4.28.23-Korea-4M-Therapeutics

BEN WILLIAMS: Hey, everyone. Thank you for inviting me today. Pleasure to be here. My name is Ben Williams, and I'm the head of corporate development at 4M Therapeutics. We're benefiting from a revolution in neuroscience in that we can take cells from an adult, turn them into stem cells, make neurons, and use them in drug discovery and development.

Our founders have decades of experience understanding the mechanism of action of drugs like lithium, valproic acid, ketamine, and then have done some very famous things like perhaps the largest high throughput screening in an academic setting, looking at 325,000 compounds' effects on Wnt enhancement in the GSK-3 beta-catenin kind of pathway. We have some hits from that.

Our MIT connection is through Steve and Li-Huei. Steve runs chemical neurobio at the Broad. Li-Huei is an MIT neuroscience professor who also is the director of the Picower Learning and Memory Science Institute, sorry, the Institute for Learning and Memory. Don, thought I would give him a mention, he was the president of the worldwide pharmaceutical business at Bristol Myers Squibb. He end-licensed aripiprazole from Otsuka, highest grossing drug in 2014 at $6.5 billion annual sales.

So we have a good team that has done this before. Pablo, our CEO, 25 years experience in pharma. He's gotten a few drugs approved in different indications. And he's the first person to get a CNS-specific kinase inhibitor through proof of concept. And he's here to do it again.

Our first program is in bipolar disorder. We have several assets. But our first is tackling lithium's mechanism of action. Lithium is a great drug, taken by a million people every year in the US. The problem is toxicity, thyroid, kidney problems. Atypical antipsychotics are a decent alternative but they too have black box warning, for example, increased mortality in the elderly, which obviously makes it difficult in certain populations.

So the solution is just what you would imagine, targeted therapy, something that's really specific for the target, selective, you know, for better safety and efficacy. One way to think about the opportunity is there are many different analogs in these other markets. There are no lithium analogs in bipolar.

We don't understand why. So we're here to make one. So we think it's a very good drug. It's just, side effect suck.

Some data on our lead compound, the half-life is really good, the potency of your GSK-3 beta good. Our lead was in clinical trials all the way to Phase III. 2,000 people took it for over a year.

It was very well-tolerated, which obviously contrasts with lithium. So we're excited to advance it. I'll also mention that we don't like the dirty repurpose word, especially now that we've identified a salt form with better bioavailability and a novel crystal structure that we can get composition of matter production on. So we think we have kind of the best of both situations, a de-risked opportunity from a safety point of view, which in CNS obviously a concern, but composition of matter. We also anticipate synthetic route and then formulation patents.

And one of our connections at MIT is we end-licensed a use patent for the parent and we filed one also for the primary metabolite, which is what we're advancing. Happy to talk more, talk shop, later. So we also have efficacy in animals with our lead. And we actually just ran our second compound, which is an even more potent GSK-3 and more specific GSK-3 inhibitor than even our lead. And it was also efficacious.

This is a ultrasonic vocalization model in Wistar rats, a validated model for bipolar mania and other mood disorders. The rats are given d-amphetamine and they're pretreated with lithium vehicle or compound. And you can see on the orange is more rat-positive vocalizations of excitement, a positive affect mirroring mania.

Lithium is in the gray bar. And then you can see our compound is the orange. And it's important to note that from a molar concentration point of view, our compound is about 1/1000 of lithium's concentration, which we think speaks to, again, the targeted therapy opportunity. We've checked many boxes to the clinic with our lead.

We're going to get non-GLP animal tox back in June, which a lot of folks are waiting to see, although we consider it a formality since the compound's already been in clinic. But we're excited to advance this to clinical trials. So we think we can be in clinic in less than two years.

We have some other promising compounds and hits not on this list. One targets the same kinase, GSK-3 beta, and it's perhaps the most potent and specific ever reported. We've tested it against everything else and it just kills everything. So we hope it's safe. Looking good, though. We have a glutamate antagonist as well in our pipeline.

We're looking for any and all strategic partnerships. I'm not supposed to talk about money too much, but very open-minded. We'd love to chat with anybody about especially I think if you have an interest in GSK-3 beta inhibition, and a reminder that it's a very validated target according to ChatGPT, many, many, many indications. For example there are three clinical trials in the US of GSK-3 beta inhibitors for cancer. So very interested in outlicensing opportunities as well, since we're focused on CNS. Thank you.

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