SNSE Morgan Stanley 24th Annual Global Healthcare Conference

Okay. Good morning. Thank you everyone for joining here for the third day of the Morgan Stanley Healthcare Conference. My name's Jason Russell. I'm managing director with the team. It is a pleasure to be joined by CEO Anand Parikh, CEO of Faeth Therapeutics. First time joining the conference, first time being Faeth, I think, at this time of the year, so it's exciting. You've got a big period in front of you moving quickly, so I think it would be great to get oriented. Let's jump right in. Maybe at the 10,000 foot level, you're a new public company under this name. Maybe give us perspectives around the two or three minute overview of Faeth and what you're trying to do.

Yeah. Faeth's a company focused on multi-node inhibition of crucial cancer pathways. We're starting with the PI3K/AKT/mTOR pathway, which is the most frequently mutated pathway in all solid tumors. It's actually a pathway that was discovered by my co-founder, Lew Cantley. We have two drugs, sapanisertib and serabelisib, which inhibit PI3K alpha and mTORC1 and 2. Those drugs have shown a 47% overall response rate in a phase I-B. We're excited about some data that's coming up here at the end of the year in endometrial cancer. We believe that multi-node inhibition of the PAM pathway has been de-risked, but that there are some important challenges still to be addressed, including oral administration, lower rates of stomatitis with no prophylaxis, and also greater target coverage.

That's really what we think we can bring, is really unlocking the promise of the PAM pathway and hopefully other pathways in the future as well. We're well-funded with about $186 million as of the end of Q2, which is more than enough capital to get us through the endometrial phase II readout at the end of this year, and then a phase I-B/phase II in breast cancer at the end of next year.

Great. That's a great summary. Maybe to dive in on the pathway, so the PAM pathway, to your point, it's been something that's studied for decades at this point. Your approach is pretty unique in trying to inhibit across the PI3K/AKT/mTOR pathway all at once. Why is that going to potentially produce a different outcome here? Maybe underlying my question is what's the value of being across all the nodes versus a single node?

Yeah. I think the way we look at it is that single node inhibitors are really partial pathway inhibitors. They don't fully shut the pathway down. When you do that, you don't have a solid lower bound to your therapeutic window. It means that the only way you can drive any efficacy is by continually dosing up. When you do that, you see challenges in terms of toxicity. That's really what's bedeviled the PAM pathway for a long time, is the toxicity associated with single node inhibitors. We believe, paradoxically, that multi-node inhibition, hitting the pathway at more points, but at lower dose, is actually going to provide better efficacy and better tolerability. I think we've borne that out, and some of our competitors have borne that out in clinical data.

Got it. So better tolerability, better pathway inhibition, don't have to be as at high a dose because you're across the pathway. This is quite simply just finding a way to prevent the tumor from having a workaround, being across all nodes.

It's something that we've seen in other pathways, right? Even if we look at KRAS inhibition, instead of inhibiting just G12D being pan-KRAS.

Yeah. BRAF-MEK. This is a story that's been told many times in cancer.

We see that with these evolutionarily conserved pathways like PI3K, that inhibiting these pathways up and downstream often leads to better results from an efficacy and a toxicity perspective.

Got it. Let's get deeper. On the dosing strategy, the PK strategy, it is somewhat unique. You talk about maximizing your time above the IC90, avoiding the peaks, rather than in most oncology development we are always just trying to take it to the MTD. There is the intermittent dosing concept as well. Walk us through that and again, what you hope to see out of that.

Yeah. Maybe I will start with intermittent dosing. The PAM pathway is such a central regulator of homeostatic metabolism that really inhibiting it 100%, 7 days a week, 365, is going to cause tremendous toxicity. What we have seen with gedatolisib and capivasertib to an extent, is that you can have intermittent dosing. Gedatolisib is dosed once weekly and falls below IC90 relatively quickly. Capivasertib is dosed 4 days on, 3 days off. We dose 3 days on, 4 days off. It has been proven time and time again in breast cancer that this pulsatile dosing can work for this pathway. We are really excited about bringing that to bear in an oral package. You mentioned the unique PK profile that we have, even within the context of pulsatile dosing. Since we are not intravenous, unlike gedatolisib, it has a very high Cmax, actually about 50X IC90.

We are never more than 2 to 3X IC90, and that means that we avoid some of the toxicity seen with that drug, particularly stomatitis, where they have a prophylactic regimen and still see significant stomatitis well above 50% and 20% grade 3. We, on the other hand, have very low-grade stomatitis, sub 20%, with no grade 3 at this point. That is one of those things that I think is a very meaningful differentiator for patients. The other nice thing about our PK profile is we have much greater coverage above those critical thresholds like IC90. I always say internally, cut the peaks but not the coverage. We have 2 to 3X greater duration above IC90, which typically, as you know in oncology, translates to greater efficacy.

Right. Okay. I do have to compliment you, by the way, whoever came up with the decision to name it PIKTOR, it is impossible to forget. Kudos to you for that. The oral, just to pull the thread just a little bit more, how important is that? We are going to get to endometrial and breast in a second, and there are other places this could go, but just from a combinability perspective, where the landscape is going, how important do you see that attribute?

Yeah, particularly in breast cancer, we think oral is crucial. Duration on therapy for these patients is significant, and if you also get in the mindset of a patient for a second, maybe you've been on adjuvant therapy for a number of years. You had a recurrence several years after you finished adjuvant therapy, usually. In first line, you've been on CDK4/6 plus AI, again, oral therapies. You're not sitting in an infusion chair three days on with a port, potentially, right. So the treatment burden feels very different for an oral therapy than it does for an intravenous therapy. We think that's important for these breast cancer patients. We've seen it in our own trials in breast cancer. These patients don't feel the same treatment burden as they might in other diseases where they're willing to sit in an infusion chair.