Parabilis Medicines, Inc. Common Stock Investor update

Welcome to Parabilis phase I/II study desmoid data update at ESMO. At this time, all participants are on listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Thomas Kotarakos, Chief Financial Officer. Please go ahead. Thank you, operator.

Good afternoon and good evening to those of you here in Europe. Greetings from Madrid. Today, we will discuss updated phase I/II data for zolucatetide in desmoid tumors presented earlier today in an oral session at ESMO, along with an update from our recent FDA discussion supporting our planned advancement to a phase III registrational study. The ESMO presentation is posted on our corporate website, and you will find the press release and today's slides in the Investors section. Before we begin, please note that today's presentation and discussion will include forward-looking statements, including statements about the clinical data of our phase I/II trial, design and timing of our planned phase III PEDESTAL trial, our interactions with the FDA, the potential of zolucatetide in our pipeline, upcoming milestones, and our cash runway.

These statements are subject to risks and uncertainties that could cause actual results to differ materially, including those described in the Risk Factors section of our SEC filings. The clinical data we will discuss are interim and preliminary as of a June 22, 2026, data cutoff. Zolucatetide is investigational and not approved for any use. Except as required by law, we undertake no obligation to update or revise any forward-looking statement, whether as a result of new information, future events, or otherwise. With me today are Dr. Mathai Mammen, our Chairman, CEO, and President, and Dr. Helen Ho, our Chief Business and Strategy Officer. Mathai will take you through the data and our path to phase III, and then the three of us will take your questions. Mathai? Thank you, Tom, and thank you all for joining.

We are really excited to be here in Madrid. It has been a big few months for our zolucatetide franchise, our company and its portfolio, and our team. Today, we are thrilled to share two important updates. Earlier today, Dr. Mrinal Gounder from Memorial Sloan Kettering, presented our updated desmoid data at ESMO. In a larger data set than at the February data cut shared in our S-1, zolucatetide continues to demonstrate compelling efficacy, favorable safety, and tolerability, reinforcing what we believe is its potential best-in-disease profile. Second, following our very recent and productive end-of-phase 2 meeting with FDA, we now have a clear FDA-aligned path to phase III. Next slide. Before we dive into the data, I want to briefly remind everyone what makes zolucatetide unique.

β-catenin is a genetically validated driver of cancer, with mutations in APC or β-catenin found in more than 10% of all cancers. Yet for more than three decades, this target was considered undruggable. The interaction between β-catenin and TCF occurs across a large, flat surface inside cells that conventional small molecules just can't engage. This is precisely the kind of challenge our Helicon platform was designed to overcome. Zolucatetide directly binds β-catenin, blocking its critical interaction with TCF and the downstream transcriptional program that drives disease, regardless of whether the underlying mutation is at APC or β-catenin protein. To our knowledge, zolucatetide is the first and the only investigational β-catenin TCF inhibitor in clinical development, uniquely positioning us to directly address the causal biology underlying a range of Wnt-driven diseases, including desmoid tumors, familial adenomatous polyposis, adamantinomatous craniopharyngioma, hepatocellular carcinoma, and many more cancers.

Today, our focus is gonna be desmoid tumors, where mutations in this pathway are found in nearly all patients, making it a compelling setting to evaluate the impact of directly targeting this causal driver of disease. Next slide. What does living with desmoid tumors look like for patients? Desmoid tumors are locally invasive. They can grow almost anywhere in the body, including the abdomen, the limbs, the chest wall, the head, the neck. Patients may be living with chronic and excruciating pain, limited mobility, disfigurement, breathing difficulty, organ dysfunction, and many tell us that the disease entirely controls their daily lives, and for many, for their entire lives. There are 30,000 people in the U.S. living with desmoid tumors, with about 11,000 currently actively managed, and only several thousand of these are started on systemic therapy today. A big reason for that is today's options are not optimal.

The sponsors creating gamma-secretase inhibitors, or GSI, have been pioneers. They brought this appreciative patient population the first-ever approved treatment for desmoid tumors, and that's really amazing and a true impact on health. But the GSI treatment experience leaves substantial room for improvement on efficacy, safety, and tolerability. Side effects like diarrhea, rash, ovarian toxicity are a very real burden, especially since many patients are young women who may be thinking about starting a family. As seen numerous times in medicine, the initial approved therapy opens the door, but it's the next generation of medicine, what brings most patients through that door. We've seen this before in hepatitis C, cystic fibrosis, myasthenia gravis, and obesity.

We believe the same can happen here in desmoid. What patients need is therapy that works faster and deeper and more reliably and can be reasonably tolerated as a chronic therapy in exchange for the benefit offered. With that background in mind, here's what I want you to take away from our update today, which all reflects data from our June 22nd data cut. First, we continue to see really compelling and uniform efficacy, reinforcing the potential of directly targeting the causal biology disease. We observed 72.2% objective response rate at the 32-week landmark among response-evaluable patients who started at 450 milligrams or higher. We also observed 100% disease control rate across all 46 response-evaluable patients at those doses with no disease progressions at all.

Notably, we saw strong efficacy both in patients previously treated with GSI and in GSI-naive patients, pointing to the broad potential of our therapy across patients, regardless of past treatment history. Second, safety and tolerability remain favorable and entirely consistent with data we have reported earlier, despite a much larger data set. Side effects continue to be largely low grade. There have been no treatment discontinuations due to TRAEs. We have had no disease progression to date on treatment, and zolucatetide has not been associated with ovarian toxicity or with any high-grade diarrhea, high-grade rash, all three of which are commonly associated with GSIs. Third, we have a clear FDA-aligned path to registration. As a new update, we just had a really productive end-of-phase II meeting with FDA, where we have aligned on key components of our phase III design.

Hot off the press, we just received minutes from this meeting yesterday evening. Based on our FDA interactions, we anticipate initiating PEDESTAL in the first half of 2027 and can now share that we expect top-line phase III data in 2029. We are also continuing to recruit patients ahead of phase III and estimate that we will treat and follow about 100 patients in our phase I/II through approval, which will provide us with longer-term data as we progress through blinded phase III trial. Next slide. Let me walk you through the highlights of what Dr. Gounder presented earlier today, along with a few additional slides for context. The full ESMO presentation is on our website. Next slide. Since February, we roughly doubled the number of patients in our trial, with much of that enrollment occurring in just the last few months.

This includes patients in both dose escalation and our randomized dose optimization study, where we evaluated three different induction and maintenance regimens. The thinking behind this approach is rooted in something I believe in strongly, patient-centric drug development. Develop drugs in a way that matches the patient experience. When a desmoid patient comes into a physician, they are often in acute distress, be it excruciating pain, inability to walk or breathe, and so on. They need their tumors to shrink, and they need that relief as quickly as possible, and they also need a treatment they can stay on over the long term. That is the rationale for our induction maintenance approach. Start with a higher dose to drive rapid tumor shrinkage and symptom relief, then transition to a lower, less frequent maintenance dose that sustains and potentially deepens that response with a tolerability profile appropriate for chronic treatment.

That brings us to the regimen we have now selected for phase III, 450 milligrams weekly for 4 months, followed by 300 milligrams every 2 weeks for maintenance. This regimen is informed by arm B of our dose optimization study, which evaluated 450 milligrams weekly induction for 4 months, followed by 150 milligrams weekly maintenance. By moving to 300 milligrams every 2 weeks, we match drug exposure with half as many maintenance infusions, which is more convenient for patients participating in the multi-year phase III study. Before we transition to a self-administered commercial product, which is the plan right now, we are very pleased to have reached full alignment with FDA on this regimen for phase III. Next slide. A couple of points on the patients in this trial. They are representative of desmoid tumor patients. The median age is 37, about 70% are women, consistent with the real-world desmoid population.

We've included both treatment-experienced and treatment-naive patients. 71% had already received nirogacestat and failed that therapy. Some failed because they simply couldn't tolerate the drug, others because their tumors actively grew on that therapy. This gives us a fairly large number of patients who have failed the GSI, a population where there's been no clinical data to date. We're also seeing treatment-naive patients choosing our trial over any approved GSI, demonstrating strong demand for a new therapy. Over a fifth of our patients have never taken a systemic therapy before. Next slide. Let's start with safety, because in desmoid, tolerability matters. At our phase III induction dose of 450 milligrams weekly, side effects have been predominantly low grade, and nobody has dropped from the study due to side effects. The most common AEs during this induction phase were fatigue, alopecia, and nausea.

Notably, fatigue and nausea are associated with desmoid tumors, with high rates of both in the placebo arms for both GSIs phase III trials. We'll explore the extent to which there's a drug effect in a placebo-controlled setting. Also note that the rates of alopecia have been 20%-30% for nirogacestat and varegacestat in their phase III studies. At the chronic maintenance dose, side effects have been substantially less frequent, less severe than during induction, and generally low grade and quite manageable, which is important for longer-term treatment. We anticipate seeing significant improvements in TRAEs when patients drop from the induction to a lower maintenance dose. We also see the potential for clear differentiation from GSIs, where the recurring TRAEs reported are skin, GI, ovarian toxicity. Across all 76 patients treated, zolucatetide has shown no high-grade skin or GI toxicities, and it's not been associated with ovarian tox.