Alector, Inc. Common Stock 12th Annual Cantor Fitzgerald Global Healthcare Conference

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 3 or 6 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.

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 A-beta plaques in the brain, yet it retains full ability to recruit immune cells. We have a full functionality with regard to removal of A-beta 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.

The first generation of anti-A-beta antibodies, as you know, are antibodies without brain shuttles. These are lecanemab and donanemab, and both of them basically remove A-beta 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 A-beta 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-A-beta drugs with a brain shuttle.

These brain shuttle-enabled drugs remove A-beta plaques at least 3 times faster than the naked antibodies. It removes A-beta 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, Corsana 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 A-beta 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 A-beta, 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 A-beta plaques, we think will be significantly more potent or possibly more potent than donanemab.