Parabilis Medicines 3rd Annual Guggenheim Healthcare Innovation Conference

Yeah. Thanks for that question. Parabilis is on a journey to do something, I think, pretty unique in our ecosystem, where we've developed a platform that is called the Helicon platform. It's a special kind of peptide-related platform that allows us to access proteins inside cells that don't have traditional pockets. They don't have traditional binding cavities. So that turns out to be about 80% of proteins inside cells. Using that technology that's been developed first at Harvard for about 15 years and then starting at Parabilis about 10 years ago, it's been in development for about 25 years. I'd say at this point, it's fully reduced to practice, and it's working phenomenally well, and I think we're alone at the moment doing that.

Yeah. The Wnt/β-catenin pathway has been on the table as having a close causal association with cancers since Bert Vogelstein published in 1990. This is a well-known pathway, and most every pharma, including myself when I was at Merck and J&J, had a go at the key node, which is β-catenin:TCF, but have all come up empty. Using Parabilis' proprietary platform, we've been able to make a very, very strong, potent, selective, competitive, reversible inhibitor of exactly the interaction that everyone's wanted for a long time.

Yeah. Excellent question. I think for us and for maybe in oncology in general, there's certain indications where if you're sitting on a mechanism like β-catenin:TCF, zolucatetide, there's certain indications that are the best test beds and represent substantial unmet need because testing is likely unnecessary because the population is homogeneously driven by the particular pathway that you're trying to modulate. That's the case for us with desmoid tumors, FAP, adamantinomatous craniopharyngioma, ACP. Those three, and there's potentially more than that, are homogeneously driven by either β-catenin or APC mutations. They made a lot of sense. There's a whole suite of indications that are rare and also homogeneous and less rare and less homogeneous, like hepatocellular and colorectal, that are right there waiting for us to complete our first wave.

Yeah. First of all, we have gotten to know the desmoid community particularly well through the foundations, the patients, the patient journey, the plight of these poor patients. They are phenomenally painful or debilitating tumors that really have no great therapies today. There are gamma-secretase inhibitors that are ones approved and ones coming that have been approved for treatment, but they are not optimal with respect to either efficacy or safety tolerability. What we see right now is we have been able to dose our zolucatetide, our β-catenin:TCF inhibitor, in a manner where we see highly differentiated efficacy and highly differentiated safety tolerability, offering these patients something that is far more definitive for their illness than has been available to them in the past. We are feeling really good.

The achievement of getting zolucatetide was a big deal, but the achievement now of having dosed 76+ patients now and having a very nice induction maintenance dose selected, agreed with FDA, that maximizes efficacy and minimizes any safety tolerability and creates this well-tolerated medicine, that is a second great achievement. Because sitting here three, four years ago, that was not self-evident that that would be achievable. We are very proud of that going into the phase III study that we are calling PEDESTAL, and we are still committed to initiating that study in the first half next year.

There are three learnings since the S-1 published in June of this year that are new learnings. One is that we have agreed a dose and schedule regimen with FDA. That is a big deal, and that was the result of a very carefully constructed dose optimization study with three arms, looking at induction maintenance. That is number one and very important because now that enables us to take the next step forward, of course, with a global registrational study. We are looking to have this product approved globally. Second, we have more than doubled the safety database. It is a novel mechanism, and we have gone from a fairly large database to twice or more that database with this update. We have seen no new issues at all, and it continues to be well-tolerated, well-managed safety profile.

Third, we have more modestly increased the amount of efficacy data that we have seen, looking at extensions beyond what we were able to cut in February, which was the June disclosure, to now, where we continue to see just incredibly good efficacy. We were able to report at 24 months a 62% ORR, and at 32 weeks, we were able to see a 72% ORR. Generally speaking, patients come on this product, zolucatetide, and generally speaking, they all move downward in their tumor volumes and tumor diameters. All the symptoms, all the discomfort, all the debilitation that comes from having desmoid tumors is because these tumors have mass that push into adjacent tissue. It could push into your trachea and deviate it and keep you from breathing. It could push into your chest wall and cause just exquisite pain.