know, have talked about a number of internal efforts. Maybe just sort of square that projected mix with, you know, all the stuff that's going on in terms of innovation and inflammation.
Sure.
Thanks.
Yeah. First on the buyback, Chris, we think we can return capital to our shareholders through a buyback without impairing our ability to do the kind of strategic M&A that we talked about, looking to do. We'll continue to look in the areas of our stated interest. We have a very strong balance sheet, and we think our balance sheet supports both the returning of equity capital to our shareholders, as well as the prospect of going out and doing further transactions. We're looking forward to that. As regards the portfolio of products, you know, we feel pretty good about the balance that we have today, and feel pretty good about how that balance evolves through time. We think there'll be a lot of activity in our inflammation portfolio between now and the end of the decade.
You got a pretty clear sense of that, I hope, from our remarks, where we talked about the reasons why we're confident that Otezla will grow throughout its life cycle. We'll be adding, obviously, other inflammatory products or anti-inflammation products to our portfolio starting in January of next year with our biosimilar to Humira. Then, as Murdo said, we'll follow that with a biosimilar at some point during the rest of the decade to Stelara. Of course, we have Soliris, not directly in inflammation, but Soliris and EYLEA, as we referenced as well. Then we'll have an opportunity to launch our own innovative programs, 451 and several other programs that Susan summarized from our portfolio. A lot of activity in that therapeutic category.
We think it will remain an important area for us, and we'll continue to look for sure from an M&A perspective at everything that's happening in that area. We have great expertise across the spectrum now with the addition of Tezspire for respiratory disease, and you know, we'll continue to look.
Your next question is from Jay Olson of Oppenheimer.
Oh, hey, congrats on all the progress, and thank you for this comprehensive update. We really appreciate the work you're doing on elevated lipoprotein(a), which is such an important unmet medical need and also a well-validated predictor of cardiovascular disease. Could you talk about the potential for using lipoprotein(a) as a biomarker for accelerated approval of Olpasiran contingent upon a MACE outcome study? Related to that, many patients have both elevated LDL-C and lipoprotein(a). Are there any plans to study Olpasiran in combination with Repatha? Finally, any work that you're planning to do to increase awareness to drive diagnosis and treatment, especially with guidelines?
Yeah. Thanks, Jay. It's, I think, an interesting series of questions that fit well with what we've tried to communicate this morning. Dave, why don't you pick up on the human data thread and share our thoughts?
Yeah. Thanks, Jay. Great questions. You know, first is around the potential regulatory path for Olpasiran and Lp(a) lowering agents. You know, we're in new territory here. You know, with LDL cholesterol, of course, we've got more than a half a century of evidence that shows unequivocally that lower is better and lowering LDL cholesterol improves outcomes. The same has not been demonstrated yet for Lp(a). Of course, we will have extensive discussions with regulatory authorities once we have the phase IIb data in hand, and as we're designing the phase III program. It's not possible to say right now that one can definitively achieve registration through Lp(a) lowering alone. More to come, as we learn from regulators as those discussions move forward.
Another thing to note about Lp(a), and you implied this in your remarks, is that as Murdo said, this is a genetically fixed level. Lifestyle, diet, exercise, they don't modify Lp(a), nor do pharmacologic interventions that are currently available have much effect, if any, on Lp(a) levels. It's clear that new therapies are required, and our own internal genetic and proteomic work suggests that you need a pretty profound reduction in Lp(a) in order to likely achieve the improvement in outcomes that we're shooting for here, and that's why we're building that thinking into the design of the phase III program.
You know, this is an area that's in its infancy, but, you know, given the epidemiologic and genetic evidence, I think the dice are loaded as much in favor of a program as they can be, right here where you don't have precedent. Murdo?
Yeah. I think the other question, Dave, was, do we see Olpasiran being used in combination?
Oh, yeah.
with other lipid-lowering therapy?
Yeah, sorry. Let me address that. Yeah, absolutely. In fact, in the Lp(a) program, patients entering that program who have elevated LDL cholesterol should be on optimal lipid management for that. That's a prerequisite that should always occur. Some of them, as you note, will then also have elevated Lp(a) levels.
Yeah. One of the things that we'll do in the market is try to describe how the overlap of LDL, elevated levels of LDL-C and high levels of Lp(a) conspire to dramatically increase the cardiovascular risk for a subset of patients. You know, a lot of work that we can do here to describe the epidemiology in more detail.
Thank you very much.
Your next question's from Alethia Young of Cantor Fitzgerald.
Hey, guys. Thanks for taking my question, and I appreciate all the color and detail. I always love these things. I guess I just wanted to ask maybe two, but just one on the inflammation, when you had the breakout between 2020 and 2030. It you know looked like it was a little bit smaller on inflammation. I know you have some interesting biosimilars, but can you talk about kind of innovative inflammatory products? I know it's kinda always like kind of find a needle in a haystack to find a kind of first in class or best in class. Then my second question is just should we think about nephrology as an investment business anymore, or is it just kind of a runoff business? Thanks.
Sure. Thanks, Alethia, for the question. Maybe I can address the second piece, and then Dave, you could just reiterate some of the things we're excited about on the inflammation portfolio. But as regards nephrology, we're very interested in innovative medicines that can help improve the state of kidney health. We obviously have now several decades of leadership in that area. We're very active supporting the patients in the clinical community in kidney disease. We obviously have ongoing interest with Parsabiv, and we continue to support the market with Epogen and Aranesp. We will continue to look for opportunities. We're not doing as much active research in nephrology now, and that's partly because we don't see as much unmet medical need as we do in the other areas where we are concentrating our efforts.
We will continue to look, and if we see innovation that we think we can add value to, we'll do our level best to pursue it. Dave, maybe you could complement what we said earlier on the inflam portfolio.
Yeah. Alethia, I think it's really a lot of the molecules that I reviewed earlier today. Of course, AMG 451 in atopic dermatitis, and then in lupus, the AMG 592 program, increasing T-regulatory cells, as well as the AMG 570 program designed to target both the T-cell and B-cell compartments. You know, those are the programs we're keeping an eye on. Right now our focus is absolutely on executing the clinical development programs, and I'll give more guidance as we go along in terms of when we can expect data readouts from those studies.
Your next question's from Yaron Werber of Cowen.
Great. Thanks for taking my question. Quick, I have a couple. On Lumakras, we're getting a lot of questions about when you launched Lumakras on your presentation to us, it looks like you pegged the market opportunity in second-line plus at 13,000 patients in the U.S. It looks like in the slides today in second line it's 7,000 patients. Just trying to understand what led to that change. Is it still sort of second line to second line, or did something change? Secondly, when Amjevita biosimilars or Humira biosimilars will launch early next year in the U.S., do you expect any impact on Enbrel pricing or Enbrel share-
Mm-hmm.
In the U.S.? Thank you.
Sure. Thanks, Yaron. We can take that in two parts. Murdo, go ahead. Why don't you jump in first?
Yeah. Yaron, we haven't changed anything in the assumption of the market. We've just refreshed our epidemiology numbers in second line specifically, so that number is now 7,000 patients in KRAS G12C second line and beyond. We are seeing that's generally where Lumakras is being used. We see some off-label usage in other patient types, but again, it's very early in the launch, so I wouldn't read too much into that. On the Humira biosimilar question, I think what you'll continue to see is, you know, our position is very competitive here.
First wave, all the attributes that I've mentioned before, I think that, as you look at how that impacts other agents in the category and whether there are knock-on negative price effects, there's a few things I would call out here. First off, we're the ones doing the negotiation on the first biosimilar, so that puts us a little bit more in the driver's seat on what we can do for Enbrel. The other thing that's happening in the market right now is, of course, the safety issues around the JAKs are actually bolstering the growth of the TNF class, and we've actually seen, I think Peter mentioned in his prepared remarks, we've seen the volume growth of Enbrel actually stabilize, and we had some growth in fourth quarter in unit volume growth of Enbrel.
That should help mitigate some of the price pressure. The other thing just to bear in mind for 2022 specifically for Enbrel is, we did have in 2021 roughly $250 million of accounting adjustments that may not repeat in 2022. The unit volume, the underlying unit volume of Enbrel is quite positive. Yes, there will be some price pressure on the entire RA class as the biosimilars come in in early 2023, but given our strength that we're participating both in the biosimilar market and in the innovative market, we feel good about our ability to manage that.
Your next question's from Colin Bristow of UBS.
Hey, good morning, and thanks for all the helpful information. Really just one big picture question from me. Just curious, what, you know, what's behind the decision to do this long-term guidance today, and why make it an end-of-decade guidance, just given that it requires, you know, really such a large leap of faith from investors in terms of bridging from where consensus is now to what you put out versus putting out like a maybe a more sort of tangible three or five-year guidance. I'd be curious to get your thoughts. Thanks.
Sure. Thanks for the question, Colin. We have felt for a while internally that things were setting up pretty well for us for the long term. We felt that it was clear now what opportunities we had in hand and what the potential of those opportunities were. We felt that we were at a point where we had pretty good insight into what the assets are that we're gonna count on to grow through the end of the decade. Obviously, you know, we could have considered giving three-year guidance, but of course, that would've begged some questions around what happens in the middle of the decade as we face potential competition for some of our important products.
Of course, towards the end of the decade, we also face some pressure on potential loss of exclusivity. Our focus was on first understanding the opportunities that we have in hand and what we think we can do in terms of achieving the full potential of those, and then wanting to be helpful to you and to our investors, as you think about the long-term outlook for the business. We've had quite a lot of questions about whether we're confident we can grow through patent expiration, even frankly, patent expirations that occur at the end of the decade. All in all, Colin, we felt we were in a strong position to be able to share with you what we're seeing internally, and that's what we've tried to do this morning.
Great. Thank you.
Your next question's from Kennen MacKay of RBC Capital Markets.
Hi. Thanks for taking the question. Just wanted to say I really appreciated Dr. Deshaies' presentation and the discussion of Amgen's strategy for targeting the higher hanging fruit, so to speak, regarding molecular targets. The diversity of Amgen's pipeline really speaks to that therapeutic approach, agnostic drug development strategy. There were a few therapeutic approaches that were notably absent. For instance, the antibody-drug conjugates, which have grown into a pretty large field, and cellular therapeutics as well, both of which maybe have the promise to tackle some of those therapeutic index challenges that are keeping the high hanging fruit high hanging, so to speak. Just wondering if those were absent by design or if any of those technologies really do appeal to the team and maybe why that is.
Yeah. Great.
Thank you for doing this.
Yeah, thanks for asking the question and giving us the chance to address that. I'll do that in one part and then ask Dave to share his thoughts. You know, strategy is about making choices and about being focused. We've tried to be very clear internally and tried to share with you this morning externally where our focus is gonna be in discovery research. We're excited, as you can tell, about the things that we're doing, but we recognize that there are some things that we've chosen not to focus on internally, and we have a very clear, active plan to participate in business development.
We know the assumptions on which we've rested or based our decision not to be as active in cellular therapy, for example, and we'll watch carefully and see if any of those assumptions require a revisit. If they do, you know, we'll look at ways to make investments or to make acquisitions or to enter partnerships to give us positions in those areas where we haven't chosen to explicitly focus in what we took you through this morning. Dave, why don't you feel free to add your thoughts?
Yeah. Thanks, Bob. It's a great question. As Bob said, strategy is all about choices. We've been very clear about the choices we've made. Now, that said, we keep a very close eye on emerging technology, as you mentioned a couple. Now let me talk about antibody-drug conjugates or ADCs. This is obviously a field that's undergone what I think is a pretty significant evolution over the last six or eight years with the emergence of new generation technologies. We're taking a close look at this. As we take a biology-first approach, we wanna fit the modality that's optimal to a target. You know, it's quite possible that we'll open the aperture to things like ADCs over time, cellular therapy, gene therapy, or other RNA-based therapies.
For the moment, we are focused crisply on the areas that we outlined today.
Your next question's from Robyn Karnauskas of Truist Securities.
Hi, guys. Thanks for taking my question and for all the color. Just to follow up, don't wanna be a dead horse, but regarding the comment you made, Bob, about valuation being low, the follow-up question to that is, do you think that these companies are willing to sell at this low valuations? Is there a sort of an acceptance that, you know, the valuations of yesterday may be gone? Is there more willingness in your diligence for companies to be open to being acquired in your work?
Well, Robyn, maybe what I would do is give you an answer to that question based on sort of 30 years of being part of this. You know, I think it takes a little bit of time. You know, I think when valuations reset as they are doing at the moment, it takes a little bit of time for them to age into the mindsets of the different companies. You know, clearly the terms of trade have been very strong over the past couple of years for the smaller, innovative companies that have had access to an abundance of capital, and the terms of trade are not as favorable now, either in the public markets or potentially, you know, in collaboration agreements as a result of the shift in the public markets.
you know, we think that there will be opportunities in the future to buy or even today to buy assets at better valuations than we would've been able to buy them at a year ago. It doesn't happen overnight, you know, it's more of something that sort of gradually mindsets change. I think directionally, Robyn, it's likely that we will see again more attractive prices for us to deploy capital against than what was the case a year ago.
Great. Thank you.
Your next question's from Mohit Bansal of Wells Fargo.
Great. Thanks for taking my question, and again, thanks for providing all this information. Maybe a couple of questions. One on Enbrel and Humira biosimilars. Should we look at both of those assets in your franchise combined? Do you think on a combined basis the franchise as a whole could grow till the loss of exclusivity of Enbrel? Also another question on margins. You mentioned that biosimilars also have high margin at this point. Is this because a lot of these biosimilars you have launched or launching till end of the decade are also in the I and I business, so there's a lot of synergy there? How confident do you feel about these margins staying high going forward? Thank you.
Great. Thanks for the question. I think maybe we can tackle that in two parts. Murdo, if you take the front end, Pete might wanna offer a few thoughts on the back end.
Sure. Thanks for the question, Mohit. We generally think of the inflammation category in its totality, so you're right to point out the fact that we've got Enbrel, which continues to have exclusivity through the decade, and then we have, of course, our biosimilar products. It's not just Amjevita, right? Amjevita followed by Stelara, and then other launches of other biosimilars and, you know, not necessarily in order, but we've got EYLEA and Soliris in there as well. I think the way I would think about it is, yeah, Amjevita, a very strong growth driver just given that, you know, Humira, roughly over $17 billion in annual revenues, bigger probably by the time it loses its exclusivity. The TNF category, as I mentioned earlier, is strengthening given the JAK safety issues, so that's a tailwind on unit volume.
Of course, having multiple biosimilars coming in one after the other allows us to grow the biosimilars business. As we've said, we expect that business to double in revenues comparing 2030- 2021. Now Enbrel will have some pressure on it. Enbrel will have some pricing pressure, but the unit volume evolution on Enbrel should be fairly robust. The other thing just to think about in the category is many patients see more than one TNF, and that trend is actually increasing as well. If a patient doesn't get the response they desire on adalimumab, they may experience trial on Enbrel. We still think Enbrel's an important part of the portfolio going forward. Peter?
Yeah. Mohit, on the margin question that you have on biosimilars, I would note, as I mentioned this morning in my remarks, that biosimilars are not, they're not dilutive to our overall corporate margin. Secondly, I think, and just briefly, our commercial group operates the biosimilars as a key part of each therapeutic area, and we think that's a really key efficiency for us. It allows us to maintain a strong margin on the biosimilars with that. Certainly it's, you know, part of the competitive nature where we're just really good in the market with these and as Murdo just said, but also it's the way we operate the business. It's very effective the way we go to market with the biosimilars.
Wanna talk about royalties at all, Pete, in the future for biosims?
Yeah. Royalties for biosimilars, they'll then in the future, you know, they'll continue to run off at some point. Those will reduce through the end of the decade.
Your next question's from Cory Kasimov of JP Morgan.
Hey, good morning, guys. Thank you for taking the questions.
Morning.
I wanted to ask more about your growth expectations for Otezla. Sounds like you remain very confident in the product's outlook as you're predicting low double-digit annual sales growth until loss of exclusivity. Given that it grew just 2% last year and there's competition looming, can you talk a little more about what goes into your assumption here? For example, how much does the outlook hinge on or take into consideration newer market opportunities like mild psoriasis patients? Quickly, a second question is, what do you assume is the LOE for Repatha? Thank you.
Okay. Why don't we, Murdo, you wanna jump on that?
Yeah. Thank you, Corey. We're quite excited about the growth opportunity we have with Otezla. Susan commented in our prepared remarks about the trends that we've seen recently on Otezla, where we saw some softness in 2020 due to the pandemic on new psoriasis, bio-naive psoriasis patients, and that's where we source most of our growth from. The biologics in psoriasis will source a lot of their growth from one another. We're dependent on those new post-topical, pre-biologic patients getting diagnosed. Because of the softness in the market in 2020, we saw some softness in our total business in 2021. Now, the good news is in 2021, the new patient growth returned, and so that helped set up a much stronger profile for 2022.
As you rightly point out, we have also the expanded indication now, and we're the only product in the category, in the systemic category, including the biologics, that's indicated across mild, moderate, and severe psoriasis. For Otezla, given that it's an oral, it's really well-positioned for that early mild patient, and mild's a bit of a misnomer here, but milder patient that has persisted with topicals despite the challenges of that treatment. Given that psoriasis is really a systemic disease, they need something stronger to treat their psoriasis. You know, Otezla, at its price point, at its positioning in the market is really ideal. We see it as a very good catalyst for growth. Early days of the launch of the broader indication are very good.
We're seeing a little bit of an increase in our new patient starts through our co-pay programs and other things. That gives us confidence that we've got a good long-term growth profile and why we've extended the guidance on low double digits. We have assumed in our modeling for the product that there will be additional oral competitors like the TYK2. But we've also modeled in some of the feedback we're hearing from our dermatologist customers that they'll be a bit more guarded in their adoption of novel therapies on the basis of what we're seeing in RA from the JAK inhibitors and their safety.
That has factored into our confidence of being able to continue to grow Otezla, which has hundreds of thousands of patients experienced in treatment and a very strong safety and efficacy profile going forward.
As regards Repatha, we think the intellectual property in Repatha is strong, and we don't expect to face any loss of exclusivity challenges until the very end of the period that we're giving you guidance on. You know, before 2029-2030, I don't think we'll face any pressure there.
Thank you.
Your next question's from Michael Schmidt of Guggenheim.
Hey, guys. Thanks for taking my questions. I had another one for David Reese on Lumakras. Just confirming, I guess, what frequency of KRAS G12C positivity should we now be assuming in lung cancer? And with those new epi data, I was just wondering if you could share your updated view on the peak sales potential for Lumakras. I think in the past, you talked about roughly 4x the size of the ALK inhibitor market, and I was wondering if that's still your view at this point.
Yeah. Actually, Murdo, why don't you pick up the thread there?
Yeah. Michael, it's the epidemiology is still roughly 13% of all non-small cell lung cancer patients. Yes, that's roughly a multiple of 4x the ALK category. Obviously, KRAS G12C expression is a little lower in some other malignancies, but in lung cancer, it's about 13%.
Okay. Thanks for confirming.
Your next question's from Matt Phipps of William Blair.
Hey, good morning. It's Hunter on for Matt.
Okay.
Maybe just on AMG 451, I was wondering if you could provide a little bit more color on sort of the clinical program that you outlined today, sort of what you're thinking in terms of potential comparator arms in those studies, as well as, you know, any plans for a comprehensive biomarker strategy there.
Sure. Okay. Hunter, Dave can take that for you.
As I noted, we expect the ROCKET program, which we're calling the suite of phase III studies, to launch roughly in the middle of this year. It's going to target a broad swath of patients, so those who are naive to biologics, those who have had a prior biologic or a JAK inhibitor, range of ethnicities, age ranges, including adolescents. You know, I think a pretty comprehensive look at the patient population here. In addition, we'll be looking at different strategies, combinations, monotherapy, and different schedules, regimens, dosing and scheduling regimens to really try to optimize the patient experience and patient outcome. I'll provide more detail as we get ready to launch those trials in roughly the middle of the year or so.
Your next question's from Carter Gould of Barclays.
Okay. Morning, Carter.
Great. Good morning.
Morning.
Thank you so much for hosting this and all the color. It's been very helpful. I guess two questions from me. First, Bob, I guess just in terms of the commitment to heme/onc here, obviously Amgen's been very strong there historically. You know, Kyprolis is sort of nearing the end of its life. BLINCYTO's been very strong, and the sort of level of intensity there relative to solid tumors is pretty stark. Just sort of how committed you are there, if that's something you'd maybe look to add via M&A or if there's sort of been sort of a bigger picture strategic decision made there. Then on tarlatamab, the data continues to look you know, encouraging.
I don't know if you guys are ready to provide any color on the dosing you'll carry forward, if the expansion arm potentially could be pivotal and maybe just how you're planning for potential disruption of IO/IO combinations in first line if they play out successfully. Thank you.
Two great questions. First on heme/onc, I'll answer at the strategic level and then invite Dave or Murdo both to jump in, and then I know Dave would be happy to talk in detail about tarlatamab. On heme/onc, we remain very focused in trying to make a difference for these patients. You know, as you're aware, we think BLINCYTO has the potential to change the practice of medicine for patients suffering from relapsed refractory acute lymphoblastic leukemia. It's a great product. The data remain very encouraging. We look forward to continuing to explore ways to see that product used earlier and earlier and to potentially, again, transform the practice of medicine in that disease. We think that our approach in other malignant liquid malignancies is also robust, and we're looking forward to continuing to advance innovative new therapies.
We continue to look at AML, for example. I don't know that I would agree that Kyprolis is near the end of its life cycle. We're excited about, again, continuing to grow Kyprolis. Nplate continues to grow very strongly for us, and as I mentioned earlier, we expect to be launching Soliris as well. We'll be supporting the community of heme/onc specialists well through the balance of the decade. Dave, Murdo, feel free to elaborate further.
Let me speak to the tarlatamab program, which was one of your questions, and then I'll ask Murdo to jump in. As I noted, we, you know, we're quite enthusiastic about the emerging data that we're seeing here, including complete remissions in patients with advanced disease where the prognosis is often mentioned, you know, measured in weeks or months. The preliminary median duration of response among confirmed responders now is beyond a year, which is really exceptional data. The ongoing phase II trial is a potential registrational trial. The design of that trial is such that we've got two doses going forward. In an initial phase of this study, there will be an interim look, and then we will potentially select one or both doses to move into the fully pivotal portion of that trial.
We'll provide more guidance as we go along. I would say that this has also been designed to be consistent with recent FDA guidances under Project Optimus that encourages dose ranging, look at a variety of doses in phase II in pivotal oncology drug development. We feel very good about that program. We're moving very quickly, and more to come as the data emerge. Murdo?
Yeah. I think, you know, it's really exciting to be able to be another first mover in a really tough malignancy like small cell lung cancer, so we're very excited about what we're seeing in the clinic there. I also flinch, Carter, at your comment on end of life cycle for Kyprolis. Just, I know you know this, but just a reminder that despite the fiercely competitive multiple myeloma sector, we have some important new data that we're out promoting to oncologists with the combination data with CD38 products, and most recently the combination with the DARZALEX FASPRO administration. The hematology teams are fighting hard out there and continuing to generate good revenues on Kyprolis. Thanks for the question.
Your next question's from Dane Leone of Raymond James.
Hi, thank you for taking the questions, and really appreciate the deep dive into the corporate strategy. One of the interesting things from the presentation that really stood out was when you look at the projections for the composition of the business and the different drugs in the portfolio out to 2030, you have this interesting stack of the growth areas, Lumakras, Tezspire, and some of the other pipeline assets, predominantly in oncology and inflammation. Biosimilars, which again actually does overlap in oncology and inflammation quite a bit. At the bottom of that, Repatha, Otezla, and the rest of the currently branded, on-market drugs.
It begs the question from a shareholder perspective, in being such a long-standing company, you know, as you said, one of the original class from the eighties. I think the only other one that you implied mentioned was actually Biogen that's still around. Do you think there could be a strategy in terms of unlocking valuation for the different components of the business if you thought about a strategic review in terms of a growth co and potentially cash or return cash co that actually separated out some of the assets, growth assets in the oncology inflammation area paired with some of the overlapping biosimilars, and then carved out the remainder of the business, which looks to be about slightly down to flat to 2030, depending on your belief in the Repatha estimates.
Can you just take us through the logic from, you know, the board and senior management level of maybe doing something a little bit more aggressive to unlock value for what could be applied to a multiple of a growth business versus the investors that wanna be in Amgen for that dividend yield and return of cash flow? Thank you.
Yeah, that's a question we regularly assess. We look at all the different ways of creating value for our shareholders, and we've always said that nothing's off the table and that includes the nature of the question you just asked. We've never found through the years of repeatedly looking at that question that that's been a way for us to unlock value. Our focus for unlocking value has been and remains on trying to advance innovative medicines that can make a big difference for patients that are suffering from serious disease. We have, again, a very focused business, a very supply chain that's a single supply chain concentrated on providing these markets, excuse me, these products across our global markets. We have a tax structure that has been very efficient.
A combination of the way that our business has evolved from manufacturing, process development, the supply chain, tax, standpoint, et cetera, has made it very difficult for us to find efficient ways of getting at what you're describing. Unlike some of our peers in the industry who've been able to disentangle small molecule supply chains, for example, or unlike what you see in other industries where that issue isn't as significant as it is for us. We're confident we can grow this business and continue to develop innovative products, and off the back of that, generate significant value for our shareholders.
Your next question's from Salim Syed of Mizuho.
Great. Thanks for the questions, guys, and appreciate the caller. So just a couple from me on the 2030 guidance. So I wanna make sure I'm just doing this math correctly, guys. So when I look at consensus, it looks like there's a $12 billion decline in the key products through 2030, and there's an $8 billion growth in those, in the key products. So that's a shortage of $4 billion. Your guidance implies about $35 billion in revenue in 2030. So you need another $9 billion-$10 billion on top of what we just calculated. Would you agree that's the right way to think about the delta here, at least, between consensus math and what your guidance implies? And then the second question is just on slide 20, the multi-slide chart.
I still don't understand where this growth in Repatha is gonna come from. The orange slice here looks like you're implying about $6 billion-$8 billion in Repatha revenue by 2030, and there's even a slight inflection in 2028. Took five years to make this a $1 billion product, so you need 5x more in the next five years to even get close to this $6 billion. I'm struggling here. This wasn't a leap of faith guidance, as you guys suggested. Can you just maybe point out what's the exact trigger here that's gonna open this market up? Thanks so much.
Sure. Maybe we can do it in two parts, Salim. I'll ask Murdo to pick up on the Repatha piece. With respect to the revenue guidance that we provided, again, Salim, we've tried to be very clear about what we see as the building blocks. I'm not gonna address the details of consensus. You know, I think your long-term model, for example, was a little bit different from how we see the business, Salim, and I suspect others probably now have more information, and they can go back and think about what the long-term revenue outlook is, for example, through the end of the decade off the back of some of the information that we shared today. Repatha is clearly a molecule that we have a lot of confidence in.
It addresses the biggest public health problem in the world, which is cardiovascular disease. It addresses one of the most important root causes of heart attacks and strokes. As you know, there are 800,000 heart attacks in this country every year and 820,000 strokes, and a lot of those can be prevented if LDL cholesterol levels are brought down low enough and maintained low enough over a long period of time. There is a huge mass of opportunity for us. By the way, it's most acutely needed in those who are aging and going across the 65th threshold. We think there's a demographic opportunity here which is substantial over the coming decade and still a huge unmet medical need.
Murdo, feel free to elaborate further.
Yeah. Thanks, Bob. I won't recap the epidemiology. I think you've summarized it really well, just perhaps some of the catalysts that help drive Repatha growth through the decade. Right now we've been focused on unlocking access and reimbursement barriers. A lot of that work now has been accomplished. You know, lowered the list price, and we grew through that. We got 40% volume growth year-over-year in 2021. Now what we're doing is unlocking the physical and administrative barriers inside healthcare systems, so the integrated delivery networks in the U.S., unlocking the growth there. Over 122 healthcare systems in the U.S. now routinely discharging patients with proper lipid panels and more aggressive treatment of their LDL-C, including Repatha.
We also, later on in 2022, will be increasing our primary care investment, where we're now seeing more and more primary care physicians comfortable initiating Repatha, given the ease of prescribing it and the ease of getting prior authorizations through their PBMs for their patients. Later on, Dave Rees mentioned this trial, but the Vesalius study, assuming we're successful in that trial, that brings in another 750,000 addressable patients in the U.S. So that's a very important event in the lifecycle of Repatha. Recall the design of this trial, people who have not had an event but have LDL elevated levels of LDL that are not at goal. That allows us to extend the event reduction profile, and it also has a temporal nature to it.
It's a speed to which you can get that event reduction, and that should increase the urgency to treat. Look, this is a really, really important strategic growth driver. I've worked in the cardiovascular arena for many years. I've seen the curves of many products now with access restrictions and management in these categories be much slower than they used to be. I don't think Repatha is atypical of that, but I do think we've now got momentum to grow the product through the end of the decade.
Okay. Ashley, I understand we have one or two questions remaining. Why don't we take those last couple questions, and then we'll thank our callers for their patience and for their support. Thanks. Let's go to the next call.
Your next question's from Brian Skorney of Baird.
Hey, good morning, everyone. Thank you for taking my question. I guess I just had a question on what you currently think of as sort of the right cash and debt position. I think you had $33 billion in debt at the end of 2021 and about $8 billion in cash. Do you think you can buy back shares of the magnitude you're talking about as well as pay the dividend without taking on additional debt? And what debt level do you think you would be willing to go up to and just how climbing interest rates make taking on that debt sort of something to think about in the more near term?
Again, we think we have a strong balance sheet, and we're comfortable with the plans that we outlined. Pete, feel free to jump in and elaborate.
Brian, thank you for the question. What I would say is, as I said in my remarks earlier this morning, we build it on an efficient capital structure that results in an optimal WACC. We think it's important to constantly look at our capital structure to keep it efficient, and make sure we're in an optimal weighted average cost of capital for that. We're very confident, as we suggested, that the dividend will continue to grow. It's grown meaningfully since 2011 when we implemented it, and we're very confident that we've got the right structure to continue to return capital to shareholders through stock repurchases. And at the same time, we've got room, as we showed last year, though.
To invest in external innovation. We spent more than $3 billion in upfront payments, and we also layered in about $300 million of operating expenses, as I mentioned earlier this morning, you know, from our acquisitions and our licensing arrangements in 2021. We're confident in the way that we run the business from a capital perspective, and we intend on remaining predictable and safe stewards of our shareholders' capital.
Okay, Ashley, I think we have.
Your last question
one last question. Yeah, thanks.
Will come from Ronny Gal of Bernstein.
Okay. Ronny, you're back.
I am back. Thank you very much for the follow-on question. You gave us a lot to think about today, so really appreciate all the effort you've made in giving us this presentation. Given it's the last one, I'm gonna make one big picture, one small picture. I guess the big picture is, you know, it's such a strong bio business and biosimilar and the engine you have. I'm wondering if you considered this idea of follow-on molecule that you seem to be kinda, you know, well-positioned to participate in that if you'd want. You pursuing first in class obviously makes sense, but is there a logic within this as well? Second, the specific one, AMG 133, obviously management of obesity, kinda like a really important long-term field.
Can you tell us a little bit about this asset further? When should we see proof of concept data and kinda like the path forward until we see a good body of data to allow us if we can. There's enough to put us in the model.
Sure. Maybe I'll address the first question, and then we'll ask Dave to address the second question, Ronny. We have an open mind. We look regularly at whether we think we can add value to you know, pathways that may have been de-risked, which is what I think you're asking about. We tend to think about it from the standpoint of what value we can add above and beyond that which is already being addressed by products that are ahead of us. We think, you know, it's particularly important right now to be first or best, so if we see ways to do something different or better than other competitors, you know, in those circumstances, we may be willing to follow in behind others.
we keep an open mind and try to find ways that we can leverage our capabilities to add value for patients, obviously. If we can do that, we can do it for shareholders. Dave, please address Ronny's specific question.
Yeah. Thanks, Ronny. AMG 133, elegantly designed molecule targeting two of the key pathways that are at the center of much of the deranged metabolism that occurs in both obesity and other pathologic states. We're in phase I right now. Those data continue to unfold. I shared some of the preliminary data with you, which we think look quite good. Our plans, as that study progresses, will be to move into proof of concept trials in phase II, and I'll provide additional guidance as we get ready to do that. Again, the end game here is not strictly a weight loss drug, but rather a drug that can ultimately affect cardiovascular disease, other metabolic diseases that have as a driver, obesity and then some of the deranged metabolism that accompanies that.
All right. Well, let me just thank you all for your time this morning. We know we asked for a meaningful chunk of your time, so we appreciate your support and your willingness to hear from us this morning. As you can tell, we're excited about the outlook for our business, and we were pleased to have a chance to share with you more detail than we would have ordinarily had in the context of a normal earnings call. Thanks for, again, giving us this opportunity. Arvind and his team will be here all day, and they're available to answer any further questions you may have, and we look forward to seeing you at the next call. Thank you.
Thank you for attending the Amgen Business Review. Please enjoy the rest of your day.