Deck Review with Alector
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Alector is a biotech company developing new medicines for neurodegenerative diseases. Founded in 2013, the company is pioneering neuroimmunology in drug development. Founded and led by Arnon Rosenthal, who played an important role in the development of Fremanezumab for migraines and being a leader in neuroscience in general, Alector has a broad pipeline of clinical drugs to activate microglia to treat Alzheimer’s, frontotemporal dementia, and beyond.
The first slide of their latest corporate presentation clearly lays out the mission of Alector. Pretty inspiring.
Then the company uses genetic information to communicate their clinical strategy of focusing on microglial activation. GWAS studies in Alzheimer’s patients have the majority of disease-driving genes related to microglia, which make up ~10% of all brain cells and are responsible for reducing inflammation and managing infections - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653290/
With a simple but powerful mission and the scientific basis of their approach clearly laid out, Alector brings it all together to position themselves as a leader in a new field in neuroscience: neuroimmunology - relying on genetically validated targets, the company searches for areas for immunology and neuroscience overlap.
With this approach, the company has built out a pretty broad pipeline of medicines targeting new targets like TREM2 and older ones like Progranulin. Pipeline slides are pretty straightforward but companies pursuing entirely new classes of biology or pipeline-within-a-drug can do land grabs across multiple indications. This often compels incumbents to want to work with a smaller upstart to gain access to new inventions and discoveries. Another way to put it, is that this is a pipeline of futures.
Alector’s lead product is AL001, an antibody to inhibit Sort1 that reduces Progranulin (PGRN) degradation, a secreted protein expressed by neurons, microglia, among other cell types to upregulate the inflammatory response, to treat frontotemporal dementia (FTD). Genetic studies suggest that reduced or KOed PGRN levels are causal of FTD. So the idea for AL001 is to maintain the activity of PGRN to increase the activity of microglia in FTD patients. The slide lays out the drugs mechanism while mapping out the market opportunity in terms of patients and need.
Then Alector connects the idea of maintaining PGRN levels to FTD.
The antibody inhibits the Sort1 receptor to reduce PGRN degradation.
In models, Alector’s antibody shows clear increases in PGRN levels.
The next slide is the milestones for the product. The advantage of focusing on genetically-validated targets is that pivotal studies can recruit patients with particular mutations and hopefully increase the odds of success.
The final set of slides is centered around the phase 1 data for AL001 that established its safety and validates that it works through the project mechanism of increasing PGRN levels. The initial data shows that the antibody restores PGRN levels within a few days of dosing.
The next slide shows that AL001 can restore PGRN levels back to normal for 5 patients with GRN mutations suggestive of FTD.
Alector is able to replicate the data in non-human primates in humans for restoration of PGRN levels. This is the key experiment to suggest that AL001 has a good shot at showing efficacy in a phase 2 trial.
The secondary assay is to show that Alector’s lead candidate produces changes in gene expression across a set of biomarkers known to have a role in FTD.
Another secondary marker is NfL levels, a gene found to be elevated in FTD patients.
In 5 patients, Alector shows that AL001 decreases NfL levels ~14%.
Like every great life sciences company, the deck concludes with its milestones across its product pipeline.
The deck is extremely clear. The business model is so simple and unique: genetic studies have shown the microglial genes have a major role in neurodegeneration. Alector designs antibodies to drug those targets. With this approach the company is one of the first, and likely the most successful, company to build a pipeline of neuroimmunology drugs.
The initial data is safe and suggests that its lead candidate works as expected. Efficacy readouts will come down the line. From a business perspective, Alector’s leadership position in neuroimmunology sets it up for more partnerships across neurodegeneration and the potential to dominate a new field.
Follow up questions for the team:
Trials in neurodegeneration become very expensive in phase 2/3 trials. How does the company plan to finance them? Solely through equity-based financing, partnerships, or something else?
What sort of initiatives like large-scale sequencing projects and patient-advocacy is Alector planning to aggregate more patient data discovering/validating new targets and making trial execution easier.
For Alzheimer’s in particular, what types of endpoints and controls will be laid out for the pivotal study? Any use of synthetic controls? Beyond the underlying biology, trial design can lead to a promising drug failing.