Relay Therapeutics, Inc. (RLAY) Earnings Call Transcript & Summary

Hello, and welcome to today's Relay Therapeutics Corporate Webinar. My name is Don Bergstrom, and I'm President of Research and Development at Relay Therapeutics.

And I'm Brenton Mar, Head of Clinical Development.

And today, we're going to cover in detail the disease landscape of vascular anomalies where Relay is currently developing our mutant selective PI3K-alpha inhibitor, zovegalisib. As a reminder, during this call, we will make certain statements that are considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including expressed or implied statements regarding our strategy and business plans, the expected therapeutic and clinical benefits of our product candidates and progress timing and execution of our clinical trials. Such forward-looking statements are not guarantees of future performance, and therefore, you should not put undue reliance upon them. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. Please refer to our SEC filings on our website for a discussion of risk factors. The forward-looking statements in this presentation speak only as of the original date of this presentation, and we undertake no obligation to update or revise any of these statements. Vascular anomalies is an umbrella term for a variety of conditions with a wide range of clinical presentations. There are many separately named syndromes and conditions that fall into this category. Their commonality is that they consist of malformed vasculature and in some cases, other surrounding tissue types. And they share common genetics, of which PIK3CA is among the most common driving mutations in vascular anomalies where patients seek medical therapy. Current treatment options today leave a large unmet medical need as local treatments like surgery and topical ointments only treat symptoms for isolated accessible lesions and nonselective systemic treatment options carry a toxicity burden that is unsuitable for chronic use and severely limits the ability to inhibit the disease driving mutation. Zovegalisib is the only mutant selective PI3K-alpha inhibitor currently in clinical trials for patients with PIK3CA-driven vascular anomalies. Its mutant selectivity allows for greater target coverage while maintaining tolerability, which we believe could lead to improved efficacy. It may also be suitable for chronic treatment, which is important as this disease is known to recur once treatment is paused. Let's start at the beginning with some basic biology. Vessels can be characterized as arteries, capillaries, veins or lymphatics. For the purposes of today's webinar, we'll focus on lymphatics and veins as they are most commonly affected by PIK3CA mutations. Lymph vessels, like blood vessels, branch through the body and collect lymph fluid from different parts of the body and return it to the blood. The lymph system is an important part of the immune system to protect the body from infection and disease. Historically, there have been observations of disorders involving these types of vessels. They are diagnosed according to their clinical presentation and visible phenotype and in many cases, treated as disparate conditions. However, over the last 10 to 15 years, along with the rise of genotyping, it was determined that there are underlying genetic commonalities. Many genes in common were known for their roles as oncogenic drivers of cancer. It turns out that amongst the mutations that are driving the anomalies in veins and lymphatic vessels, PIK3CA is the most common driver mutation. Like in cancer, these mutations cause aberrant growth signaling, leading to disorganized vasculature and tissue overgrowth, which can include other tissue types that surround the vessels, ultimately culminating in the development of several types of vascular anomalies. To note, unlike in cancer, PIK3CA is the single somatic mutation in the affected cells. So features of cancer like genomic instability or acquired resistance mechanisms are not features of vascular anomalies. To explain in more detail, in vascular anomalies, somatic mutations occur in utero, impacting different parts of the vasculature. These mutations are said to have somatic mosaicism as the body becomes a mix of cells that carry the mutation and cells that have an unmutated PIK3CA. The timing and location of the mutation event are very important for how the disease manifests and persists throughout a patient's lifetime. Mutations earlier in embryonic development can lead to broader involvement with multiple lesions across tissues and organs. Where the mutation occurs also impacts the disease. Even a single lesion occurring close to an essential vessel or organ can have a significant impact on organ function and cause serious clinical symptoms. And ultimately, the phenotype depends on all of these underlying mutational dynamics and determines the symptoms that are experienced by the patients and the types of therapy that can be considered for treatment. These symptoms occur with a range of severity from more superficial cosmetic abnormalities to symptoms that impact daily life like pain and reduced mobility, up to life-threatening risks like bleeding, infection and impact to critical organ function. Again, these are all part of the same underlying disease, PIK3CA-driven vascular anomalies. Today, we group these anomalies into the following buckets based largely on the type of vessel involved. The most common are isolated lymphatic and venous malformations. Then there are the syndromic conditions that impact multiple tissues, which are diagnosed clinically based on presentation and include: KTS, CLOVES, FAVA, MCAP and others. Collectively, these syndromes are called PROS for PIK3CA-Related Overgrowth Spectrum and unified genetically by having a PIK3CA mutation. And finally, cerebral cavernous malformations, which occur in cerebral blood vessels and are generally diagnosed later in life. We'll talk about these subtypes in more detail in the following slides. Starting with the PIK3CA-Related Overgrowth Spectrum or PROS. PROS is an umbrella term for a collection of syndromes with vascular anomalies and tissue overgrowth caused by PIK3CA mutations. Symptoms can vary widely, but include bleeding, infection, loss of mobility and pain. The conditions are syndromic and are often more severe cases. These syndromes are primarily diagnosed clinically based on disease presentation. Studies have shown that essentially all patients with these syndromes carry a PIK3CA mutation. A confirmation of the mutation is generally not required for medical decision-making once the clinical diagnosis is made. Currently, alpelisib is the only approved systemic therapy for PROS, which is marketed under the brand name Vijoice. It has accelerated approval, which we'll cover in more detail later in the webinar. Sirolimus, an immunosuppressive drug developed 30 years ago to help transplant patients to avoid organ rejection by suppressing a patient's immune system has also been used off-label in these patients for the past 15 years or so. Next is lymphatic malformations. Lymphatic malformations can occur throughout the body, but often occur in lymphatic-rich areas such as the head and neck region. Symptoms can include swelling, infections, pain, compromised airways, difficulties with swallowing, difficulties with speech and other functional impairments that can greatly affect patients' quality of life. They can be characterized as either complex, which are rare, but are systemic and usually affect multiple organs, bones or tissues or more commonly simple or isolated cystic LMs, which are, as they sound, usually confined to one area of the body. They are further characterized by the size of the resulting cysts, either micro, small cysts or macro, large cysts or mixed if there are both. Our work with experts in the field suggests that the majority of LMs have mixed presentations, consisting of both micro and macro cystic disease. The vast majority, about 80% of lymphatic malformations are driven by PIK3CA mutations, leading to an estimated 65,000 PIK3CA-driven patients in the U.S. with lymphatic malformations. There are no approved systemic therapies for LMs, but our understanding is that alpelisib and sirolimus are used off-label in some instances. Next is venous malformations. Like lymphatic malformations, these conditions are defined by abnormally formed vasculature. The lesions often have a bluish color and are comprised of distorted vein channels surrounded by disorganized extracellular matrix. Being part of the circulatory system, blood clots can occur, including pulmonary embolism, which can lead to significant medical complications and consumption of clotting factors, which in severe cases, can lead to bleeding complications. Pain and swelling can occur ranging from localized to diffuse. About 20% to 25% of VMs are driven by PIK3CA mutations, equating to about 25,000 patients in the U.S. There are no approved systemic therapies for venous malformations. Finally, we have the PIK3CA-driven cerebral cavernous malformations or CCMs. These are abnormal clusters of dilated blood vessels in the central nervous system. These typically are diagnosed later in life when patients develop neurological symptoms secondary to the malformation. Depending upon the severity of symptoms and the risk of progression, primary treatment may include local control of the lesion with surgery or interventional radiology procedures. CCMs are not a current focus in the development of zovegalisib, but can be addressed in future trials. Across all of these subtypes, there are roughly 170,000 patients living with PIK3CA-related vascular anomalies in the United States. Because of the size and concentration of the PIK3CA mutations within the subgroups, the initial focus of our development program is in PROS and LMs. PROS with 5,000 to 10,000 patients with about 1/3 of patients seeking systemic treatment for their disease and LMs with about 65,000 patients with about 1/4 of patients likely to seek systemic treatment. So with that, I'll hand it over to Brenton to talk about the patient journey.

Thanks, Don. Now let's take a look at the patient journey. I know It can sometimes get pretty complicated to get a proper diagnosis and a good care team. And I want to go over this, this is a generalization and not necessarily representative of every patient's health care experience. And in reality, because this disease is not well understood, patients tend to have a wide range of paths leading to their current therapy. It depends on the disorder, but generally signs and symptoms typically present in the first years of patient's life often at or even in utero, sometimes found on ultrasound. These are typically treated by local health care providers such as primary care pediatricians, dermatologists or even surgeons when intervention is required. And in these settings, treatment is usually focused on the isolated symptoms. The correct diagnosis can often be delayed or misdiagnosed as many providers will not recognize these symptoms as part of a larger syndrome or broader underlying condition. Therefore, proper diagnosis can sometimes 6 years, often requiring referral to an expert provider who is very familiar with vascular anomalies to make a clinical diagnosis. Over the past 10 years, there have emerged a number of vascular anomaly centers or VACs, which feature a colocation of experts and capabilities, collaborating closely across the entire diagnosis and treatment spectrum, focusing on both clinical care and research. The VACs include a multidisciplinary team with specialties like hematology, oncology, surgery, interventional radiology and dermatology, focusing on comprehensive integrated care for genetic testing, access to clinical trials and reimbursement support, which are not a given in this nascent nature and space. These VACs are often part of major children's research centers in the U.S., Europe and around the world. Treatment of vascular anomalies varies based on the severity and the availability of effective treatment options. The vascular anomalies driven by PIK3CA, isolated LMs, VMs, PROS and CCM tend to have a more progressive lifelong symptoms and complications. Care teams may take a watch-and-wait approach initially and hopes that lesions will not show progression or become symptomatic, but this is usually only for milder presentations. Supportive treatment is used when symptoms develop. For example, compression garments can manage the venous or lymphatics following anticoagulation for blood clots or pain medication may be used for head and neck lesions, sometimes a feeding tube or even a tracheostomy can be placed to protect the airway. In other cases, symptoms are localized and a local invasive therapy might be offered such as a sclerotherapy in which an interventional radiologist introduces sclerotic agents via catheter directly into the malformed vessel, in order to kill the abnormal cells where surgery can just frankly debulk or try to resect the lesion. But unfortunately, lesions often regrow, sometimes multiple times and multiple recurrent procedures may be needed. And also some lesions are just inaccessible or too extensive or in places that are just too dangerous to attempt the procedure. So for these reasons, many patients may be better served by a systemic therapy targeting the PIK3CA, mTOR pathway, the driver of these diseases. As mentioned, more than 10 years ago, sirolimus, and mTOR inhibitor was first used off label here. More recently, alpelisib, a PI3 kinase inhibitor was approved in the U.S. for the treatment of PROS. And these first systemic therapies have showed proof of concept that the PI3-kinase, mTOR pathway inhibition could lead to benefit for patients and patients could take them chronically for years to control their symptoms. But because these agents nonselectively inhibit the wild-type PIK3CA and mTOR pathway, they must be given at low doses chronically to avoid unacceptable long-term toxicities in this population. Ultimately leading to suboptimal efficacy and leading patients to seek more effective alternatives. Our goal is to provide a systemic therapy zovegalisib that selectively targets the mutant driver of the disease. Mutant selective targeting of PIK3CA may offer the powerful inhibition of the abnormal vascular cells at chronically tolerable doses, potentially leading to robust activity on lesion size and substantial improvement on patient symptoms. We believe that this has the potential to change the way vascular anomalies are treated with systemic therapy being considered earlier in the disease severity spectrum in concert with localized therapeutic options like topical surgery or sclerotherapy. And hopefully provide a safe and effective chronic therapy for as many patients as possible that could benefit from a systemic therapy for their disease. To put in perspective, let's review a couple of case studies. Starting with a patient born of CLOVES syndrome, a subset of PROS. She presented at birth with multiple vascular anomalies and affected body parts and was initially misdiagnosed. She had multiple rounds of surgery and sclerotherapy in her first year of life with multiple recurrences, and she began sirolimus at age 6, which unfortunately was ineffective and ultimately discontinued after infection occurred, a common side effect of the immunosuppressant nature of the mTOR inhibition. Shortly after, a PIK3CA mutation was identified in the kinase domain, leading to the use of alpelisib, which resulted in a partial regression of the lesion. In another case, we have a pediatric patient with a lymphatic malformation of the face and mouth, which was identified at birth. The symptoms severely reduced the quality of life in the first year, dealing with breathing and feeding difficulties and multiple rounds of hospitalization. Around 1 year old, sirolimus was used and showed some reduction in lesion volume, but ran into toxicity issues like stomatitis, infections and triglyceride elevation. And over the next 4 years, sirolimus was used intermittently to try and manage the lesion size while avoiding the worst of the expected side effects. While undergoing local treatment, including a partial surgical resection of the tongue, a PIK3CA mutation was identified in this patient. So now we'll spend some time going over the current systemic therapy options. We've already mentioned a few of them in these patients as well, but I wanted to put them into context right now. The earlier generation of these therapies include the mTOR inhibitor of sirolimus, which targets mTOR, which is downstream of the PIK3CA mutation. And there are also nonselective PI3 kinase alpha inhibitors, serabelisib or KP-001 as well alpelisib. These drugs actually have been around for decades. Originally, they were both studied in patients with solid tumors in cancer. And they more recently got into looking at vascular anomalies. Only alpelisib is ultimately approved, with an accelerated approval in the U.S. for the limited indication of PROS. And we'll go through each of these in details, but they all share this common shortcoming, as I mentioned, about being nonselective and having toxicity related to the wild-type inhibition. So starting with alpelisib, it was first approved in breast cancer in 2019. And shortly thereafter, a single investigator in France initiated a compassionate use study in PROS patients called EPIK-P1. This was not a typical registrational study by any means, a retrospective chart review from 8 sites with the majority of patients from his 1 site. No true dose optimization was done, and they used 250 milligrams once daily of alpelisib, which is slightly lower than the 300-milligram label dose for oncology. It supported a conditional approval for PROS in the United States in 2022. They then started the confirmatory trial in 2021 called EPIK-P2. Here, the PIs in the study lobbied for using a lower dose of alpelisib given the lack of previous dose optimization and toxicity concerns. And so the dose was halved from EPIK-P1 to 125 milligrams. The study read out last year and unfortunately failed to meet its primary endpoint of a lower bound of the response rate confidence interval, excluding 15%. The response rate in adults was only 17%. The next confirmatory study, EPIK-P4, initiated late last year and has reverted back to the 250-milligram dose given the lack of efficacy for EPIK-P2. Vijoice remains on the market in the U.S. given the clear evidence that it has some impact on the disease. It's worth noting that Novartis is running another trial studying alpelisib in lymphatic malformations called EPIK-L1, which initiated in 2023. Let's dig a little bit deeper into the results of the data from the EPIK-P2 study in which, as I mentioned, adults were started at 125 milligrams once a day and allowed to escalate. 54 patients were in this cohort. Initially, it was a randomized study up to week 16. And at the 16-week time point, you can see 11% of patients had a volumetric response, 0 on the placebo control. After 16 weeks, everybody crosses over to week 24, but we're just following the alpelisib patients right now. And you can see that it marginally came up a little bit to 17%. And then over time, they've updated the data. Again, it's still at 17% at week 48. So it has been relatively stable at that point. And as noted before, because of the confidence interval did not clear the prespecified 15%. Looking at the maximum reduction observed at any time point on the EPIK-P2 trial, this is data that was presented last year at ASPHO, the American Society of Pediatric Hematology/Oncology. And you can see from the waterfall plot there, the median reduction was about 11% and the max reduction seen was about 46% in the trial. Moving on to safety. Because the study was run at half the label dose, which clearly impacted efficacy, the reported safety profile is difficult to assess. We can, however, look at the safety data at the 48-week time point, where about 30% of patients stayed at the 125-milligram dose and about 70% of patients escalated to 200 or 250 milligrams once daily. Based on those numbers, you can approximate to an average dose of about 180 milligrams a day. And even with this average dose, we see the rate of severe adverse events at 30%. Recall that the second confirmatory trial, EPIK-P4 is dosing back at the full label dose of 250 milligrams higher than the dose used in EPIK-P2. We don't have very much data from a prospective trial and how alpelisib performs in vascular anomalies patients at these doses. However, while it's a much different patient population, we can look at the AE profile of alpelisib in EPIK-B5 in breast cancer, where the starting dose was 300 milligrams and the estimated average dose was roughly 220 milligrams. Here, there's clear evidence that higher doses of alpelisib bring a difficult tolerability profile with high rates of Grade 3 hyperglycemia, diarrhea and rash. And importantly, in this metastatic breast cancer population, where tolerance for toxicity is presumably much higher than it is in a chronic use setting. In sum, we feel there is meaningful unmet need for these patients. Zooming out to all systemic therapies for which we have data in this disease space, when we look at the efficacy of all these therapies, it leads us to believe, like we did in oncology, that there is an unmet need for a more efficacious therapy. Now let's move to a summary of zovega and why we believe it could address the unmet need for these patients. Zovegalisib is the first mutant selective PI3 kinase alpha inhibitor to enter the clinic and was discovered at Relay using our Dynamo platform. Relay scientists discovered a novel allosteric pocket that was key really in being able to gain not only a mutant selectivity for PI3 kinase alpha, but also exquisite selectivity over the rest of the kinase as you see in the first figure. Zovega has been studied in hundreds of breast cancer patients at this point and has the selectivity profile that has resulted in encouraging efficacy and safety. And we hypothesized similar potential in vascular anomalies as you can see in this in vivo model on the right, which I'll go into more detail. Here is preclinical data, which we have previously presented, supporting our hypothesis that greater target coverage can lead to greater lesion shrinkage without impairing glucose regulation. The graph on the left compares the size of PIK3CA-mutated vascular malformations in mice that received either a dose of alpelisib approximating the approved dose in pink or 2 doses of zovega in blue, one approximating the oncology Phase III dose and half the dose. The alpelisib treatment modestly decreases the malformation size. But on the other hand, each dose of zovega reduced the size of lesions more than alpelisib, which suggests that it can potentially be more effective in people. Now shifting to the graph on the right, which looks at insulin induction in this model, zovega induced insulin to a lower degree than alpelisib did even when a higher dose was tested. So the ReInspire Phase II clinical trial was initiated in Q1 of 2025 and is evaluating zovega in eligible individuals living with PIK3CA-driven vascular malformations, which includes PROS, lymphatic malformations and other subtypes. Part 1 of the study works for 3 different doses of zovega randomized in patients 12 years and older, including adults, and that's 400 milligrams twice a day, which is the oncology Phase III dose and 2 biologically active lower doses, 300 milligrams and 100 milligrams twice a day. The initial clinical focus will be in adults and adolescents 12 years and older. However, upon reviewing the safety, tolerability, PK and initial clinical activity, we are excited to announce that as of this quarter, we have opened up a pediatric cohort for individuals 6 to 12 years old. As we gain more experience in this patient population, we'll then select one or more doses per cohort to bring into Phase II expansions. And the protocol is also written to contemplate a randomized placebo-controlled study in Part 3 should we choose to pursue a study. The regulatory endpoint used in alpelisib accelerated approval and being used in other studies as a response rate defined as a 20% or greater volumetric reduction at week 24. Additionally, patient and investigator-assessed outcomes will also be evaluated, and Relay is currently in the process of validating a fit-for-purpose patient-reported outcomes tool for use in the ReInspire trial for this patient population. And with that, I'll pass it over to Don.

Thanks, Brenton. Vascular anomalies have a very concentrated prescriber base with less than 100 vascular anomaly multidisciplinary centers across the U.S. and Europe. Most systemic therapy is expected to take place within the coordinated care of these vascular anomaly expert centers. The ReInspire study is potentially registration enabling. Currently, the initial clinical focus is on randomized dose finding and then additional data at recommended Phase II doses will be generated in expansion cohorts. Given the regulatory precedent with alpelisib and the fact that no systemic therapy currently has full FDA approval, there may be potential for an accelerated approval pathway. So in summary, there are approximately 170,000 U.S. patients with PIK3CA-driven vascular anomalies. Current treatment options are limited with local treatments only addressing a subset of symptoms and systemic therapies with off-target toxicities that limit efficacy. Zovegalisib selectively targets the PIK3CA mutation that drives the disease and therefore, may provide a more tolerable and efficacious chronic treatment for patients with PIK3CA-driven vascular anomalies. Zovegalisib entered the clinic for vascular anomalies in early 2025 and continues to actively enroll patients. Thank you for watching.