Started. My name is Andrew Tsai, Senior Biotech Analyst at Jefferies. Thanks for coming to our day one of the June Healthcare Conference. It's my pleasure to have, to my right, Doug Love, CEO of Annexon. Welcome, Doug.
Thank you.
Maybe to start, give us an introduction about Annexon briefly. I do have a lot of questions for you, but what are you trying to achieve? Just walk us briefly through your milestones over the next six to 12 months.
Yeah, absolutely. Firstly, thanks, Andrew, and thanks, Jefferies. We're happy to be here. Again, always enjoy this conference. It's an exciting time for Annexon. For those who are not familiar with us, we're focused on complement, and specifically classical complement C1q, which is the initiator of the classical pathway. Why that is relevant is that it is the key target in the complement system that binds disease tissue, activates this inflammatory process, and drives disease in a host of different neurodegenerative diseases in the brain and in the eye, as well as autoimmune conditions in the body. After 10 years of advancing the company, we're at an exciting stage where we have a late-stage program in Guillain-Barré syndrome on the basis of a pivotal phase III study. We will be shortly speaking to regulators about our BLA filing upcoming later this year.
We also have a very large program, phase III program in geographic atrophy. It is a 630-patient study. Just for background, this is the only program that has shown preservation of the loss of vision on multiple endpoints in geographic atrophy. We are excited with regard to this phase III program and the potential to treat 8 million patients worldwide. Finally, our small molecule program, first and only in the classical pathway. Really excited about this program as it continues to matriculate through a proof of concept study. Our aim there is to complete this program this summer and then provide data and advance this into a host of different neuromuscular diseases.
Great. I would like to talk and start off with GBS and then the oral program, given there are some catalysts this year. If we have time, we'll talk about the GA program. Going back to GBS, taking just a big picture view, remind us the drugs that are approved, if there are any, in the U.S. and the EU, and frame the market opportunity in both regions.
Yeah, really good question. GBS is a devastating neuromuscular disease. It's an acute disease. It's the number one cause of acute neuromuscular paralysis. It impacts 150,000 people every year worldwide, 7,000 in the U.S., 22,000 in Europe. Unfortunately, there are no approved therapies in the U.S. for this disease. Standard of care is IVIG, which is nonspecific for the disease but has some effect. However, there's never been a randomized controlled study there, so substantial evidence has never been demonstrated in this disease. Our program is the first advancement from an innovation perspective in 40 years in this disease, which we're really encouraged by. The marketplace is really quite robust for the market opportunity. 90% of the patients, 90 %+ of the patients, get treated for Guillain-Barré syndrome because of its really devastating nature.
You have a ready-made market to attack with a really effective therapy. We are well underway in preparing our commercialization activities with regard to that. We look forward to bringing this drug to market and helping patients.
Excellent. Going back to the phase III, what would you say are the key efficacy measures that lead you to believe this is better than off-label IVIG in the U.S.? What are the most important endpoints to the FDA in your view?
Yeah, really good question again. This was a landmark win from a phase III study perspective in that we won on all of the key measurements with regard to Guillain-Barré syndrome. First and foremost, we won on the primary endpoint, the Guillain-Barré disability scale, where we showed patients had roughly a two-and-a-half times better likelihood to get back to a state of normal health or better health at week eight, and then normal health by month six. Winning on that was first and foremost critical, and it was highly statistically significant and certainly clinically relevant. Beyond that, we won on measures that are really important to the marketplace.
What we showed is that by taking ANX005 in a single infusion, or tanruprubart is its now marketed name, by taking that with a single infusion, we were able to get patients back in healthy or back to a better state of muscular strength by week one. We had a very rapid effect on muscle improvement. That translated to a better outcome on multiple measures. From a marketplace perspective, when you talk to patients and physicians, our ability to get patients out of the ICU, off of the ventilator 30 days earlier, getting them back to walking without assistance 30 days earlier, really, really important. All of those measurements were against a placebo-controlled population, so the gold standard, if you will, from a study perspective. However, we also studied the effect of tanruprubart against IVIG in a real-world evidence study.
There, too, we showed a two-and-a-half greater likelihood of getting patients back to a state of health versus IVIG at week four and at week eight, and similarly out to week 26 or six months. We also showed improvements in getting patients off of ventilators, not in the hospital and ICU, and walking roughly 10-14 days sooner than IVIG. Again, on every measure that you look at with regard to this disease, we had a better outcome versus placebo as well as standard of care.
If I remember correctly, in the phase I data set, the EMA even gave you an orphan drug designation. Why did they give you that orphan drug designation? What specific measure? How does the phase III overall compare to the phase I result?
Yeah, really important. One of the things we love about this program is the consistency of the data that we're seeing from study to study. As Andrew alluded to in our phase I proof of concept study, there we showed patients got better more quickly at week eight versus placebo. This was a placebo-controlled study as well, as well as improvement on all of the other measures that I alluded to in the phase III. On the basis of the proof of concept data, we were able to get orphan drug designation with EMA, which is a high bar, candidly, and certainly higher than what we see in the U.S. There you have to demonstrate a likelihood of being significantly better than standard of care.
That's where we did our first real-world evidence assessment based on the proof of concept data where we compared tanruprubart versus IVIG standard of care. EMA did a detailed assessment, wrote a 10-page single-space response to our application granting orphan drug designation. That, of course, allows us to have a great deal more interactions with EMA as we go through the approval process with them, which is going really quite well there.
Okay. Some investors, unfortunately, are just a little bit stuck about how this is just a somewhat unusual pathway pursuing the phase III in Southeast Asia. Can you just give us a yes or no whether you did get buy-in from the FDA as well as other agencies to do a placebo-controlled study? That's number one. Also in the Southeast Asian region.
Yeah, yes is the short answer.
Okay. You also had FDA agreement that you can do an IGOS, like a third-party comparison analysis to support an approval.
That's correct as well.
Also, on top of that, the phase III did have two doses. The low dose did look a little bit stronger than the high dose, but you got blessing that either dose can succeed.
Yes, that's correct as well. Pre-specified. Maybe if I could just talk a little bit about the two doses. People refer to them as high-low. We actually refer to them as short and long duration. Both doses fully suppress complement. It's a question of how long you suppress complement. GBS is a rapid neuromuscular disease, as I alluded to previously. You really want to only suppress complement through the disease phase and then allow it to come back and be part of the repair process. In the proof of concept study, we had multiple doses there. What we observed is that the lower dose or the shorter duration dose actually outperformed the longer duration dose.
As a result, we took both doses into the phase III, pre-specified both, and we took alpha on both doses so that you could win on either one in the phase III study. The phase III study replicated exactly what we saw in the proof of concept study. That is, the shorter duration dose outperformed. It is a window in which you want to be able to block complement activity, as I said, and allow it to come back. We have now defined that window very nicely in two respective studies, and we had approval to be able to do that with regulators.
To ask this just out of full respect, but I just want to pry it just a little bit because the phase III study was produced in June of last year. We're nearly one year from that phase III result. The natural investor question would be, is there something wrong with the filing? What would be your response?
Yeah, I mean, it's the right question, right? Typically, you get phase III data and you're filing within six months. We understand that fully. In this instance, we also had the additional requirement of demonstrating that we could match the patients from our study with patients in the Western world to demonstrate comparability or generalizability. As Andrew alluded to, we ran our studies in Southeast Asia because that's the only jurisdiction where you could run a placebo-controlled study. IVIG, because they had never run randomized blinded studies, was thought not to be an appropriate comparator to ANX005 to establish our efficacy. We had to do a placebo-controlled study. We had to go to jurisdictions where they did not have IVIG.
That being said, given that the study was run exclusively ex U.S., we also have the additional requirement of demonstrating that the patients in that study and the work that we did there is translatable to the U.S. Upon completing the phase III study, we're working with IGOS, the International Guillain-Barré Outcome Study. It's a 2,000-patient prospective registry housed out of Erasmus. Erasmus is actually responsible for doing the analysis on generalizability. That is, the patients in our study are comparable to the patients in the West. To do that, they looked at the patients in the phase III study, compared them with matched patients from the IGOS data set. Again, they own all of this data. This was done in-house there, completely independent of Annexon, although we have, of course, advised or counseled on their analysis. That took them a while to do.
They completed that. We got the first pass of the data at the end of December or in December. They just produced the final analysis of that data at the Peripheral Nerve Society about two weeks ago. Now we have the full package for which we can go in and submit for BLA.
Got it. To be clear, after the original phase III data set, have you had the chance to talk to the FDA in the second half, and what was it about? You are having this pre-BLA meeting. What are you talking about that is different?
Yeah, good question again. Yeah, the first meeting we had with the FDA was our kind of the standard end of phase III meeting with the FDA, something you want to do on how do you perceive the data from our study, how do you consider the study, the conduct of the study, et cetera. We had that in December of 2024. Good meeting with the FDA. A lot of feedback in and around that. We had just got in the RWE data set. It was the initial data set. We submitted that, but not in time for a full discussion or any discussion with them on the RWE data set.
This upcoming meeting that we will be having with them this quarter, shortly, actually, will be really principally on two topics, one on this topic of generalizability and the use of all of the information that we've gathered to show that the patients in our study are comparable to the patients in the West and the data are translatable. Then two, just kind of the specifics around the BLA filing, kind of what they want to see in the package, how we do the tables, listings, and all of those things. Those are the two key topics upcoming with the regulators.
That's very clear. Could a filing occur in the second half?
Yeah, certainly.
Okay, certainly. Okay.
Absolutely. Yeah. I mean, obviously, the meeting is important, so I don't want to get ahead of the FDA on that, but that's certainly our plan.
Okay. Does it make sense just because to me, the data does look quite compelling, especially after you've compared it to IGOS? Does it make sense to file for breakthrough designation?
Yeah, great question again. Yeah, I mean, look, we want to have the first discussion with them just so that we stay on the right path for BLA. Breakthrough therapy designation is obviously always a nice feather in one's cap. For purposes of where we are now with fast-track designation, et cetera, it does not really help us from a regulatory engagement perspective. That being said, the market likes breakthrough, and so we recognize that as well. We will make that determination after we meet with them in this upcoming meeting.
Great. Earlier in our conversation, it seems as if you really like the rapid improvement that you saw in the phase III results, week one benefit. Some investors then will ask, because this was a 26-week study, correct me if I'm wrong, is that enough, quote-unquote, "enough to justify a higher price ultimately"? Does it make sense to follow out for longer to convince payers to pay for this drug?
Yeah, really good question. Yeah. Firstly, no company or no study in the history of the world has studied GBS patients out to 26 weeks. This is the longest duration study that's ever been done in GBS and with full alignment with the FDA. Just important to note a couple of things. One, the primary endpoint is week eight. The 26-week is the follow-up period, so out to six months, which we did. We think that's more than sufficient for both an approval and for pricing and marketing perspectives. The thing to bear in mind with regard to GBS is the cost associated with this disease is not in drug costs. I mean, the treatment of the cost is what it is. Really, it's the fact that these patients are in the ICU. They're on a ventilator.
After that, they're in skilled nursing facilities, and they have long-term physical therapy. I mean, at one year, 20% of patients still do not have the ability to walk unassisted. One in four patients are going on a ventilator right out the gate. Those are the costs. We are in the course of doing really robust health economics work on that. We will have that later this summer. We've started the engagement from a market access perspective with the formulary committees and others in and around that, just based on the information that we already have. We know that these patients cost hundreds of thousands of dollars to the healthcare system, up to millions of dollars, depending upon how long they're ventilated, et cetera. That's really the key to really driving market opportunity here and premium pricing.
Getting them off of the healthcare system sooner is the key to being able to price this drug.
Makes sense. Are you ready to give us a price range for this drug? I mean, you did allude to the alternative being hundreds of thousands just now, but.
Yeah, right. And that's absolutely right. So without treatment or even with IVIG, we know it's hundreds of thousands to millions of dollars to treat these patients. We are not ready to announce pricing. What I will say is that the analysts have somewhere between $75,000-$150,000 for a course of therapy. That's not unreasonable and certainly reasonable in today's world of rare drug diseases. And so we'll just kind of guide people to that at this stage.
Got it. I'm flip-flopping a little bit, but just going back to the FDA, even though they gave you buy-in around this whole program and how to go about it years ago, could there be a risk they flip-flop with the new changes going on? I mean, what's your sense, especially after talking to them in the second half of last year?
Yeah, so two things. One, I wouldn't call it flip-flop because we love the regulators. I mean, these folks are doing yeoman's work. I think it is worth calling out. This is a program that they have never seen before. They have not done a full review of a GBS package other than IVIG almost 50 years ago, which is not, again, not a randomized study. They really are learning the disease and our data and what is necessary to succeed or to effectively treat patients. They're doing a really nice job, and they've been great. Our interactions with them were in December prior to many of the changes that have gone on with the FDA. Those will be new learnings.
That being said, we're pleased that many of the folks who were involved with the program when we first got kind of the green light to go forward into our phase III are still involved in various ways, not maybe day-to-day, but at higher levels, office head, et cetera, et cetera. To your question, could there be a surprise in the meeting? Obviously, we prepare for all scenarios. If there is one, I think we're prepared for it. I think if, just to be candid about it, if they ask for anything other than what has been previously asked for, it would be just some experience with Western world patients with our drug. Just ensure us that when you treat patients in the West, if you look at the PKPD, for example, at tanruprubart in Southeast Asia, does it look like in the West?
That's a scenario that we have. We don't think that's the scenario, but we're prepared for that, and we can talk about how we've kind of belt and suspended for that approach.
Sure. And then we'll get to that in a bit. And then are there precedents where a drug was studied ex U.S. and ultimately got approval in the U.S.?
Yeah, several. If you look in the literature or you look at what's the precedent that's occurred with the FDA over the last 10 years or so, you'll see multiple examples of this in multiple therapeutic areas, whether it's oncology, infectious diseases, as well as in the neurology division. One of the examples we like to point to is the RADICAVA example, which is for ALS. This was a program that was conducted in Japan in roughly 80-90 patients, single study where they went on the primary endpoint, but minimal supportive evidence, but no patients in the West. They used that. The neuro division was able to find that that patient population was translatable to the West. That's not always the case, but you have to do that deep analysis. They did that.
We think we've got a very robust package in the way we've done that as well. Yeah, there have been multiple examples.
Great, great. And then so you're meeting with them again in Q2. Presumably, you get the meeting minutes back, and then do you come back to the street about anything or what's the news flow like?
Yeah, really good question. Yeah, I think we'll update the street in some form or fashion on the go forward. I mean, again, we'll be looking to file our BLA and move forward on that. Yeah, we will update in some form or fashion.
Okay. Is it safe to assume that there would be an adcom during the review process?
Hard to know. I mean, when you look at the prior programs where they were used ex-U.S. data for approval here, half of them have had adcoms, half of them have not. There is no clear precedent with regard to that. Candidly, from our perspective, given that there has not been a lot of experience with the drug, at least in GBS, we have used tanruprubart in other diseases like ALS, HD, et cetera, here in the U.S. to dose Western world patients. Given that there has not been a lot of experience in GBS, an adcom may not be the worst thing for the program. It may be an opportunity to provide additional education in advance of launching on GBS and the effects of our drug on GBS. One of the things we talk not enough about is the safety profile of this drug in GBS.
I mean, the safety is really, really quite compelling from my perspective. These patients looked similar to placebo in the treatment arms across safety. Tolerability was a little different, but not unmanageable at all. It is a really effective and reasonably safe program with a single infusion. We will be making all of that clear, and an adcom would help kind of illuminate that even further.
Got it. Thanks. As this is going on, you've decided to start the FORWARD study on 30 patients we just alluded to, enrolling Western patients. What are you trying to achieve here? Was this informed by FDA discussions, or was it more of you just hedging a little, I don't know, just being prudent about things?
Yeah, super proactive. Yeah, it really serves two things for us, which I look, we're super excited by the Ford study. I mean, I cannot deny that at all. It has been something that we've planned for quite a while now. For those who are following us closely and you're looking at our runway, et cetera, and where we're allocating dollars, you can see our runway never changed or anything like that once we announced this study. This study has been planned for quite a while. What we know is that when we talk to physicians about GBS and tanruprubart and we take them through the data, they're all super compelled by this data, particularly, again, this earlier treatment effect by week one, patients are getting better.
Such a critical junction because that's when you're making decisions about longer-term ICU use, are you keeping them on a ventilation, et cetera. Week one, we're seeing patients get better across every study that we've done in this disease. Really, really important. The pushback that we hear from time to time in our market research with physicians is, but have you treated any patients in the U.S. in Guillain-Barré syndrome? That is a reasonable question that we get. It would make folks feel a lot more comfortable to get some experience with the drug and understand its treatment in the U.S. population. Starting this FORWARD study now with key centers around the country is allowing for that. It's an open-label study. We'll be able to provide data kind of real-time to the physician population, patients, and the marketplace as well.
We love that from that perspective because, again, that is the number one question we get on this program for physicians in the U.S. is just experience in the U.S. with the drug. The second piece is just what you were alluding to, Andrew, which is that to the extent there is a question with the FDA on just, we'd like some patients dosed here in the U.S., it answers that as well. It is a belt and suspenders approach. It is kind of two birds, one stone. We purposely designed it where the primary endpoint is PKPD and then week one efficacy and then, of course, safety, et cetera. It is designed in a very limited fashion to kind of meet the objectives that we have for the study.
I see. So presumably the data could be pretty fast.
We expect it on a rolling basis. If the FDA wanted to see something while we're reviewing the BLA, we would be able to do that. Obviously, GBS is episodic, but we did start at the centers where we know they see x amount of GBS patients on an annual basis. That is how you try to do this in a way where you can do it efficiently and effectively.
Right, right. Going to the EU then, how are EU EMA discussions and when could you file?
Yeah, love the discussions with the EMA. I would say on some level, they're a bit more advanced than where they are with the FDA. I mean, starting the discussion on the orphan drug designation in Europe is a really good question, and we don't get that enough, and we probably should talk about that more. That's allowed us to have more interactions with EMA earlier. We've started with country-specific meetings. They've gone really, really well. We have an upcoming meeting with EMA before too long as well. Like I said, we'll just say that. We are very much on pace to be filing in Europe by the end of the year, first part of next year is kind of where we are targeting for that. Upcoming meetings will clearly define that, but that's our kind of base position today.
Okay. That's very helpful. Maybe let's shift gears to the small molecule program because there is a data readout mid-2025.
Yes, correct.
Okay. I guess big picture for people listening, why is this a game changer in your view?
Yeah, listen, the role of complement has been validated clinically in a host of neuromuscular diseases. You see that with C5, C1s types of approaches. These are done with monoclonal antibodies that are dosed everywhere from every other week to once a month. You're now seeing the advent of subcutaneous approaches that are coming forward and whether or not they're better than the infused monoclonal antibodies or not, TBD. Coming forward with a small molecule in these conditions is really, really important. For example, if you look at Myasthenia gravis, all patients or most all patients start off with cholinergic inhibitors. These are orals. These patient populations are already trained to take orals. It's only after that when they move forward into kind of infused therapies, et cetera, et cetera.
Bringing them back to an oral feels like a really straightforward marketing approach from our perspective. Just the convenience of it. Again, these neuromuscular diseases, they all have their respective titles, MG, CIDP, et cetera. To actually know the patients and what they're going through is really, really significant. There's a significant amount of pain, fatigue, lack of mobility associated with these diseases. For a person to go to the grocery store, they really have to schedule their week to do that because for two or three days after, they're wiped out. They can't do anything. Having to go in and get infusions in a chair, et cetera, or finding someone to administer a Sub-Q in your stomach multiple times over the course of a week or every other week, whatever, is not trivial.
The ability to give them an oral and help them get their lives back more fully, we think could be very disruptive in this space. We are encouraged by that. We continue to mention the neuromuscular diseases, but because it is an oral, we think it gives us an opportunity to pursue other diseases outside of that space that you can probably more tractably run clinical studies in as well.
Great. You are in a phase II program. Originally, it was supposed to read out year-end of last year. You pushed it back a little bit. What exactly happened? Can we feel confident it will not be pushed back again?
Yeah, two things occurred there. One, our initial read was done with a film-coated version of the drug. What we saw in our healthy volunteer studies, which healthy volunteer studies went really well. We got the exposure levels that we wanted to get there, safe, generally well tolerated. We did see some tolerability topics with regard to nausea and emesis in the gut. What we saw with the film-coated was it was releasing in the gut and causing that issue. Late in the year, we were working in the background on an enteric-coated tablet, which we have now completed. What that allows the drug to do is to bypass the gut and then release the drug. What we saw in the healthy volunteer study, we ran an additional healthy volunteer study with the enteric-coated.
We saw a significant reduction in that tolerability topic. Still achieved the same kind of exposure levels that we wanted, et cetera. We're really pleased by that. We thought, again, made great sense to push back the program. Now, I didn't say this, but I think you guys all know this. This is an early stage translational program for the first oral ever. It's really not a program you probably should even be talking about publicly. I can tell you if this were in the hands of J&J , you wouldn't even know about it, right? We're small biotech. We know we've got to keep things interesting. We're doing that, but we're taking you on the journey of how you actually develop drugs that have never been developed before. I think it's important for people to put this into context. This is not an infused monoclonal antibody.
That being said, we pushed back because of the enteric-coated . What we've also done is we've added to the size of the study. The study was initially only going to be three patients. We determined that's probably too small in today's market that people would want to see a more robust data set. It also gives us an opportunity to better characterize kind of just the dosing properties with more patients. We're saying roughly seven patients or so. We're on track for that. The key topic for this, just so people understand, is we're doing this in cold agglutinin disease. In cold agglutinin disease, you want to treat patients who are in hemolysis. The variability on that is really quite large. All of these patients are being taken off whatever standard treatment they are on. We wash them out.
They then go into hemolysis, and then we treat them. That path to hemolysis is quite variable between patients. It could be a month to six months. You have your patients identified, lined up, enrolled, but you're waiting for them to get to a state of hemolysis before you treat them. That's just biology. Again, early translational stage program that people were hanging on every topic, but it's important that people understand all of these kinds of nuances in development.
Makes sense. Maybe in the last minute then, in the data readout, what is the go, no-go threshold for you? What biomarkers are you looking for to make you?
Yeah, beyond safety and tolerability, given you got to achieve that, very, very important, obviously. After that, really want to show impact on two things. One, complement. We want to be able to show that we can reduce or bring complement down to its normal state. Complement really spikes in these diseases, as you guys are probably aware. The second is bilirubin, really objective measurement of hemolysis. We know that now from multiple other studies that have been done in cold agglutinin disease, including a study we did with Ted Yednock so that we could understand the disease on that. Those are the two primaries. We will also look at hemolysis, but the thing I'll tell you with hemolysis is it takes a while or hemoglobin, sorry, hemoglobin levels. Hemoglobin levels really vary among patients.
Whether we will see that in a four-week study or not, likely to see some levels of trends, but that's why we've made it a secondary as opposed to a primary.
Okay, very good. We did not even talk about the GA program, but.
You got to come back and talk about GA in the next month.
Next month. In the second half of next year, we'll have data. Thank you so much for giving us an update. It was very helpful today. Thanks everyone for listening.
Thank you all. Appreciate it.