Let's go and get started with our afternoon session. My name is Dae Gon Ha, one of the biotech analysts at Stifel. So with me for the next half hour, we'll be discussing Prime Medicine. From Prime, we have the Chief Medical Officer, Mohammed Asmal. So, Mohammed, thank you very much for taking the time. So, as I typically do, I figured I would turn it over to you to just start off with an overview of Prime Medicine, and we'll dive right into Q&A. Yes. Thank you, Dae Gon. Thank you, first of all, for having us. It's a real pleasure to be here. As Dae Gon mentioned, I represent Prime Medicine. We're a clinical stage gene editing company based out of Cambridge, Massachusetts, founded on the seminal publications coming out of the laboratory of Dr. David Liu and Andrew Anzalone in 2019. The Prime Editing technology is based on pairing two very powerful instruments. It's based on pairing the precision of the CRISPR-Cas9 moiety with the versatility of reverse transcriptase. And to us, this really brings forward the true fruition of what I think in many minds is the apex of gene genetic medicines, which is the ability to really correct pretty much any genetic mutation that causes a monogenic illness. So, using Prime, the Prime editing platform, we're able to correct single point mutations, transitions, transversions, small deletions, small insertions, and with slight modifications to the technology, we're actually able to precisely insert large pieces of DNA into an exact location in the genome. We're also able to excise large tandem repeats. So, with this technology, we believe that we can address 90-plus% of mutations that give rise to monogenic illness in humans, and beyond being able to address these, we address these in a very specific manner. So, we're able to correct genetic mutations in situ, which allows restoration of genetic function in its normal context or normal promoter, and at normal physiologic levels. We're also able to do this with unprecedented safety. The Prime editing mechanism has three safety checks. So, we thus far have a very clean track record with detection of off-target. And in addition, we do not introduce any double-strand breaks, so not at risk for translocations, so as I mentioned, we're a clinical stage company now with our lead asset moving forward in chronic granulomatous disease, with subsequent programs, liver-directed lipid nanoparticle program in Wilson's disease, and a program in cystic fibrosis. We also recently announced a major partnership with Bristol Myers Squibb to advance our technology to the use of CAR T cells, so thank you very much for the opportunity to introduce ourselves. Yeah, let's dive right in. The PM359 program, which you just briefly introduced us to CGD, can we just take a step back and remind for the audience what the trial design is and what the supportive preclinical data were that led you into the clinic for phase 1/2? Yeah, certainly. So, PM359 is an autologous hematopoietic stem cell therapy targeting p47 CGD. p47 CGD is the result of a mutation in the NCF1 gene that results in a defect in NADPH oxidase, which is responsible for killing ingested bacteria and fungi in neutrophils. So, individuals with this particular disease have defects in the immunity. They have a truncated lifespan of about 40 years. The only curative therapy is allogeneic transplant, and that's usually reserved to children with matched related donors. So, a limited number of individuals are eligible for that. So, as I mentioned, our therapy is ex vivo autologous stem cell therapy. So this particular type of platform has been extensively de-risked with several programs already approved in autologous gene therapy. And this will be the first demonstration that Prime editing is able to similarly follow in those footsteps. The trial design is a very sort of streamlined and straightforward one. We're able to, you know, initially dose adults, and then very quickly move to adolescents and pediatric patients. The ability to rapidly progress from adults to adolescents and pediatric patients is a validation of, we think, the high-end medical need in this particular disease where there is both a risk of catastrophic punctuated events at any given time period in a patient's life when, you know, they can be struck by a life-threatening infection and also by the very cumulative progressive nature of this disease in which, you know, there's cumulative organ damage over the course of many, many years that takes place. Mm-hmm. Can you speak to then the commercial opportunity when it comes to CGD? I mean, ultimately, was it the commercial opportunity or more as a validation of the Prime editing technology? Right. So, between p47 CGD and then X-CGD, which is our second program, following in its footsteps, we think there are about 1,000 to 2,000 patients who would be eligible for this treatment in the United States. You know, it's a disease of high unmet need, as I mentioned, and so we think we will be able to get to the substantial portion of the addressable market. Now, it's not a huge disease, clearly, but you know, patients are in dire need. We definitely believe this will be a very straightforward and fast proof of the ability of Prime editing to manifest both a very precise correction to a genetic defect as well as a very safe correction to a genetic defect. Mm-hmm. Mm-hmm. So then the phase 1, 2 trial, you've recently, or I guess in 3Q, you've reiterated guidance for data in 2025. Bearing in mind this is ex vivo, it probably takes quite some time on the front end, but once they're dosed, you also have to follow for quite some time. What's the latest kind of progress and how should we think about within that window of 2025, how much data, what kind of metrics you're gonna be touching on, and ultimately any kind of inclination as to whether that's gonna be more on the front end or the back end of 2025? Yes. So, it's tough to provide exact guidance in a cell therapy program. As you pointed out, the process of manufacturing cells is a potentially long one. And this is a disease in which we are, or the nature of the therapy as a transplant is one that the FDA requires a sort of staggered approach to treating patients, waiting for an initial patient to engraft before treating the next. So, that's why the exact timeline is a little bit difficult to predict. We have opened up several clinical trial sites as we've noted on ClinicalTrials.gov. But as to when data will be available once we have manufactured and treated a patient, that's one of the real advantages of this disease. So, this disease is a disease of neutrophil functions. After engraftment of the transduced cells, neutrophils are among the fastest cells to repopulate, and so not only will we see evidence of engraftment when neutrophils reappear, which is the most important element in safety in these therapies, but also assuming the gene correction works, we should see reconstitution of the vital neutrophil function that is missing in individuals with CGD. We're measuring a quantity called the dihydramine, sorry, dihydrorhodamine test, which is an assessment of the ability of a neutrophil to kill ingested microbes. Presumably within a few months after treatment, once the neutrophils have reconstituted, we should be able to measure this function and detect the ability of Prime editing to restore normal physiologic capabilities. Mm-hmm. So, to that extent, I mean, is it the number of responders you're looking for or number of, I guess, how high above the certain threshold on DHR assay? So, I think it's both. It's not an either/or, right? I think, you know, there's another great advantage of this particular disease is there's natural history data that suggests there is a nice neat set of thresholds in terms of this DHR function. So, above 10% reconstitution of DHR and there is some amelioration of disease, and above 20%, individuals that have 20% of normal DHR function seem to be able to resist the normal infections that these individuals are prone to. Now, obviously, you know, demonstrating it at one subject I think would be fantastic and really prove the mechanism is working, but obviously we'll need to, you know, show it in multiple subjects to show the reproducibility. Mm-hmm. So, on that multiple subject element, just going back to my earlier question, in 2025, how many dose cohorts are we expecting? How many size of the data are we expecting? Bearing in mind this is rare, but also investors probably wanna know fairly compelling and consistent kind of data. Yeah, I think so. We haven't guided to that, but I think it's safe to say it's gonna be fairly, you know, tidy number because, again, as I mentioned, we are rapidly progressing from adults to adolescents in pediatrics. So, the FDA does want the time, the data to mature a little bit before they allow you to progress down to those age groups. So, you know, our clinical protocol currently covers dosing a couple of patients in each cohort before progressing to the next, but then with an interval during which patients have to be monitored before opening the next cohort. Got it, and how many cohorts are there? There are three cohorts. Okay. I guess when you think about sort of a read-through or platform approach, you earlier talked about X-CGD as your next ex vivo approach from a read-through, bearing in mind it's a different gene, but the manifestations are pretty similar in the sense that it's a neutrophil defect, neutrophil disease. So, how much can we get from a phase 1/2 data overlooking into an X-CGD as your next program? Yeah, I think there's a phenomenal amount of read-through. Number one, I think it validates the mechanism of reconstitution of DHR function. So, both X-CGD and p47 CGD are both characterized by loss of this DHR function, which then translates in an inability of neutrophils to kill microbes. So, I think demonstrating in one of these that we've reconstituted DHR and that we then subsequently, you know, restore function of neutrophils will carry through to the next. I think it'll also demonstrate that Prime editing is safe in that, you know, that the hematopoietic stem cell system reconstitutes appropriately after Prime editing. Mm-hmm. From a regulatory standpoint, thinking about Lyfgenia and Casgevy, which are pretty remarkable drugs on their own, do you see that as kind of setting a bogey for your development going forward? Specifically, I mean, phase 1, 2 that becomes a pivotal trial as you just dose more patients on the most efficacious dose, or do you see this as requiring a separate phase 3 demonstration? Yes, so I think this would be interesting. We'll have to obviously have discussions with the regulatory bodies around this, but there is good precedent for converting phase 1s seamlessly into a pivotal trial, you know, pending, of course, exceptional data, which we hope to have demonstrating efficacy and safety. But I think the FDA is certainly sympathetic to rare disease populations and, you know, the need to expedite these therapies to patients if they are shown to be efficacious and safe. Okay. I guess given the rare disease indication and your promise of being a one-and-done, question arises in terms of, you know, how do you kind of reconcile demonstration of efficacy in a larger, more promising consistent group versus kind of depleting, if you will, into sort of that prevalent pool that you could be, addressing as a commercial product? Yeah. No, I mean, I think anytime you talk about what one hopes is a curative definitive therapy for individuals with rare diseases is always, you know, a very valid question. You know, I think it is, as a physician, I say it is an ideal really to provide the best possible treatment for patients. And I think almost any patient will tell you that a cure is certainly preferable to a medication that they require, having to take throughout their lives. So, I think, you know, this will be an ideal solution to patients. I think hopefully payers certainly seem to be now getting receptive to the idea of these kinds of therapies. I know there was initially some challenges, but now I think, you know, with the successes of Casgevy and Lyfgenia, I think the reimbursement landscape for these kinds of one-and-done therapies is certainly improving. So I do think there is, you know, to getting to the underlying subtext of your question, there is definitely a very valid business model underlying all of this. And then furthermore, I think the modularity of the Prime approach is, it is our hope that with demonstration of safety and efficacy in one disease state, we can use that information and leverage that information to streamline our development for subsequent diseases to the same organ system and in that way significantly reduce conventional development costs. Mm-hmm. Are you able to comment on the number of mobilizations that you had to conduct in these CGD patients? Just kind of curious how it compares to a sickle. Not able to comment on that just yet. Okay. Okay. All right. So, is the idea then in 2025 when you come to the street with a phase 1, 2 data update that the next step would be an end-of-phase 2 meeting with the FDA to talk about streamlining the development? Yeah, we certainly hope once we have some even, you know, modicum of positive data in hand to start the discussion with the FDA. Again, you know, I think the FDA is now more comfortable with this. They've been through the surgical world already with the prior treatments for sickle cell and thalassemia, and so I think, bringing that data to get a clearer sense of an alignment with the regulatory bodies of what exactly a pivotal trial looks like is gonna be very important for us. Gotcha. At this point, the technology being sort of a pioneer on its own, building on the CRISPR-Cas9, what's the latest feedback you're getting from the FDA on off-target editing, which obviously it's not, you know, apples to apples comparison, but that is a point of concern. Yes. So, certainly because it is a new platform, we have had to develop an extensive suite of new assays that, you know, our predecessors have not. And we have certainly, you know, with the evidence being an accepted IND and CTAs that, you know, the regulatory bodies are happy with the suite of assays that we've provided. And I can happily say that within this suite of assays, we have seen an extremely clean off-target profile. And it is a more robust suite of assays than has been certainly requested of our predecessors at this point. Mm-hmm. When would be the right time to launch X-CGD program, given there is some similarity not only on the endpoints, but the read-through that we're not privy to, but you're obviously observing a lot of the trends with your PM359 program. So, it seems like you don't necessarily have to wait for the full data to start thinking about launching that trial. Yeah. No, I think, you know, we will launch the X-CGD trial, I think as soon as, you know, we have the appropriate, you know, therapeutic modality, not modality, but I should say the therapeutic product nailed down, but I think we'll be hopefully within close on the heels of PM359. We haven't guided to exact timeframe yet, but within on the heels of the program. Got it. When we get the CGD data, given that we don't really know the dose levels yet, but there are three cohorts, like is it the idea that whatever efficacious dose you see in CGD should be broadly applicable to X-CGD? Yeah. So, interestingly enough, so within the autologous HSC space, there's no real dose finding. We sort of have a minimal dose threshold. And in most trials, that dose threshold that was set at the initial trial rarely changes. So, for our trial, it's based on precedent for others in this field, and we set it at 3 million CD34 cells per kilogram, and that's about comparable to what others in the field. And then, you know, patients will have a variable number of CD34 cells that we collect and manufacture and comes out at the other end. And as long as they exceed that minimum, we'll treat them with whatever dose they have. But there isn't, so patients do receive variable doses, just depending on how much you collect. And that's just sort of how the field has, has evolved in this particular area. Got it. And from your standpoint, well, what's sort of your sense of what the regulatory strategy might be on the European side? And is it your intention to go into independently in a European commercial model, or is that something of a partnership opportunity? So, that is still something, you know, under discussion. I think we don't, we haven't really provided guidance on that yet. We have a trial opened up in the United Kingdom. We're opening up in the United Kingdom, but that's about as much as I can say about European strategy at this point. Okay. Okay. I vaguely recall this company called Orchard Therapeutics had a lentiviral program in X-CGD that they never pushed forward. What do you think about Prime editing vis-à-vis an integrating gene therapy? I mean, is there a better efficacy potentially? Yeah. Safety probably. Yeah. So, safety I think probably goes without saying given, you know, recent lentiviral gene therapy outcomes. But, I think from an efficacy perspective, I do think, as I mentioned, in situ gene correction will result in appropriate gene dosage and gene regulation. So, if you have, you know, ectopic gene integration under a, you know, a variable promoter, you know, you are always concerned with either gene overdosage or, you know, inappropriate expression of that gene in cell types that shouldn't be expressed. We don't have that concern. So, we expect, you know, you sort of uniform correction across all cells, and uniform activity of the NADPH oxidase complex. So, we do expect the efficacy to be more predictable with a Prime editing approach than it is with a random integration approach. Okay. Okay. At this point, can you maybe speak to briefly about safety as it relates to conditioning? Have you observed anything? 'Cause we were pretty surprised by Beam Therapeutics' recent disclosure that there was some toxicity involved. Yeah. So, I mean, I think it, you know, you can't dismiss the fact that currently, autologous gene therapy requires the use of busulfan chemotherapy to for myeloablation. Now, the track record of using busulfan myeloablation for autologous cell therapy is actually remarkably good through hundreds of patients treated previously in the various sickle, thalassemia, adenoleukodystrophy, and other trials. To my knowledge, the pulmonary toxicity observed, the lethal pulmonary toxicity observed in the Beam trial is the first, you know, subacute lethal event related to busulfan. So, overall, a relatively good track record, not to be dismissed, but much, much safer than the alternative, which is allogeneic transplant. So, the type of toxicity seen by Beam is much more common in the allogeneic setting when you have both the issue of the graft versus host disease, as well as the use and necessity of a second, T cell, B cell depleting agent such as cytarabine. So overall, the safety profile for autologous transplant in general is substantially better than for an allogeneic, for the reasons of, lack of graft versus host disease and, lack of graft rejection. But in particular, for individuals with chronic granulomatous disease, because in allogeneic transplant, you need immunosuppression as well as T and B cell depletion in order to get an allogeneic transplant to stick. And you don't need that for autologous transplant. Individuals like, CGD patients who are already prone to infection have already one arm of their, immune system knocked down in terms of their neutrophils. Knocking out T and B cells is just one more insult that they can't tolerate, and so we don't have to do that, so I think that's a significant advantage that autologous therapy has over existing allogeneic therapy. Okay. You mentioned as part of the earlier commentary some strategic reprioritization that you announced as a company recently. What's the conclusion coming out of that reprioritization and as it pertains to timing? Why was now the time? Yeah. No, it's a great question. So, you know, when I joined Prime two years ago, and pretty much from the inception of Prime, very close to the inception of Prime, there were about 18 different programs on the pipeline. And they spanned, you know, pretty much every organ system. We had several neuro programs, liver programs, eye programs, ear programs, lung, and obviously the heme program, right? And, you know, we expected these to drop off quickly with the science, but actually most of them, the science, at least Prime editing, continued to show that, to be, to exhibit activity in the disease we're going after. So, at some point, you know, the expenditures become much higher as you get closer and closer to the clinic, filing an IND, and then actually going to the clinic. So, there's only a limited number of diseases one can actually prosecute in the clinic at any given time. So that, you know, a lot, you know, caused us to step back, take a look at, you know, which diseases, you know, from a sort of assess them from a multiaxial perspective, looking at, you know, the probability of technical success, looking at the commercial valuations, looking at the competition. And so, that is sort of what brought us to where we are now, where, you know, chronic granulomatous disease provided us with a very quick ability to demonstrate the safety and efficacy of Prime editing, the fastest way to do that, of all of our programs, right? Mostly because the autologous HSC space is just so well described for gene modification technology, right? Then the liver LNP program also was one that was very attractive, again, being de-risked in terms of bringing CRISPR moieties to the liver, with you know, Intellia and Verve leading the way. So you know, that brought Wilson's forward. Wilson's also provides a you know, a great commercial opportunity with well over 10,000 patients that we can address with our therapy. The other advantage of that lipid nanoparticle platform is that it is extremely modular. So we developed the lipid delivery platform. That platform can be used for any disease that we choose to target in the liver with Prime. So that's not gonna change. Similarly, the Prime editor does not change between any of the diseases. All that we change is a few nucleotides that guide where the Prime editor goes and a few nucleotides that specify the correction that we're making. And so, that's less than, that's about 1% of the total, you know, therapeutic product. And, you know, the biodistribution, the toxicity profile are gonna be the same. So, that modularity means that once we've demonstrated proof of concept and therapeutic effect and safety in Wilson's disease, we can very quickly pivot to other diseases of the liver. And then we announced a partnership with the Cystic Fibrosis Foundation. That represents a little bit more of a, you know, a more blue sky effort since, you know, delivery to the lung is still something people are working on, but we think we have a great opportunity to make a huge difference for patients. You know, there's a substantial fraction of cystic fibrosis patients that cannot be addressed yet by the existing treatments, because their mutations are not friendly to the current correctors or because they are intolerant of them. Prime editing can fix those mutations. We think, you know, we have quite a bit to offer there. Now, obviously, when we did the strategic prioritization, we had to, you know, painfully sort of temporarily shelve programs that were near IND ready. That included, you know, a very advanced program in our retinal diseases portfolio, which seeks to address either a RHO mutation or two RHO mutations that lead to progressive blindness, as well as a program in GSD1b, another liver program. You know, we're actively searching for partners who might be interested in bringing these programs forward. Mm-hmm. Mm-hmm. As it pertains to Wilson's program, how should we think about your approach and the efficacy you guys can bring versus say, like the Alexion compound ALXN1840, as well as the most recent Ultragenyx data? Yeah. So, I think there are two baskets, I think, of generally where therapeutics fall right now in Wilson's disease, right? On the one hand, there are treatments such as Alexion's, similar to the current standard of care chelators. So, chronic therapies that are meant to sort of reduce the copper burden within individuals. You know, these are very life-extending treatments. There's no doubt about it. The chelators are very, you know, are essential for individuals with for patients with Wilson's disease and have been instrumental to the increased life expectancy. That said, I think we are recognizing that even with the existence of these effective therapies, the average life expectancy of individuals with Wilson's disease is still compromised. It's still just in its fifties, suggesting that, you know, there is not complete amelioration of disease. And it's tough to remain, you know, fully compliant with a disease-modifying regimen, where strict compliance is absolutely necessary to prevent very sort of subtle, latent, asymptomatic, but ultimately potentially lethal disease progression within the liver, right? So, I think there is definitely room for improvement in the outcomes in individuals' liver with Wilson's disease that can be offered by a one-time curative therapy. So, that's, you know, the comparison of what, you know, potentially Prime editing has to conventional standard of care chelation therapy. Now, to compare it to other attempts at one-time therapies. So, Ultragenyx's platform is an AAV-based platform. So it's an AAV therapy in which the sort of the missing gene, ATP7B, is provided episomally, via the expression from AAV. Now, first of all, because of the size limitations of the AAV capsid, the full ATP7B gene, the gene that's defective in Wilson's disease, cannot be carried in the AAV. So, it's a mini gene. And so, mini genes have a mixed track record of being able to completely recapitulate the function of a full gene. And further, mini genes sometimes do have the problem of being immunogenic because they don't look like the natural gene. In contrast, Prime editing corrects the genetic mutation in situ. So, you have complete restitution of the normal full-length gene. In addition, you have the normal regulation of that gene. So, AAV will be, you know, arbitrarily distributed amongst different liver cells. So, some liver cells may have more, some less. So, you'll have different expression levels of the protein from different liver cells. Whereas you can, you know, if you correct one mutation per cell or two mutations per cell, you'll have that very controlled recapitulation of normal function. That's from a sort of an efficacy standpoint. Oh, the last thing on an efficacy standpoint is, you know, AAV does not dilute well. So, when you have a regenerating liver, as is expected to happen if you, if you fix Wilson's disease, many patients have, you know, 40%-50% of patients have underlying cirrhosis or fibrosis. And the hope is with therapy, you actually get regeneration. With that regeneration, AAV gets diluted out and you have loss of efficacy. Similarly, with organ growth, as happens from as kids mature, you can get dilution of AAV. Because Prime editing corrects the gene in the chromosome itself, you have high fidelity replication of the therapeutic effect in all daughter cells. So, we expect no dilution effect with liver regeneration or with treatment of children. So, you wouldn't have to redose a child. From a safety perspective, you know, AAV, you know, a certain fraction of the population has already immunized to the virus. And significant amounts of immunosuppression have to be given around the administration of AAV. And it's probably limited. Redosing is probably limited because of that. Because we're dealing with an LNP here, we don't have any problems with pre-existing immunity. There's really no substantial immunosuppression required. And you know, redosing is certainly something we could consider. Cool. So maybe last question quickly, we can touch on your cash position and the runway. Yes. So, we've disclosed that, let's see, we have $245 million at our last disclosure. And our cash runway is through the first half.