All right. Welcome, everybody. My name is [Andrzej]. I am with the [inaudible] team here at Guggenheim. I am going to be leading the discussion today, and joining me today is Giuseppe Ciaramella, President of Beam.
For those of us who are not very familiar with the company, just overview where the company is and maybe what is currently happening.
Yes. Beam Therapeutics is a company based in Cambridge, and uses next-generation gene editing technology, primarily called base editing. This technology is a CRISPR editing technology, but 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. We have eliminated the ability of 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. What we have also done, we have attached to an additional human enzyme to that Cas9 protein, which is called the deaminase.
What that enzyme is capable of doing is actually directly on the DNA, changing the chemical structure of one base to another. We can change an A to a G or a C to a T. 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. We are now, we are 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 LNP-based technology for correcting the mutation of several liver-based gene metabolic diseases. Yeah, sort of—
Fantastic. 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 BEACON trial, which is a trial for risto-cel, this is the ex vivo product for sickle cell disease, has met all the primary and secondary endpoint, both in terms of efficacy as well as in safety. We remain on track to file the BLA, the first BLA for the company, as early as the end of this year. We have demonstrated through a variety of different data reporting that risto-cel 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 in itself is very important.
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 CASGEVY and LYFGENIA, and to some extent contributed to the slow uptake of those programs.
You actually have both ex vivo and in vivo approaches. Can you just maybe talk about where each one of those is?
Yeah. The next more advanced program is the program that we call BEAM-302. This is actually for the correction of the single point mutation 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, go into the lung, and protect the lung from the unchecked activity of neutrophil elastase. As a consequence of that mutation, this protein misfolds, accumulates in the liver, and so causes toxicity to the liver. But importantly, it doesn't go into the lung to protect the lung, 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're moving 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. 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. We're really the most advanced program for the correction of this disease. The other one is what we call BEAM-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.
They actually, for night and day, need to go on a very cornstarch, heavy cornstarch diet every two to three hours in order to avoid hypoglycemia, which can be fatal in these individuals. As you can imagine, it starts even from 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. That's progressing. It's a rare disease. We are now completing dose escalation and going to the 60 mg sort of treatment dose. But we've demonstrated already at the 40 mg 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 hypoglycemic 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 hypoglycemic crisis that could cause them to die.
Are those 15 hours limited by the protocol or—
Yeah. That was the maximum basically that the protocol allowed. Potentially they could have gone even longer, but frankly, who wants to be without food for more than 15 hours.
Correct.
That is basically, and we will see. 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. It remains to be seen as to whether which of those two things, if not both, have contributed to that lower response. We are now testing the 60 mgs, and hopefully we will be able to dose additional patients in the not-too-distant future.
The patients who received lower doses, are they going to be redosed at any point?
Yeah. 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 as 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. We commit to these patients that we will come back with an optimal biological dose.
Fantastic. 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 clinical trial?
One of the accepted sort of protective threshold is the 11 micromolar level of total AAT in the blood. This has been established, frankly, from clinical genetics. The individuals that have the disease are homozygous for the ZZ proteins. The Z is a misformed protein. They never reach 11 micromolar of total AAT. However, when you do that, then 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. An MZ individual has about 1.2x, 1.3x. That 0.2x or 0.3x is if they're actually smoking or if they're heavy drinkers. If they don't do that, essentially they have no risk. Our data clearly has demonstrated that we have restored essentially these patients in the MZ phenotype.
In fact, if you look at the ratio between M, which is the good protein, relative to Z, the bad protein, we're actually even better than MZ. 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. That was the dataset that they found approvable from their perspective. 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 shared data for.
Fantastic. Maybe just going back to the FDA and the recent guidance that they released about basket trials.
How does that influence or how does it affect Beam?
Yeah, it is definitely something that actually even our BEAM-301 and BEAM-302 programs we're already starting to benefit from in the sense that because we use the same LNP RNA platform, we can cross-reference data from one program to the other without having to unnecessarily repeat GLP tox studies, for example, biodistribution. I think the most recent guidance, which is obviously still draft, actually goes even further than that. In fact, we have the third program that's in clinical development 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 also using the same clinical protocol. That gives us the opportunity really to enter the clinical phase with the first mutation, which is R408W, 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.
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 with in vitro data, without needing any clinical data. We think that this really continues to open up the opportunity for this essentially once-and-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. Really, we have the opportunity to modify and really address the causes of the disease at its closest mechanism so that eventually we can provide lifelong cures for these individuals. We think that this is going to be a transformational medicine.
We feel that this is going to be part of the medicine toolbox, certainly of my children and their children, and I think that that's where we see Beam's future hopefully in not many years from now.
What kind of data did you have to supply to the FDA to convince them to allow you the BLA?
For the—
The basket BLA, yeah.
For the sickle cell program?
Yeah.
Yeah. It's basically the data that we have 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 upregulation 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 hemoglobin 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 it 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 the hospital.
We feel that actually, like all of these once-and-done therapies that we can establish, there will be a benefit also to the healthcare 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 dose. Because we don't make double-stranded breaks and base editing is so much gentler, actually, we need a lot less cells to start with in order to make the dose.
Typically, these cells are much healthier because they do not 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 risto-cel trial has only been one, with more than the vast majority requiring two or less. That is also an impact of our process, which has been optimized to use essentially automation from the get-go. It is not only more efficient but also more reliable.
Can you share how many cells do you actually need?
The dose is 3.5 x 10^6 , 3.5 million cells per kilogram. Basically, you can go higher than that. That is not an issue. But really, lower than that is linked with a lack of engraftment or reduction of engraftment. That is fairly standard, frankly, in the field.
In terms of pricing, how are you thinking about pricing one-off therapies? Kind of related to that, how many patients do you have to treat with risto-cel to kind of break even?
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 already clearly demonstrated in ASH, as demonstrated that even at $2 million or so, like CASGEVY and LYFGENIA, there's actually an overall net benefit for the healthcare. 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, 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 issues that were surrounded 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?
Yes.
The Cas9, we have basically the Broad side of the Cas9 rights. Through a deal that we did with Editas several years ago, we have basically the rights to Cas9 from the Broad point of view. As you know, there is still an ongoing dispute between Berkeley and Broad and see where we land. At least we are protected from that point of view, and then it remains to see who ultimately will have the overall sort of gain on that dispute, and we will act accordingly. We are definitely in a very good position as far as Cas9 is concerned.
And maybe just to wrap up, last 30 seconds. Where will Beam be in the next 12 months when we sit here again? What will we talk about?
Hopefully we would have launched risto-cel already. It depends on whether the FDA will do a priority review or not, but it could be sort of certainly during the course of 2027, we expect to launch risto-cel. That would be our first sort of program that we do. As I mentioned, the pivotal phase for alpha-1 is moving very quickly. We plan to dose PKU very soon, and then BEAM-301, because of its ultra-rare disease status, stands the opportunity to really be approved on the basis of a relatively small number of data points. We feel that we have basically, before the end of the decade, an opportunity for at least four programs to launch. We are working very actively on many other programs and actually including delivering to tissue beyond the liver.
Okay. Thank you very much.
Thank you.