Annexon, Inc. (ANNX) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to the Annexon Business Update Call. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Annexon website following the conclusion of the event. I'd now like to turn the call over to Doug Love, President and Chief Executive Officer of Annexon. Please go ahead, Doug.

Thank you, operator. Good morning, and welcome, everyone. Earlier this morning, Annexon issued a press release announcing that we have expanded our ARCHER II Phase III vonaprument program in geographic atrophy, in a press release announcing key business updates and second quarter financial results. Copies of these press releases are available on the company's website and through our SEC filings. On today's call, we will be making forward-looking statements, including statements relating to the existing clinical data and the therapeutic and commercial potential of our investigational drug candidates. Joining me today are Dr. Jamie Dananberg, our EVP and Chief Medical Officer; and Dr. Lloyd Clark, SVP of Ophthalmology Strategy and Innovation, who will discuss our GBS and GA programs, respectively. I will then close before we open the call for questions, where we will be joined by Dr. Ted Yednock, EVP and Chief Innovation Officer; and Jen Lew, our Chief Financial Officer. Before we turn to the updates, I'd like to briefly frame Annexon's broader opportunity and our excitement about building a leading, fully integrated biotech company, driven by our mission to help millions of people live their best lives. Annexon was founded on discoveries from Stanford University to create a new class of targeted immunotherapies that stop C1q-mediated neuroinflammation at its source with the goal of rapidly and meaningfully preserving and potentially improving function for patients of serious neuroinflammatory diseases of the body, the brain and the eye. Built on more than 2 decades of foundational C1q biology and a highly translational approach in the clinic, we have generated robust, compelling evidence supporting the potential of C1q inhibition across multiple diseases. Indeed, leveraging our pioneering science and our warrior spirit culture to tackle some of the most pressing diseases in our industry, Annexon is the first and only company to successfully conduct fully randomized placebo-controlled trials of GBS, a life-threatening and debilitating disease that is sudden and completely indiscriminate in who it strikes, depriving otherwise healthy people of their normal lives. Annexon is also the first and only company to demonstrate significant vision preservation in a fully randomized sham-controlled study in geographic atrophy, a mass population disease, irreversible blindness that robs millions of people of their independence. Lastly, Annexon is the first and only company to develop and clinically study an oral small molecule designed to selectively inhibit the classical pathway with the potential to offer those with serious complement-mediated autoimmune conditions, a convenient and flexible oral dosing option. While disruptive science is not always quickly recognized, we are more energized than ever by the opportunity to create significant value with not just one, but with multiple potential blockbuster, paradigm-shifting programs designed to bring hope and better outcomes to millions of people worldwide. Turning to our GBS program update. This program reflects the foundation of Annexon and our determination to take on challenges others have not. We are pleased to have generated the first positive placebo-controlled pivotal data in the 110 years since GBS was discovered. Tanruprubart is now under regulatory review in Europe, and we are on track to submit the U.S. BLA in the fourth quarter of this year. Last week, we reported clinical outcomes from the first cohort of patients enrolled in our FORWARD study across the United States and Europe, marking an important milestone for Annexon and for the GBS community. Tanruprubart flat out works, and these data are more than the next step in our development program. They provide compelling evidence that the rapid meaningful clinical improvements seen in our Phase III study, where approximately 90% of treated patients responded by week 1, are reproducible in western patients. All 10 patients treated to date in FORWARD improved rapidly, with many showing outsized gains. These unprecedented outcomes together with a well-tolerated safety profile support a highly differentiated benefit-risk profile for the roughly 150,000 people worldwide diagnosed with GBS each year. We plan to include these data in our BLA submission in the fourth quarter. Turning next to our GA program. Our second drug candidate, vonaprument, is advancing in the pivotal ARCHER II Phase III trial for patients [indiscernible] to irreversible vision loss. Today, we announced a strategic expansion of the program by adding an independent month 24 dual primary endpoint alongside the existing month 15 primary endpoint. To be clear, we remain excited and confident about the month 15 readout expected in the fourth quarter of this year, supported by a powerful mechanism of action, robust preclinical package, compelling dose-dependent proof-of-concept data and a well-powered, well-executed Phase III study designed to replicate those results. With masked event tracking on plan, month 15 remains our base case for success. At the same time, adding the month 24 endpoint meaningfully strengthens the program and a potential $100 billion-plus franchise. The endpoint is well powered, requires no change to the conduct of the already masked 24-month trial and gives vonaprument additional time to demonstrate the growing treatment effect observed in the proof-of-concept trial. Lloyd will discuss this shortly, but in short, the ARCHER program is stronger with this enhancement. Related to the GA program, we were also pleased to announce the initiation of the ARCHER II open-label extension, or OLE study. This allows all patients to enter the OLE after month 24 to receive vonaprument, while enabling us to assess its longer-term safety and benefit profile. Shifting to corporate matters, as both the tanruprubart, GBS, and vonaprument, GA, programs advanced towards registration, we also, in the second quarter, took a strategic step to further strengthen our financial position. During the quarter, we entered a credit facility with Oxford Finance that provides access up to $200 million in non-dilutive capital, extending our cash runway into 2028. This facility enhances our financial and operational flexibility as we prepare for global commercialization while further diversifying our capital structure, strengthening our balance sheet and supporting both near- and longer-term growth strategies. With that overview, I will now turn the call over to Jamie to review the recent data for our GBS program, following that, Lloyd will then discuss our vonaprument program updates in more detail. Jamie, over to you.

Thanks, Doug. Before reviewing the FORWARD data, I'd like to briefly highlight the significant unmet need in GBS. As Doug mentioned, GBS is an indiscriminate life-threatening neuromuscular emergency with a rapid devastating onset, compounded by long-term life-altering consequences. GBS can strike anyone anywhere causing paralysis, respiratory failure and even death. Without immediate intervention, patients face continued neuroinflammation and peripheral nerve damage caused by GBS that leads to muscle weakness or paralysis, with lifelong residual deficits impacting their health and quality of life. Approximately 22,000 patients each year across the U.S. and Europe are afflicted with GBS, and carries an estimated annual healthcare burden of more than $20 billion in the U.S. alone. Despite more than 110 years since GBS was first described, there is still no approved targeted therapies that meaningfully alter the course of the disease. Current standard of care intravenous immunoglobulin, or IVIG, is not FDA approved for GBS and provide incomplete benefit for many patients. Despite treatment, 1-year mortality remains as high as 10% overall and approaches 25% of patients over the age of 65, many patients continue to deteriorate during or shortly after 5-day IVIG treatment, requiring mechanical ventilation, prolonged ICU stays and experiencing months or even years of disability and persistent physical limitations. These challenges underscore the urgent need for therapies that can rapidly stop the underlying disease process and improve patient outcomes. Turning now to the FORWARD study. We are very encouraged by the initial results from the first cohort of 10 patients treated with a single 30-milligram per kilogram infusion of tanruprubart. Across this initial cohort, every patient demonstrated rapid, clinically meaningful improvement in loss of strength within 4 days of treatment. Importantly, 4 patients who are bed-bound early in the course of their disease, regain the ability to walk with or without assistance between days 2 and 8. We also observed outsized improvements in some of the most severely affected patients. The 1 patient who required mechanical ventilation early in the disease course was successfully weaned from the ventilator within 4 days. 5 additional patients experienced marked functional improvement within 48 hours of treatment. Bear in mind that these outcomes with tanruprubart occurred well short of the 5-day span that is typically required to deliver a full course of IVIG. From a safety perspective, tanruprubart was generally well tolerated. The most significant adverse events were related to GBS itself and expected complications of disease, and were consistent with the safety profile observed in our Phase III study. It's also worth noting that this initial cohort represented a broad cross-section of GBS patients, including both males and females, ranging from 12 to 78 years of age and spanning moderate to severe disease. Importantly, these findings are consistent with the outcomes we observed in our Phase III study, where approximately 90% of patients demonstrated rapid, clinically meaningful improvement by day 8. Taken together, we believe these results provide further evidence of targeted inhibition of C1q with tanruprubart as the potential to fundamentally change the treatment paradigm for patients with GBS, by delivering rapid and meaningful clinical benefit after a single infusion. Finally, I'd like to briefly touch on where we are from a regulatory and clinical development perspective. Our marketing authorization application is currently on track and under review by the European Medicines Agency and is supported by a comprehensive data package. This includes robust placebo-controlled studies demonstrating rapid improvement in function and disability as well as real-world evidence showing favorable outcomes compared with current standard of care, including IVIG and plasma exchange. At the same time, we continue to advance the FORWARD study across the U.S. and Europe. This study is designed to expand our experience with tanruprubart in western patients, including pediatric patients, while further characterizing its pharmacokinetic and pharmacodynamic profile, early effects on function and biomarkers and overall safety. Importantly, the FORWARD data are expected to support our planned Biologics License Application, or BLA, submission to FDA in the fourth quarter of this year. Together with ongoing EMA review, these data are intended to further support the generalizability of tanruprubart's rapid clinical benefit across diverse populations and geographies and reinforce the broad treatment label we are seeking for patients with GBS. With that overview, I'll turn it over to Lloyd to discuss the GA ARCHER II Phase III program. Lloyd?

Thanks, Jamie. Before reviewing the vonaprument Phase III program, I'd like to briefly highlight the significant unmet need in geographic atrophy, or GA. As Doug mentioned, GA is a neurodegenerative disease that leads to gradual loss of central vision, difficulty seeing in low light and blurry or distorted vision. The GA patient whose average age is nearly 80 years old suffers most from the loss of their independence when everyday activities like reading, driving and recognizing the faces of loved ones becomes more challenging as their disease advances over time. GA meaningfully impacts the lives of approximately 8 million patients worldwide, including 1.5 million patients in the U.S. alone. And the incidence is projected to increase due to the aging population. A vision preserving treatment in GA is the greatest unmet need in the retina space today. Currently, current approved treatments have not shown to preserve visual acuity, and new innovations are needed. Now turning to our vonaprument program, which has the potential to be the first vision sparing therapy for patients with GA. Notably, our Phase III ARCHER II trial enrolled 659 patients, 30 more than our original target to slightly enhance powering. Powering has been further enhanced with strong trial execution, where the patient discontinuation rate has been less than 10%, and dosing compliance has been more than 95% and both which exceeded our targets. All eligible patients have now received at least 12 months of treatment in the trial and the masked event accruals continue to track in line with our projections. This [indiscernible] gives us further confidence in ARCHER II. The strong power and execution of our Phase III ARCHER II trial provide a clear opportunity to seamlessly incorporate a month 24 dual primary endpoint while maintaining the month 15 priority endpoint. The overall study is highly powered at more than 90% for both time points. Importantly, as ARCHER II was already designed to remain masked through month 24, this strategic addition allows us to evaluate the longer-term profile of vonaprument for inclusion into the label without change to the study operation. Here's how the timeline works from here. An independent data monitoring committee, or DMC, will assess the study's month 15 primary endpoint, and we expect to report that assessment on schedule in the fourth quarter of this year. At that point, the DMC may find that we've met the month 15 primary endpoint, which would allow us to move into the separate and additional planned analysis of the trial's 2 substudies, with results expected in the first quarter of 2027, or the DMC may recommend the study continue through the month 24 analysis. The ARCHER II study, including month 24 analysis is expected to be completed in the third quarter of 2027. On the regulatory side, recall that vonaprument has Fast Track designation from the FDA. It is also the only geographic atrophy program with PRIME designation from the EMA and has been selected for the EMA's product development coordinator pilot, which provides enhanced regulatory support including expedited scientific advice and MAA submission readiness. Together, these designations facilitate more frequent engagement with regulators as we advance this program towards potential registration. We at Annexon, along with retina specialists and the broader GA community, are highly enthusiastic about our vonaprument program and its potential to help the 8 million patients globally with geographic atrophy. With that, I'll turn the call back to Doug.

Thanks, Lloyd. Thanks, Jamie. Nice job. After more than a decade building the scientific and clinical foundation of our platform, we are now entering a pivotal period where the work can translate into new medicines for patients and significant value for shareholders. The time is now. Imagine a world where GBS can be halted within a week and people at risk of GA related blindness have a real choice to preserve their vision. Simply put, we're playing to win for patients, stakeholders and each other. To support that goal, over the course of this year, we have strengthened the balance sheet with non-dilutive debt capital, bolstered our ophthalmic capabilities at the Board of Directors level with the recent appointment of renowned retina specialists and biotech leader, Dr. Mark Blumenkranz, and the addition of key internal talent across the organization. We've established the most comprehensive and compelling GBS data package ever generated, including the first U.S./EU trial in over 40 years, where patients treated to date rapidly improved. We've also effectively executed and are executing the GA Phase III program, have now expanded the program to enhance the probability for overall success and we're continuing the steadfast work to deliver on the first and only oral therapy targeting the complement classical pathway. Each element is significant on its own. Together, they create the potential to drive substantial asymmetric value for Annexon and for others. So in closing, I want to thank the patients, medical teams, supporters, employees and advisers who have joined us on this journey. We look forward to continuing to partner with you as we fully leverage the foundation we've laid over the next 6 to 18 months. And I want to thank all of you who are joining us this morning on today's call. With that, I will now ask the operator to begin our Q&A session. Operator?

[Operator Instructions] So our first question comes from Anupam Rama at JPMorgan.

Congrats on all the progress. I just want to confirm that you guys have shared the dual primary endpoint strategy for ARCHER II with regulators, both in the U.S. and globally. And what feedback you may have gotten on the strategy from the regulators.

Yes. Thanks, Anupam, and appreciate you joining us this morning. Yes, the short answer is, yes, both regulators on both sides of the pond have been very clear that if we want to include month 24 in the label, we would need to apply alpha to month 24. As you know, month 24 was already the design of the study for safety purposes. This addition we've made here this morning allows it to be counted in the label from an efficacy perspective. And I don't know, Lloyd, is there anything you'd like to add on to that?

No, I think that's very clear. I mean we have full alignment at month 15, and we've had several discussions with both regulatory bodies about the importance of putting out at month 24 if we want to include efficacy data from that time point.

Our next question comes from Derek Archila at Wells Fargo.

Congrats on the progress here. So I guess maybe the first one is just, kind of bring us back like what kind of really drove the decision for the 24-month endpoint? Obviously, it's something that you can do. I guess the main thing that I feel like people are going to be asking us is, what did you see in the blinded data? Is there worry around the 15-month endpoint? So maybe give us a sense of like the decision process but also your confidence in that 15-month endpoint.

Yes. Derek, really good question. I'll start, and then invite the others to join in. So first and foremost, super confident in month 15. We are -- it is our base case, and maybe just a little bit of history on how we got here today. We passed the 12-month point for all patients receiving their dose. So we have a really strong handle at this particular point in time on how the study is faring. We're very confident in our targets for masked event rates, as we've said, it's continued to track over the last several months, and it continues to do so today. So we're very pleased by that. To be completely candid, we fielded questions from various investors and strategics on the idea of adding a month 24 endpoint. It absolutely creates a stronger overall profile for vonaprument in this disease. And in effect, builds a moat around this franchise in a way that it will be very difficult with the win for others to come in and use service in a reasonable period of time. And so the notion that being able to run a really effective study that gave us additional power, and sure, Lloyd or Jamie will talk more about that, applying that to month 24 just became increasingly attractive. But really, it was not until we crossed the 12-month hurdle on this study, which is, in effect, the ARCHER I study that we began to really consider, whether or not it can be opportunistic, if you will and playing a bit of offense here. So Lloyd, maybe I'll turn it over to you if you have anything to that.

Yes. Derek, thanks for the question. I mean I think I'm going to borrow from Doug. Doug likes to use sports analogies, and this is how it's made a lot of sense to me. We effectively went to the locker room at halftime as we were assessing the month 12 progress of the trial. And we came to 3 important conclusions about the study. The first was that we went to month 15, which gave us additional powering over our initial 12-month calculations. The second was that we overenrolled the study by 30 patients. If you remember, we had such brisk enrollment at the end that we ended up overenrolling by 30 patients. So we had additional power there to spend. And then finally, we've had really, really encouraging patient retention in the study over single-digit percentages of dropouts, which is significantly lower than we anticipated. So sort of at this halftime evaluation of the study, we found ourselves with increased power. And so we made the strategic decision to apply that power to a second time point. So we have not weakened the study at month 15 by any way. We're still extremely confident for where we stand at the month 15 time point. But we've given ourselves the flexibility through execution to look at a second time point.

Our next question comes from Andrew Tsai, Jefferies.

Congrats on the updates. This is [ Matt Barges ] dialing in for Andrew Tsai. We wanted to know what the -- would you expect lesion growth to hit stat sig to by month 24? Is it secondary?

Yes. I mean we've talked about this before. I have 2 thoughts on it, and maybe not -- 1 is maybe not the most popular. On some level, we [indiscernible]. On another level, we don't as it relates to vision, and that's not because we don't think it's important to protect our RPE cells. It is. They provide trophic support under their neurons that are responsible for vision. But it's not important to protect lesion growth for the purposes of protecting vision. And that's been borne out not only by our data, but clearly, the first generation approved therapies, we have 4, 5 years' worth of the data of protecting lesion growth, but no impact on vision. It's a bit of a curious circumstance for in this particular therapeutic area that we continue to get that question because it's just not the biology for what we're seeking in this disease, right? And I think that's very well elucidated. That being said, we were encouraged that by protecting photoreceptor cells over time, we're showing a healthier overall neuronal unit, which is showing greater protection to the lesion over time. And so when you look in the second 6 months of the study, we have a 10% protection over just a 6-month period of time in RPE growth in the second 6 months of the ARCHER study. So we expect that will continue, whether that will be at 15 months, 24 months, a little bit TBD, but we do expect we will get there in time. So Lloyd, I don't know what you want to add on to that.

Yes. No, I totally agree with that discussion. We recognize that RPE lesion growth is still important for us to discuss. We recognize that, that's where the community is today. The committee will not be there tomorrow. The community is going to be more interested in protecting photoreceptors and neuronal cells as measured by ellipsoid zone. We do anticipate seeing protection of RPE lesion at the later time points based on our Phase II data, and we recognize that we continue to have to discuss this from a historical perspective. But I would encourage you to continue to pay close attention to ellipsoid zone as a primary biomarker for this neurodegenerative disease.

Our next question comes from Salveen Richter of Goldman Sachs.

What would be the commercial outlook if there -- when you think about what you plan to see for separation at month 15, but more of a static outlook at 24 months? And how would a delayed time to response be perceived despite vision preservation here?

Thanks for your question. I guess, maybe a couple of things. We expect to be positive at month 15. So month 15 is not kind of just kind of a speed bump, look, but we expect they get month 24. We are -- the base case is still winning at month 15. And I guess what I would say, would invite others to weigh in on this, whether that positive outcome occurs at month 15 or month 24, the word delay certainly cannot be associated with it. No drug has ever done it. The approved drugs out 4, 5 years' worth of data, and they haven't done it. So doing it more than half the time quicker than anybody has ever done it would be certainly not a delay. But I don't know, Lloyd, if there's anything you'd like to add on this.