Good morning. My name is Todd, and I will be your conference operator today. At this time, I would like to welcome everyone to the Halozyme Financial Update Call. Please note, this event is being recorded. I will now turn the call over to Tram Bui, Halozyme's Vice President of Investor Relations and Corporate Communications. Please go ahead.
Welcome to the Halozyme Financial Update Call. Let me begin by briefly reviewing today's format. We will have a presentation followed by a Q&A session. During the presentation, we will be displaying a slide deck that will advance with each speaker's comments. On today's call, we will be making forward-looking statements as outlined on slide two. I would also refer you to our SEC filings for a full list of risks and uncertainties. During the call, both GAAP and non-GAAP financial measures will be discussed. Certain non-GAAP or adjusted financial measures are reconciled with the comparable GAAP financial measures in the slide presentation. I will now turn the call over to Dr. Helen Torley, President and CEO.
Good morning, and happy 2024. Here we are in January 2024, a key milestone year for Halozyme. Over the last month, many investors have been asking about our confidence in the durability of our revenue, specifically in the revenue durability and growth we forecast in 2024 and in 2027. Each time I answered, saying that we are confident that we will continue to demonstrate strong royalty revenue growth and total revenue growth in every year from 2024 to 2027. Each time I answered this question, I also reminded everybody that we project to achieve $1 billion in annual royalty revenue in 2027. Each time you ask for more granular revenue information, including about the relationship between royalty revenue and patents related to rHuPH20, our proprietary enzyme in ENHANZE.
Today, we're dedicating this call to a presentation of the rHuPH20 patent dynamics that are expected to drive revenue durability and to a presentation of our revenue guidance for 2024 and our revenue guidance until 2028. Yes, we have confidence in the visibility of our revenue and are delighted to share our five-year view with you. For the presentation today, I'm joined by Mark Snyder, our Chief Legal Officer, and Nicole LaBrosse, our Chief Financial Officer. Our presentation of the patent dynamics will be meaty, so listen well. I'm very glad that Mark, who's an expert in the area of patent dynamics and intellectual property licensing, will be leading this discussion. Nicole and I will then present our financial guidance. Today, we will not make any comments about pipeline progress. We will update pipeline progress at the regularly scheduled February earnings call instead.
Now, let me start with some key strategy highlights to best situate the discussion. Over the last decade, we have built a compelling, de-risked, and proven business with multiple competitive advantages that is positioned for durable revenue growth. We work with leading companies and with breakthrough products that are often approved or have completed phase 3 testing. This results in our lower-risk model. We have a high success rate in IV to subcutaneous conversion. This has resulted in seven approved products to date, driving our royalty revenues, and this is projected to increase to eight approved products in 2024 and 10 products in 2025. Having 7 regulatory approvals demonstrates how de-risked the ENHANZE platform is, and this is a real competitive advantage. Our contract structure and innovation, resulting in multiple co-formulation patents, creates extended, durable royalty revenue streams for many years to come.
Our broad compatibility brings the confidence of our ability to continue to expand the number of partners and subcutaneous products. Finally, our commercial products, including XYOSTED, which is delivered subcutaneously with our small volume auto-injector, add an additional diversified and growing revenue stream. As the leader in rapid subcutaneous large volume drug delivery, our vision is to transform patient treatment. Today, many breakthrough therapies require the patient's life to fit the treatment. Often it requires frequent and lengthy visits to a hospital. Our vision and our passion is to enable a world where breakthrough therapies fit the patient's life. Today, receiving an IV treatment is not possible over a patient's lunchtime, as an example. With subcutaneous treatment with ENHANZE, we have created this option for patients. We have two commercially validated subcutaneous delivery technologies that we license to partners and generate revenue through royalties, milestones, and product sales.
7 ENHANZE-enabled products have been approved in at least one region, with many of the products approved in approximately 100 countries. Importantly, approximately 800,000 patients have received treatment that include ENHANZE, creating a large, well-characterized database that has helped establish a positive benefit-risk profile. This large safety database is unmatched by competing technologies and represents another substantial competitive advantage. Our second platform is our small volume auto-injector business, which comprises today of one approved proprietary small volume auto-injector plus drug product, XYOSTED, and two approved partners, small volume auto-injector plus drug products.... We have deep experience with auto-injectors, with more than 40 million devices supplied. It's this auto-injector experience, plus the ENHANZE technology, that allowed us to create the first ever high-volume auto-injector, demonstrated to enable delivery of 10 mL of a biologic in just 30 seconds.
We also have two commercial products, which add to our revenue diversification and growth. XYOSTED is our proprietary testosterone replacement treatment, delivered in just seconds subcutaneously using our small volume auto-injector. And HYLENEX is our proprietary recombinant human hyaluronidase that is predominantly used in ophthalmic surgery. Importantly, these products are projected to contribute meaningfully to EBITDA, growing from approximately $15 million in 2023 to a projected greater than $150 million in 2028. Let me move to why we are focused on subcutaneous drug delivery. Shorter and simpler, subcutaneous drug delivery can have many advantages. With shorter treatment times, subcutaneous delivery reduces the burden of treatment for patients and their caregivers. Subcutaneous drug delivery with ENHANZE can result in reduced infusion-related reactions, as we have seen with DARZALEX. Now, why does this matter?
There can be a range of infusion-related reactions, which can range from mild symptoms, such as a slight fever, to severe symptoms that can include low blood pressure, nausea, vomiting, and breathlessness. These side effects have a negative impact on the patient's experience and can even impact future adherence. The ability of ENHANZE to enabling subcutaneous injections to reduce infusion-related reactions is a real innovation. It is an innovation that benefits the patient and can also impact treatment outcomes. Subcutaneous drug delivery with ENHANZE can also enable treatment closer to the patient's home. For example, in a community hospital, doctor's office, or even the patient's home itself. This can help reduce inequalities to access by reducing the barriers for the elderly, frail, rural, and poorly mobile patients.
It really is no wonder that 85% of PHESGO patients and 90% of Herceptin patients preferred subcutaneous delivery of their treatment over IV. Nothing speaks better for this than the fact that 92% of total DARZALEX sales are for the subcutaneous version, DARZALEX FASPRO, in the United States today. There's no doubt that the time is right for subcutaneous delivery of important medicines. In the U.S. and outside the U.S., as a result of advances in medicine, many centers are experiencing and reporting capacity constraints. There simply are not enough chairs available to deliver all of the lengthy intravenous treatments that are being prescribed.
As shown here, the move to subcutaneous delivery can reduce chair time, opening up the opportunity for more patients to get treatment and reduce costs to the healthcare system and to patients, due to the lower resource utilization needed to deliver treatment subcutaneously. Here is a summary of our Wave one, two, and three products. Each wave has been designated by actual or estimated launch time. These products are wholly or largely de-risked from a regulatory approval standpoint, and it is for this reason that we're focusing on them for today's update and for inclusion in our royalty revenue guidance.
Wave one and two products are launched and established, with the Wave two products, Darzalex Subcutaneous and PHESGO, the key drivers of royalty revenue growth that is resulting in the royalty revenues of $445 million-$450 million in 2023, in line with our guidance. Wave three is comprised of launches that are projected to occur between 2023 and 2025. This is now expanded to five products and includes VYVGART HYTRULO, Tecentriq Subcutaneous, Ocrelizumab Subcutaneous, Nivolumab Subcutaneous, and we have recently added Amivantamab Subcutaneous into Wave three, based on the projected faster development progress on this exciting product. We are just at the beginning of Wave three, which we project will begin contributing royalty revenue in 2024 and become meaningful in 2025.
Importantly, Wave 3 is the key driver on top of Wave 2, to achieve the projected $1 billion in royalty revenues in 2027. I will note that we have future waves 4 and 5 that will add to and build on top of this. These are not included in our royalty projection, as we're focusing on products that are wholly or largely de-risked from a regulatory standpoint. I'm very pleased now to move to the next agenda topic, which is Halozyme's innovation, past, present, and future. This is a section where we'll be providing granular information on the relationship between our rHuPH20 patent and revenue. I can think of no one better to lead this discussion than Mark Snyder, our Chief Legal Officer. Mark joined Halozyme two years ago, joining from Qualcomm, where he was Deputy General Counsel.
At Qualcomm, Mark led the global litigation, regulatory, and intellectual property policy groups for more than 10 years. He successfully enforced and defended Qualcomm's patent licensing business, talking up countless value-creating litigation and regulatory wins. Mark, I'll turn it over to you.
... Thank you, Helen. You have heard from Helen about a number of ways that we work with our collaboration partners to innovate exciting new products to improve patients' lives. I will now discuss how those innovations lead to durable royalty revenues in our licensing platforms today, and in several cases, extending out beyond 2040. At the end of my remarks, I will address our current efforts to protect our exciting new high-volume auto-injector innovations that will continue to contribute to our licensable patent estate. I will start by giving you an overview of the patent rights that are important to our ENHANZE licensing platform and collaborations. Halozyme is the recognized pioneer in developing human-derived hyaluronidases for subcutaneous administration of medicines.
Our patents, which we refer to as a patent portfolio because of the large number of patents that we have obtained worldwide, protects our innovations in a number of ways. Halozyme has patented the recombinant human hyaluronidase we call ENHANZE, through composition of matter patents and through patents covering our methods and products of manufacturing and the use of ENHANZE. We also protect our technology resulting from our collaborations with licensees through collaboration patents, which you might hear us refer to from time to time as co-formulation or co-form patents. Collaboration patents typically cover the combination of our ENHANZE technology with a licensee's drug therapy, including the composition and methods of administration or methods of treatment of disease. While our ENHANZE patents are owned solely by Halozyme, our collaboration patents are typically jointly owned with our licensees.
All of the collaboration products that we will discuss today have at least one granted or pending collaboration patent, and some have several. Most importantly, Halozyme is continuing to innovate, continuing to file new patent applications to cover its new innovations, and we are receiving newly granted patents for those innovations. Let me now turn to a brief overview of key terms in our licenses relating to the royalties we are paid in our collaborations and how our patent rights relate to our royalty revenues. What I'm going to describe are typical terms in our licenses and what we strive for in our negotiations with potential licensees. Bear in mind that our licenses are the result of negotiations, so in some licenses, these terms may be modified. In general, what I will discuss today holds true for nearly all of our licenses.
In general, our licensees pay us royalties and milestones during the term of our licenses, and that term is typically the longer of a fixed period of at least 10 years and extends out to the expiration of any Halozyme-ENHANZE patent or collaboration patent covering the subcu product. The royalty rates we are paid are set at the time we sign a license, and the royalty rate that applies typically increases with sales volumes. The rate can also be reduced, in some cases up to 50%, when our patents covering ENHANZE expire, and there is no collaboration patents covering the licensee's subcutaneous product. As previously noted, our license with Janssen is a bit different, and the collaboration patents do not extend the term for paying royalties fully through the expiration of the collaboration patents or prevent reduction in royalties once Halozyme's ENHANZE patents expire.
Having discussed Halozyme's ENHANZE patents, I will now provide more color on our collaborations and innovations from our collaborations and discuss how those innovations lead to durable royalty revenues in our licensing platforms today and extending out beyond 2040. There are three main points that I will make. First, we expect our collaborations to continue to result in innovations that can be protected in the United States and around the world with patents. Second, that these collaboration patents do and will continue to extend the period for which we expect to receive royalty revenues under our ENHANZE platform. And third, that the royalty rate we receive generally remains at the original mid-single-digit starting rate for the entire royalty period when a collaboration patent covers a licensed product.
When we work with our collaboration partners to develop new products in the past, that has always resulted in innovations that we tried to protect with patents. These innovations include co-formulations with ENHANZE and administration of partner's therapies using ENHANZE, which we refer to collectively as co-formulation patents. Our collaboration partners are also incentivized to obtain these patents to protect their investments and innovations. We expect that dynamic to continue due to the extensive ways in which we can demonstrate to patent offices around the world that the innovations and results from those innovations are surprising and not obvious to support patentability. Those surprising results, typically identified during clinical trial work, can include improving the pharmacokinetic profile of the partner's therapy, improved therapeutic results, improved drug stability or potency, and altered duration of events, and reduced adverse events, just to name a few....
All of our collaborations have generated data and results, as I will share with you momentarily in more detail, for issued collaboration patents, or are anticipated to generate data and results that can be used as the basis to apply for and obtain co-formulation patents. Since pending patent applications are confidential for 18 months from the filing date, we cannot share any additional details of unpublished co-formulation patent applications. We have provided examples of the non-obvious innovations and results that have been used to demonstrate patentability in the United States and around the world for the launched Wave One and Two partner products. Due to the unique characteristics of every therapy or drug, the differentiated modalities of action, and methods of treatment, we do not expect prior non-obvious results to block patentability for future innovations that utilize ENHANZE.
What is non-obvious is highly dependent upon the unique circumstances and known state-of-the-art for each product and therapy. I am now going to address in more detail the impact of co-formulation patents on our licenses with graphical illustrations. To make our licensing program easier to understand, we have graphically represented the typical royalty payment period terms I mentioned previously in our license agreements. Across the top of the slide is a gray banner that represents the timeline of a typical collaboration with a partner from clinical trials through commercial product sales. In general, our ENHANZE licensees pay us royalties for a minimum of a fixed period of at least 10 years from when commercial sales begin, represented in the slide as the purple bar at the middle of the page.
More typically, our ENHANZE licensees are expected to pay us for a longer period, that is, for the life of a co-formulation patent that covers the licensed product, represented here as the green bar at the bottom of the page. You may have noticed from a previous slide that once a patent is filed, we expect the patent to remain valid for at least 20 years from the filing date. In most of our collaborations to date, we discovered innovation and obtained unexpected results during clinical trials that lead to the filing of patent applications for co-formulation innovations. That starts the 20-year clock to expiration of the patent, as shown on the left bottom of the slide.
The minimum fixed royalty payment period is usually shorter than the life of the co-formulation patent, so the extended period for paying royalties as a result of a co-formulation patent is demonstrated in the green box at the end of the purple bar, representing the time period for which the patent life remains beyond the fixed period. We will show the expected impacts on royalty payments for most of our Wave One, Two, and Three products in just a moment. We have graphically represented how co-formulation patents can also operate to maintain the royalty rate applied to licensed product sales, which is typically in the mid-single digits. The same gray banner representing commercial sales is also across the top of this slide. In this case, and for ease of presentation, we are illustrating just the United States royalties. Royalties on sales outside the United States would follow a similar pattern.
The Y-axis of the chart represents relative royalty rate, and the X-axis represents time. We show graphically that royalties for the fixed term are paid at the original starting royalty rate, represented by the purple shaded area in the chart, and are reduced once the Halozyme ENHANZE patent in the United States expire in September 2027 and remain at that level until the end of the fixed term. However, when a co-formulation patent covers a licensed product, as represented by the green shaded area, both the time period for paying royalties is extended, as we discussed in the previous slide, and the royalty rate is preserved for the remaining royalty period to prevent reduction when Halozyme's ENHANZE patents expire. The combined effect is meaningful and demonstrates how impactful co-formulation patents can be to maintaining the durability of Halozyme's royalty revenues, even well beyond the expiration of Halozyme's ENHANZE patents.
I want to now focus on how this translates into durability of our royalties for many of our Wave One, Two, and Three licensed products. This is the first time that we have shared information at this level of granularity for our existing licenses, but we think this information is important for you to better understand the durability of our expected royalty revenues. On the left side, we list the licensed products and summarize the expected durability impact of the issued or pending co-formulation patent, unless the pending patent has not yet been published. The bar chart shows how far out into the future we expect to obtain royalties under our ENHANZE licenses for each product. You can see that royalties are expected to at least 2030 for all products, beyond 2030 for most products, and out to 2040 and longer for several Wave Three products.
Indeed, royalties are expected to be paid at the original starting rate for nearly all products for the life of the applicable co-formulation patent. This demonstrates visually the extraordinary durability of our royalty revenues and impact of co-formulation patents. I am going to conclude with some remarks about our high-volume auto-injector innovations. You have heard from Helen on the great pioneering work being done and groundbreaking results from our high-volume auto-injector innovation and clinical trial. We have already filed, and will continue to file for patent protection on those breakthroughs that we discover as we generate even greater volumes of data. Some of these innovations relate to the product designs and form factors, the design criteria for the auto-injectors based on various drug characteristics, and the injector mechanism designs, and how we deliver the drug quickly to patients while attempting to minimize patient discomfort.
We are rapidly adding to our patent estate with the new patent filings that we are making, and we expect to create long-term value for Halozyme and a competitive advantage for our high-volume auto-injector licensees. I will now turn it back over to Helen.
Thank you, Mark. Nicole will now present our five-year guidance. We developed these projections based on the latest partner updates on their program, their publicly stated product strategies, and on publicly available information on yearly sales projections for each of the Wave one, two, and three partner products. For the subcutaneous conversion rate, we applied the uptake seen for the most comparable of the ENHANZE launch products, if available. And I will also note that the 2024 royalty revenue is anchored by each partner's input. Nicole?
Thank you, Helen. Seen here are estimated results for 2023. These are narrowed and refined estimated ranges, all within our previous guidance ranges. These are preliminary estimates, and final results for 2023 will be reported on our February earnings call. Growth rates on this page are calculated from the midpoint of 2023 ranges to the low end of 2024 ranges, and to the midpoint of 2024 ranges. I will begin with our guidance for 2024, and then for the first time, we will share five-year guidance. In 2024, we project another record year, reaching new heights with a projected $915 million-$985 million in total revenue, growing 10%-15% year-over-year. This continued revenue growth is driven by royalty uptake, which represents greater than 50% of total revenue in 2024.
The drivers of royalty growth in 2024 continue to be our Wave two products, DARZALEX SC and PHESGO. Even with factoring in the expected step down of 50% of DARZALEX SC royalties in Europe in March 2024, the year-over-year growth continues to be projected due to strong underlying brand growth. While royalties are the main driver of total revenue growth, we have diverse revenue streams and also see continued contribution from product sales and milestones, which I'll review in more detail in a moment. Our high-margin revenue mix translates to EBITDA expansion, growing year over year by greater than 25%. Strong EBITDA growth, when coupled with our prior year's share repurchase activity, results in accelerated EPS growth of greater than 27%.
This strong growth trajectory, driven by royalty revenue, sets us on a clear growth path for many years to come, and it provides us the conviction to share guidance for each of the next five years. Growth rates for our long-term view are calculated from midpoint to midpoint of the ranges. Beginning with total revenue, which includes royalty revenue, product revenue, and collaboration revenue. We project year-over-year growth greater than 10% in the next two years, and 20% in greater growth in 2026 and 2027, achieving $1 billion in total revenue by 2025. This growth is largely driven by royalty growth, continuing to project achievement of $1 billion in royalty revenue by 2027. The increasing royalties, and importantly, increasing growth of royalties over the next five years, is driven by the growing contribution of the Wave 2 and Wave 3 product launches.
By the end of 2025, we project that all Wave 3 products will be launched in virtually all geographies, resulting in a projected 27% annual growth in royalties in 2026, and 30% annual growth in 2027. We are excited to share details on 2028 revenue, which projects a preservation of royalty revenue and total revenue, even while accounting for the expected step down in DARZALEX FASPRO U.S. royalties beginning in September 2027. This is a result of the continued revenue growth of Wave 3, offsetting impact of the U.S. DARZALEX SC step-down. Furthermore, these royalty projections exclude any impact from potential Wave four or Wave five product launches, which would be additive to the growth seen here.
What's most exciting about our royalty projection is that these projections only include all the products that are currently approved across our two technology platforms, and three additional products projected to be approved by 2025. Beginning at the bottom, included are our approved auto-injector products and seven currently approved ENHANZE products. These include our three Wave one products and our two Wave two products, which are drivers of the royalty revenues today to achieve $445 million-$450 million in 2023, and $500 million-$525 million in 2024. We showed you that due to the patents in place, these products will pay royalties until at least 2030. The first of our Wave three products were approved last year. VYVGART HYTRULO in gMG in both the U.S. and EU, and TECENTRIQ SC in Great Britain.
We showed you that Wave three products have the potential to pay royalties out to at least 2040. Therefore, these already launched products are expected to drive substantial growth for years to come. Then we add on the expected approvals in 2024 and 2025. These are de-risked approvals, all approved as IDs and have positive SD data, with only one awaiting phase III data. With the announcement yesterday of the approval of TECENTRIQ SC in Europe and HYQVIA in CIDP in the US, and the expected addition of TECENTRIQ SC in the US, Ocrelizumab SC, Nivolumab SC, and Amivantamab SC, as well as projected expansion of indication for VYVGART HYTRULO in CIDP. You can see the clear line of sight to royalty revenue growth and durability with just these 10 ENHANZE products.
Imagine the potential for additional growth when additional Wave four and Wave five products are added to the portfolio. The impact to the bottom line is meaningful. We project growth in adjusted EBITDA in the 20s-30s% year-over-year. We expect to achieve $1 billion in adjusted EBITDA in 2027. Similar growth rates are seen in non-GAAP EPS, which only includes the impact of share repurchases through 2023, and the potential benefit of additional share repurchases are not reflected. Here, we have provided more detail on the growth year-over-year, and I will highlight what I find most impressive about our five-year projection.
The first is that we are continuing to project $1 billion in royalty revenue in 2027 and into 2028 from Wave one, two, and three products only, growing from $445 million-$450 million in 2023, a CAGR of 14%. The second is that the total product sales are growing throughout the period while achieving our goal of being the cost leader for API. Our rHuPH20 API sales are projected to grow only modestly over this horizon, reflecting the impact of efficiency improvements to reduce costs that we pass on to our partners as a source of competitive advantage. The growth we see in product sales is achieved thanks to the high growth rate from XYOSTED. We continue to see contribution from collaboration revenue, driven by our partners achieving development and commercial milestones.
The third is that the total revenue is projected to achieve $1 billion a year in 2025 and grow to greater than $1.5 billion in 2027 and 2028, a CAGR of 14%. Last, and importantly, I'll focus you on EBITDA. You will note that EBITDA is growing faster than revenue in every year of the five-year outlook with a CAGR of 23%. This is due to expansion of the contribution of our revenue mix, largely driven by increasing royalties. Each dollar of royalty revenue drops almost entirely to the bottom line, resulting in adjusted EBITDA margin expansion from approximately 50% in 2023 to approximately 70% in 2028. This, coupled with our business model and ability to keep our expenses relatively flat, creates the higher rate of growth for EBITDA.
I think you will all agree that the EBITDA amounts are impressive, and this is what will allow us to allocate capital to actions such as future share repurchases and M&A.
... With that, I'll now turn the call back over to Helen.
Thank you, Nicole. There has been a lot of talk about the cliff in 2024. As you've just heard, 2024 is yet another year of strong royalty and total revenue growth in a trend that started several years ago and one which is projected to continue for many years. There is no cliff. Today, we showed you our royalty revenue projections. They're based on waves one, two, and three, now including Amivantamab . This results in robust royalty and total revenues each year, and that includes 2027 and 2028. I hope you leave today's call with a deeper understanding of the design and impact of our co-formulation patents that maintain the mid-single-digit royalty rate unchanged for all products in wave one, two, and three, except DARZALEX, and which can extend our royalty duration to as late as the 2040.
With that, we are now pleased to open the call to take your questions. Operator?
At this time, we will open the floor for questions. If you would like to ask a question at this time, please press star one on your telephone keypad. You may remove yourself at any time by pressing star two. Once again, if you would like to ask a question, please press star one. Our first question will come from Mohit Bansal with Wells Fargo. Please go ahead.
Very much for taking my question, and thank you for doing all this. Really appreciate it. I have one question, one clarification. So one notable miss in the patent slide, if I missed it, was talk about OPDIVO or your checkpoint plus co-formulation. So can you please, do you have an issued patent there? And I know one player is trying to develop a different version of hyaluronidase. So could you talk a little bit about your IP estate and potential where this could be the only hyaluronidase combo drug that could be out on the market? Thank you.
Yes, thanks, Mohit. I'm going to ask Mark to address the why we weren't in a position to talk about Nivolumab and the co-formulation patent today, and then I'll say a few comments about the other hyaluronidases in development.
Thank you, Helen. So we did not receive permission from our licensee partner to be able to present information for OPDIVO as we did for the other products that we listed in that chart in the presentation.
Got it.
All right, and Mohit, with regard to other hyaluronidases in development, we're aware of a South Korean company called Alteogen that is purported to be developing an alternate hyaluronidase. There is speculation that that may be the one that's being used by Merck. Limited information is available on that to date, but it's certainly a space we're watching carefully. As you heard from Mark, we have a robust patent portfolio, and we watch carefully and ensure that we are protecting our inventions, and we stand ready to take appropriate actions if we were to see any infringement on that portfolio.
Super helpful. Thank you very much, and appreciate this.
Thank you. Our next question will come from Jessica Fye with JP Morgan. Please go ahead.
Hey, guys. Good morning. Thanks for all the detail. I have a few, so, bear with me. First, just wanted to confirm, the guidance reflects only approved products or just what's in there and, and what's upside? Second, on the slide with the green and purple boxes illustrating the step downs and kind of what co-formulation that IP can do to prevent step downs and extend the royalty term, it looks like the reduced royalty rate is greater than half of the original rate in those boxes. Is that the right way to think about it, or, or should we think of the royalty rate just being reduced by half in all of these agreements? For Ocrevus, can you clarify if there's potential for co-formulation IP there to take your full royalty rate beyond the 2030 shown on the slide?
Lastly, while you're giving more disclosure on the royalties, can you characterize, broadly speaking, if the mid-single-digit royalties you've talked about sort of across the board, if those are sort of higher for some partners, lower for others, and if possible, provide a little context on, like, which are kind of at the higher end or the lower end? Thank you.
All right. Thanks, Jess. I'm glad I was writing those down. I will ask then Nicole to go through what's included in the guidance, and, it's slightly different for what's included obviously in the royalty guidance and the milestone guidance. So, she will start with that, and then I'll move to Mark on, being ready to talk about the, degree of step downs we may see.
Yeah. Hi, Jess. So when we look at... I'll start with royalty guidance, and you'll see there, we did only include waves 1, 2, and 3 products there. That was just really because we wanted to show the contribution from those already launched or nearing launched products, and as you mentioned, anything in wave four or five will just be additive to what you see there. On the collaboration side, you will see we have included an estimated range of $130 million-$160 million in each year, and this is our estimate of our partners moving through development programs throughout the year. And this also includes a modest amount attributed to our expectation of new study starts, new programs being added. And so that is all of our outlooks for the period.
... All right, Mark will now address the question on the green and purple boxes and how much step-down will be. And Mark, if you'd also talk about the possibility for extending the Ocrelizumab at the sole royalty rate.
Thank you, Helen. Yeah, so the slide with the green step-down that you've mentioned, Jess, that shows just relative step-down. And I'll just point out that our licenses are the product of negotiations, and the step-down will vary from license to license. The 50% that you've mentioned, I think, refers to there's only one license where we've addressed that, and that's, and I think that's the Janssen license. But think of that as just a relative, and it does vary among our licenses. With respect to the Ocrevus question you asked, the chart shows ocrelizumab SubQ, and it shows a fixed royalty payment period. And the bar is a darker green, which reflects a pending patent application that dates back to 2010.
And so that patent, if granted, will extend until 2030, and of course, we have conviction that that patent will in fact be issued. In terms of future extension of the royalty rate or extension of the period of time for which royalties can be paid, I think I mentioned earlier that we cannot mention any details with respect to any pending unpublished patent applications.
All right. With regard to the ranges of royalties, you're right, Jess, there is a range around that mid-single digit, and as Mark mentioned in his prepared remarks, there also can be increasing royalties, depending on sales tiers. They still maintain us around that mid-single digit royalty rate, but also that's why we stay in the mid-single digit royalty rate even after we experience some step-downs, for example, for DARZALEX. So, we can't go into any more specific detail on the specific rates, but as you're thinking about it, yes, definitely think of it sitting there and increasing in some products as sales increase.
Nicole just wanted to add a little bit to her answer with regard to what's included in the collaboration milestone, specific to waves four and five.
Yeah, Jess, I did just want to add that, when we, when we looked at our collaboration milestones for these projections, we did apply a risk adjustment, to the programs that are currently in the clinic and in development with ENHANZE, so in our wave four pipeline, really just in recognition of the fact that there is risk when we are dependent on those partners', programs and their plans. So one example would be that we excluded programs, where the target has not yet demonstrated phase 3 success in any administration setting. Sorry, so just to clarify, the some wave four risk-adjusted contribution is in the guidance? Only in collaboration revenue and not in royalty revenue.
Okay. Okay.
Thank you. Our next question will come from Mike DiFiore with Evercore ISI. Please go ahead.
Hi, guys. Thanks so much for taking my question, and thanks so much for doing this call. I really, really appreciate it. Two questions for me, actually, one question, one clarification question. We've recently seen two Halo's big pharma partner companies enter into new competitive collaboration agreements for, presumably sizable drugs. Just want to get any thoughts on these competitive deals and how they may have impacted long-term royalty expectations. My follow-up is, and I may be reading into this too, too closely. On slide 21, the OUS DARZALEX FASPRO line is the same length as the US DARZALEX FASPRO line. Has there been any developments on the OUS IP front? Thank you.
Right. I will address the first question there, Mike, and allow Mark to talk about the duration rate of royalties, both U.S. and outside the U.S. You know, I will say, and just to specifically talk about our relationships with our partners, Janssen being, I think, one of the companies you were talking about, obviously, we're delighted with our long-term relationship with Janssen. We're working with them on a $9+ billion brand that actually has been what passed us at Halozyme to be able to be a multi-hundred million dollar company. So that is again a great demonstration of our ENHANZE technology, and as we mentioned, we're also delighted to be working on Amivantamab , where phase three data is expected soon.
So our relationship continues to be incredibly strong with Janssen. We continue to have an open research collaboration with them, where they can test ENHANZE with additional other products. So any new technologies and companies are doing that all the time they may be working with, we do not expect to impact our relationship, because all of the value that we've been able to demonstrate to the product helping, because DARZALEX FASPRO become, if it's not already, soon to be the number one drug for J&J. Let me have Mark talk about the length of the line.
Thank you. Yes, so the chart that we provided shows today what we expect with respect to the royalties for DARZALEX, both outside the United States and in the United States. I will point out that we are constantly reviewing our patent portfolio, looking at our innovations and how best to protect our innovations.... and if there are any changes, we'll communicate updates with any further developments.
Great. Thanks so much.
Thank you. Our next question will come from Joseph Catanzaro with Piper Sandler. Please go ahead.
Hey, guys. Thanks for the call and all the details here. Really, really helpful. I actually wanted to follow up, I guess, on the, on the FASPRO dynamic. I guess, if I'm understanding correctly, the FASPRO co-formulation patents will also have no impact on the duration of that royalty. That chart seems to show that it will go beyond 2030, but could you just say exactly when your expectations are that the DARZALEX royalty will go away, both U.S. and ex-U.S.? And then my second question, I guess, are your expectations around potential future deals for ENHANZE, and whether you think you could command the same deal terms that you currently have as it relates to royalty rates and royalty duration, even with the ENHANZE patent expiries approaching? Thanks.
Yeah. Mark will address the first question.
Yeah. With respect to the FasPro dynamic that you've mentioned, and the duration of the royalties that are paid, with the collaboration patents, patents that are out there, the duration is extended given the existence of a collaboration patent, and it extends for both ex-US and in the United States to 2032.
Thanks. And, Joe, with a question on royalty terms, so far we have done deals mostly on exclusive target licensing. And we do expect to be able to retain and gain a very similar value in future deals for exclusive licensing of targets. And this clearly is because all the value we are able to demonstrate we bring to those products. We've always worked on, and we continue to work on non-exclusive deals as well. And as you saw recently with Acumen, because we anticipate being able to do non-exclusive deals with several companies, those have slightly different rates. But, I will say that, we do expect it to be very similar. And this is a very important part, that the co-formulation patents are key to what having us able to maintain a mid-single-digit royalty rate.
If there is no co-formulation patent, then the royalty rate steps down. That is very logical for partners as we talk to them. But if we're providing protection with the co-formulation patent, the mid-single-digit royalty rate, again, is market rate and very logical. So, that's why we do expect non-exclusive to be a bit lower, but exclusive to be in a similar value range.
Okay, got it. That's very helpful. Thanks for taking my, my questions.
Thank you. Our next question will come from Jason Butler with JMP Securities. Please go ahead.
Thanks for taking the question, and again, really appreciate all the detail here. Just one—I guess, maybe can you speak to your confidence around litigation challenges for any of the co-form patents? And I guess, specifically, we, you mentioned that each patent's obviously unique, but how do you think about, you know, aspects of the patents having similarities, that if one patent was to be found invalid, that it wouldn't have read through to other patents and, you know, for other products across the portfolio? Thanks.
Definitely a question for Mark. Mark.
So with respect to your question on confidence challenges, there haven't been any challenges. There has been an opposition to a Janssen patent in Europe that is up on appeal today. But with respect to all the other collaboration patents, there are no challenges. In terms of whether or not a decision in one of them will impact others, it really depends upon what were the reasons for allowance and issuance of the collaboration patent. And you put a chart into our presentation that shows there are a variety of different reasons why patents have been granted and claims have been allowed in the United States and Europe.
We think that because there's often very different reasons, remember, each of these drugs or, or biologics has a different modality of action, method of administration or treatment, and those combined with the knowledge of the existing state-of-the-art, which is the existing state of the technology, that's what determines patentability. It is not the same across all the various, biologic and PH20 or ENHANZE combinations.
Thanks, Mark.
Great. Thank you.
Thank you. Our next question will come from Mitchell Kapoor with H.C. Wainwright. Please go ahead.
Hi, everyone. Thanks for doing this call, and congrats on the two approvals yesterday. I wanted to ask a question around the co-formulation patent process and at what point you typically can file that co-formulation patent, you know, what kind of triggers that for Halozyme to file that? And separately, on the BD front, are you exploring more partnerships and getting interest from phase I type partners or more like phase III type partners? And how is this evolving or not evolving?
Yeah, I'll ask Mark to talk through the process as to what triggers and when we typically start working on this topic.
Thank you, Helen. Yes, we typically file with our partners the co-formulation application after data is received in a clinical trial program, and that's indicated on one of the slides. That's where we receive data that we can work through with our licensee partner to assess whether or not there are any innovations, unexpected results, or what we call teaching away. That is something that's very different than what might have been expected in the prior art or the state of the technology at the time, and that's when decisions are made to file for co-formulation patent protection.
... Right, and with regard to the BD partnership question, Nick, we're really going to be focusing this call on the patents and the guidance. We'll be providing a full business update at our regularly scheduled February call. I will just say, in summary, we continue to talk with the companies as we always have done across a range of stages of development, from phase one through commercialized products.
Thank you. Thank you. Our next question comes from Corinne Jenkins with Goldman Sachs. Please go ahead.
Good morning. Maybe one from us. In terms of the considerations that you're using that inform your underlying assumptions for a subcutaneous conversion across each of these products, like, what are you using to kind of make those estimates, and how do they compare to what we've seen with the prior product launches, namely Darzalex and PHESGO, to date?
Yeah, I'll ask Nicole to address that.
Thanks, Corinne. When we look at these royalty projections, you know, we do use the best information available to us. For example, we are using sales projections from Evaluate Pharma, and then we apply our assumptions on the conversion rate. Where applicable, we do use a comparable ENHANZE launch product, and all of these are based on our best assumptions on the conversion rate over this period. And I'll also just highlight that when we look at the brand opportunities here, it does remain consistent with a $20 billion brand opportunity for the wave two products and a $35 billion opportunity for the wave three products.
Okay, and maybe just as a follow-up, how much variability is there in terms of the conversion you see across different products? Or are they all kind of shaking out in a similar range as you look at the launches that are still to come here?
Yeah, Corinne, we actually have quite a range there. As Nicole mentioned, we look for a comparable, we also take into account perhaps the company's stated strategy, and we use our judgment. But there is a wide range as a result of that, and I think that's an important part of you know how we seek to be as accurate as possible on these. Darzalex, you know, just to be very clear, has been an amazing success story. I'll just be clear and say we don't assume that for many other products that just really has been a terrific story. But we've got examples, for example, with PHESGO update and with Herceptin update.
Those are other ones to think about as you think about the range. But other companies have got slightly different strategies, so we do layer in that information as well, perhaps a little bit more focused on market growth than conversion. So a lot of great thinking and judgment and a good range on that.
Great. Thank you.
Thank you. As a reminder, if you would like to ask a question, please press star one. We'll take our next question from David Risinger with Leerink Partners. Please go ahead.
Yes, thanks very much. And, yeah, let me add my thanks for hosting this call. So I have two questions. One is on patents and one is on cash flow. So I know that you've addressed this to some degree, but just going to a higher level on future collaboration patents, could you discuss how there can be serial or persistent novel findings that result in valid new patents for co-formulations after so many core formulations with ENHANZE and biologic drugs have been granted or are pending? And then second, with respect to future cash flow, clearly your EBITDA guidance is suggestive of very strong cash flows in coming years. How does the company expect to deploy that cash? And, you know, how might that evolve over time, particularly as you pay down debt, will the company consider diversifying, et cetera?
Thank you.
Thanks, David. Mark, we'll start with the patent question.
Hi, David. The question you had with respect to will there continue to be collaboration patents as collaboration patents have been granted? Essentially, the way you should think about it is that every molecule, every biologic is different, and what holds true for one particular drug or biologic does not hold true for others. And so patents can be granted for similar type of dynamics that we might see, that would not be expected for that combination for these different biologics or different molecules. To give an example, with respect to Herceptin and Rituxan in our chart, you'll see that unexpected stability because there was some concern about the stability of those two protein molecules in the same formulation.
To the extent that it would not be expected in other combinations, that could still form the basis of patentability for other combinations. So I, I think that's really the way to look at it, is that there's a lot of complexity around the different molecules. There's a lot of complexity around the modalities of action, and so that could lead to unexpected, or what we call, teachings away from the prior art or the existing state of technology at the time that the patent applications are filed.
Thanks, Mark. Nicole?
Yeah, thanks, David. Very happy to see the great EBITDA growth, and as you mentioned, that does indicate the same growth in our free cash flow. Just for an example, for the first three quarters of 2023, we had free cash flow of about $280 million. And so the growth rates you see here for EBITDA will correlate to growth rates and free cash flow. As you know, we are a strong growth company, and this is what's driving our growth, and this is what will allow us to continue to make investments in that growth. We will continue our balanced three-pillar capital allocation approach of continuing to invest in growth in the business and continuing to identify the best return for our shareholders.
Thank you. At this time, we have no further questions in queue. I will now turn the call back to Helen Torley for any additional or closing remarks.
Yeah, thank you, everyone, for joining us today. We are delighted to have shared this strong total revenue, royalty revenue, and EBITDA, each year for the next 5 years, including importantly for 2024, 2027, and 2028. We hope you're leaving the call with a deeper understanding of the impact of the co-formulation patents that are helping us maintain this mid-single-digit royalty rate on average, throughout the period and extending our royalty duration out to at least as the 2024 date. Thank you, everybody, for joining us today.
This does conclude the Halozyme financial update call. Thank you for your participation. You may disconnect at any time.