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

Greetings. Welcome to Annexon's GBS Program Update. [Operator Instructions] Please note, this conference is being recorded. At this time, I'll now turn the conference over to Jen Lew, CFO of Annexon. Jen, you may now begin.

Thank you. Good morning, and welcome to Annexon's GBS Program Update Conference Call and Webcast. Earlier this morning, Annexon issued a press release reporting top line Phase III results for the ANX005 in Guillain-Barr Syndrome or GBS. A copy of this press release is available on the company's website and through our SEC filings. Joining me on the call today are Douglas Love, President and CEO of Annexon, who will start with a brief overview of the program, followed by Dr. Jamie Dananberg, our EVP and Chief Medical Officer, who will discuss the GBS clinical program and new pivotal data. Dr. Ted Yednock, Annexon's EVP and Chief Innovation Officer, will then review the pathogenesis of GBS disease and mechanism of action for ANX005. Finally, Doug will talk about next steps and the commercial opportunity for ANX005 before we open the call up for questions, where we will be joined by Dr. Hugh Willison, Professor Emeritus of Neurology at the University of Glasgow in Scotland, a recognized expert in autoimmune neuropathy; and Dr. David Cornblath, Professor Emeritus of Neurology at Johns Hopkins University School of Medicine and a recognized expert in inflammatory neuropathy. Please note that 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 product candidate, ANX005. These forward-looking statements are based on our current expectations and assumptions, which are subject to risks and uncertainties. These statements reflect our views as of today and should not be relied upon as representative about views of any subsequent dates, and we undertake no obligation to revise or publicly release the results of any revision to these forward-looking statements in light of new information or future events. These statements are subject to a variety of risks and uncertainties that could cause actual results to differ materially from expectations. For further discussion on the material risks and other important factors that could affect our financial results, please refer to our filings with the SEC including our most recent annual report on Form 10-K and quarterly report on Form 10-Q. With that, I'll now turn the call over to Doug. Please go ahead.

Thank you, Jen. And thank you all for joining us on the call this morning. We're very excited to be reporting the positive outcomes from the first placebo-controlled pivotal trial in GBS in decades. Our third trial in this disease, our aim has remained steadfast to help scores of GBS patients, separate from this indiscriminate and devastating disease, get better sooner. At Annexon, we are pioneering a novel and intentional approach to tackling an array of classical complement-mediated diseases. Founded 10 years ago on the bold thesis that stopping the immune system's classical complement pathway where it starts could result in unique functional benefit. We are developing first-in-class therapies with game-changing potential for patients living with serious neuroinflammatory diseases. Our foundational research and deep knowledge of the classical complement pathway has enabled us to translate important learnings into the development of multiple drug candidates and formulations tailored for complement-mediated diseases of the body, brain and eye. We now have a late-stage clinical platform built on a well-supported mechanism of action that has consistently and robustly demonstrated functional benefits across multiple diseases, and we are poised for a transformative year and beyond with several significant near-term value-creating catalysts. Today represents a step on the journey, and today, it represents an important step on the journey for the GBS community and for Annexon. As we report positive top line Phase III pivotal data for lead candidate ANX005. Often striking without warning, GBS is a rapid and acute neurological emergency with a narrow therapeutic window that hospitalizes over 22,000 people annually in the United States and Europe. Globally, it is the most common cause of acute neuromuscular paralysis and robs too many patients of their independence and ability to live their best lives. And so we are encouraged that our approach and outcomes from the Phase III trial potentially offer a new possible to meaningfully impact the devastating disease for patients globally. With the potential to be the first FDA-approved treatment for GBS, ANX005 demonstrated consistent improvement in functional benefits in the Phase III trial on key primary, secondary and prespecified endpoints important to patients and the health care community. After over 30 years of nonspecific immunotherapy, ANX005 has achieved a breakthrough as a potential targeted and transformative treatment for GBS. ANX005's treatment effect is evident by its demonstration of a 2.4-fold higher likelihood of being in a better state of health based on the FDA-accepted primary endpoint, GBS disability scale at week 8, and the data was highly statistically significant. The findings were supported by consistent and significant results from multiple prespecified analyses, including ANX005 treated patients gaining muscle strength earlier being able to walk earlier and having less nerve damage over patients receiving fleet placebo. Durable treatment effects were also observed across the full course of the 26-week study, and improvements over placebo were maintained at all time points across multiple measures, including enabling patients to spend less time on ventilation and having less overall disability. As in our Phase Ib study, ANX005 was generally well tolerated with no new safety signals, no increased rate of infection and no difference in all-cause mortality. Annexon is the first and leading company to target upstream classical complement pathway inflammation. The GBS Phase III outcome represents an important scientific breakthrough, reinforcing our filing thesis that C1q inhibition is a powerful mechanism to stop the start of neuroinflammation and further underscores the potential of our platform to treat a host of complement-mediated diseases of the body, brain and eye. Today, our team will review key efficacy and safety data in more depth and discuss the next steps of our program. We will present the Phase III data at the upcoming Peripheral Nerve Society Meeting later this month. And finally, we anticipate real-world evidence comparability data in the first half of 2025 in support of a BLA submission. With that, I will now turn the call over to Dr. Jamie Dananberg, EVP and Chief Medical Officer at Annexon, who will discuss the pivotal top line efficacy and safety findings of ANX005 for the treatment of GBS. Jamie, over to you.

Thank you, Doug, and good morning, everyone. This is an important day for Annexon, but more importantly, an exciting day for patients with GBS. I'll start with a brief overview of GBS, which as Doug mentioned, is considered an acute neurologic emergency with long-term sequelae that requires an immediately effective and targeted intervention. It's the most common cause of acute paralytic inflammatory disease of the peripheral nervous system and typically follows an infection in otherwise healthy individuals. This infection leads to the generation of complement activating autoantibodies that directly attack nerves, leading to their damage and acute paralysis. Importantly, GBS can happen to anyone at any time. The unmet medical need is high, with 7,000 patients in the United States and 15,000 patients in Europe diagnosed and hospitalized each year. Currently, there are no treatments that specifically and rapidly target complement-mediated nerve damage. The current standard of care for GBS is plasma exchange and more often, intravenous immunoglobulin or IVIg, but the latter is not approved by the FDA for use in this disease. IVIg requires 5 days of treatment that has an ill-defined mechanism of action. GBS can lead to significant morbidity and mortality. Notwithstanding IVIg treatment, GBS results in severe weakness in paralysis that can require long stays in the ICU or even on a ventilator and weeks or months to regain the ability to get on a better walk. Ultimately, the early nerve damage caused by GBS can result in poorly reversible or irreversible loss of function with incomplete recovery that prevents patients from returning to a normal life. There have been no advancements in the treatment in GBS in over 40 years and new targeted immunotherapies with rapid intervention are needed. Let's begin with the trial design, which was consistent with previous trials in GBS and developed with input from global GBS experts, which led to a well-designed and executed pivotal Phase III trial. This randomized, double-blind, placebo-controlled multicenter Phase III clinical trial evaluated the efficacy, safety, pharmacokinetics and pharmacodynamics of ANX005 at 2 doses compared to placebo in patients with moderate to severe GBS. It is important to note that this is the first stand-alone placebo-controlled trial in decades. These patients received Western level best supportive care and were not otherwise treated with either plasma exchange or IVIg. The study was designed to determine the effective dose based on data from our early Phase Ib study, showing the improvement in muscle strength and function at week 8, with doses providing between 1 to 3 weeks of full complement inhibition. In this study, we evaluated 2 doses that provided either 1 or 2 to 3 weeks of complement inhibition to identify the effective therapeutic treatment window. Eligibility criteria included patients diagnosed less than 10 days from onset of weakness and who had a baseline GBS disability score of 3, 4 or 5, representing patients who could walk assisted, were bedridden or on ventilation, respectively. Patients were stratified based on known prognostic factors of muscle strength and time from onset of weakness. Patients were treated with a single infusion of ANX005 at 1 of 2 dose levels for placebo, each given over a period of less than 24 hours and followed for 6 months post treatment. The primary endpoint used was the GBS disability scale at week 8, which is a well-accepted clinical and regulatory measure assessing functional status. Key secondary endpoints included assessment of muscle strength by MRC sum score, motor disability, as measured by the Overall Neuropathy Limitation Scale, or ONLS, and time requiring mechanical ventilation. The study was conducted in Bangladesh and the Philippines due to the high prevalence of GBS patients of all types, their internationally recognized scientific leadership in GBS and the limited availability of IVIg in these areas, thereby enabling the conductible placebo-controlled trial. There were 241 patients enrolled and randomized in the study with representation across the spectrum of GBS patients. The baseline characteristics of patients were well balanced across treatment groups, and patients were stratified by key prognostic factors, including MRC sum score and time since onset of weakness. Both the AIDP and AMAN neurotypes were well balanced as well. Of note, the overall time to treatment was rapid once the patients were randomized into the study. On Slide 8, ANX is designed to target multiple key aspects of disease mechanism of GBS, allowing patients to get better sooner. ANX is intended to deliver rapid and complete complement inhibition during an active disease progression to stop acute and ongoing complement-mediated nerve damage while then allowing complement activity to return for its normal role in nerve repair. The therapeutic goals of ANX005 in GBS include rapidly blocking complement activity through C1q, which is expected to lead to an immediate reduction in nerve damage as assessed by the biomarker, NfL, Neurofilament Light, leading to improved health status of the patient by multiple measures, including the GBS disability scale, the program point of the study, and early improvement in muscle strength as assessed by MRC sum score and a reduction in time on ventilator. GBS-DS is an FDA-accepted and clinically used measure and before the study, we gained FDA alignment on the statistical analyses used. Before sharing the data, it is important to understand the method used to analyze the GBS disability score at week 8 as the primary endpoint. To help enhance clinical interpretability, we collapsed the 7-point scale to a 3-point scale. The first category, including GBS-DS 0 and 1 represents a good state of health. The second category, including GBS DS 2 and 3 represents the disabled state. In the third category, including GBS-DS 4 through 6 represents a severely disabled state or deceased. The rationale for this approach was to focus on the subject's actual health status at week 8 after receiving ANX005 or placebo and across all health states so that the impact of the treatment can be assessed across a full range of the scale compared to a dichotomy responder analysis that would only evaluate a shift at a single location on the scale. This offers the most efficient statistical analysis approach. For context, the eligibility criteria for the Phase III study population was a GBS-DS score of between 3 and 5 at baseline. The study met its primary endpoint. ANX005 achieved a highly significant and clinically meaningful treatment effect on GBS-DS at week 8. Patients who received ANX005, 30 milligrams per kilogram or 2.4-fold more likely of being in a better state of health compared to placebo which, as Doug mentioned earlier, is a resounding and much-needed win for patients with GBS. There is a higher proportion of patients treated with ANX that are in a good state of health, which can be observed by the green portion of the upper bar. This represents many more patients who were fully recovered or able to run by week 8. Further, there were fewer patients that were bedridden or requiring mechanical ventilation when treated with ANX005, as shown in the red portion of the upper bar. In a prespecified analysis of GBS-DS at week 8, 28% of patients treated with ANX005 at the 30-milligram per kilogram dose demonstrated -- I'm sorry, demonstrated a significant and clinically meaningful 3-point or higher improvement in GBS-DS versus 13.6% of patients with placebo. This is an important prespecified assessment corroborating the GBS-DS score. This 3-point improvement represents a substantial improvement on the outcome score. As an example, it would represent a patient who required ventilation at the outset and was able to walk independently by week 8. Patients who achieve this level of function are often able to be discharged from the hospital and return to many aspects of their life. These findings are consistent with the results from our Phase Ib study. Now let's turn to the MRC score, which is an important prognostic factor in GBS, and as such, was a key secondary endpoint of the study. The MRC sum score uses a quantitative scale to measure muscle strength across 12 muscle groups in both arms and legs with a maximum of 60 points. ANX005, 30 milligrams per kilogram dose, showed an early and meaningful 10-point improvement, a month faster than placebo. This early improvement in muscle strength suggests an early treatment effect and is associated with a faster recovery. This early improvement is particularly important, given that the gain of muscle strength of this magnitude occurred a month earlier in ANX treated patients than those on placebo. Moreover, the time advantage at every point of MRC gain continued to grow throughout the study between ANX005 treatment and placebo. At the 75-milligram per kilogram dose, ANX005 was not statistically significant at the prespecified primary endpoint. It did demonstrate an early effect on muscle strength, performing similarly to 30 milligrams per kilogram up to the first 4 weeks, as seen on the right. These data suggest that for most patients, the prolonged inhibition of C1q with the 75-milligram per kilogram dose is beyond the therapeutic window and limit C1q mediated tissue repair. Ted will discuss this in more detail in a few moments when he discusses GBS pathophysiology and ANX mechanism of action. Another key endpoint, OLNS -- OLNS is another key secondary endpoint. Using a 12-point scale down is better in this case, OLNS measures the ability to perform daily tasks. Similar to MRC, we are seeing an early and significant nearly 20% improvement in OLNS, which is occurring 20 days earlier with ANX005 compared to placebo. This improvement was sustained and even increased further throughout the study. Importantly, these early improvements translate to major functional improvements in the arms and legs, which are extremely important to patients, their families and the health care system and further support how ANX005 is helping patients get better sooner. ANX005 accelerated the time to recovery across clinically important measures that have been used for decades with the 30-milligram per kilogram treated patients walking 31 days earlier and being off ventilation 28 days earlier. Importantly, what this means is that patients may require less intense resource utilization and be discharged from the hospital sooner, can be more independent, can return to work and ultimately, get their lives back. Importantly, beyond just 8 weeks, when a number of important measures were analyzed across all study points through 26 weeks, patients treated with ANX005, 30 milligram per kilogram had better outcomes relative to placebo and were more likely to be in a better state of health, have more muscle strength and be able to perform daily tasks. These GBS Phase III results are highly relevant to Western populations. In fact, we are seeing a stronger effect with ANX005 30 milligram per kilogram 30 milligram per kilogram in patients with western characteristics, which include lesser severity at baseline in the AIDP neurotype. Among U.S. and European patients, 80% have mild to moderate disease with a baseline MRC score greater than 20 points. In the Phase III study, about 47% of patients had an MRC score above 20 and were 3x more likely to be in a better state of health compared to placebo. Similarly, 60% of patients in the U.S. and Europe have the AIDP neurotype of GBS among the 21% of patients in the Phase III study with the AIDP neurotype, those treated with ANX005 30 milligrams per kilogram were more than 5x more likely of being in a better state of health at week 8. Turning to safety. ANX005 was generally well-tolerated with no unexpected safety signals. Most adverse events were mild grade 1 to moderate grade 2 events. The most common related adverse events were infusion-related reactions, with the majority being mild, transient rashes. There were no autoimmune-related adverse events reported and infection rates were comparable across those groups and consistent with typical hospital-acquired infections. Three patients discontinued the treatment one in each group. There were no differences observed in incidence of all-cause mortality with 3 deaths in each group, which were around 3.7% of all patients. Deaths occurred in older and more severe subjects. With that overview, Ted, our EVP and Chief Innovation Officer, will now further discuss GBS Pathophysiology and the targeted mechanism of action of ANX005. Ted, to you.

Thank you, Jamie, and good morning, everyone. After hearing the data, let's take a closer look at GBS and its acute course of progressing. GBS is an autoantibody mediated disease usually triggered by an infection from which the patient recovers, but antibodies generated by the infection in cross-reactive components of peripheral nerves. As auto antibody levels rise over subsequent weeks, they're binding to peripheral nerves, triggers the activation of the classical complement pathway, causing rapid nerve damage and paralysis. These initial days and weeks highlighted by the blue column represent the active phase of disease in which autoantibody levels reach their peak. Fortunately, the levels decline naturally, but then the acute active phase of disease transitions into a prolonged and variable phase of nerve recovery. [indiscernible] phase of disease transitions into a prolonged and variable phase. As shown on Slide 21, the classical complement pathway is also known to play a role during the recovery phase, facilitating nerve repair by helping to clear the extensive level of tissue debris caused by acute injury. In designing the Phase III trial, we examined 2 doses of ANX005 differing in their duration of complement inhibition. The idea was to identify the most effective treatment window, blocking aberrant function of C1q during the active phase of disease in the presence of nerve reactive autoantibodies while allowing normal C1q function to return for debris clearance and nerve repair. The doses were chosen based on results from our Phase Ib study where we examine multiple dosing levels. As shown on Slide 22, both doses provided the expected PK/PD results. On the left, ANX005 30 mg per kg provided measurable drug levels for about 1 week within the inhibition of serum C1q during this time. C1q activity then returned to normal levels. The 75 mg per kg dose on the right provided drug levels of C1q inhibition for about 2 weeks. What we now know based on the strong efficacy results that Jamie shared is the short duration of C1q inhibition with ANX005 30 mg per kg during the active phase of disease defines the most effective treatment window. Slide 23 shows that ANX005 targets C1q, the initiating molecule of the classical complement cascade by blocking C1q interaction with auto antibodies on the nerve surface turn disease, ANX005 shuts down the entire classical pathway before it starts, cutting off classical cascade amplification and expanding -- and the expanding tissue damage. This approach is differentiated from downstream complement inhibitors because it shuts off all inflammatory mediators downstream complement components while avoiding potential bypass or breakthrough mechanisms. ANX005 with its rapid on and off mechanism as ideally suited to address the narrow treatment window associated with the acute nature of GBS, while administered in a single 30-milligram per kilogram dose. I will now turn the call back over to Doug, our CEO, to discuss next steps for our GBS program.

Thank you, Ted. As you heard today, this is a pivotal time for our GBS program, and we have several upcoming important value-creating catalysts related thereto. The Phase III study was conducted in Bangladesh and the Philippines, due to high prevalence of GBS and limited access to standard of care, IVIg. Following our Phase Ib findings and based on FDA feedback, Annexon has pursued a single pivotal study to demonstrate substantial evidence and comparability between the Phase III patient population of Western patients for BLA submission. To support the comparability and relevance of our Phase III findings to the Western population, we have initiated a real-world evidence comparability protocol with the international Guillain-Barr Syndrome outcome study, or IGOS, which is a global prospective observational multi-center cohort study that has enrolled 2,000 patients who were [ followed ] for 1 to 3 years. Preparations for a matched cohort for comparison with IVIg are underway and importantly, approximately 50% of all Western IGOS patients met the entry criteria for our GBS Phase III study. We are very much on track to report real-world evidence data and submit our planned BLA in the first half of 2025. We, at Annexon, are very excited about the opportunity to potentially bring a new medicine to patients who've been waiting decades for something new and who deserve more than what they have today. ANX005 has the potential to be our first commercial launch as a company, which is a transformational event we have been working towards since our inception. We view a GBS launch as a significant commercial opportunity with around 22,000 patients hospitalized with GBS every year in the U.S. and Europe. Despite available treatments, there is a significant unmet need for people stricken with GBS. Currently, 90% of patients with GBS in the U.S. receive off-label IVIg, a nonspecific treatment approach requiring daily infusions over 5 days, a time period that consumes a significant portion of the active GBS disease window. Additionally, GBS results in greater than $2 billion a year in annual acute and long-term cost burden on patients, caregivers, hospitals and payers. At Annexon, we are targeting ANX005 as a first-line monotherapy treatment for GBS. As shown today, ANX005 help patients with GBS get better sooner. As a single infusion, ANX005 dosing is ideal for a neurological emergency like GBS. It allow patients to get off a ventilator earlier and help them walk earlier, both of which are important drivers of long-term outcomes for patients and provide opportunities to reduce the cost of burden of the disease. We intend to demonstrate this reduced cost of care through a robust health economics and outcomes research plan. Since most patients are treated in major metro areas and large community hospitals, we can bring ANX005 to market through a focused and targeted commercial launch, if approved, and will supply our launch through a commercial manufacturing partnership with Lonza, a gold standard CMO. Finally and importantly, our positive data in GBS is a beachhead for further investment into mechanistically related neurodegenerative and autoimmune indications, of which we are actively working on. To close, the Phase III data represent a profile moment for the GBS community by opening a new therapeutic area beyond the use of nonspecific approaches with potential for ANX005 to be the first targeted therapy and first FDA-approved treatment for GBS. We are confident the results from our Phase III trial demonstrate the potential for ANX005 with this novel and unique mechanism of action to potentially change the treatment standard in GBS. And more importantly, help the tens of thousands of patients stricken with GBS around the world every year with their best lives. Our Phase III trial met the primary endpoint, as you heard, the GBS disability scale at week 8 and patients treated with ANX005 were 2.4x more likely to be in a better state of health compared to placebo. ANX005 also help patients with GBS get better sooner by delivering early, robust and clinically meaningful benefit on multiple outcome measures by week 8, including ability to walk earlier and less nerve damage versus placebo. Durable treatment effects were observed over the course of the 26-week study. And moreover, these improvements were maintained over placebo at all time points across multiple measures, including less time on ventilation and less overall disability. The convenient single infusion of ANX005 is generally safe and well tolerated, had a safety profile similar to placebo and no increased rates of infection. And with our Phase III data in hand, we are creating a clear path to BLA submission and launch. We are prepared to engage the FDA later this year to support a planned BLA submission in the first half of 2025 and initial data from a real-world evidence study is on track for the first half of 2025 to support that BLA submission. And we are preparing a powerful launch strategy with a focused commercial team. All in all, ANX005 is the most advanced candidate from our pipeline and these positive data today further reinforce our platform approach, targeting upstream C1q in the class complement cascade to stop neuroinflammation at the start to effectively treat a host of diseases of the body brain and eye. We will be presenting the Phase III data at the upcoming peripheral nerve society meeting at the end of this month in June, and we hope to see you all there. Thank you. In closing, I want to specifically thank all of the patients, families and caregivers, physicians and medical teams who participated in our trial. We are eternally grateful for your support and contributions. I also want to thank our employees, collaborators and advisers who listened while you work with a warrior spirit and all-for-one commitment. Finally, we would like to thank the GBS/CIDP Foundation International, IGOS and the countless advisers, including our speakers here today for their continued support and partnership. Thank you, we thank all of you for joining us today. With that, I will now ask the operator to begin the Q&A session, where we will be joined by Dr. David Cornblath, Professor Emeritus at Neurology at John Hopkins University, School of Medicine, a recognized expert in inflammatory neuropathies and Dr. Hugh Willison, Professor Emeritus of Neurology at the University of Glasgow in Scotland, also a recognized expert in autoimmune neuropathy. Operator, over to you.

[Operator Instructions] Thank you and our first question is from the line of Anupam Rama with JPMorgan.

Congratulations on the data. A couple of quick ones for me. Maybe for both KOLs on the line, kind of with these data in hand, how do you think about incorporating ANX005 into your practice with IVIg, potentially available in the U.S. and U.K.? And then, Doug, I wanted to maybe expand on one of the comments you said in passing, which was GBS is just sort of like the initial maybe beachhead indication here for 005. What kind of optionality is there potentially in other acute complement-mediated diseases and for the KOLs, if they could also comment on what other indications for 005 might be interesting.

Thank you, Anupam. Really appreciate you joining and really good questions. I'll start and then turn it over to David and Hugh. So as it relates to your second question on what this data means in the approach with ANX005 into other potential indications, GBS is an acute neuromuscular indication. It is in fact, arguably the most aggressive neuromuscular disease out there. And we like to read through on this outcome into mechanistically related neuromuscular disease, in particular, many of which are chronic like CIDP, often viewed as a cousin to GBS in a chronic form, Myasthenia gravis, MMN. And so there is a suite of indications that we've been doing work on for many years that are related to GBS mechanistically and which we think, based on the data here, give us an opportunity to pursue with great vigor. With that, I'll turn it over to Dave and Hugh to answer 2 questions. One on what this might mean for treatment practices as well as thoughts on other indications in which we may use ANX005. Maybe David, we'll start with you and then we'll go on Hugh.

So I think from the standpoint of where this might fit into the future of [indiscernible] is once it gets approved and goes through all the usual processes, so doctors can order it. There are a number of advantages I see to ANX005, including the single administration during which time the drug takes effect immediately as opposed to IVIg, where you have to get it over 5 days and the effect is sort of slow going. It's going to be easily done. As you saw from the clinical trial data, you can give it essentially the same day that the diagnosis is made and you're done and it provides really robust evidence. The other thing is this will be really the first approved drug in America. And so hopefully, this will a set a standard by which we can use it to compare to other drugs to see if adding to IVIg, there are a whole host of things that will come after it. I think Doug has mentioned the other indications, these are all complement disorders at some level, and they're being pursued by other companies as well. But I think there's plenty of room here in this space, CIDP, MMN and the then and myasthenia are the ones that come very quickly in line.

It's Hugh Willison here. I think David Cornblath has raised the main points. And I would add that 005 has a very good safety profile as well and could well be used in situations in which intravenous immunoglobulin is not appropriate or [indiscernible] change is not appropriate. So apart from being having many general features of benefit to GBS patients is also has potential advantages over other existing treatments.

And I'd also like to just add that we have -- are looking at this drug for other neuro emergency situations such as traumatic brain injury, and we have publications there as well.

Our next question is from the line of Andrew Fein with Jefferies.

Congratulations. So 2 questions. The first one is you guys have long said either dose arm in the study is needed to hit stat sig at week 8. I just wanted to reconfirm this was agreed by the regulators, including the FDA in support of the filing. And then notice the secondary endpoints have nominal P values. Why are they nominal? And was there a testing hierarchy. And then maybe for the doctors, to the best of your knowledge, what would IVIg monotherapy show on GBS as well as some of the secondary outcomes out to week 26. Are you guys in a position to say whether 005 is more comparable or even better than IVIg at this juncture? Or do you feel like you're not in a position to make that assertion yet?

Thank you, Andrew. Good questions, and I appreciate you joining. Maybe we'll take these on turn, and I'll start and kick them around to others. So as it relates to 2 doses in the study, you're absolutely correct. We've taken 2 doses into the study with alignment with the FDA. The study was powered to win on either dose. So separately powered with alpha attributed to either -- to both doses. So we only need to win on one of the doses to be forward for a submission towards the BLA. So we're really pleased with regard to that. I think I lost track of your second question, apologies. The question in regard it was around nominal. I get it. It was the question around nominal, yes. So we did have a hierarchy with regard to endpoints in the Fab and missed on one of the endpoints in that hierarchy or did not achieve statistical significance. And so all of the end points thereafter were nominal as we noted. And then the third question is with regard to IVIg, I'll turn it over to the doctors for much more depth to be on this. The one thing I will say, though, is that there's far less information out there in IVIg candidly, when you look at the studies, they go back many decades. And we have not seen an IVIg data set that provides a comprehensive review of all of the assessments that we have in our Phase III study. Some of them are assessed, but in different ways like the GBS disability scale, which is often good looked at with a responder analysis but not a proportional odds analysis. And we've not seen robust data, whether it be on NFL or some of the other endpoints that we have in our study. But maybe I'll turn it over to you -- Hugh and David to respond to that question.

Yes. It's Hugh Willison here in Scotland. Thank you very much for that important question. Of course, the -- I do think it's too early to definitively say whether or not this is more 005 is more efficacious than current existing therapy. However, just looking eyeballing for data without any formal statistical assessment. It does look to be at least as equivalent to existing therapies and possibly better -- and I think there are a number of very, very specific advantages of having a targeted immunotherapy in the therapeutic armamentarium rather than using nonspecific immunotherapies like plasma exchange and intravenous immunoglobulin. So this is a real extraordinary advance in our conceptualization of the therapeutic approach to GBS. And I'm pretty certain it would be well taken up by the medical community when it becomes assuming it becomes licensed and approved.

Got it.

David, any thoughts on your end sorry.

Yes, I think the difficulty is that there is no placebo-controlled trial of IVIg in GBS as the study done in 1990 was against the then standard of care plasma exchange. So I think the real-world evidence study in which we can look at data that's more current than 30 years ago or 25 years ago, will give us the answer to your question specifically. But some of these endpoints are extraordinary. If you look at the time on a ventilator, was cut from 48 days to 20 days. I mean that's an extraordinary the important view. And the other thing that you mentioned that I failed was in people who are going to be older, where this is a much more common disorder in America, as you see from the age distribution in the 005 study, where it's mostly younger people in the West. It's mostly a disorder of the older people, there's going to be a reluctance to use IVIg when there's an alternative that doesn't have the potential IVIg side effects.

Yes, the next question is from the line of Phil Nadeau with TD Cowen.

Congratulations on the data. A few questions for us. First, a follow-up on the statistics. Doug, you mentioned that there was an end point that was missed, and that's where the secondaries are nominal. Was that endpoint the higher dose primary? Or was there a separate secondary end point in the hierarchy that was missed that made the subsequent secondaries nominal?

Yes, it was a secondary endpoint. So it was -- and maybe, Jamie, I should turn it over to you. You can answer this better.

Yes. Thanks, Doug. It was the ONLS at week 8 that because of -- as Doug mentioned, we split the alpha to get both doses as the part of the primary. It's a pretty conservative threshold that had to be met and it was only a week date. So it missed that one. And so everything else is novel beyond that.

That is very helpful. And then Second, in the presentation, you mentioned that there's early estimates for -- or the reduced cost of care will be a case that you make. Given the relatively dramatic benefits on some of the secondary endpoints, like time on ventilation, do you have any early preliminary estimate of what reduced cost of care is likely to be on when patients use 005?

We did. We're in the process of doing that now. I mean, our early read is it's hundreds of thousands of dollars like because the costs associated with the disease is not drug cost. It is the cost of care. And so you think about date in the ICU, days on ventilation, days in the hospital, time for miss work, et cetera. So it is a really significant number. As I think we said earlier, they cross more than $2 billion a year in the U.S. alone to treat roughly 7,000 patients. And so that is really due to the disability associated with the prolonged disability associated with the disease. And so we -- just based on this data, it looks like that when we very much are going to improve upon that. But we'll wait until we complete the health economics work before we start coming out with specific numbers.

Great. And then last question.

Sorry. This is David Cornblath. Let me just bring up decades ago when we did the plasma exchange study. The same thing was the same question was asked and I'll just give you the sort of answer that we gave then. That is, if you assume that roughly 1/4 to 1/3 of the people who enter a hospital with GBS were going to be on a ventilator. And then the number of days on a ventilator is cut roughly in half or more. You can then multiply that number by today, it's probably $10,000 a day to be in an ICU. You can get a rough estimate of the number of dollars you can save in health care. And that's just on ICU care, not counting the days earlier to walk, which gets you to out of the rehab hospital and home independently without home OT [indiscernible].

That is very helpful. And then last question, just a follow-up question for the physicians. And it goes into where 005 could be used in the standard of care? Would you imagine 005 will be used as a monotherapy when it's initially available? And if so, first line or just in those patients who can't go on IVIg or plasma exchange for some reason? Or do you imagine it would initially be used as combo therapy, just added on top of standard of care in those patients who are particularly severely affected?

Yes. It's Hugh Willison here from Scotland. I think that's a very, very interesting question. And I think what this study has really shown us and brought to the -- into the headlights is that GBS is a medical emergency and needs to be very, very promptly treated as early as possible in the course of the disease with the fastest acting treatment. And one of the fantastic things about this current study is that, that early treatment was achieved. So I see this as being instituted as a monotherapy at first point of diagnosis in new patients presenting to hospitals, probably through their actions and emergency rooms very, very quickly after diagnosis or suspected diagnosis. after diagnosis or suspected diagnosis. It can be given extremely quickly by a single infusion and has immediate full inhibition of the classical confluent pathway. And the current therapies of plasma exchange, which, of course, is quite complex to deliver an intravenous immunoglobulin take days to weeks to fully complete those treatments, which is far too long. So it's this acute early possibility of treatment with 005, which I think is such a useful possession to current [indiscernible]

Yes, this is David Cornblath. The only thing I would add is that I think it's going to be unlikely, frankly because of insurers, to try and give both of these at the same time. I just don't think in the current state of American medicine, that they'll pay for them both. And so physicians will be forced to choose one or the other. And for the reasons you and I have already mentioned, we think that's going to start to move fairly quickly toward ANX005.

Our next question is from the line of Tazeen Ahmad with Bank of America.

Doug, congrats on the data. I just wanted to get some color on what is going to be looked for on this RWE comparability study. Now based on the data that you've got in hand as of this morning, can you point to specific items that FDA might have been specifically looking for, and would there also have been certain thresholds that you would have agreed to FDA to look for? And then secondly, to just elaborate with the physicians about their view of the market opportunity, how do you think pricing will matter for this product versus what the average cost for IVIg is right now in order to help make the launch of the drug deep in the initial launch.

Yes. Great questions, Tazeen, and thanks for calling in. And I'll start on RWE and I'll kick it over to you, Jamie. So FDA discussion is around demonstrating comparability for the patients in our study with Western World patients, given that our trial was run completely outside of the U.S. we need to demonstrate that GBS is the same all over the world, whether you're in Southeast Asia or you're in the U.S. that match patients to progress similarly. And so that's what we will be doing. We're encouraged by the data we see in this study, particularly when you look at our baseline demographics, characteristics of the patients in our study and knowing that a large portion of those patients in the, I got data set, match those characteristics from which to do this comparability analysis. But Jamie I will turn it over to you to see if you'd like to anything for that.

Yes. Just a couple of things. Thanks Doug. Thanks Tazeen for the question. So in general, we'll look at just the baseline characteristics of the 2 populations understand. The real question the FDA is asking is whether this product would be the data from this study is translatable to the Western population. And we'll use the IGOS comparison for that. But as we mentioned in the presentation, the data we have from this study already demonstrates quite good potential transferability of the results, given the fact that the patients who are milder which is more common in the Western World and patients with the AIDP-neurotype are more common in the Western World, we had an even better effect in those patients, threefold better and fivefold better in the AIDP patients. So I think we are off to a really good start on that and we will do that work with IGOS, in terms of the direct comparison or the indirect comparison using the IGOS data set and do a direct comparison with IVIg as well. So I think we're in a really good place to conduct that work.

Thank you Jamie. And then your second question related to kind of the market opportunity and pricing, maybe just a bit on pricing. So we are not going to obviously disclose pricing until we get approval, but we certainly have the intent with pricing to match our overall mission as a company, to help millions of patients around the world suffering from complement-mediated diseases with their best lives. We recognize the healthcare system today as it relates to that. And so we're going to price this drug reasonably. I feel very confident in saying that at this stage. But again, the costs associated with Guillain-Barré is not drug cost. It really is the cost of care and missed time from living independently. So again, we'll be reasonable in our pricing. We will recognize the significance of this disease and go after it from there. But I don't know if Jamie or Hugh, if there's anything you guys want to add to Tazeen's question.

It's Hugh here. And I would agree with what's been said. I think it's important to recognize that around the world, there are over 100,000 cases of Guillain-Barré syndrome per year and the time likelihood of any one of us getting it is about 1 in 1,000. And once you have Guillain-Barré Syndrome, you're off work for months, and if you're self-employed and -- or in other critical jobs or financial situations, this can really devastate your life and create huge financial burden. So from a patient point of view, anything which has a rapid and effective inroad into the pathophysiology and leads to early recovery is very, very important indeed irrespective of the massive hospital costs of people on intensive care and in rehabilitation for months. So I think that it will have -- it could have a profound economic effect. And in situations such as the Zika virus epidemic, which occurred not so many years ago which produced thousands of cases of Guillain-Barré Syndrome around the world where hospital intensive care units become completely overwhelmed, which happened in Brazil, for example, an effective early drug like this could be really, really important in that kind of situation.

This is Dave Cornblath. Obviously the drug pricing is very -- still complicated an issue in America and the treating physician has such little impact, except when drugs are terribly overpriced, they have the option not to prescribe them. And this is something, for example, we could talk about it, like that you see in the myasthenia field. If this drug is reasonably priced, it will be used dramatically.

The next question is from the line of Derek Archila with Wells Fargo.

Congrats on the data. Two questions for management and then one for the physicians. So for management, I guess, based on the data, is there any plan to file for breakthrough designation and maybe if you could discuss like what benefit that bring at this stage of the regulatory process? And then a second question is what additional data are you likely to be sharing at the PNS meeting later this month? And then for the physicians, just any commentary on kind of the baseline characteristics as you look at the GBS-DS scores for placebo and the 30 mg per kg arms relative to MRC. I guess, which are more important here?

Derek. So good question. As it relates to breakthrough, we are assessing our regulatory strategy now. We've had the data a very short period of time. Breakthrough, obviously is important for a closer relationship with the regulators and oftentimes, speeds up review times, et cetera. So more to come on that. We certainly are assessing that in light of these data. I think it meets many of those criteria as you think about the impact on important biomarkers like Neurofilament light chain as well as showing a real functional benefit in this study. And then so as it relates to -- I'm sorry, Derek your second question was -- I can't remember.

Just no additional data. PNS.

Yes. I mean we're certainly doing a ton of different sub analysis, et cetera. But maybe, Jamie, I'll turn it over to you to comment on PNS and additional data that we're maybe looking at.

Yes. Thanks Doug. We're still going through the data as you can imagine, we've had it for a very short period of time. Most importantly, we will be sharing some of the data, looking at the trends overtime of the data, the relative impact of 30 milligrams per kilogram, especially on how much more quickly ANX005 achieved key milestones. So there's really some very important data to make sure we educate the world on in terms of how stopping classical complement at the start is extraordinarily relevant to downstream pathophysiology and why this works the way it does. So, we're very excited about the engagements we have planned in PNS, which are extensive. I'll turn it back to you, Doug.

Thanks Jamie. Derek, did you have a third question?

It's Hugh here in Scotland. The third question that you raised was related to the use of these scales. I think what I'd say to you is that the MRC sum score, the GBS disability score, the ONLS, the scales which all tell you slightly different things, and they've been meticulously developed by the GBS research community, clinical research community over decades and are very, very widely accepted. I think what is important in this study is that they are all pointing in the same direction, and that is a substantial improvement and benefit. So it's not as if one has been cherry picked over the other. They're all pointing in a successful direction. And that is an extremely important finding. Unlike some diseases like multiple sclerosis, et cetera, where you can have imaging, MRI imaging or other biomarkers, GBS is very much defined by it's clinical characteristics rather than by any laboratory or imaging findings. And that's why we, in the GBS community, have spent so much time developing these clinical scales because there is no other alternative to that as things currently stand. The neurofilament data which is the one biomarker that has been used in this study is also pointing in the right direction. And I think it's when you collectively add all these elements of that we really see that this drug has had a dramatic effect on the disease.

This is Dave Cornblath. The last comment is, in fact, the slide set that you've seen, most of the people in our community will not have seen because they don't get on these kinds of calls. So my own view would be if they show this slide set alone, given, as you said, all of these markers all going in the same direction, people will be wild.

The next question is from the line of Pete Stavropoulos with Cantor Fitzgerald.

Doug and team, Congrats on the data. Just a couple for me. I know the data is fresh, and you're going to do more analysis. However, is there anything you can speak to in terms of time to treatment and response? Was there a greater response in those that were treated earlier? Or is it just dosing before they [ time to treat ]. Also what was the distribution of patients between Bangladesh and Philippines. And was there -- was the efficacy comparable between the 2 groups?

Pete, both good questions. Jamie I am going to turn that over to you. Time to treat and the distribution.

Yes. Yes. So I will just mention the distribution first and that's simple one. 80% of the patients from Bangladesh and abour 20% from the Philippines. In terms of time to treat, if you remember the slide on the baseline demographics, we actually were able to treat patients very quickly. So pretty much everyone got treated rapidly from the time point that they were diagnosed and then followed up by the time to treatment. So that period of time was very narrow. So there's not a lot of variation to see people who are treated earlier than later. We will be looking at some of those analyses, we do not have them to present at this point but are considering what we can do for that on the P&L side. I think in general what we have shown, what's interesting about the 30 versus the 75 is that the treatment window is very well defined. And I think the design of the study helped us identify that getting in early, having an early treatment effect and then having it come off is essential to the long-term outcomes for the patients which we've established are predominant here, even through -- all the way through 26 weeks, we can see the impact of treatment just in the very first day, the impact of treatment lasts all the way through the end of the study. And so that's a very encouraging finding for us and something that we think will be an important aspect that we highlighted in PNS.

And I don't know if I missed it, apologies if I did. The efficacy between Bangladesh and Philippines, was it comparable?

Oh yeah. Go ahead. I'm sorry. when you adjust -- Yeah there was no impact based on country. So it was consistent between the two. And as Jamie said, just kind of just quickly on the time to treat, really important because, in our mind, it really speaks to the quality, in which the study was run. So these patients were treated and they're meeting with 6 days, they came in on day 6 and they were treated on day 6. So they were immediately randomized and got into the study and dosed. So we really are thankful for the many sites that just did a fantastic job in executing the study.

Okay. And just a quick question for the KOLs on the call. I think you briefly touched on it a couple of minutes ago, but where do you think the community's awareness is currently on 005? And especially as you speak to your colleagues who may not be at academic institutes but community hospitals. And with the background, they understand what complemented inhibition is since they do treat patients with complement inhibitors.

Yes. I would say Pete before the [ therapy going ]. We're on the front end of the curve in terms of educating the community of ANX005 In our approach. So we're just getting started. There are lots of green fields in front of us with regard to that but I will turn it over to the physicians for your responses.

Yes, it's Hugh here. Maybe I'll start first, and then David can follow. I think that the neuro community has well woken up to targeted immunotherapy. If you look at the disease like multiple sclerosis, which, of course, occurs in acute relapses and remissions in addition to having chronic phases, there are a raft of immunotherapies now targeting all kinds of immune molecules, which are very widely used, the same applies to diseases like rheumatoid arthritis and all kinds of different things, cancer therapies, et cetera. So I think it will be a breath of fresh air and it certainly hits to me that finally, we have a targeted immunotherapy available for Guillain-Barré Syndrome other than simply reversing back to Immunoglobulin and plasma exchange are historical favorites. And the complement system is very well understood by most doctors. They may not know the details of all the different molecules in it but it's a very clearly understood pathway. And I think that, I don't anticipate is going to cause any major sort of problems in it being appreciated by the non-specialist communities.

Our final question is from the line of Joseph Stringer with Needham & Company.

Just a follow-up question for the KOLs' -- perhaps maybe asking in a different way -- which of the efficacy endpoints do you think will resonate most with -- or be most important for both the treating physicians and importantly, payers in terms of real-world applicability and potential uptake? And then a question for management. Your expecting to readout of the comparability results in the first half of next year. Is this gating to start the submission? Or could you initiate potentially rolling submission given the data today and the fact that you do have fast track designation for 005?

Joey, maybe we'll start with the regulatory first. So we will, as I said, we're just starting to assess what this data needs in terms of our regulatory strategy and we will be down with the FDA. So we'll update on that at some point this year. We do think that these data emerges for a quick look at, right? So we want this to be as expedited as possible, but we'll work within the confines of partnership with the FDA. So over to the physicians for your first question.

Yes, it's Hugh here. I think that's a very interesting question you've asked about whether one would prioritize any one of the outcome criteria over another. And what I would say is what is so powerful about this is that it is multiple outcomes. It's time on ventilation, time to walk. GBS-DS, ONLs, MRC sum score. And we, as neurologist, we'll put those together in a single wrap and say -- and as I've already said what's remarkable about this study is how they are all consistently moving in the right direction. So I wouldn't pick one out over another. Healthcare economists will obviously be maybe more interested in time on ventilators whereas individual patients may be more concerned about time to get back to their work. So there isn't a favorite outcome. It's the fact that all are pointing in the same direction. And maybe David would like to add to that.

I think that's exactly correct. But if you looked at the one of their slides that was just showed, the time to independent walking, which has been used since the first GBS trials as a primary outcome measure. And then if you look at the time on a ventilator, those 2 graphs alone will persuade people.

At this time I will now hand the call back to Douglas Love for final remarks. Mr. Love, the floor is yours for closing remarks.

Yes. Thank you, everyone. Really appreciate you making time to join us today and for the good questions. We're really quite excited by the outcomes from this study. As you've heard here today, there's not been a meaningful advancement in Guillain-Barré Syndrome in multiple decades and this targeted immunotherapy approach has the potential to really transform this landscape. And so we're working feverishly to do all that we can to get this drug to patients and improve their quality of lives. And we look forward to continue to update on this program as the year progresses. We thank you all. I wish you all a very good day.

This will conclude today's conference. You may disconnect your lines at this time. Thank you for your participation.