Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Conference Call to discuss Roche Partnership. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. To ask a question during this session, you'll need to press star one one on your telephone.
You will then hear an automated message advising you your hand is raised. To withdraw your question, press the star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to the company. Please go ahead.
Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, Chief Executive Officer; Pushkal Garg, Chief Medical Officer; Evan Lippman, Chief Corporate Development and Strategy Officer; and Jeff Poulton, Chief Financial Officer. Tolga Tanguler, our Chief Commercial Officer, is also in the room and available for Q&A.
For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today's call, as outlined in slide two, Yvonne will offer introductory remarks and provide general context for the deal.
Pushkal will discuss our zilebesiran program and the opportunity to address unmet needs in hypertension with RNAi Therapeutics. Evan will go over the terms of the collaboration agreement, and Jeff will review financial implications for Alnylam.
I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor Provision under the Private Securities Litigation Reform Act of 1995.
Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with SEC.
In addition, any forward-looking statements represent our views only at the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to Yvonne. Yvonne?
Thanks, Christine. Thank you, everybody, for joining the call today. We're absolutely thrilled this morning to discuss the announcement of our new global strategic collaboration with Roche for the development and commercialization of zilebesiran, our investigational RNAi therapeutic for the treatment of hypertension.
This partnership aims to realize the full potential of zilebesiran to address significant unmet medical needs in patients with hypertension by combining Alnylam's leadership in developing RNAi therapeutics with Roche's global commercial footprint, regulatory expertise, and proven track record of successfully launching innovative medicines.
Hypertension is a highly prevalent disease, with over 200 million people affected by primary hypertension in just the seven major markets. Despite the widespread availability of treatments to manage the disease, there remains a critical need for new differentiated therapies that can provide tonic control of blood pressure and improve adherence with the potential to improve outcomes.
Through this partnership, we believe we have a remarkable opportunity to bring forward a transformative program with the potential to disrupt the global treatment paradigm for hypertension, a therapeutic area that has lacked meaningful innovation for decades.
Through this arrangement, we intend to progress a robust development plan for zilebesiran, generating cardiovascular outcomes data prior to launch, thereby optimizing the commercial opportunity. As with our other partnerships, we've aimed to retain significant product rights while balancing that with highly attractive financial terms.
We believe this new partnership with Roche very much achieves that goal. The combination of an upfront payment, potential for substantial near-term milestones, favorable development cost-sharing, and co-commercialization economics will enable investment across our broad pipeline in the years to come and supports the advancement of our Alnylam P5x25 goals. This is a very important aspect of this transaction.
Given our recent achievement of first-in-human knockdown of a gene in the CNS using RNAi therapeutics, we're driving ever more closely to significantly expanding our ability to treat a wide range of diseases, both in and out the liver, in patient populations, both small and large.
We believe our ability to invest in and pursue these opportunities will bring much-needed innovation to diseases with unmet medical needs, creating value for many years to come. This deal underscores the strategy behind one of three key long-term growth drivers for Alnylam, our expansion beyond solely rare diseases to include treatments for prevalent indications as well.
As we've discussed previously, we believe the pharmacological features of RNAi therapeutics are uniquely suited for the treatments of chronic, prevalent diseases, where durable effects could enable infrequent dosing to maximize adherence and where clamped pharmacology creates the potential for improved efficacy and outcomes.
As Evan will discuss later, realizing that potential will require us to smartly scale many aspects of our operations, and we believe this partnership with Roche offers the financial and structural resources to continue to build on Alnylam's leadership in RNAi therapeutics.
With that, let me now turn the call over to Pushkal, who will further discuss the unmet needs in hypertension and our zilebesiran program, which is the cornerstone of this exciting new partnership. Pushkal?
Thanks, Yvonne. Good morning, everyone. This is an exciting day for our zilebesiran program and for our ability to maximize the potential of this innovative medicine. We believe zilebesiran has the potential to substantially lower the risk of cardiovascular morbidity and mortality by providing better control of high blood pressure.
It's well recognized that hypertension is a highly prevalent disease, with over 200 million people with primary hypertension in the seven major markets. Unfortunately, despite widespread availability of therapies to manage the disease, over 80% of hypertensive patients are not at their target pre-blood pressure goal.
Furthermore, increased cardiovascular risk is exacerbated by variability of blood pressure control, inadequate nighttime control, and poor adherence to therapy.
All of these factors contribute to a substantial risk of cardiovascular events, making hypertension the number one preventable cause of cardiovascular morbidity and mortality, and highlighting the critical need for new, differentiated therapies that can provide tonic control of blood pressure over extended periods of time.
Zilebesiran is an investigational GalNAc conjugated, small interfering RNA targeting the hepatic production of angiotensinogen, or AGT, the most upstream product of the renin-angiotensin system. The renin-angiotensin pathway is one of the key regulatory systems underlying blood pressure control, and in essential hypertension, this system can become inappropriately activated.
Therefore, blocking the production of angiotensinogen with zilebesiran essentially removes the key upstream factor needed to activate the renin-angiotensin system, and given its durable pharmacology, could potentially provide both consistent and effective blood pressure control, as well as improved medication adherence.
You may have seen the phase 1 data on zilebesiran were published this past week in the New England Journal of Medicine, along with an expert commentary. These data really highlight zilebesiran's transformative potential.
We observed over 90% dose-dependent knockdown of AGT that was sustained for at least six months after a single subcutaneous dose. This translated into robust reductions in both systolic and diastolic blood pressue, with tonic control over 24 hours and excellent durability that resulted in over 20 millimeters of systolic blood pressure reduction at six months after a single injection.
We believe these attributes offer a highly differentiated profile from all existing antihypertensives, including currently available oral RAS inhibitors. Across all parts of the study, zilebesiran treatment was shown to be generally well-tolerated, with no treatment-related serious adverse events or instances of hypotension requiring intervention.
As you know, we are conducting the KARDIA Phase 2 clinical program to further evaluate zilebesiran and its potential profile in hypertension. This clinical profile includes two studies: KARDIA-1, which is a double-blind, placebo-controlled study to evaluate the effects of zilebesiran as monotherapy in close to 400 patients with mild to moderate hyp ertension.
This study is designed to identify the best dose and regimen to advance into pivotal trials. Enrollment in KARDIA-1 was completed in December 2022, and we expect to report top-line results in mid-2023, with full results at a future medical conference. KARDIA-2 is a double-blind, placebo-controlled study in patients with uncontrolled hypertension.
This study is focused on evaluating the safety and efficacy of zilebesiran when added to each of the three most common classes of antihypertensives: the angiotensin receptor blocker olmesartan, the calcium channel blocker amlodipine, and the diuretic indapamide.
I'm delighted to announce today that enrollment has been completed with 672 patients enrolled. We now expect top-line results in early 2024. Part of today's announcement, we also want to share important updates to zilebesiran's clinical development plan.
We've always said, we believe that zilebesiran has the potential to reduce cardiovascular morbidity and mortality in uncontrolled hypertensive patients at high CV risk.
These are patients for whom the urgency to treat is the greatest, we believe this innovative therapy has a significant role to play in this population by helping more patients achieve high blood pressure targets, maintain tonic control, and mitigate the adherence challenges that are well known with current standards of care.
To realize this full potential of an innovative therapy like zilebesiran, we believe it's critical to launch the product with a robust and comprehensive data set.
To that end, we plan to conduct a large cardiovascular outcomes trial as the pivotal trial for approval, which we believe, if successful, would enable the greatest uptake at launch, remove barriers to access, and ultimately maximize impact for patients, providing the most compelling value proposition right out of the gate.
We'll have more details to share in the future, but at a high level, this CVOT would enroll hypertensive patients at high CV risk, and the primary endpoint would be a composite MACE-type endpoint that includes endpoints such as CV death, non-fatal stroke or MI, and heart failure hospitalizations.
In addition, in order to most efficiently design the CVOT study, we've also decided to amend the Phase 2 KARDIA program to include another study, KARDIA-3, which will be a multi-agent combination study looking at zilebesiran versus placebo in patients with uncontrolled hypertension at high CV risk on at least two other antihypertensive therapies.
We see this as an important stepping stone to characterizing the blood pressure effects and safety in this intended target population and to helping us efficiently design and power the CVOT. We will share further details about the design of KARDIA-3 at a future date, but we expect this study to initiate in 2024.
I want to close by stating how excited I am by this partnership with Roche. Throughout our discussions with them, it's clear that they share our vision for zilebesiran as a potentially transformative agent.
For the management of hypertension in patients at high CV risk, and to bring that innovation to patients around the world. With that, let me hand it over to Evan to describe the structure of the collaboration in more detail. Evan?
Thanks, Pushkal, good day, everyone. As Yvonne mentioned, Alnylam and Roche have formed a new alliance to develop and commercialize zilebesiran, an RNAi therapeutic in development for the treatment of hypertension.
We're excited that this transaction will enable the pursuit of a bold and comprehensive development and commercialization plan, potentially disrupting the current hypertension paradigm globally, to allow this innovative therapeutic to achieve its full patient potential.
The partnership combines Alnylam's leadership in RNAi therapeutics with Roche's global commercial footprint and proven track record of successfully launching innovative medicines. Operationally, through this arrangement, Alnylam and Roche will share responsibility and co-commercialize zilebesiran in the U.S., and with profits split equally 50/50.
Roche obtains exclusive rights to solely commercialize zilebesiran outside the U.S., for which Roche will pay Alnylam low double-digit tier royalties on sales of zilebesiran.
Alnylam will lead all development in U.S. regulatory activities through the initial NDA submission. Alnylam and Roche will split development costs on a 40-60 basis. In other words, Alnylam will cover 40% of the development costs, with Roche responsible for the remaining 60%.
Let me now review additional economics associated with the collaboration. This agreement has a total potential value of up to $2.8 billion, including upfront, development, regulatory, and sales milestones.
This is a significant transaction where Alnylam maintains future benefit from sharing equally in U.S. profits. Roche will pay Alnylam an upfront cash payment of $310 million. Alnylam is also eligible to receive additional substantial near-term development milestones, which assists with our portion of clinical spend.
The combination of a strong upfront payment, the potential to receive significant near-term milestones, having an active U.S. co-commercialization, and a favorable R&D cost-sharing arrangement will further enable us to invest across our robust and high-yielding pipeline of investigational RNAi therapeutics, while also enabling us to advance our Alnylam P5x25 goals.
I'd like to provide some additional context on this partnership. First, we believe this new alliance with Roche has the potential to drive enormous impact for patients. Alnylam brings deep expertise in RNAi therapeutics and a demonstrated track record of developing innovative and differentiated medicines in areas of high unmet medical need.
Roche provides the benefits to Alnylam of a best-in-class partner with global commercial presence, regulatory expertise, and a proven history of innovating and commercializing medicine for patients worldwide.
They have a history of entering new markets through innovative modalities and developing blockbuster products. We believe Roche's extensive global footprint across 60 countries will enable zilebesiran to reach more patients, more quickly, accelerating our commercial ramp globally.
This has the potential to disrupt the global treatment paradigm for hypertension. We and Roche are committed to positioning zilebesiran as a foundational therapy for hypertension, and through this partnership, we'll be advancing a development plan that includes CV outcomes, as well as potentially evaluating meaningful subpopulations for the most optimal market-ready label and life cycle management plan.
Secondly, the collaboration framework allows Alnylam to invest in late-stage development, regulatory, and commercial capabilities. As the leading RNAi therapeutics company, we are maintaining leadership of global development and U.S. regulatory activities.
At the same time, the equal commercial partnership structure in the U.S. allows us to invest in cardiovascular sales force to further expand our reach and strengthen our capabilities, building upon our RNAi expertise.
Finally, this transaction further establishes the foundation for Alnylam's continued expansion into more prevalent indications, an important growth driver for our business. The cost-sharing mechanism of this partnership enables significant continued investment across our entire robust pipeline, which spans rare and prevalent diseases.
The expansion of our regulatory, clinical, and commercial capabilities can be leveraged for the future advancement of additional wholly owned programs. I'm now going to turn it over to Jeff for some perspective on the accounting associated with this transaction. Jeff?
Thanks, Evan. Hello, everyone. I would like to make just a few brief remarks summarizing our preliminary assessment of the accounting for the collaboration from an Alnylam perspective. Starting first with the upfront payment, which will be recognized in collaboration revenue as our performance obligations within the collaboration are completed.
The key performance obligations include advancing zilebesiran through development, as Pushkal described earlier, as well as completing manufacturing tech transfer to Roche. Development milestones will be recognized in collaboration revenue as the development performance obligation is performed.
Commercial milestones will be recognized as collaboration revenue when earned. For the global development cost share, Alnylam will book 100% of R&D expenses, with Roche's 60% reimbursement of development costs being recognized as collaboration revenue as the costs are incurred.
For the 50/50 U.S. profit split, Alnylam's share of the profits will be recognized as collaboration revenue. Ex-US royalties will be recognized as royalty revenue.
One final point of clarification on the collaboration, Roche will record 100% of global product sales associated with zilebesiran. With that, I'd like to turn it over to Christine, who will take us to Q&A. Christine?
Thank you. Thank you, Jeff. Operator, we will now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question each, and then get back in the queue if you have additional questions.
Thank you. As a reminder, to ask a question, press star one one on your telephone and wait for your name to be announced. Please stand by while we compile the Q&A roster. Our first question comes from Maury Raycroft with Jefferies. Your line is open.
Hi, good morning. This is Farzin on from Maury. Thank you for taking our question. You have talked about potentially using REVERSIR to actually, to acutely reverse the effects of this RNA. Can you talk more about the developmental state and timelines to clinic?
Just maybe that's one for you. It's about REVERSIR and, you know, how are we thinking about that going forward, particularly with respect to development plan?
Yeah, thanks. REVERSIR is really an exciting opportunity that we have, based on sort of advances in our RNAi platform, to actually develop a way of reversing the impacts of the knockdown associated with an RNAi therapeutic.
We do have an REVERSIR in development for zilebesiran. A couple points I'll just mention. We've done an extensive amount of work showing that that's possible in vitro. In parallel, in the clinic, we've actually seen a really encouraging safety profile for zilebesiran to date, and we're looking forward to expanding on that with the upcoming readouts from both KARDIA-1 and KARDIA-2.
The REVERSIR is something that's part of the partnership with Roche, we'll be announcing more details around that as we go forward in the development plan.
Yeah, Evan will be responding.
Evan will be responding. Absolutely.
Okay, next question, please.
One moment. Our next question comes from Salveen Richter from Goldman Sachs. Your line is open.
Good morning. Thanks for taking my question. When we look at Leqvio's launch, there's been some challenges here. Can you just help us understand the dynamics around that, and, you know, whether the phase three cardiovascular outcomes trial being conducted earlier could help mitigate some of the aspects that are being seen in the market there, and how, you know, difficult it is to create a buy and bill model in a cardiovascular landscape?
Yeah, no, that's a kind of a great question, and I think it, I think it allows us to focus on really the primary rationale for us to, you know, collaborate with Roche with respect to zilebesiran, because our intent here is to make sure that we're able to maximize the value of zilebesiran by being able to bring what we believe is going to be a game-changing opportunity to a large number of patients globally.
To do that, we think it's really important to have the most robust profile available to patients, prescribers and payers at launch, to really allow them to truly understand the opportunity that zilebesiran provides to potentially transform the outcomes of patients. It also explains one of the reasons why we've decided to partner with Roche.
We believe that they have very strong capabilities. They have a broad and robust global commercial footprint, together with a track record of bringing real innovation to patients. again, zilebesiran is an area where we think we're gonna be able to transform the management of hypertension.
Roche also brings to bear some impressive capabilities with respect to their go-to-market models. I think maybe this is an opportunity for Tolga to specifically comment on some aspects of the Roche capabilities that we think will be particularly pertinent to achieving success with a product like zilebesiran.
Thanks, Yvonne. Thanks, Salveen. As Yvonne indicated, the potential for zilebesiran is immense. Obviously, in this very competitive process, we were looking for a partner that will help us build the capabilities and partner with us in the right way.
If you look at the track record of Roche, particularly in the U.S. with OCREVUS in MS, HEMLIBRA in hemophilia, they've done a phenomenal job of bringing new innovative treatments that have the potential to be a game changer and to completely change the market dynamics.
That's what we're looking for given the potential of zilebesiran, we're looking for a partner who can actually have not just the playbook, but also would be able to approach the customer engagement model and in an innovative way, through account management with the expertise in buy and build.
They really check all the boxes for us, and we're incredibly excited to really build this category, given the potential and the high unmet medical needs in this particular disease area.
That's great, Tolga. Obviously, you know, taking from the learnings of the, you know, Leqvio launch, I think that really underscores the importance of being able to bring these capabilities to bear in the marketplace. Thank you for that question. Next question?
One moment. We have a question from Ritu Baral from TD Cowen. Your line is open.
Good morning, everyone. Could you walk us through the structure of the commercial strategy development group in charge of the partnership? Like the committee, I'm assuming there's a committee.
Could you walk us through sort of what committee makeup between the two companies, how that's balanced, and sort of what aspects, other than geography, constitute Roche's lead on development of their commercial strategy? Thanks.
Sure. you know, we've been very encouraged, actually, as we've, you know, been working with Roche over the last period. I think what is particularly impressive is the shared vision that we have you know, the cardiovascular therapy area and specifically the opportunity that we have with zilebesiran to really change the paradigm of hypertension treatment.
Tolga, maybe you could go a little bit detail in terms of how we're thinking about working with them going forward?
Yvonne, as you indicated, this is like, the partnership is like marriage, what's really important is that we need to have the same exact mindset. In this case, what we're really excited about is how they actually approach the account management with a single accountability.
How we actually build the, this market together with Roche is gonna be dependent on working together as a joint steering committee in terms of commercialization, make sure that we actually have the 50/50 partnership.
Obviously, it's too soon to specifically, you know, discuss how that model is going to work, but what we're really impressed is the fact that we actually have very similar vision about how to approach the account management, how to jointly target key customers and patients.
Maybe, Ritu, just the other point, just to underscore, that the course of field structure therefore allows us to scale and build on the current capabilities that we have in the cardiovascular space. Working together with Roche, we can do this in a way that makes sense, as we continue to build our U.S. capabilities, whilst, of course, ensuring that we deliver success with respect to TTR globally.
Got it. If I could squeeze one more in. Is there an equity portion?
Go on then, one more.
Is there an equity portion to the deal, especially the upfront?
No. No, there's no equity portion. Robust economics, no equity portion. Next question?
One moment. Our next question comes from Paul Matteis from Stifel. Your line is open.
Hi, this is James on for Paul. Thanks for taking our question. Just a quick one around timing. When do you think you can get an outcome study started? It sounds like you want the KARDIA-3 data to help inform the design and powering of the outcome study, so just curious there. Is that commitment to outcomes data at all a result of regulatory discussions, or is it purely a commercial consideration? Thanks.
Pushkal one to you, I think.
Yeah. Thanks, James. You know, what we've decided to do is we think that it's really in the best interest of patients and to ensure the optimal uptake of this medicine into the treatment paradigm, shape guidelines, ensure access, et cetera, and get this drug to the maximum number of patients to launch with the cardiovascular outcomes trial.
Our, you know, our collaborators at Roche share that same vision. And as part of that, as you noted, we are going to be doing an additional phase 2 study, KARDIA-3, which will help us really understand better in the target population, what the blood pressure lowering effects are, and that will help us properly size that outcome study. What I can say is that we expect that KARDIA-2.
KARDIA-3 will initiate next year in 2024, and within a couple of years after that, we would imagine kicking off the cardiovascular outcomes trial. We don't have more specific details yet, but we'll put more meat on the bones as we get more information.
That's what I can update you on now. We'll have ongoing discussions with our collaborators, with the regulators, as we shape the development plan going forward.
It's important to say that the decisions that we've made because we believe it maximizes the value of our contract, affecting as many patients as we can. Of course, all this is built on, you know, the very impressive data set that we generated in our Phase 1 studies that as we mentioned in our introductory remarks of this call, there's an excess analysis in the Journal of Medicine.
Thanks.
Our next question comes from David Lebovitz from Citi. Your line is open.
Thank you very much for taking my question. Given the nature of the mechanism of giredestrant, how do you think the drug will ultimately fit in the paradigm?
Yes, it is long-acting, which certainly is a convenience aspect, but doctors who prescribe these types of drugs are very used to titrating, and this drug doesn't really lend itself to titrating. What's the strategy for managing that to limit potential risks of overshooting on blood pressure reduction?
Yeah. Dave, thanks for the question. Look, as I tried to outline in my introductory remarks, what's really important to note here is where the unmet needs are in this disease space, and the challenges that currently patients and physicians face in terms of trying to manage blood pressure, and particularly to reduce cardiovascular risk, which is the ultimate goal here.
That's because patients can't get to goal despite being on multiple therapies. There's tremendous variability in blood pressure control that happens day to day, week to week, month to month. Patients don't adhere to their therapies as well as we would like. All of those things independently, and there's lack of nocturnal dipping. All these factors independently promote the risk of cardiovascular disease.
The profile that we've seen emerging from the phase 1 study that were just published in the New England Journal this past week, really show an incredibly differentiated approach. Now, you're right, that there's been an established paradigm of using, you know, once a day, twice a day acting medicines to treat this disease, but that hasn't gotten us out of this pickle.
Those have been remarkable advances, there's time for more innovation to kind of disrupt this paradigm. That's what we're out to do, is to actually transform the way this disease is managed. Ultimately, we think that's what's going to be required if we want to make a dent in the huge burden that is cardiovascular morbidity and mortality in the United States and around the world.
There's a lot for us to figure out along the way, but we and our colleagues at Roche are committed to investing in a development plan, and educational activities, et cetera, to help change the way that this disease is treated.
Thanks, Pushkar.
Thank you for taking my question.
A great answer. Yeah. Next question.
Okay, one moment. We have a question from Tazeen Ahmad, from Bank of America. Your line is open.
Hi, good morning, guys. Thanks for taking my question. I had a question just about the timing of this particular deal. As you reiterated, KARDIA-1 is due, I guess, in the next couple of months, and KARDIA-2 would be in the next several months.
We understand why it makes sense from Roche's perspective to want to lock this in early, but from your perspective, why was now the right time to sign a partner rather than perhaps waiting to see the data? Because mechanistically, this is highly likely to work. Wanted to get your thoughts on why not wait until you see the full data sets read out. Thanks.
Yeah, no, that's a great question. I think as we've sort of explained in our presentation through some of the Q&A, really, if we want to maximize the opportunity with Salvestrant, it requires, you know, the size and scope of, you know, a disease like hypertension.
It really requires a partner like Roche, where we can move forward expeditiously to deliver a comprehensive development plan, as Pushkar has outlined. You know, and build the capabilities and infrastructure required to maximize commercial success. While in addition to doing this, we also focus on delivering success in the TTR franchise.
With great phase I data in hand, we believe that now is the right time to partner so that we can move this program forward in a rapid but also as comprehensive a fashion as possible to meet the needs in kind of an area which really hasn't seen any innovation for decades.
One moment for our next question. Our next question comes from Kostas Biliouris from BMO. Your line is open.
Good morning, everyone. Thanks for taking my question and congrats on the partnership. One question on me from us on the phase one, the KARDIA- 1 data that we are expecting. As we know in drug combinations for hypertension, the effect of two drugs is typically lower than the additive effect of individual drugs.
I'm wondering, when we see the KARDIA- 1 data, how should we be thinking about read through to KARDIA- 2, KARDIA- 3, and potentially the cardiovascular outcomes data? Thank you.
Pushkar, that's one for you, maybe talking about, you know, the phase 2 studies that are ongoing, but also thoughts about our plans with respect to KARDIA-3.
Sure. Kostas, you know, again, I'll just remind you that what we saw in phase 1 was really encouraging in terms of durability and the magnitude effect, tonic control of blood pressure. What we're doing in KARDIA-1, KARDIA-1 is a monotherapy study, where we're looking at zilebesiran alone, without any other background medication.
It's really expanding in some ways on the phase 1 experience that we had. The goal there is to really figure out what is the optimal dose and frequency of administration to take into the next stage of clinical development.
That'll tell us, you know, about the frequency of administration, quarterly, biannually, or less frequently, and what's the right dose. We're looking at doses between 150 and 600 milligrams.
You're right, the next study, KARDIA-2, we'll be looking at combinations. I think there is a number of combinations that we're looking at with a diuretic, with a ARB, and with a calcium channel blocker.
I think based on prior precedent, what we know is that, you know, oftentimes the combination of a RAS inhibitor along with a diuretic, there are some synergistic effects.
We might expect to see, you know, larger blood pressure changes in that group. But we're also encouraged to see what the combination will look like with an angiotensin receptor blocker.
I'll remind you that in our phase 1 study, we saw actually additive effects on top of the angiotensin receptor blocker, and that may be part of the differentiation of this medicine by sparing the renal RAAS.
system, zilebesiran may be able to be effectively combined with currently available RAAS inhibitors. We're looking forward to those results. All of that together will help us design and shape the KARDIA-3 study, which will start next year, and then obviously the CVOT. Lots more and lots of exciting data coming later this year, that we'll be sharing with you in due course.
Thank you so much.
One moment for our next question. We have a question from Michael Ulz with Morgan Stanley. Your line is open.
Good morning, thanks for taking the question. Just in terms of the development milestones here, can you just comment maybe on what some of those triggers are, and maybe, give us a sense of the size of those milestones as well? I think if I caught the prepared remarks correctly, they were referred to as substantial. Thanks.
Evan?
Thank you, Mike. You know, while we can't provide details on the full value associated with the program, we do want to understand that there is related to continuing progress as well being seen over the next few years, we can achieve substantial development milestones, and these are related to near-term trials under the collaboration, and this is going to assist with our portion of the clinical spend.
We can't provide any additional details at this time, but it's relative to the upfront and to the $2.8 billion, they are meaningful for us.
Thank you.
Thank you. We have a question from William Pickering with Bernstein. Your line is open.
Good morning. Thank you for taking my question. Congrats on the deal. Could you share a bit more color on how you got comfortable with the financial consideration of this transaction, and specifically the assumptions on the development timeline that informed that? Thank you.
Yeah, maybe, kind of, Evan, if you talk about some of the financial aspects of the deal, how we got comfortable with that. Then maybe, Pushkal, I think you've touched on it already, but maybe just reprise, you know, how important we believe it is to bring a comprehensive data set to patients and probably describe them payers at launch.
Thank you, and thank you for the question. As Yvonne has mentioned, we are looking to maximize the potential of this product as we bring it forward to patients. When we look at the totality of the deal, we believe that this does reflect very good value for Alnylam.
As we look at the multiple sources associated with the upfront, the near-term significant milestones, the development split, which is 60% gross, 40% Alnylam, and we are maintaining a 50/50 share in the largest market, which is the U.S., on the commercialization side.
The totality of that deal, the $2.8 billion, the meaningful upfront, the near-term aspects, and the funding associated with, as we've heard from Pushkal, the CVOT, that Roche will be managing to pay 60% of that, gives us the certainty around advancing this product.
We can also focus on our other programs and invest across our broad portfolio and deliver significant value to all of the stakeholders associated with Alnylam. That's how we looked at the totality of this transaction, and we're very comfortable with what Roche and Alnylam are going to do in order to bring this forward. Pushkal, do you have to add?
Look, in terms of the development plan, we're looking forward to K-1 data coming, you know, relatively shortly, in the third quarter, K-2 in early 2024. Those data will inform the start of the K-3 study. That's really going to allow us to really focus on the target population.
That will be the population we'll be intending to study in the cardiovascular outcome study. While I can't give you a lot of specifics on the timelines, you know, what I can say is that the K-3 will start in 2024. Imagine that'll take, you know, year and a half to two years to complete, and that will then allow us to kick off the CVOT, which will be a several-year study in thousands of patients.
I think that gives you a rough sense of how we're thinking about the overall development plan and timing, and we'll provide more details as we have them.
That's great, Evan and Pushkal. Thank you. Next question.
Our next question comes from looks like Gena Wang from Barclays. Your line is open.
Hi, Gena.
Hi. Hi, good morning. This is Hersita on for Gena. Just wanted to extend our congratulations. I just had a quick question on KARDIA on top line expectations. As you noted earlier in the, in the call and before, while we understand KARDIA 2 and of course, KARDIA 3 will be important pieces to consider, what do you see as the bar for KARDIA 1?
If I remember correctly, you previously noted anything greater than equal to five millimeters of mercury SBP reduction would be considered clinically meaningful, but we were wondering, what kind of reduction would you need to be competitive with current standard of care? Thank you.
Yeah. Look, I think what's widely regarded in the field as clinically significant is a five millimeter reduction in systolic blood pressure, which, you know, roughly equates to about a 10% lowering of cardiovascular morbidity and mortality.
I think that's widely recognized as being clinically meaningful. What we saw in the phase 1 study was considerably larger than that. We're looking forward to seeing, you know, what is that level of reduction. I think I'll also point out that beyond looking at the absolute reduction in blood pressure, we're also looking for durability and tonic control.
It's that full package of the pharmacologic profile of this medicine that we think really offers the differentiation. We'll be looking for blood pressure control over the entire dosing regimen, as well as safety and tolerability as important differentiating aspects of this medicine.
You know, we and Roche are excited to be advancing this into this very ambitious development plan. We look forward to sharing those results when they become available soon.
That's great, Pushkal. You know, we kind of confirming what we saw in phase 1. I think our, you know, phase 1 data were kind of very, very robust and, you know, we're hoping to continue to confirm that picture going forward. Next question?
We have a question from Luca Issi from RBC Capital. Your line is open.
Great, congrats on the deal. Thanks so much for taking my question. Can you maybe give us a sense of the cost of the cardiovascular outcome trial? Is it fair to assume roughly $200 million to $300 million based on prior history, or would that estimate not be within the right ballpark?
Then maybe circling back on a prior question, is running a cardiovascular outcome trial something that the FDA asked you to do, or simply your decision to maximize access? Any call there much appreciated. Thanks so much.
I'll answer those questions quickly. I think, you know, obviously, can't comment on specific costs of a cardiovascular outcomes trial at this stage. I, you know, I think we can all appreciate that it requires substantial investment to deliver a cardiovascular outcome study.
With respect to the question around, you know, whether regulators, you know, have asked us for cardiovascular outcome, absolutely not. I mean, I think this is the plan to conduct the cardiovascular outcome study is a decision that we're fully aligned with, together with our new partners,
Roche really aimed at, you know, maximizing the value of zilebesiran, ensuring that we can come to market with really compelling data for all the various stakeholders.
Got it. Thanks so much.
Thanks, Luca.
One moment. We have a question from Liisa Bayko with Evercore ISI. Your line is open.
Hi, congratulations on the deal from us as well. Just curious, and wanted to confirm, it seems like you're honing in on the resistant hypertension market as your go-to-market strategy. Are you gonna stick with that, or longer term, do you intend to kind of move this into earlier lines of therapy, or is that the right place for this method?
Pushkal, maybe you can kind of clarify the patient population that we're planning to address in planned clinical development program.
Liisa, just to clarify, we are actually not specifically targeting the resistant refractory hypertension program population. Certainly, those patients may benefit from a therapy like zilebesiran. As you know, there's a number of other products out there that are being developed and have been developed in that space.
While there's a clear unmet need there, we think it poses challenges. Where we really are focused on is where we think the need is the greatest. That's really on patients who are at high CV risk and actually reducing cardiovascular morbidity and mortality. That's why we treat high blood pressure, not to treat the number, but to actually reduce cardiovascular morbidity and mortality.
We think the profile of zilebesiran offers us a unique, unprecedented opportunity to actually try and do that and make a meaningful difference in cardiovascular events. That's why we, you know, it's this very tonic control of blood pressure.
You have 77 million people who are at high CV risk with uncontrolled high blood pressure. That's a huge number of patients who would benefit from a drug that can tonically lower their blood pressure over a period of time, reduce variability in blood pressure, control, improve nocturnal dipping, improve adherence, and hopefully prevent events.
That's what our goal is. That's why, you know, to all the questions that have come up, why we are proposing to launch this drug with a cardiovascular outcome study.
That's what we think the benefit of this drug is, and we wanna show that benefit, and bring that value and innovation to patients, to prescribers, to payers, and to the healthcare system, and launch with the strongest label that we can. That's really the thinking here.
That's a great clarification question. Thank you.
Thanks.
Our next question comes from Olivia Brayer from Cantor Fitzgerald. Your line is open.
Hey, good morning. Thank you for the question, congratulations on the partnership as well. Has Roche seen any initial data from the phase 2 program, or was their investment based just on the totality of the phase 1 at this point?
Then a follow-up on regulatory discussions. Have you guys had any recent conversations with FDA on the registrational path forward, or will those happen after we get the phase 2 combination data? Thanks very much.
Yeah, no, great question. No, all that are available at this point in time are the data that we generated from our Phase 1 study. As Pushkal highlighted, I mean, those data really indicate, you know, the potential of zilebesiran in terms of blood pressure lowering, in terms of, you know, early evidence of tonic control, kind of encouraging early safety, et cetera.
That's really the data set that we have available to this to us at this point in time. As Pushkal indicated, we'll be seeing top line from KARDIA-1 in mid-2023. It's just around the corner, and we'll be, we've just fully enrolled KARDIA-2 as well, and have top line data at the beginning of 2024.
Again, just to underscore this, the view around the clinical development program required to maximize the value of zilebesiran is a decision that we've taken together with Roche. At this point in time, you know, we haven't discussed the details of our forward-looking development plan with the regulators.
Yeah, I'll just add, just to underscore that last point. You know, we're looking to bring together all the data from K-1, K-2, et cetera, we'll approach the regulators in due course about the, you know, the registration development plan.
What you're hearing from us today is really our vision for what we think will bring forward the best path to bring this zilebesiran to the maximum number of patients and have maximum impact.
Okay, I think we've got one last question.
Yes, our last question comes from Mani Foroohar from Leerink. Your line is open.
Yes, thanks for taking the question, and congratulations on on the deal as well. Given Roche will be taking a substantial operational role, especially in the CVOT, should we think of this as indicative in terms of other potential large cardiac indications, that you don't see building out that global infrastructure for a CVOT as core or within your bailiwick?
You know, for future indications or for other products, do you think this is an infrastructure and ability that Alnylam will eventually have to build out as you approach larger global scale prevalent diseases?
I'm not sure if I heard all of your question, but I just want to kind of clarify, to make sure that there's full understanding that, you know, TTR is not part of this collaboration, right? We're gonna progress, we're gonna be progressing our TTR franchise, you know, independently as Alnylam, and we see that as a significant value driver for the company.
You know, I'm delighted by the progress that we've made with respect to polyneuropathy. Obviously, we're looking forward, hopefully, to an approval in cardiomyopathy, firstly, for Onpattro, and subsequently for Amvuttra. I think what this partnership allows us to do, actually, is to build our own capabilities, to allow us to, you know, at a point in time, be able to prosecute prevalent diseases within Alnylam.
This is a tremendous opportunity for us to work alongside with an established, large pharma company with a proven track record like Roche, to build our commercial capabilities. Which I think will set us up for, you know, the ability to be able to prosecute the very rich pipeline that we have in front of us going forward.
Tolga, I don't know, you've spent some time, you know, with the commercial colleagues at Roche, maybe, you know, perspective on how you see that working?
No, I mean, Yvonne, I just wanted to repeat two points. One is, obviously, we're incredibly pleased with the progress that we made with PN, and subsequently, we're expected to do the same with our cardiomyopathy indication.
Just to remind everyone, we do have a global footprint. We are active in several all major European markets and Japan, and we continue to build that capability. As Yvonne indicated, we obviously want to be able to build the muscles that will allow us to actually commercialize more prevalent, more specialized medicines alone.
This certainly, collaboration is a great opportunity for us to partner with a like-minded partner that has a proven track record of bringing innovative treatments in a way that will allow us to maximize this great potential asset.
Pushkal?
Yeah, may I just, I think I want to correct one thing that maybe have been a misunderstanding what you said. I want to be really clear that on the development side, building what Tolga and Yvonne said, Alnylam leads all development, including the CVOT, all the way through that initial launch, okay?
Around the world. Alnylam will be leading it. Obviously, we'll be working closely with our colleagues at Roche, but the development is fully led within Alnylam. I just want to make that point clear.
Yeah, that was helpful, Pushkal. Look,
Thanks, guys. I'm sorry if I misspoken, if I said TTR, and zilebesiran.
I was just making sure.
Thanks for clarifying.
We have everything we need to deliver success in TTR. Okay, well, look, thank you everyone for joining us on this call. You know, I think you can clearly see that we're excited about the future of zilebesiran. Really, I think what is a unique opportunity to bring meaningful innovation to patients with hypertension.
Look, this new partnership with Roche will allow us to realize the full potential of what we have in our hands. Whilst at the same time, enabling us to deliver success in TTR, but also continue investing into the many exciting opportunities that we have across our pipeline and platform as we progress towards our Alnylam P5x25 goals. Thanks, everybody.
Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.