Welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a Biotech Analyst with Cantor. With us, we have Alector, and I'm pleased to introduce Dr. Arnon Rosenthal, CEO. Let's start off with an introduction of yourself, followed by a snapshot of the company, and just sort of touch on the milestones that are going to shape the company over the next 6 to 12 months or 12 to 18 months.
Great. Thank you for hosting me, and welcome everyone. That's one of the more crowded biotech chats that I've been at. Alector is a neurodegeneration-focused company. We've been around for a decade now. We've taken six drugs to the clinic, and we are now developing a portfolio of antibodies, enzymes, and nucleic acid therapeutics that are propelled by our blood-brain barrier technology. Our most advanced drug is an anti-Aβ antibody that we think combined like possibly best-in-class features. It recognizes the pyroglutamate epitope on the Aβ that seems to be the most potent epitope for Aβ plaques. It has a potent blood-brain barrier technology that uses the transferrin receptor as a Trojan horse, using a unique epitope that maximizes brain penetration and at the same time significantly reduces the anemia risk that's associated with transferrin-based brain shuttles.
It has a full effector function that would ensure complete removal of Aβ plaques, and because of its potency, it's targeted to be delivered monthly subcutaneously. This drug is designated to be in the clinic by April next year. Our next set of drugs are brain-enabled siRNA programs. We have Tau siRNA, that's a knockdown siRNA, and that knockdowns Tau mRNA in non-human primate by over 70%. Again, it's going to be monthly subcutaneous delivery. We have an alpha-synuclein siRNA that knocks down mRNA in non-human primate by over 90%. Again, it's going to be subcutaneous every three or six months delivery. We have a GCase, which is a lysosomal enzyme replacement therapy. GCase is the most prominent genetic mutations that leads to Parkinson's disease and Lewy body dementia.
We are the first, I think, and as far as I know, the only one who were able to engineer a very unstable enzyme to make it 50 to 100 times more stable and link it to our potent blood-brain barrier technology, enabling peripheral delivery of this lysosomal enzyme. So we have a portfolio of, again, enzymes, antibodies, and nucleic acid therapeutics that are going into the clinic.
All right. Can you just give us an overview of your ABC platform? What makes it able to address the hurdle of the blood-brain barrier, as well as target selection for transporting therapeutics across the blood-brain barrier and modalities that can leverage it?
Our platform is based on the transferrin receptor. As you know, the transferrin receptor is expressed on the blood-brain barrier. The brain requires iron for functioning, and we, as multiple other companies, are using the transferrin receptors that normally transport irons from the blood to the brain as a Trojan horse to deliver drugs to the brain. We are using this shuttle, again, to deliver antibody therapeutics, primarily anti-Aβ antibodies, enzyme therapies, the GCase is an example, and multiple nucleic acid therapies. We are, again, as I mentioned, developing Tau siRNA, alpha-synuclein siRNA, NLRP3 siRNA. NLRP3 is a major anti-inflammatory or inflammatory mediator in neurodegeneration, as well as multiple other targets. We tailored the technology for each drug modality. Although we are not the only one who are using transferrin as a Trojan horse, what's unique with our technology is the tunability.
Means, again, for each drug modality, we are using different shuttle structure, different affinity, and most fundamentally, we are using a unique epitope on the transferrin receptor that again maximizes brain penetration, while minimizing the intrinsic side effects associated with transferrin receptor, which is the anemia. Specifically, the epitope that we are using on the transferrin receptor significantly reduces the ability of the drugs to simultaneously bind reticulocytes and immune cells. Anemia with this technology is caused when you have a drug that on one end binds the transferrin receptor, and on the other end has the ability to recruit immune cells to the drug. You need it because in the brain, for example, when you want to remove Aβ, you want that drug to bind the Aβ from one side of the antibody and then recruit immune cells to eat or remove the Aβ plaques.
But the same mechanism also recruits immune cells to reticulocytes, and that's what causes the anemia. The specific epitope that we are using largely prevents that or avoid it. When the drug binds reticulocytes, its ability to at the same time recruit immune cells is significantly reduced. At the same time, when the drug binds Aβ plaques in the brain, yet it retains full ability to recruit immune cells. We have a full functionality with regard to removal of Aβ plaques, but significantly reduced adverse effects. What's unique in our technology is really the epitope. The epitope enables us to use a much larger range of affinities, which enable optimized brain delivery for different drug modalities. We think we really have proprietary good technologies, again, that can deliver antibodies, enzymes, and nucleic acid to the brain at very high potency and safety.
Let's get into your amyloid beta program. Lead candidate is AL137, which is, as you mentioned earlier, it's going to enter the clinic in April. Let's just go into the details of this molecule and why you believe it's designed to overcome shortcomings of the first, second, and third generation amyloid betas.
The first generation of anti-Aβ antibodies, as you know, are antibodies without brain shuttles. These are lecanemab and donanemab, and both of them basically remove Aβ plaques over a period of 18 months. They show modest clinical benefit of slowdown in cognitive decline of 25%-30% over 18 months. Until very recently, they were delivered by intravenous application, which is not very convenient, requiring infusion centers. The main safety issues with this type of drugs is the ARIA, basically, the antibodies likely bind Aβ plaques on blood vessels, recruit immune cells to the blood vessels. The immune cells release inflammatory mediators, cause leakage of blood vessels, and that's what cause basically brain inflammation and blood leakage. That's a major side effect of the first-generation drugs. Roche developed a second generation anti-Aβ drugs with a brain shuttle.
These brain shuttle-enabled drugs remove Aβ plaques at least 3 times faster than the naked antibodies. It removes Aβ plaques more extensively. The ARIA-related side effects largely disappears, likely because of the mode of entry of the antibody drug to the brain. But instead, what they now see is cases of anemia and significantly higher cases of infusion reactions, and the drug is still being delivered intravenously, and because of the infusion reactions, patients require IV steroid pre-treatment. Even though the drug shows significantly increased potency, it's still being delivered IV, which is not convenient, and it is associated with anemia and infusion reaction-related adverse effects. To overcome these issues, there is, in a way, a third-generation group of drugs that Denali, AbbVie, Korsana are developing, where in order to reduce the anemia risk, they crippled the ability to recruit immune cells.
They basically reduce the potency of the antibody to bring immune cells to the target. This indeed leads to better safety, like there is reduced anemia, but the same mechanisms that recruit immune cells to reticulocytes is also required to recruit immune cells to Aβ plaques. As a result, you basically increase safety, but you significantly reduce efficacy. We didn't really want to pay in efficacy for safety. That's why we really developed a unique epitope on the transferrin receptor that enables us to really retain a full ability to recruit immune cells with significantly reduced anemia risk. We think we have the best of both worlds. We have maximal potency because we have a full ability to recruit immune cells, and we have very manageable safety because our epitope on the Aβ, on the transferrin receptor enable significantly reduced anemia.
So again, the potency of our antibodies will enable very low dose subcutaneously monthly delivery. The unique epitope, we think will reduce both the anemia-related adverse effect and the infusion reactions-related adverse effects. Again, sort of the unique epitope on the Aβ plaques, we think will be significantly more potent or possibly more potent than donanemab.
Right. AL137 targets pyroglu. Donanemab, de- risked the target, but what's your rationale for choosing that versus another Aβ species? Sorry, epitope.
It's a great question. If you look at the naked antibodies, if you compare donanemab to lecanemab, donanemab which binds the pyroglutamate versus lecanemab, which bind a general N-terminal aggregated Aβ. Donanemab reduced Aβ faster and incrementally showed some better clinical outcome. So it suggests that the pyroglutamate, which donanemab is targeting, is a better target. The pyroglutamate is only present in Aβ plaques and in fibrils and protofibrils. It's not present as part of a monomeric Aβ. So we think it's specifically targeting the toxic versions of Aβ, which tends to aggregate, and it spares the monomeric Aβ that's not toxic, and it's present also in the blood or in the serum. So targeting this epitope, I think, will lead to faster Aβ plaque removal. It's not going to be sequestered in the periphery because this epitope is not present in the periphery.
Overall, I think that it's a better epitope, but it's a good question whether the brain shuttle will really nullify these differences.
All right. Going into some of the details of the exposure levels in preclinical models, what gives you confidence that you tune the affinity of a transferrin binding module for optimal delivery into the brain?
Yeah. We compare the whole range of affinities, and we compare to what's published in the literature and what we can discern from the trontinemab exposure, and from what we can tell from non-human primates, our technology can deliver several-fold more antibodies to the brain compared to any competitor that published data in non-human primates. If we look at brain exposure, if we compare trontinemab to our drug, we see significantly better brain exposure. It's half the dose of trontinemab when we deliver subcutaneous, versus the IV delivery of trontinemab.
Basically, based on multiple non-human primate studies and based on multiple modeling that we have done, and based on published information that we have collected, the epitope that we are using, the affinity that we are using, the binding kinetics that we are using to the transferrin receptor leads to several fold better brain exposure compared to other drugs that we know of.
All right. The epitope, the transferrin binding module binds to, may impact safety profile, like we discussed earlier. Preclinical data, what does this suggest about AL137 in terms of safety?
Yes. We see if we compare the same affinity of binding to transferrin receptors, what we call the exposed epitope that Roche and Denali Therapeutics and Korsana and AbbVie are using, to our masked epitope, we see that at the same affinity, our epitope is significantly safer. In non-human primate, the companies that are using the exposed epitope, we see significant reduction in red blood cells, significant reduction in hemoglobin. We do not see it with our masked epitope. We think that our epitope is significantly safer, and this enables us to go to significantly higher affinity of transferrin binding. The higher affinity enables, again, several fold better brain penetration. Basically, we can gain much better brain penetrations with much more manageable safety profile.
Part of the target product profile is a monthly low dose subQ. What are the properties of the antibody that will facilitate this, and how can a low dose impact the adverse event profile versus other transferrin binding platforms?
The properties of the antibodies that enables us is, again, it is a very high potency in brain penetration, and the general drug features, it is easy to concentrate it to at least 150 mg per ML, which enables subcutaneous delivery. We calculate that with 2 ML injection, we can reach significantly above the calculated efficacious dose. The potency of the antibody, the ability to enter the brain at high concentrations, and the ability to concentrate the drug that is a pharmacokinetic feature is ensuring that we can deliver it subcutaneously. I think that significant portion of the side effects, for example, the anemia related adverse effect, are associated with what is called the Cmax, the highest level of the drug can reach in the serum.
When you inject intravenously, you reach much higher level of maximal level of drug in the serum compared to subcutaneous injection, that is at least tenfold in what is called Cmax, so the higher level of antibodies that can be reached. Subcutaneous delivery, as a result, is much safer. You do not reach higher level that elicit adverse effects. You reach a much lower chronic dose. In the periphery, our drug does not reach high dose, and it is therefore much safer. But in the brain, the exposure is much better than IV delivered drugs. We have a really good combinations of relatively low exposure in the periphery that mitigate adverse effects, and very good exposure in the brain that facilitate efficacy.
Right. You are starting a phase I in Australia in April. How wide of a dose range will you be evaluating? Is it going to be IV or subQ?
All our doses are going to be subQ from the very beginning, like in healthy volunteers and then in patients. We are only delivering subQs. Based on our non-human primate studies and modeling, we are quite certain that we can reach efficacious dose very easily with regular subcutaneous delivery. We are planning to test at least four dose cohorts, both in the healthy volunteers and then in the patients at threefold increments. Again, we have extensive modeling of what we consider to be the efficacious dose. So it's going to be two doses from each side of the efficacious doses, like threefold increments.
Okay. Hematological AEs will likely be the key events that you'll be looking out for. Were these AEs observed in other phase I SAD studies for other platforms? What percent of subjects experienced, if so, these AEs, and what will you find as an acceptable level?
Adverse hematologic events are considered if you reduce red blood cells count or hemoglobin, I think by more than 15% or 20%. We have not seen it in our non-human primate studies. We see transient reduction in reticulocytes that recovers very quickly and do not lead to adverse events in red blood cells or hemoglobin. In the clinic, Roche with donanemab reported somewhere between 10% and 20% anemia rate in their phase I and phase I-A or II. I think that they argue that it's manageable. The fact is that in the clinical trials, in all the Alzheimer clinical trials, there is significant underestimations of the anemia rates. In Alzheimer patients, the anemia rate is about 30%. In the clinical trials, the anemia rate is about 15%.
A lot of the more severe anemia patients are being excluded as part of the general health exclusion.
I got you.
Criteria. I think the clinical trial really underestimate the issue around anemia, and I think once Roche or other companies going to the real world treatment, the anemia rate could go significantly higher. It is an issue, even though in the clinical trial setting it is manageable.
Okay. Key gating factors to actually initiating the phase I?
Yeah, the only key gating factor for us now is completing the manufacturing. We have very good manufacturing process of very high yielding cell lines. Again, we are able to concentrate the drug to high concentrations that's very amenable to subcutaneous delivery. It's just the time that takes to manufacture clinical drug to start the clinical studies.
Then you are planning to move into a phase I-B MAD study in Alzheimer's patients, 3Q, is that correct?
Yes.
What's the overall design?
Again, it's going to be four cohorts. It's going to be 15 patients per cohort. It's going to be placebo controlled. It's going to be at least six months treatment with open label extension. It's going to be monthly dosing, and we are going to frequently look at Aβ plaque reduction with PET imaging every two or three months. We are going to look at multiple serum and CSF biomarkers, including p-tau217. That's a good indications of Aβ plaque burden. We are going to look at anemia rate, infusion reactions rate, ARIA rate. With this phase I-B will have, I think, a pretty extensive package of biomarker and imaging-based efficacy and a pretty good safety analysis.
You said it is a six-month study. Will you go to completion before we start seeing data, or is it possible
No, we are going to, I think, report data as an ongoing basis as we generate them.
Right. Can you just remind us how quickly donanemab reduced plaque and changes in p-tau217 levels?
Roche reported that after two injections, almost 40% of the patients went down to basically below Aβ positivity by PET imaging. By six months, I think over 90% of the patients were below Aβ positivity. So within three to six months, you should see statistically significant reduction in Aβ plaques. For tau, even after the first injection, you start seeing reduction in Aβ, in phospho-tau-217.
Yeah.
Even after the first injection, you see reduction in phospho-tau. After six months, donanemab reported, I think, 51% reduction in phospho-tau. We do expect to see reduction in phospho-tau within, again, three to six months period.
All right. The first study, the SAD, is in Australia. The second one, phase I-B, will be?
The phase I-B will be in multiple sites in the U.S., means just it's faster and easier to do the healthy volunteers in Australia. I think 50%-70% of the phase I's.
Yeah.
Are now conducted in Australia. For Alzheimer's patients, Australia is a relatively small population. There are 20 million people in Australia, so it's harder to find patients, so we are going to go back to the U.S. Although we conducted two Alzheimer's trials in the U.S. in the past, we may keep some sites in Australia, but the bulk of the trial will be in the U.S.
Okay, last several minutes, let's just touch on the tau knockdown program. You generated a lot of preclinical data. What are the key data points that you'd like to highlight about this program?
Yes, we have generated data. We show the non-human primate that by subcutaneous delivery, we can reduce Tau mRNA by 70%-80% in every brain tissue that we analyzed. The drug appeared to be generally safe, means the effect is durable, means we have measurements of up to three months, and the reduction in tau is sustainable. We think that we have a durable, potent drug that can be delivered subcutaneously, peripherally, and I think it's going to be a very competitive tau drug. As you know, Biogen and Ionis have reported ASO that's delivered intrathecally. They did show significant reduction in tau by PET imaging, by soluble biomarkers. I think they show consistent positive clinical trends.
Yeah.
It didn't reach statistical significant, and the higher dose did not do as well as the lower dose. There are some questions on the trial, but I think overall, in my view, it was a positive study. It's, in my view, possible that the intrathecal delivery was associated with some of the confusing data and maybe the less than stellar efficacy results. Intrathecal delivery was shown to be, in some cases, associated with confusion.
Yeah.
That really is a counterindicative for Alzheimer's disease. It's possible that, again, peripheral delivery of Tau siRNA that's homogeneously distributed throughout the brain does not lead to side effects that intrathecal delivery could lead to significantly better efficacy and safety. I'm very optimistic about the Tau program.
When can we expect it to enter the clinic?
Yes, by next year, sometime next year.
Okay. In the last two minutes or so, how are you thinking about BD? Are you looking at partners to partner on specific candidates, or are you looking for?
Yes, there is a lot of inbound interest in partnering. We are focusing on actually partnering our Parkinson's programs. We didn't talk about our GCase enzyme replacement therapy. We just mentioned it at the beginning, and maybe then Tau siRNA that's brain enabled. Again, we just put a new corporate deck on our website. We show that by subcutaneous delivery, we can knock down the alpha-synuclein by 95%, 94%. It's very potent. We have very potent alpha-synuclein siRNA. We have, I think, first-in-class GCase enzyme replacement therapy, and we are focusing on really partnering these assets, and there is a lot of interest, and we are targeting to have a partnering deal by the end of this year.
Perfect.
And the Alzheimer's programs, we are going to retain and take them.
You're going to retain that, all right
Parkinson's disease is a great indication. There are like 10 million Parkinson's patients worldwide, but the clinical trials are a lot more complicated. There are no imaging tool, there are no biomarkers. So you really need to run a complete clinical trial, and large pharmas are better set to do that. Alzheimer's now, the imaging tools, the biomarker tools, are much more established and look forced with a small cohort as a short clinical trial. You can look at the efficacy.
Yeah.
So that's.
All right. So if we're sitting here 12 months from now, what would you like to say your key value-creating accomplishments have been over the past year?
Yes. We will have complete set data of our anti-Aβ antibody in healthy volunteers, which show exposure in the CSF and serum, which show safety, again, anemia, infusion reaction. So we'll have pharmacokinetics and safety in healthy volunteers. We will start having data in patients like the first or second cohort that actually should possibly start showing a biomarker-based clinical outcome with PET imaging and with soluble biomarkers. So we'll have a complete data set in healthy volunteers and an initiation of data in patients. We will advance Tau siRNA, alpha-synuclein siRNA, and GCase toward the clinic next year. So we'll have, again, four programs that are either in the clinic, in patients, or are becoming very close to the clinic.
Well, I would like to thank you for participating in the Cantor Healthcare Conference. Always love seeing you. Really excited to see the ABC platform go into the clinic and see those full results next year.
Thank you.
Looking forward to watching all the progress. Thanks.
Thank you.