RGNX - NASDAQ

Good day, and thank you for standing by. Welcome to REGENXBIO's Third Quarter 2023 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be question-and-answer session. [Operator Instructions] Please be advised today’s conference is being recorded. I would now like to hand the conference over to your host today, Patrick Christmas, Chief Legal Officer. Please go ahead.

Good afternoon and thank you for joining us today. Earlier this afternoon, REGENXBIO released financial and operating results for the third quarter ended September 30th, 2023. The press release is available on our website at www.regenxbio.com. Today's conference call will include forward-looking statements regarding our financial outlook, in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties. These risks are described in the risk factors and the management's discussion and analysis sections, REGENXBIO's annual report on Form 10-K for the full year ended December 31st, 2022, and comparable risk factors sections in REGENXBIO's quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website. Any information we provide on this conference call is provided only as of the date of this call, November 8, 2023 and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events, or otherwise. Please be advised that today's call is being recorded and webcast. In addition any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially. I would like to now turn the call over to Ken Mills, CEO of REGENXBIO. Ken?

Thank you, Patrick. Good afternoon everyone and thanks for joining us. I'm pleased to begin today's call with an explanation of our updated strategic plan. Dr. Steve Pakola, our Chief Medical Officer, will then provide an update on our clinical programs. And Vit Vasista, our Chief Financial Officer, will provide an overview of financial results for the third quarter ended September 30th, 2023. At the end of the call, we will be opening up the line for questions. At REGENXBIO, our mission is to improve lives through the curative potential of gene therapy. Earlier today, we began work on a pipeline prioritization and corporate restructuring plan that will enable REGENXBIO to focus our capabilities and resources on large commercial opportunities where product candidates are differentiated, can be expedited, and support meaningful value generation soon and for the long-term. I want to be clear about what this sharpened focus means moving forward. Our highest priority programs our ABBV-RGX-314 program for the treatment of wet age-related macular degeneration and diabetic retinopathy being developed in collaboration with AbbVie, RGX-202 for the treatment of Duchenne, and RGX-121 for the treatment of MPS II or Hunter Syndrome. Now, in the last two months, we've experienced exciting progress from each of these programs. We've reported positive clinical data from investigational treatments from diabetic retinopathy and Duchenne and we've held a very encouraging RMAT meeting with the FDA about expediting the BLA for the treatment for MPS II. These milestones demonstrate how our science is supporting avenues to accelerate the development of new gene therapies. And today, we're following that encouraging data and announcing updated strategic plans for REGENXBIO. We believe that there's a multibillion-dollar potential for RGX-314 as a single injection treatment to become the first-in-class gene therapy for Wet AMD and the standard of care to treat and prevent the progression of diabetic retinopathy. Initial efficacy data from patients treated with RGX-202 is enabling us to accelerate this program. Duchenne is a market where there is a large unmet need for new therapies, and that is capable of supporting multiple gene therapies and we believe RGX-202 has unique differentiating features that support its potential to be a best-in-class product. During a very constructive RMAT meeting with the FDA just recently in October, we received encouraging feedback and confirmed alignment with the FDA on key elements of an expedited BLA. So we remain on track to support a BLA filing in 2024 using the accelerated approval pathway. RGX-121 would be the first gene therapy treatment for MPS II. In today's challenging market, the ability to create value quickly and efficiently is critical. Importantly, these restructuring decisions extend our cash runway much deeper into 2025, allowing us to progress our pipeline to a number of key inflection points. These would include initiating and dosing the first pivotal trials for 314 using suprachoroidal very, enrolling the pivotal program for our RGX-202 program, and completing performance qualification locks to support a plan BLA for RGX-202, and also achieving the BLA approval for RGX-121 and MPS II. Now it's worth noting that successfully achieving certain of these milestones between now and then would also trigger hundreds of millions of additional funds, such as milestone payments from our collaboration partner, AbbVie, for initiating suprachoroidal pivotal trials, which these milestones represent a meaningful portion of the over 560 million in development milestones eligible through this partnership for us. And the potential receipt of a pediatric review voucher for approval of RGX-121. Generally, we've been observing POV sales are resulting in nearly $100 million to DLA sponsors at the time of receipt. So our updated strategic plans are intended to generate significant value for shareholders as we ensure resources are allocated to our most valuable assets, to be able to accelerate the development of these assets and to extend our operational runway in order to achieve even more milestones that can unlock value. These additional non-dilutive sources that I just highlighted, for instance, are not in our current runway guidance. And if received, would allow us to bridge to additional value creating milestones, such as more product approval and potentially to profitability. Now I'll turn the call over to Steve so he can review some of our clinical progress and guidance for the prioritized programs in greater detail. Steve?

Thank you, Ken. I'll begin with 314, which is being developed in collaboration with AbbVie to treat Wet AMD and diabetic retinopathy via subretinal and suprachoroidal routes of administration. 314 utilizes our NAV AAV8 vector to deliver a gene encoding of therapeutic antibody fragments to inhibit VEGF. The anti-VEGF market opportunity is poised to grow significantly as the population ages. 314 for the treatment of wet AMD via subretinal delivery is being evaluated in two ongoing pivotal trials ATMOSPHERE and ASCENT, which are expected to enroll a total of 1,200 patients in the US, Europe and Japan, supporting the global development of the program with anticipated global regulatory submissions in late 2025 through the first half of 2026. We also have two ongoing Phase 2 trials that fall under our collaboration with AbbVie assessing the in-office suprachoroidal delivery of 314 for treatment of wet AMD in the AAV8 study, and diabetic lechnopathy or DR in the ALTITUDE study. AAV8 is an active controlled dose escalation trial evaluating 314 for the treatment of wet AMD. We most recently presented safety data in July from Cohort 6 evaluating the dose level 3 that included short course prophylactic ocular steroids following administration of 314. The initial data presented continues to support the safety profile of 314 and highlighted the inclusion of short course prophylactic steroid eye drops, which resulted in zero cases of intraocular inflammation. We plan to present full six-month results from Cohorts 5 and 6 at the Hawaiian Eye and Retina Meeting in the beginning of 2024. ALTITUDE is an observation controlled dose escalation study of 314 suprachoroidal delivery for the treatment of DR We're very excited about the opportunity in DR, given the size of the market, which exceeds that of even wet AMD and because we believe this patient population can benefit the most from a potential one-time gene therapy. At AAO this past weekend and on a call with retina physicians on Monday, we presented positive data from dose levels 1 and 2 Cohorts at one year. Patients at those dose levels did not receive prophylactic steroids before or after 314 administration. 314 was reported to be well tolerated at both dose levels. One-time in-office 314 injection demonstrated clinically meaningful improvements in disease severity with reductions in vision-threatening events, Importantly, 100% of the patients with baseline NPDR treated with dose level 2 achieved stable to improved disease severity. Moreover, dose level 2 in these patients reduce the risk of visioning threatening events by 89%. We are encouraged by this data and the potential of a one-time in-office injection for patients with diabetic retinopathy. Moving now to RGX-202 for the treatment of Duchenne. RGX-202 is a potential one-time gene therapy for the treatment of Duchenne being developed as a highly differentiated product, designed to deliver a transgene for a novel microdystrophin that includes the functional elements of the C-terminal domain, found in naturally occurring dystrophin RGX-202 is designed to support the delivery and targeted gene expression throughout skeletal and heart muscle using our NAV AAV8 vector and a well-characterized muscle-specific promoter. Our AAV8 capsid also represents an alternative for boys who may not be eligible for other AAV mediated microdystrophin therapies due to the presence of preexisting neutralizing antibodies. At World Muscle held in October, we shared interim clinical data from the Phase I/II affinity Duchenne trial. Initial results from the first two patients for whom results were available showed robust microdystrophin expression and appropriate localization to muscle cell membrane. In the 4.4-year old patient, microdystrophin expression was measured to be 38.8% compared to control. A reduction from baseline in serum creatine kinase or CK levels of 43% was observed, supporting evidence of clinical improvement. The 10.6-year old patient had microdystrophin expression measurements of 11.1% compared to control and a reduction from baseline in serum CK levels of 44%. Microdystrophin expression was measured by Western Blot with comparable results observed when measured by the LC-MS/MS. Overall, the data showed that RGX-202 was well tolerated with no drug-related serious adverse events in all three patients treated as of the time the data were presented. As Ken shared earlier, we recently held an RMAT meeting with the FDA for RGX-121 for treatment of MPS 2. I'm pleased to share that this was a very positive and constructive discussion. We were able to align with the FDA on our manufacturing strategy, the adequacy of our safety database and confirmatory study design. Patients treated with RGX-121 continue to do well on follow-up, and we expect to share top line data from the Phase 1/2/3 CAMPSIITE trial in the first quarter of 2024. While we are no longer moving forward with our RGX-111, 181 and 381 rare neurodegenerative programs, we believe in the potential of these therapies and are committed to finding strategic alternatives for them, including potential partners or leveraging public private partnerships. So to conclude, we have made significant progress with data updates and trial progression across all programs in our pipeline as we continue working to advance our prioritized programs. Lastly, I'd like to thank the patients, families, clinicians and patient advocacy representatives who have been involved in and supported all of these trials. And with that, I turn the call over to Vit to review our financial guidance. Vit?

Thank you, Steve. REGENXBIO ended the quarter on September 30, 2023, with cash, cash equivalents and marketable securities, totaling $365 million compared to $565 million as of December 31, 2022. The decrease was primarily driven by cash used to fund operating activities during the nine months ended September 30, 2023. R&D expenses were $58 million for the third quarter of 2023 compared to $63 million for the third quarter of 2022. The decrease was primarily attributable to an increase in development cost reimbursement from AbbVie under our Eye Care collaboration. With the strategic reprioritization plan and 15% workforce reduction announced earlier today, we expect to save at least $100 million over the next two years. We now expect the balance in cash, cash equivalents and marketable securities of $365 million as of September 30, 2023 to fund our operations into the second half of 2025. This cash runway guidance is based on the company's current operational plans and excludes the impact of any payments that may be received from AbbVie upon the achievement of developments or commercial milestones under our 314 collaboration. With that, I will turn the call back to Ken to provide final thoughts. Ken?

Thanks, Vit. As we look ahead, our extended cash runway will now enable us to reach additional meaningful value-driving milestones for our programs, which I've outlined. We also want to bring focus to the fact that we have a lot of important near-term value-driving catalysts expected at medical conferences upcoming in the first half of 2024. This would include new six-month data from recently dosed cohorts of the AAVIATE trial for wet AMD suprachoroidal, additional dose level one, an initial dose level two data from the AFFINITY DUCHENNE trial, and top line data from the pivotal Phase III CAMPSIITE trial. I want to reiterate that our updated strategic plans are intended to generate significant value for our shareholders as we assure resources are allocated to our most valuable assets to accelerating the development of these assets and to extending our operational runway and to achieve more milestones that can unlock additional value, including access to non-dilutive capital that we talked about from the AbbVie partnership or other sources like anticipated sale of a PRV that could, all of which extend our runway even further. With a renewed sense of focus, I expect that we'll continue to perform at a high level as we execute on our mission. And as a result of these updated strategic plans announced and implemented today, we believe REGENXBIO is well-positioned for long-term success. With that, I think we can now turn the call over for questions. Operator?

[Operator Instructions] Our first question will come from the line of Gena Wang with Barclays.

Thank you for taking my questions. Okay, I will follow just one question, Lou [ph]. I know there are tons of a question I can ask. So one question I have is what you can learn from Sarepta's experience in terms of clinical development for the DMD program and regarding primary endpoint selection and also efficacy bar?

Thanks, Gena. This is a good question. Obviously, we've ourselves been engaged in dialogue with regulators about RGX-202 and especially as we've been able to emerge with our own clinical data, it's been an important focus for us since World Muscle Society to think about how to accelerate the program, and we've given guidance next year that we believe we have the ability to both dose select and start a pivotal phase program. I think that what we're seeing in the landscape of microdystrophin continues to be encouraging that it's clearly helping boys. I think it's something that we viewed since we entered the space beyond a sort of increment, but something that in certain boys it certainly is having more response than in others. We believe that the C-terminal domain hypothesis for RGX-202 is a meaningful differentiator. And I think where it can be an important differentiator is on clinical function, the long-term clinical function. So we're very much engaged about how to design trials to accelerate and still continue to borrow the endorsement and the use of microdystrophin in the surrogate endpoint to support accelerated approval -- think about how to further support that in a pivotal setting and even in a commercial setting with respect to looking at long-term function. So I think that the domains that are part of the scoring that's used in Duchenne boy. I think some people are starting to recognize both at the regulatory level and at the clinical level, that some of these domains are more reliable in terms of prognostic indicators for improvement. We're very much dialed into that and think that having an opportunity to have our own direct dialogue about our data and seeing the evolution of what's happening on the regulatory landscape actually puts us in the best position to start executing next year on a really great package.

Thanks, Dan. I'll probably let Steve address the comment about the regulatory landscape. I guess, with respect to ALTITUDE and AAVIATE. I think what's been an important part of the update today with respect to the strategic plan is that the extension of the runway for REGENXBIO, I think, for us, increases the likelihood of current capital supporting the transition of suprachoroidal into pivotal phase in achieving some of these milestone value events that can be unlocked. We have $0.5 billion of potential development milestones over and a large proportion of that is associated with transition of suprachoroidal delivery for wet AMD and DR occurring and patient dosing beginning there. So we view that the data that's starting to come off that we're particularly excited about right now with respect to diabetic retinopathy is really shaping up for support of decisions for that transition, and we have additional data coming up just early in 2024 with respect to the AD8 study. So I think we're, I think, as confident as we've ever been about the science that we're seeing and the likelihood of these events occurring in the future for us, I think are improved particularly with respect to the updated strategic plan and the extension of the runway that we have to focus on those events. Steve, do you want to pick up the regulatory parts?

Sure. Hi, Dan, thanks for the question. Yes, interestingly or maybe not surprisingly, this was a discussion point at AAO this past weekend and also some of the ancillary meetings that were held there, the issue of sham-controlled. And I think there's a couple of key points here that a big component of the FDA's view on the challenges of masking with a sham control relate to intravitreal injection and that's due to the fact that there's a general belief within the FDA, in particular, that getting an intravitreal injection, the patient can actually sense that they're getting a real intraocular injection and may even be able to see something in the visual axis to suggest that there's actually been a fluid injection. So for our suprachoroidal programs, that's not an issue because we're not actually injecting into the eye, and we've had regulatory interactions we're aligned on an approach for giving a "shaminjection" that preserves masking. The other aspect that's come up from the FDA's discussion of this are, there's other ways to address this, such as considering having two active arms of different dose level of your given drug that at least then preserve the masking between active arms. So there's several approaches that companies can consider. But fortunately for us, the fact that we're not an intravitreal injection really shields us from this issue.

Thanks for the question, Dan. I guess the level of detail that Steve is giving about thought that's going into the application of suprachoroidal delivery and later-stage trials is, I think, additional evidence of the work that's going on inside the company and in the partnership to support these types of things.

Our next question comes from the line of Vikram Purohit with Morgan Stanley.

This is [indiscernible] on for Vikram. We have one question for potential partnerships for RGX-181and 381. Do you have a time line in mind for establishing a partnership? What would you be looking for to partnership outside of capital? Thank you.

As for the strategic update plans today are really focused on assuring and sourcing capital for RGX-314, RGX-202 and RGX-121 to achieve what we think is the strongest potential value that we have in the pipeline today. So with respect to 111 and other things that's going to be a discontinuation of any clinical development work and exercise that will result in looking for opportunities in the short term for partnering, but it won't become something that will be viewed as a meaningful contribution to the operating plans going forward.

Thank you very much.

Our next question comes from the line of Alec Stranahan with Bank of America.

Thanks for taking question. Just one from me. Could you maybe expand upon the positive FDA interactions you've had after the update for 202 dose Level 1 and did you get any input on the pivotal study design as well, particularly as it relates to different age cohorts? Thanks.

Thanks. Yes. Thanks for the question, Alec. I think that it's been a very dynamic process for us with respect to contact with the FDA on RGX-202 and that's because of the landscape of what's happening in microdystrophin in general. We want to understand how FDA is sort of thinking about our data and other data sets and the evolution of things with respect to microdystrophin as a class. I think for us, incredible opportunity to early on at dose level 1, talk about safety and microdystrophin expression and sort of the pathway to making a dose selection. I think there's also a lot of interplay that we see on, let's say, for instance, manufacturing, Alex, right? We're working through basically BLA readiness for our manufacturing facility and a manufacturing process with 121, that is also something that is a path for us with respect to 202. And so we're -- I mean, this is for us between an RMAT meeting and interaction around 121 and between the opportunity to sort of update leadership and people at FDA with additional information and data about RGX-202 and also get feedback about what is going on with respect to the landscape of microdystrophin in general. It's a really rich time. I think that we're setting us up well for thinking about strategies and operational plans that are about acceleration. And I think the best example of that was just being able to modify the clinical protocol to reduce the number of patients from 3 to 2 before moving into a parallel enrollment scenario with the dose levels that we're at. I think -- that was something that was informed by data. It was informed by safety. It was informed by updates to our dossier with respect to the IND and having alignment with FDA on that, I think, was a meaningful signal.

Great. Thanks, guys. Very helpful.

Our next question comes from the line of Ellie Merle with UBS.

Hi. This is Sarah on for Ellie. Thanks so much for taking our questions. Just quickly on potential milestones from AbbVie, I know they're not currently in your guidance. Can you remind us what the milestone would be for moving into pivotal studies with suprachoroidal. And then any color around the timing of other near-term milestones there that we should be thinking about?

Sure, Sarah. Thanks for the question. Yes, we've disclosed that we have over $560 million of eligible development milestones associated with the partnership and a large proportion of those milestones are associated with the suprachoroidal programs transitioning into pivotal phase. So I think those are things that we view with this change in guidance and runway guidance are increasing likelihood for them to occur across the operational runway that we have now. And obviously, they've been answering questions already about specific timing or things that have been going into how that decision is made. What I can say about some of the updates that we've given recently like data we’ve with respect to the exciting data that we've seen from diabetic retinopathy and some of the thinking that has been going on within the partnership is that we really think that the data sets are starting to mature now to a point where those types of decisions can be made soon. So we have the Hawaiian Eye data update coming also in the beginning of next year. These are things that now with a runway guidance into the second half of 2025 I think, are achievable. And again, I tried to frame this in the overview. I think these are opportunities to sort of bridge to obviously, we're talking to hundreds of millions of dollars in milestones here that can occur that can bridge the company even further into years 2026, 2027, for instance. And those start to be years now where we're talking about BLA filings of the subretinal program and potential if you think about acceleration for our Duchenne program, additional product launches. So we really like how the strategic update plan here and the interplay of some of these milestones are coming together to think about effectively having opportunities to capitalize ourselves with things that are currently assets of the company, all the way to a whole row of product approvals and potentially even profitability.

Great. Thanks.

Thanks.

Our next question comes from the line of Luca Issi with RBC Capital Markets.

Good. Thanks for taking our questions. Just maybe one -- this is Lisa on for Luca. Just maybe one on DMD. We know the AFFINITY trial is enrolling patients up to 11 years of age. However, from the EMBARK data, it appeared harder to discern a benefit in older children versus younger children. So just wondering what gives you confidence that 202 will show a benefit in older children, because especially when it appeared that the Western blot suggested that there was higher expression in the younger patient. Any color there would be helpful. Thanks.

Yes. Thanks, Lisa. I mean look, we have an older patient enrolled already. And so I certainly acknowledge the remark about the differences that we've seen in microdystrophin expression, but we're going to be able to see sort of unfold in front of us and continue to be able to update on the progress of that patient. I think the meaningful differentiator here is the C-terminal domain design of our expression consent. We just think that scientifically, from a biological plausibility perspective, amounts of microdystrophin that are expressed with the C-terminal domain are going to translate into improved function. And I think that gives RGX-202 better and as good as any other treatment but really better than any other treatment that's bringing forward to-date to show improvement in older voice. So we continue to view that the opportunity to enroll in that age range is something that's going to be important for our profile clinically and ultimately, commercially. And we do think that there's strong validation in the 4 to 5 and the emergence of more data in 6 to 7 is also sort of helping inform the benefits there. But we really feel strongly that the C-terminal domain, the functionality associated with it, what we've seen from our preclinical data and the early evidence that we've reported on and we'll continue to update on in an older patient. I think, is something that we're excited about for that age range. Thanks, Lisa.

Our next question comes from the line of Brian Skorney with Baird.

Hey, good afternoon everyone. Thanks for taking my question. It just sounds like you're getting your decision point on pivotal programs with the superchoroidal administration. So just wondering what's sort of the rate limiting factor here in terms of AVA and ALTITUDE to kind of make a decision you really need like one-year data from Cohorts 6 and Cohorts 4 and 5 to trigger that point. And you've been talking very enthusiastically about Diabetic Retinopathy, do you see sort of the pivotal program moving forward in the DR and wet AMD at the same time? Or will one of these indications potentially move forward earlier than the other?

Yeah. Thanks for the question, Brian. I think, again, like we have a lot of enthusiasm about the recent data update. And there's a recency effect there. Of course, the AAO was just a few days ago, and I think the new DR data has now been communicated and has been a focus for us in terms of communication in the last few days. With respect -- and then we have AVA update coming only in January. I think our vision has been from the beginning that wet AMD Subretinal, wet AMD suprachoroidal, wet AMD for Diabetic Retinopathy. They are obviously all interrelated because of the same pharmacological agent, but each one of them because of the difference in delivery or in the last case and the difference with respect to the potential market and the sort of evidence that's needed clinically to think about how to transition in a pivotal, they're all slightly different path, but they derive from the same consideration in variables that we would look at for any kind of advancement of a program like this, almost independent of modality into a pivotal phase. I always like to point out that we are the company that is the first to have transitioned into a pivotal phase program with respect to an AAV Gene Therapy in a large market indication in wet AMD. And now we also have the strength and sort of the robust decision-making to sort of bring additional variables into the equation with us with AbbVie. Yeah, the decisions though are going to be different and separate between the suprachoroidal, wet AMD and the suprachoroidal Diabetic Retinopathy. I mean they rely on different data sets and different inputs. So it's certainly possible that they could happen at the same time, but it's -- it's as likely that those decisions are independent variables and would come forward. But I think the message today is how strongly we feel about reinforcing our excitement about the value of RGX-314 and the opportunity to continue to realize that value and continue to make that focused investment with an extended runway here, I think, really improves the probability of success of meeting some of these milestones in terms of transitioning the pivotal. Therefore, realizing some of these monetary milestones that are associated with the partnership in a way that is improved, right, just with that extended runway alone, but at the same time, we've also started to become really encouraged about the newer and longer-term data that's been coming out of the investments that have been made in things like AVA and ALTITUDE. So we excited for things to come here moving into 2024.

Thank you.

Thanks Brain.

[Operator Instructions] Our next question comes from the line of Annabel Samimy with Stifel.

Hi. This is Jack on for Annabel. Thanks for taking my question. So for the Subretinal formulation of 314 in wet AMD, what's the right amount of follow-up time that FDA is looking for to establish safety and durability there? And what might the value proposition be here for the payers when you think of pricing this, considering that many of these patients are elderly and may not see the maximal benefit of a long-term treatment?

Steve, do you want to take the regulatory part here?

Sure. Hi Jack. Yes. So, taking the first part of your question, the duration from a regulatory standpoint as far as follow-up. We've gotten very clear feedback back as far as the end of Phase 2 meeting that allowed us to finalize the pivotal program that really is a class requirement having one-year safety and efficacy data, which also was somewhat informed by efficacy, but predominantly by gene therapy aspect. We'll also have longer term follow-up data from a lot of the patients from our pretty sizable safety database. And we actually already have from our Phase 1/2 data base out through four years, good safety and also good durability from an efficacy standpoint. So, I think both based on other programs, even outside the eye that have shown durability out even beyond a dozen years, for example, in hemophilia with the same AAV serotype AAV8. And then now our own data gives us a lot of confidence on duration of efficacy. And I think that's obviously going to inform the value proposition, having durable efficacy evidence. And the value proposition importantly is more than just decreasing treatment burden and visit burden. Really, the big unmet need here is by breaking the barrier of the treatment burden, it ensures that these patients aren’t going to have the ongoing sustained anti-VEGF activity that they need to prevent vision-threatening complications that they simply aren't getting now both in terms of wet AMD and diabetic retinopathy because of the treatment burden. So, there's various layers of the value proposition, treatment burden, visit burden, and actual vision and complication outcomes.

Yes. And I would add, Jack, that I think it's pretty well-established by a lot of different sources that the cost of the cost related to blindness that's associated with wet AMD is on an annual basis, something that can be in excess of $100,000 a year and that's separated from the cost of drug. So, when we think about a wet AMD patient, you're talking about the life expectancy might be on the order of 10 to 15 years. I think in the real world, there's a need there for recovering the vision that is being lost because people aren't staying compliant with the existing treatments and the cost and the -- obviously, the effect that that's having on a productivity basis with respect to the effect that it has on the families of those patients as well, is significant. And so durability is everything. I like how Steve brought up the four-year evidence, which just continues to grow. It's there as a backstop for things on a regulatory basis, but I think also important in the commercial setting.

Great. Thanks so much.

Our next question comes from the line of Mani Foroohar with Leerink Partners.

Hey, guys. Thanks for taking the question. Obviously, you have fund decisions to make, but obviously the right thing to do. You've outlined the press release a little bit of detail around about $100 million of savings, et cetera, couple of years. Could you give us a sense of where that tempo is? Like should we expect that to drop in immediately starting in 1Q and be fairly linear on a quarterly basis? Or is it something that's a little more front loaded, a little more backward over the first couple of years? And beyond that, how should we think about post that two-year period, what is the implication on OpEx longer term?

Vit, you want to chime in on this one?

Sure. Thanks, Mani. I think that as you're thinking about that $100 million, it would be not 100% linear as much as it slowly gets split into our operating plan going forward. Some of it will be a little bit lumpy as we start to discontinue programs. And then obviously, with that 15% headcount reduction, that's a little bit more front-end loaded. And then, as we think about OpEx, I would start to be looking at the models and determine what's the appropriate kind of run rate, what I’ve seen, looking at different analyst models as their estimates for OpEx seems to be a lot higher than what we're tracking against. And I think coming out of this quarter into next year, you'll have a better idea of what the run rate is on an OpEx perspective. And then on the other side of 2025, obviously, with the non-dilutive capital that we're talking about and we have the opportunity to possibly the markets will unlock finally. I think post 2025, we're going to still maintain our discipline as it relates to OpEx, but we'll also have to some moving programs forward as they become commercial opportunities then also start to think about our pipeline going forward.

That's helpful. Thanks. I’ll hop off.