GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - BEAM THERAPEUTICS INC

All right, welcome everybody. My name is Anger, I am with here at Guggenheim. I'm going to be leading the discussion today and joining me today is Giuseppe Ceramella, president of Beam. So maybe just to kick things off, for those of us who are not very familiar with the company, just overview where the company is and maybe what's currently happening. Yes, Beam Therapeutics is a company based in Cambridge and uses next-generation gene editing technology, primarily called base editing. And this technology is a CRISPR editing technology that has improved the CRISPR technology in two important ways. The first one is it uses the ability of CRISPR to land on a specific spot in the DNA just by changing a small stretch of RNA, which is almost a miracle, I think, sometimes when I think about it. But we have eliminated the ability for that protein to make double-stranded breaks. And we feel that that brings a lot of advantages because double-Stranded Breaks typically create some degree of genotoxicity in the cells, and so we avoid that. But then what we've also done, we've attached to an additional human enzyme to that Cas9 protein, which is called the deaminase. And what that enzyme is capable of doing is actually directly on the DNA changing the chemical structure of one base to another. So we can change an A to a G or a C to a T. And obviously because those pairs are present pretty much in every base pair, we have a lot of flexibility in terms of the edits that we can make. And so we are now, we're a clinical-phase company, and we have four programs in clinical development spanning from an ex vivo product for sickle cell disease, and then in vivo LMP-based technology for correcting the mutation of several liver-based gene-metabolic disease Fantastic. So, there was some data released this morning, exciting data about sickle cell disease. Can you just walk us through that and how is that important? Absolutely. I mean, we're extremely pleased to share the fact that the BCOM trial, which is a trial for RistoCell, this is the ex vivo product for sickle cell disease, has met all the primary and secondary endpoints, both in terms of efficacy as well as in safety and so we remain on track to file the BLA the first BLA for the company so that's an important milestone as early as the end of this year and we have demonstrated you know through a variety of different data reporting that Ristocella actually has a very differentiated clinical profile achieving the highest level of hemoglobin F that has been reported so far and as a consequence of that also ensuring that we reduce the hemoglobin S to less than 40% that that in itself is very important and that we've optimized the manufacturing process very significantly to the point that it is fully automated and that gives us a much greater reliability in terms of the product that we make which has been one of the challenges with the existing products like Casgervie and Lifgenia and to some extent contributed to the slow uptake of those programs. So you mentioned you have both ex vivo and in vivo, can you just maybe talk about where each one of those is? Yeah, for the next more advanced program is the program that we call BEAM302. This is actually for the correction of the single permutation that causes alpha-1 antitrypsin deficiency. This is a protein that is made in the liver, but its job is actually to be secreted from the liver going to the lung and protect the lung from the unchecked activity on neutrophil elastase. And as a consequence of that mutation, this protein misfolds. It accumulates in the lever and so causes toxicity to the liver. But importantly, it doesn't go into the lung to protect the lungs. And so these individuals over time develop emphysema. Literally, the density of the lung is reduced very significantly, to the point that obviously can lead to premature death. This program is actually now in the pivotal phase. We have achieved agreement with the FDA about an accelerated approval path, and so we move in very steadily through this, and we've announced actually most recently that we expect completion of that pivotal phase in the first half of next year. So that's really a very important disease with an unmet medical need. There is only an enzyme replacement therapy that's available for these patients, but that does not lead to cure. It actually slows the progression of the disease, but ultimately does not halt it. And so we're really the most advanced program for the correction of this disease. The other one is what we call BIM 301. This is basically the correction of a point mutation called R83C, which causes a mutation in the glucose 6-phosphatase enzyme to the point that individuals affected by this disease, they cannot fast. And so they actually, for night and day, need to go on a very heavy cornstarch diet every two to three hours in order to avoid hypoglycemia, which can be fatal in these individuals. And as you can imagine, it starts even from a young age, it impacts the entire family. The parents often comment that they cannot sleep because they worry that they may not hear the alarm and not feed their child and then find them dead by the following morning. So that's progressing. It's a rare disease. We are now completing dose escalation and going to the 60 mc sort of treatment dose. But we have demonstrated already at the 40 mc that there are two individuals who could actually go without any feeding for 15 hours, as opposed to two hours, which was the maximum before they went to a hyperglycemic levels prior to the treatment. That's really transformational for the lives of these patients, because now for the first time in their life they can actually sleep throughout the night and without worrying about a hyperglycemic crisis that could cause them to die. And is those 15 hours limited by the protocol? Yeah, so that was the maximum basically that the protocol allowed. So potentially they could have gone even longer, but frankly who wants to be without food for more than 15 hours. So that's basically it, and we will see. And obviously, there was one individual who did not respond as well. That individual is a compound heterozygote, so they have a single copy of the mutation, but also had a very high BMI. They were a BMI of 53. And so it remains to be seen as to which of those two things, if not both, have contributed to that lower response. And so we're now testing the 60 mgs and hopefully we will be able to dose additional patients in the not too distant future. So the patients who received lower doses, are they going to be redosed at any point? Yeah, so for all of our trials we expect eventually to provide them with the optimal biological dose that has been identified. We don't have timelines for the time being when that is going to occur, but it is our commitment to these patients obviously. You need to start with doses that are expected to provide some benefit because otherwise it's not ethical for these patients but obviously you start a little bit lower just in case for safety consideration and so we commit to these patience that we will come back with an optimal biological dose. Fantastic, so just going back to antitrypsin deficiency, you measured the amounts of protein and the reduction in the mutant protein and the kind of recovery of the wild type but what do patients and physicians care about and by extension what does the FDA care about as the endpoint for the trial so the the one of the accepted sort of protective threshold is the 11 micromolar level of total at in the blood and this has been established frankly from clinical genetics the individuals that have the disease are homozygous for the Z proteins. The Z is a misformed protein. They never reach 11 micromolar of total AAT. However, when you do that, then you are, the risk of developing emphysema or liver disease is dramatically reduced. Just to give you a perspective, a ZZ has a 35-fold higher probability of developing emphysema, in MZ individuals there's about 1.2, 1.3. And that 0.2 or 3 is if they're actually smoking or if they are heavy drinkers. If they don't do that, essentially they have no risk. And so our data clearly has demonstrated that we have restored essentially these patients in the MZ phenotype. And in fact, if you look at the ratio between M, which is the good protein, relative to the bad protein, we're actually even better than MZ. And so we have essentially eliminated the ability of the disease to continue to progress. As far as the FDA is concerned, they've seen actually our data with the 60 milligrams, which achieves that 11 micromolar or above for all patients. And that was the data set that they found approvable from their perspective. so obviously we don't comment on all the endpoints for competitive reasons but essentially the accelerated approval will be based on biomarkers and we don t need to develop any assay or new biomarker other than the ones that we already share data for. Fantastic. So maybe just going back to the FDA and the recent guides that they released about basket trials, how does that influence or how does that affect beam yeah it is definitely something that actually even our through beam 301 and 302 programs we're already starting to benefit from in the sense that because we use the same lmp rna platform we can cross reference data from one program to the other without having to unnecessarily repeat glp talk studies for example about distribution i think the most recent guidance which is obviously still draft actually goes even further than that. And in fact, we have the third program that's in clinical development. It is a program for PKU. This is a phenylketonuria, which causes, frankly, a toxic accumulation of phenylalanine because of the mutation in this enzyme that these patients carry. There is actually a large number of patients that are impacted by PKU, but unfortunately for these patients, there are many different mutations that can cause the same disease what we have agreed already with the FDA is that we actually have identified already three guide editor combination that repairs the mutations of about 50% of the patient population and the FDA has agreed to do all of those in a single IND and and also using the same clinical protocol and so that gives us the opportunity really to enter the clinical phase with the first mutation, which is R48W, which is the one that is the most prevalent of the patients, establish basically the optimal biological dose after a dose titration, and then we can go to the next mutations directly with that level without having to redo a dose titration for every single mutation. And eventually this most recent guidance goes even further than that in stating that for the very rare mutation once you've established that clinical precedence and therefore determine what is the boundaries of acceptability of that treatment paradigm it's possible to go to mutation number four five and six only within vitro data without needing any clinical data and so we think that this really continues to open up the opportunity for this essentially once it's done treatment that we have available and the range of where this can be applied now goes to the very specific single mutation all the way to very large indication like alpha 1 so really we have the opportunity to modify and really address the causes of the disease at its you know closest mechanism so that eventually we can provide lifelong cures for these individuals and we think that this is going to be a transformational medicine we feel that this is going to part of the medicine toolbox only of my children their children and and I think that that's where we see beam's future in and actually hopefully in not too many years from now so what kind of did you have to supply to the FDA to convince them to allow you the BLA for the basket BLA yeah for the sickle cell program yeah it's basically the data that we have you know already generated and published for instance at ASH and we will provide an update later on this year on that which is really showing that through the high step regulation of hemoglobin F and the consequence reduction of hemoglobin S, we are actually achieving the most complete treatment effect for sickle cell disease. These individuals have eliminated anemia. The hemoglobulin levels are back to normal. We have looked at many other different phenotypes of the blood, including reduction of viscosity and so on. And importantly, also have shown that we have the fastest neutrophil engraftment time, which is really important for the patients because eliminates some important risks like opportunistic infection and others but also to the hospital because that timeline determines how long they need to stay in in the hospital and so we feel that actually like all of these once done therapies that we can establish there will be a benefit also to their health care system in reducing the overall cost of treatment and the other important factor has been the reliability of the manufacturing process and that has been demonstrated in two things. First of all, in order to collect the cells, these individuals need to go through what is called a mobilization process. This is treatment with a compound that essentially draws the cells out of the bone marrow in circulation, so that you can generate basically the numbers that are needed in order to achieve those. Because we don't make double-stranded breaks and Bayside is so much gentler, actually we need a lot less cells to start with in in order to make the dose, and typically these cells are much healthier because they don't have these double-stranded breaks. Our manufacturing process then on top of that actually is very efficient, and therefore is capable of generating the dose much more reliably. In fact, the median number of mobilization during the risk cell trial has only been one, and with more than the vast majority requiring two or less. And so that is also an impact of our process, which has been optimized to use essentially automation from the get-go. And so it is not only more efficient, but also more reliable. So can you share how many cells do you actually need? Yeah, the dose is 3.5 times 10 to the 6, 3. 5 million cells per kilogram. And basically, you can go higher than that, that's not an issue, but really a lower than that is linked with lack of engraftment or reduction of engrafment. That's fairly standard, frankly, in the field. And in terms of pricing, how do you think about pricing one-off therapies and kind of related to that, how many patients do you have to treat with RistoCell to kind of break even? So we don't really comment on price at this point because we need to have all the conversation and the agreement as part of that. But I think it's really clearly demonstrated, and ASIC has demonstrated that even at 2 million or so, like Kastrojevian and Lefgenia, there's actually an overall net benefit for the health care. If you think about it, for a lifelong treatment for a sickle cell patient, you're probably talking about 10 million or so. And so you're saving a lot in this. And I think this is actually a general concept for this kind of once-and-done treatment. The moment that you eliminate the chronic dosing throughout one's life, actually the overall net effect, even though you have a higher initial price, is an overall reduction of the healthcare cost. Frankly, if you hear, you know, this administration actually really understands that. And part of what you're also seeing from the FDA is a recognition of the fact that we need somehow to shift to the extent possible from the chronic dosing to actually once and done. And so we'll continue to do that. Maybe just go back, actually go to kind of the legal issue that was around the CRISPR-Cas9 and the litigations and so on. Are you affected by that at all or are you protected, isolated from that? For the Cas9? So the Cas 9, we have basically the broad side of the Cas nine rights. So through a deal that we did with Editas several years ago, we have basically the rights to Class 9 from the broad point of view. And as you know, there is still an ongoing dispute between Berkeley and Broad and see where we land. But at least we're productive from that point of vue. And then we remain to see who ultimately will have the overall gain on that dispute. And we will act accordingly. but we are definitely in a very good position as far as Cas9 is concerned. And maybe just to wrap up, in the last 30 seconds, where will BNP be in the next 12 months, when we sit here again, what will we talk about? So hopefully we would have launched RistoCell already, so it depends on whether the FDA will do a priority review or not, but it could be, certainly during the course of 2027, we expect launch risk to sell and and that would be our first sort of program that we do but but also as i mentioned the pivotal phase for alpha 1 is moving very quickly we plan to those pku very very soon and then beam 301 because of its ultra rare disease status stands the opportunity to really be approved on on the basis of a relatively small number of of data points so we we feel that we have basically before the end of the the decade an opportunity for at least four programs uh to to launch and we're working very actively on many other programs and actually including the liver into tissue beyond the liver thank you very much thank you