AgomAb Therapeutics NV American Depositary Shares Study result

Please go ahead, Tim. Thank you so much, Sarah, and thank you all for joining today's webcast to discuss the open-label extension results of the phase IIa STENOVA study in patients with fibrosing Crohn's disease.

Let me introduce our speakers for today. Very glad we are joined by Dr. Rieder from the Cleveland Clinic, who's also chair of the STAR Consortium. On the company side, I'm joined by Chief Medical Officer, Philippe Wiesel, and Chief Financial Officer, Pierre Kemula. I'm Tim Knotnerus, and thank you so much for joining today. Today, we'd like to spend a little bit of time on background to educate on the fibrosing Crohn's disease. Soon thereafter, we would like to dive straight into the STENOVA part B, which is the open-label extension study of the phase IIa. Thereafter, we will spend sufficient time on next steps and potential Q&A.

At Agomab, we focus on fibroinflammatory indications, and our clinical pipeline consists of two assets. The lead compound, ontunisertib, is a gut-restricted ALK5 inhibitor in development for patients with fibrosing Crohn's disease. Earlier, we reported on the positive results of part A of the STENOVA study, with a favorable safety profile and intriguing signals on endoscopy and radiological parameters. Today, we're absolutely thrilled to discuss the open-label extension part. The second asset in development is a lung-restricted ALK5 inhibitor, which targets the same pathway, the transforming growth factor pathway, but is a distinct compound from the lead asset. The second asset is an inhaled small molecule designed to penetrate the deep lung. Recently, we reported on the positive phase Ib data in a small cohort of patients with idiopathic pulmonary fibrosis. For today, however, we will focus on the lead compound, ontunisertib.

Crohn's disease is a fibroinflammatory indication, where progression of disease is driven by both inflammation and fibrosis. Whilst the inflammatory part is reasonably well addressed by the currently approved therapies, current standard of care is simply not designed to address the fibrotic part of the disease. As a result, Crohn's patients over time develop fibrotic strictures and develop towards surgery. This is why we target the TGF-beta pathway via an ALK5 inhibitor to develop a direct anti-fibrotic drug. Our aim is to offer patients a first pharmacological treatment option for patients with fibrosing Crohn's disease. Let's zoom in on fibrosing Crohn's disease. Fibrosis leads to expansion of the extracellular matrix, thickening of the bowel wall, stricture formation, and narrowing of the intestines, especially in the terminal ileum. As a result of the narrowing or obstruction, patients develop symptoms, especially pain after meal. They apply extensive coping mechanisms.

For example, changing their diet, splitting their meals, or mashing or blending their food. But over time, symptoms worsen, and most patients progress towards surgery, despite being on anti-inflammatory background treatment. Fibrostenosing Crohn's disease is therefore considered the highest unmet medical need in inflammatory bowel diseases. These difficult to treat patients are not a small subgroup of patients. Actually, 46% of all Crohn's patients have fibrostenosing Crohn's disease. This is the group that also drives IBD-related healthcare costs, with significantly more procedures and hospital visits than the patients without strictures. What these patients really want is indicated in the middle column. They want to live a normal life without severe symptoms, especially pain. They want to eat normally with a higher quality of life. But most importantly, they want to avoid further progression of disease, especially towards surgery.

To achieve this, what we need to develop is a pharmacological approach that directly targets the fibrotic drivers of disease progression, preferably with a compound that is safe, convenient to use, and compatible with current standard of care. This has been the starting point of ontunisertib, and this is also the reason why we are so excited with the open-label extension data that we present today. We are trailblazing a new field, and today is yet another incredibly important step in that journey. With that, I would like to hand it over to my colleague. Philippe, the honor of presenting the data is yours.

Thanks, Tim, and hello, everyone. It is my pleasure to present the results of the STENOVA open-label study. As a reminder, STENOVA was a phase IIa study designed to assess the safety and pharmacokinetics of ontunisertib in patients with Crohn's disease and symptomatic strictures. Patients were required to have well-characterized ileal strictures according to CONSTRICT criteria developed by the STAR Consortium. Patients were also required to have obstructive symptoms at baseline, as defined by the minimum score of 2 for the severity domain of the S-PRO questionnaire. The STENOVA study included part A, which was a double-blind placebo-controlled study, where patients were allowed to continue their background of care and then receive either a placebo, a low dose once a day, or high dose twice a day.

Patients received study drug for 12 weeks, after which they were invited to enter an open-label extension, during which all patients received ontunisertib 200 mg twice a day for an additional 48 weeks.

The OLE was initiated once we obtained positive interim results in Part A, at which time roughly half of the patients had completed the study and were not eligible for the OLE. Of those who were eligible, 94% accepted to enter the OLE. This results in the 49 patients which are part of this analysis. The primary objective of the OLE was to assess the extended safety profile of ontunisertib. This was not trivial, since we are targeting the TGF-beta pathway, which is a major pleomorphic pathway. Demonstrating a favorable safety profile for up to 60 weeks was therefore a key objective. The secondary objective was to assess whether the efficient gut-restricted profile of ontunisertib was maintained after extended treatment. Besides these primary and secondary objectives, we plan to explore efficacy signals, focus on the incidence of surgery and endoscopic balloon dilation, stricture morphology assessed by radiology, and patient-reported outcomes.

Here, I'd like to highlight the limitations of the OLE, primarily the lack of a placebo control, but also the relatively small sample size. We believe that we see intriguing signals, but we should take these results with caution. Let's start with patient disposition. As indicated, 49 patients entered the open-label extension. A total of 37 patients were able to complete the additional 48 weeks of treatment, reaching up to 60 weeks of treatment for patients already receiving ontunisertib in Part A. Twelve patients dropped out. This defines a 25% dropout rate, which is what one would expect for a one-year study period. There was no specific pattern in terms of cause or timing for these discontinuations. Of note, only two of the 12 discontinuations occurred in patients already receiving the high dose in Part A.

We did not see a higher incidence of discontinuations in patients with the longest exposure at the highest dose. First, we wanted to make sure that the population who entered the open-label extension was similar to the overall STENOVA population baseline to ensure that there was no selection bias. This is what we show here based on baseline demographics and disease characteristics. As we see, the two populations are very similar. Patients have a long history of Crohn's disease, averaging 15 to 17 years. All patients had ileal disease, either isolated or ileocolonic disease. We know that patients with ileal disease tend to be refractory to treatment. Approximately 40% of patients had at least one prior stricture resection surgery, highlighting disease severity in these patients, as well as a recurrent nature of intestinal strictures.

It is also important to keep in mind that prior stricture resection surgery is known to be the most important predictor of further stricture resection surgery. Importantly, 75% of patients were on a stable dose of anti-inflammatory biologics. These background treatments seem to work well because of the luminal inflammatory burden was relatively low, with an average CDAI around 150, meaning that roughly 50% of patients were in clinical remission and 50 had mostly mild disease activity at the start of the study. CRP was low as well, confirming the low level of inflammatory burden. However, these patients had symptomatic stricture despite relatively good control of inflammation. This is in line with the evidence showing that anti-inflammatory treatments have limited efficacy on strictures, if any. Let's review the safety profile of ontunisertib, starting with the serious adverse events.

During the OLE, a total of 5 SAEs were reported in 4 patients. These patients included a patient who presented with 2 SAEs, a perforated appendicitis, and a small bowel obstruction, kidney stone. Overall, a low incidence of SAEs without patterns or concerns. Beyond SAEs, we assessed the more general safety profile of ontunisertib during the open-label extension, looking at adverse events to understand whether we would see any new signal or changes in the intensity, nature, or severity of adverse events during up to 60 weeks of treatment. This was not the case. No safety signal was detected. Looking at AEs, we also proactively assessed specific signals, including cardiac injury or inflammatory effect, or signs of vasculitis based on signals reported for systemic ALK5 inhibitors or signals which may be related to TGF-beta inhibition. We also did not detect signals there.