One of the biotech analysts here, and in this session, we are very pleased to have Mr. Uneek Mehra, CFO, and Julian Pei, Investor Relations Director, to join us for this session. Maybe we will start with cystic fibrosis data update. You actually presented this morning.
Yeah, Kelly, actually, hi. Good afternoon, everyone. We'll actually do a two or three slides on the whole company, and then we'll go right into your questions on the CF data.
Okay. Terrific.
So first of all, thank you for having us here at Jefferies. It's a pleasure being here. As I said, I know we have a short amount of time. Let me move into this work. So a little bit on 4DMT. 4D Molecular Therapeutics, a leading clinical-stage, next-generation AAV company. So our platform is a directed evolution platform. So we basically use this Nobel Prize-winning technology to really develop, next-generation vectors, AAV vectors. We have almost from a platform perspective, this was, tech platform that was sort of conceptualized in the academia and then industrialized at 4DMT. We've got about a proprietary one billion capsid sequences. That's what we use to begin to then, sort of create our own flavors of the AAV vectors.
It's an extremely modular platform where we can use the vector as well as any payload that can... And you will see evidence of that in all the three clinical vectors that are currently in the clinic. We are in four therapeutic areas: the eye, the lung, the heart, as well as the brain with its CNS program. Three routes of administration, intravitreal for the eye, aerosol for the lung, and intravenous for the heart. Five clinical candidates, seven patient populations, so it's four large market opportunities. It's a broad and diverse platform that we have. We are the only company, in fact, the only therapy in the ophtho space that has an FDA RMAT and EMA PRIME designation, which we are very proud of for wet AMD.
We have our own in-house manufacturing in Emeryville, California, and we have a strong balance sheet, $589 million at the end of last quarter, which we believe takes us through first half of 2027. This is our pipeline. You will appreciate it's almost like a mid-stage pharma pipeline across four large market opportunities in ophthalmology. It's particularly exciting with wet AMD, DME, and geographic atrophy. These are extremely large market indications, multimillion patients that we are targeting. On the pulmonology side, we have CF, cystic fibrosis. We released data earlier today, and we're gonna talk a little bit about that, as well as the alpha-1 antitrypsin, which we are also very excited about.
On the heart, we have the Fabry disease cardiomyopathy program, and on CNS, we have a partnership with Arbor Biotechnologies to further develop therapies in that area. This was the data on our 4D-150 program, which everybody is very excited upon, and we are also very proud. We released that in February, which is our PRISM wet AMD data. These are in severe disease activity, highly advanced high treatment burden patients, where we have demonstrated across 50 patients, single routine intravitreal injection, extremely safe profile with no significant or recurrent inflammation. That's a big bar for gene therapy, given the hangover that gene therapy historically has had. 89% overall reduction in treatment burden, 63% injection-free and 84% zero to one injections over a 24-week landmark program that we showed.
Additionally, we showed retinal control, which means there are no fluctuations or oscillations in the CST for these highly advanced patients. We've shown a great amount of control for that, and we've now started to show long-term durability up to two years, but other therapies in the eye have shown almost going to ten years, which we are also confident about. This was the data we released today on cystic fibrosis for 4D-710 program. We've now dosed 10 patients, ranging from 2.5 × E14 vector per eye to 2 × E15. We've shown two participants out of three with six months of follow-up and baseline FEV1 80%, where we showed improved FEV1 performance, +5%, +6%.
Safety and tolerability at our 1E15 dose level that we are taking forward in our Phase II program, we've shown dose-dependent transgene expression. This is the first aerosol program or gene therapy program that has an aerosolized transgene expression and widespread CFTR protein across several lung areas. And we've also demonstrated no effect from preexisting A101 immunity, which is the vector-based immunity. We will be advancing to Phase II as well as shortly in second half, and the next data update is in mid-2025. So finally, just to give you a perspective on several exciting milestones on the ophtho program, we have a Phase II population extension cohort. So these are patients who are slightly less advanced than the PRISM data that I showed you earlier. That's coming up in July.
We have an update on our Phase III clinical program in Q3 2024, with the anticipated initiation of the first Phase III study in Q1 2025. We have data for DME coming up, coming up in Q4 this year, as well as the IND filing for 4D-175 for GA, geographic atrophy. And then, as I mentioned, our next update for 4D-710 will be in 2025. Strong balance sheet, $589 million cash, as of the end of the last quarter. So with that, Kelly, back to you for questions.
Okay, terrific. So following the data update in cystic fibrosis this morning, we heard you had a lot of one-on-one investor meetings. Curious, what has been the feedback?
Yeah, no, I think overall, at least from us, the feedback has been, sort of positive in the sort of extent the program and the pace with which the program is, moving forward. I would clarify that I think there were some investors who were probably looking at or who had much higher expectations than-
Mm.
As a Phase I program. Partly also because I think there was some comparison to the clarity we've given on the wet AMD program. This is a different program, much earlier, so I think there may have been some disappointment with just the stage of development. But we feel that I think we have an exciting lung program. This program is the first time ever a transgene expression has been done in the lung with the CFTR protein in an aerosolized version. So we feel we have a great path for the program.
Mm-hmm.
That's not necessarily reflected in the stock price today, but we understand that I think, some investors are viewing with more clarity needed on the program, similar to the wet AMD.
Okay, makes sense. And also curious, looking into Cohort 1 and 2, if you'll be able to match the patient baseline characteristics and from natural history studies, what would be the FEV1 change over the same time period?
Yeah. Julian, you want to take?
Yeah. In general, when you look at kind of what pre-modulator era patients did in cystic fibrosis before they had disease-modifying therapy, generally, patients decline around 1%-2% or even 3% a year. So we've now shown patients stable or improved even in certain in those two of three patients. So I think that's, to us, is a very clear sign of early hints of clinical efficacy. If we were able to replicate both the stability as well as partial improvements in some patients in a larger Phase II and a Phase III trial, we think that would be, you know, completely approvable and also a very well successful product in patients as well.
Okay, great. And, also, curious whether you have a preclinical studies that you could actually somewhat predict the trend beyond the 12 months, like in terms of, let's say, variability, and, also the direction, based on what you have right now?
Yeah, I believe, I think you're kind of referring to durability of effect.
That's right.
So I think, preclinically, we've shown data now up to three months in animals. We haven't done kinda longer term. You know, I think the most important information we'll get from the current human studies are potentially a second biopsy at 12 months, and we've amended the protocol to include that. For the first patients enrolled in the study, it'll be elective-
Mm-hmm.
for those patients, 'cause that wasn't what they signed up for when they initiated the trial. But for new patients coming on, they'll have this option to do a 12-month biopsy. And, with that data, it'll inform us the durability of the expression that we see, mediated by the 710 product.
Okay. And, you also discussed the potential Phase II dose will be the lower dose from cohort one or could, has potential to go even lower. Curious, what are the reasons behind it to make this decision?
Yeah, so let me paint a picture. So we have evaluated four doses right now, starting from 2E15, and actually, we have dose deescalated, which is also the first time in gene therapy because we were seeing such consistent overexpression. So first, just getting an expression of CFTR in the-
Mm
... lung through an aerosolized is the first, but trying to get and consistently showing an overexpression, that made us look into 2E15. And between the 2E15 and the 1E15 dose-
Mm
... we saw very similar overexpression. So, then we wanted to, as we had in discussions with the agency, not for any safety reason, but for our own development program, explore lower doses.
Mm-hmm.
When we put and we have a slide in our website after today's data release that shows across all the four doses. In the case of the highest dose, 2E15, we were seeing not only overexpression but also expression in the interstitium, which is not normally present in-
Mm-hmm
... normal lung. So that made us look at that and say, "Okay, if you're getting similar expression at half the dose at 1E15, then let's move forward with 1E15-
Mm-hmm
... in terms of our, Phase II program." We continue to look at half of that, which is 5E14.
Mm-hmm.
We still have to go through three patients. Our last patient is coming up for enrollment.
Mm-hmm.
Between those two doses, that's where our sort of thinking is right now for the Phase II program.
... Okay, great. You also talk about the redosing and could be every 1.5-3 years. Is this based on any clinical or preclinical evidence?
You want to take it?
Yeah, I would say, based, you know, generally speaking, lung turnover is surprisingly, you know, very, very poorly understood. You know, what we're triangulating from is, in mice, there's been really good data to show the half-life of mouse lung turnover in epithelial cells is approximately one and a half years. You know, in humans, that is likely gonna be longer, and then you kinda then triangulate with the levels that we're seeing. So depending on this 12-month biopsy data, we'll see. We'll get kind of start building a curve on, you know, what that path looks like in humans. You know, that just in general for human biology will be a big, kind of, you know, learnings on just lung turnover. So we'll learn more. Generally, right now, it's based on preclinical data from other people's work-
Mm-hmm.
But we'll learn more soon in humans.
Okay. And with the new information today, should we think about any change in the future for the initial Phase III plan you have discussed, and also any impact on the regulatory pathway plan?
Not really. I think if our data... I mean, look, we have great support from the Cystic Fibrosis Foundation, who's been a strong partner, and they are involved in a lot of our analysis and decision-making. We've also got feedback from the agency.
Mm-hmm.
So the idea is we want to show more continued correlation between our high gene expression we are showing and the FEV1 clinical endpoint.
Mm.
For that, we've announced the next phase of up to nine patients. Once we are able to bring that out mid of next year, that will inform our Phase III, and I think that still remains our development path.
Okay, great. Pivot to wet AMD program. In July, you will present a Phase II population extension cohort data at ASRS. Could you help set some expectations on what should we expect from this cohort, and what is the bar for efficacy in this patient population? And also, how is this population different from the targeted population in Phase III pivotal trial?
Yeah. So let me set the stage for the population extension. So these are patients who are slightly different from our Phase II dose expansion PRISM patients that we showed in February. There we showed, as I had a slide earlier, highly advanced high treatment burden patients with an average CST of about 440 and injection burden of 6-12 injections in the prior twelve months. This population, which is our aim to broaden our sort of therapeutic program, is our patients who are slightly lower than the 440 micron CST and who have an injection burden of 1-6 in the prior twelve months. So we wanted to diversify. That's the data set of 32 patients that you will likely see.
We think this patient population resembles more closely the potential Phase III patient population that we will enroll starting next year.
How should we think about the bar for the long-term efficacy, overall reduction in anti-VEGF injection burden and injection-free rate?
Yeah, I think that's a great question. Look, we are coming up under this current standard of care, where efficacy is measured in terms of sort of the annualized reduction that you bring about, but also in terms of durability, we are talking of weeks. We. Our goal is the trifecta, which is, we want extended durability, which talks about years. In terms of annualized reduction, we've set ourselves targets of 75%-80%, which we think in discussions with payers is pretty meaningful. There is also another number, which is injection-free percentages. We showed 63% in the most difficult-to-treat patients earlier on. We feel as, sort of from a long-term data perspective, this would be anywhere higher than 50% would be acceptable.
Bear in mind, though, the current agents who are there, you know, Vabysmo is the latest one that came in, and you are still showing, injection-free much lower because patients are on label at 16, every 16 weeks. But, you know, in practice, it could be even lower. So we feel, I think those, thresholds could be pretty compelling to establish our treatment.
Okay, great. So 4D-150 is also being studied in a Phase II study for DME, diabetic-related macular edema. Could you talk about what are the key differences between the two indications for 4D-150 to elicit function? And what is the read-through in terms of efficacy and the safety from wet AMD to DME, especially on safety front?
Yeah, I think both diseases are relatively similar in the sense of, you know, very driven by vasculature growth in the back of the eye, which leads to blindness. So in terms of mechanism-wise, and everything that's worked in wet AMD has worked in DME, given that similarity. You know, the cause, original cause of how those blood vessels became about is maybe different, but generally, the genesis of those is the same. So the translatability from 4D-150, which expresses the aflibercept, which also works in both wet AMD and DME, is very high, almost certain. The question then becomes safety, which we also are very confident in, given the safety, the excellent safety we've seen in wet AMD.
So we've actually shortened the taper, for example, of the steroids because of that confidence and, you know, we don't fully expect to see similar, if not, you know, similar safety, if not even better, in DME than in past products.
Okay, so we could have expectation of similar level of clean safety in DME?
Correct.
Okay, great. And last question, 150 is so for the Phase II data, could you set a more like a specific expectation on the data presentation in Q4, and what would be the development plan? Are you also going to, like, announce the development plan, like, along with the data?
You mean for DME?
DME.
Yeah.
Yeah, so the study design of the current SPECTRA DME trial is a part one dose confirmation, where we have 3E10 and 1E10 as two dose levels. It's 22 patients. It's really meant to confirm both safety and then initial kind of signals of efficacy. You know, once those are confirmed, you would then go into a 54-patient randomized expansion study, kinda similar to what we did in wet AMD. So this is really an early look at what could come with a larger Phase II study and then quickly go into Phase III thereafter. So that's the current development plan. We think, you know, if with positive data there, we would quickly try to move into later stages.
Kelly, I'll just point out that by the time we finish 2024, we do expect to have more than 110 patients-
Mm-hmm.
-worth of safety, if you combine the DME 22 patients. I think that's going to be also a meaningful number of patients, especially in ophthalmic gene therapy.
For safety database. Yeah, I agree. And assuming if you need to reduce 150 in both indications, so what would be the ideal time interval?
So right now, our expectation by the time we file BLA is to show 3-5 years of sort of durability.
Mm-hmm.
I think we are also planning to study sort of the other eye and the bilateral sort of eye population, which we know those patients are about 42% of the overall population. And I think with that, we are confident that I think we will have a compelling product, you know, and then we can continue to look at other life cycle extensions further down.
Okay, and we'll wrap up the wet AMD DME session and pivot to 175-
Mm-hmm.
-in GA geographic atrophy. Can you discuss the rationale of sCFH as a target and timeline for this program?
Yeah. I think first of all, you know, we know that complement and inflammation in general drives geographic atrophy. So, you know, we already have confirmation from the C5 and C3 inhibitors from Apellis and, and, formerly Iveric, and now Astellas, that these are effective at reducing lesion growth. There's further clinical data from other programs. The reason why CFH is very attractive is because there's actually genetic variants in 70% of geographic atrophy patients, that are shown to increase the risk significantly for GA. So that's another validation of both CFH's role as well as complement pathway. So we licensed a short form of that that fits into AAV from University of Pennsylvania that has shown preclinically very strong inhibition of the complement pathway.
We have data and kinda shown at ARVO that shows that. So then we combine that now with our R100 vector that's very safe, low dose delivery directly to the retina, where the inhibition of the complement pathway needs to be. So I think with all those reasons, it's a very compelling program and approach to address another large market opportunity.
Terrific. For the Fabry program, can you give us an update on 4D-310, and what are the next steps to lift the clinical hold and continue clinical development?
Yeah. So the current status of that program, as a reminder, we were put on clinical hold about a year ago given severe adverse event of HUS, a result of complement activation from the therapy. That has historically shown to be very well resolved and addressed by rituximab's role in immune regimen with other programs, such as Rocket's Danon disease program. So we've now implemented that program in NHP studies to confirm that that does indeed have the same complement kind of suppression as it does for AAV9-based gene therapies, and that those results are, you know, imminently coming, and we would plan to submit those to the FDA to get off clinical hold and then, you know, resume dosing patients in Phase II.
Okay. Given our broader pipeline and also unique AAV technology platform, could you share your thoughts on BD front?
Yeah. So I think we've made the decision internally that for the larger market programs, which four of them are likely in the target, we plan to do it ourselves.
Mm-hmm.
In general, the ophthalmology space is quite constrained in the sense of you only have 2,500-3,000, so we can go through that Phase, both development and commercial, ourselves. We are open to partnerships on the pulmonology and the Fabry program, but we do feel like we have to progress the programs a little bit in terms of the next few patients, and then at the right time, we will make those decisions.
Great, thank you. We covered a lot in short 25 minutes.
Yeah, and it was like a rapid fire.
Thanks for a great discussion. Yeah, I just want to, like, touch on everything, and thanks, everyone, for attending for this session.
Thank you.