Good morning, everyone, and welcome to the Agomab Therapeutics Virtual Management and KOL event. At this time, all attendees are in listen only mode. A question and answer session will follow the formal presentations. To our analysts joining us live, we kindly ask that you limit your question to one. As a reminder, this webinar is being recorded and a replay will be made available on the Agomab website following the conclusion of the event. Before we begin, we would like to remind everyone that today's presentation contains forward-looking statements. These statements are subject to risks and uncertainties that may cause actual results to differ materially. Please refer to Agomab's SEC filings for a discussion of these risks. I'd now like to turn the call over to Tim Knotnerus, Chief Executive Officer at Agomab Therapeutics. 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- 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 five SAEs were reported in four patients. These patients included a patient who presented with two 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.
The two organs that see active parent molecules are the gut and the liver. We did not detect any signs of drug-induced liver injury with no elevations in liver enzymes. There was also no increase or change in the nature or intensity of GI-related adverse events over the extended treatment period. Furthermore, we did not detect any safety signal when reviewing the lab results, physical examination, or ECG recordings. Importantly, the DSMB indicated after each unblind data review meeting that they had not identified safety signals and had no concerns. They recommended every time that the study continues as per protocol. We can conclude that oral ontunisertib continues to show favorable safety profile with no safety signals detected after extended treatment. This favorable safety profile can be readily understood when looking at the PK profile. Ontunisertib remains efficiently gut-restricted with very low systemic exposure.
We are looking here at the exposure profile based on sparse PK data collected in Part A and B of the study. At the very bottom, we see the levels of ontunisertib in plasma at steady state, showing very low levels in both Part A and B, which are superimposed here. Average levels are very far from the IC50, as you can see. We also see the profile for the main inactive metabolite, MET-158, which is generated in the liver once ontunisertib has been absorbed. We see the profiles in light and dark gray corresponding to Part A and Part B. These profiles are almost superimposed, indicating that the gut restriction mechanism is maintained over time. In conclusion, the study met its primary and secondary objectives, demonstrating a sustained favorable safety profile and efficient gut-restricted PK profile over up to 60 weeks of treatment.
Beyond the primary and secondary objective of the study, we explored potential efficacy signals during extended treatment with ontunisertib 200 mg twice a day. Keeping in mind the limitation of an open-label study, we believe that we see intriguing signals. Let's start with the event rate, which is an endpoint based on hard clinical outcomes. Event rate is defined as the occurrence of surgery or endoscopic balloon dilation. The event rate was calculated for patients receiving 200 mg twice a day during part A and/or B. The Kaplan-Meier curves for STENOVA is shown here. Only a single endoscopic balloon dilation was supported, and no case of stricture resection surgery. While there are no prior directly comparable placebo-controlled trials in this population, there are three recently published retrospective studies by the STAR Consortium that help us provide some context for the very low event rate observed in STENOVA.
The same inclusion criteria were used to define stricture severity, namely the CONSTRICT criteria developed by the STAR Consortium. The Kaplan-Meier curve published for these reference studies show a significantly higher incidence of events compared to STENOVA. Here we showed how these Kaplan-Meier curves translate into event rates. 3% for STENOVA compared to the analyzed event rates of 23%, 26%, and 35% reported in the reference studies. While again, we should be cautious when comparing trials, the event rate reported for STENOVA is clearly significantly below these published studies. It is also important to remember that patients included in the STENOVA trial presented multiple risk factors for events, including ileal disease for all patients, a prior stricture resection surgery in approximately 40% of patients, obstructive symptoms in all patients at baseline, as well as severe strictures meeting the CONSTRICT criteria and which include features known to be associated with surgery.
It is very important to see a reduction in the event rate for several reasons. First, it is very meaningful for patients because the factors driving surgery or balloon dilation are to a great extent what defines their disease burden. This includes sustained or worsening symptoms, consults, invasive or burdensome imaging procedures, and eventually hospitalization, surgery or EBD. These are all things that patients would like to avoid. Events are also important to regulators. A reduction in the event rate could potentially constitute a robust registrational endpoint. Finally, it is important to payers because these events are a key driver of healthcare costs. Healthcare costs for patients with stricturing disease amount to EUR 80K more per year compared to patients with uncomplicated chronic disease, and these costs are primarily related to increased consults, imaging, hospitalization, surgery, and EBD.
Altogether, the low event rate is a very encouraging finding and would be a key data point for our upcoming phase IIb trial. I would like to now turn to imaging. Here we should be cautious not to over-interpret the data, not only because it lacks the placebo control, but also because we have limited information about what changes are clinically meaningful. Let us go through the MRE data, which was used to assess stricture morphology. We are presenting three MRE parameters that we already presented for the placebo-controlled part A of the STENOVA study, and which have been previously published as being clinically meaningful. These include stricture length, bowel thickness, and the diameter of the associated pre-stenotic dilation. Here we show changes from baseline in millimeters.
Each graph shows changes in part A, where patients receive different treatments, including placebo or one of the ontunisertib doses, and then changes during the open-label extension, where all patients were switched to 200 mg BID. In the graphs, the black dotted line shows the average change for all patients included in the OLE, hence showing a general trend for all the cohort. We also included lines according to what patients received during part A, because it is interesting to observe MRE changes once patients switching from placebo to the high dose of ontunisertib. As reported previously, patients in placebo tended to worsen from stricture length and bowel thickness in part A. During the OLE, when patients are on ontunisertib, these patients stop worsening. In fact, they tend to stabilize and catch up with the patients already on ontunisertib in part A.
Overall, when looking at the profile for all patients, and so the black line, we see trends of improvement for bowel thickness and maximal diameter of the pre-stenotic dilation. For stricture lengths, the data shows significant variability and less consistent profile, especially at week 48. We explore the reasons for this variability and identify changes in patients with short strictures as the main source of variability. Here we show the same three parameters in patients with short strictures on the left and with long strictures on the right. The cutoff is 5 cm, which is generally used to qualify short strictures. In our OLE dataset, two-thirds of the patients had longer strictures, so greater than 5 cm. We clearly see that in patients with short strictures, shown on the left, there is mostly noise with significant variability and inconsistent profiles.
In contrast, on the right, in patients with longer strictures, we see what looks like clinical data with limited variability and coherent profiles. On this slide, we zoom on the 2/3 of patients with longer strictures. We now see even more clearly that for all three parameters, patients on placebo were not doing as well as patients receiving ontunisertib in part A. Once they switch to the high dose in the OLE, they stop worsening and tend to catch up with patients previously on ontunisertib. For stricture length, we see greatly reduced variability and a pattern which indicates radiological stabilization over time. The switch effect seen for all three parameters is very suggestive of a drug effect in the OLE. We think that the MRE results are very encouraging, especially given the consistent trends for stabilization and improvement over time across the three different parameters.
These positive MRE data are in keeping with the low event rate. For endoscopy, we unfortunately do not have sufficient datasets to draw meaningful conclusion. Endoscopy was optional at week 48, and the vast majority of patients declined the procedure or had dropped out. As shown here, there were 79 patients with non-passable strictures, and these are the patients where we wanted to assess long-term passability. This group of patients was reduced to only 13 patients at week 48. Results obtained in 13 patients in an open-label study provide insufficient information to draw any conclusion. In the 13 patients for whom endoscopy was available at week 48, two had a passable stricture and 11 had non-passable strictures.
This data is anecdotal, adding one or two additional patients with passable or non-passable strictures could lead us to see the data as positive or negative, and we would be likely misled either way. We prefer to rely on data obtained on endoscopic passability in the larger sample size and placebo-controlled Part A of the study, which showed substantially higher passability rates in the 200 mg twice a day arm compared to the placebo or the low dose. Let's move on to the patient-reported outcome measures. Here, all the data provide a consistent trend on the different parameters which were assessed. This includes obstructive symptoms with a S-PRO on the left, Crohn's disease activity with a CDAI score in the middle, and quality of life with short IBDQ questionnaires on the right. We see a consistent reduction in symptoms and an increase in quality of life already during Part A.
A significant placebo effect had been observed, although a faster and potentially larger effect was suggested for the higher dose of ontunisertib. What is striking, however, is that patients continue to improve over time to reach minimal symptoms at week 48. This is particularly interesting as we observe that 97% of patients are in clinical remission at week 48, compared to about 50% at baseline. Achieving and maintaining clinical remission at this level is notable and can be linked to the low event rate and radiological stabilization. I will now kindly ask Dr. Florian Rieder to provide an overview of these clinical results on the next slide.
Thank you very much, Philippe, and thank you so much for having me on the call. I had the opportunity to review the STENOVA open label extension data prior to this call and put together my key takeaways on the slide as the directing co-PI of the STAR Consortium. Overall, I am very positive about these results. Most importantly, the generally favorable long-term safety and tolerability profile of the drug. This is a new mechanism of action with a broad pathway inhibition, and this was very favorable long-term safety data. The gut restricted PK profile was confirmed in the open label extension, and what stood out to me is a very impressive low annualized FSCD-related event rate of only 3%.
I am not aware of any data set in existing strictures using the CONSTRICT criteria that after one year of follow-up, had only one endoscopic balloon dilation at that sample size for a total event rate of 3%. This was very impressive. As of the other endpoints, and all of these potential efficacy-related endpoints have to be interpreted with caution, but I am still optimistic about them. There were signs of sustained disease control. What stood out to me there was a very low symptom burden at week 48, which again includes the classical obstructive symptoms that are food related. It includes the classical Crohn's disease symptom scale, the CDAI, and an increase in quality of life of the IBDQ. This is again impressive because all these patients started with already existing small bowel strictures.
When looking at the longer strictures, longer than 5 cm, there is overall a stabilization of stricture length. The best comparator here, we can talk more about that in the Q&A, is the example of pulmonary fibrosis, where regression of fibrosis is not what is being achieved. In fact, there is a prevention of decline, and this trial showed even better. There was stabilization of stricture length and a trend towards improvement in wall thickness, and then the dynamic outcome of pre-stricture dilation, which suggests increased passability of the strictures with the reduced pre-stricture dilation. Overall, the results, in my opinion, support further development of ontunisertib in fibrosing Crohn's disease in what is called the NOV-ERA study, and then potentially even an expansion to other additional IBD indications. I will be available later for Q&A. Back to you, Philippe.
Thanks, Florian. It's actually me, Tim, to take the last slide, and then we will hand over to Q&A. What's next is to run the NOV-ERA phase IIb trial, which is indeed a placebo-controlled dose range-finding study that is considerably longer, 52 weeks versus 12 weeks placebo-controlled in STENOVA. Importantly, we will even use a higher top dose of 400 mg BID, given the favorable safety profiles we have received to date. And we enroll more patients, up to 320 fibrosing Crohn's patients, so 80 per arm. We will further test and validate the different endpoints. For the primary endpoint, we will look at passability as measured by endoscopy, for which we saw a 32% response rate on patients on 200 mg BID in the placebo-controlled Part A of STENOVA. Additionally, we will look at events like EBD and surgery.
We will look at radiological parameters as measured by MRI and a new version of the patient-reported outcome and other quality of life assessments. Today's data, we cannot wait to get started, and we very much look forward to continue to work with investigators, regulators, and the larger IBD community to bring a first pharmacological treatment to patients with fibrosing Crohn's disease. Looking towards the future, with the recent IPO in February, we have a current cash position of $280 million, and we're very well financed to progress both the ontunisertib franchise and the IPF program. With this, we are now ready for the Q&A session. Sarah, the floor is yours.
Great. Thank you, Tim. Yes. At this time, we'll be conducting a question and answer session with our speakers. To our analysts joining us live, we kindly remind you to limit your questions to one. Please hold for a brief moment while we pull for questions. Our first question comes from Judah Frommer at Morgan Stanley. Please go ahead, Judah.
Yeah, hey guys. Congrats on the data, and thanks for providing this webcast. It was very informative. I guess our key question is, in terms of learnings for a potential pivotal trial, what can you take away from the data you've shared today? I guess particularly on event rate, is there a way to sort of marry that functional endpoint to maybe something that's more biomarker-based as we think about moving toward pivotal development over time?
I will defer the question to you.
Event rate is a very positive sign in this trial, as you mentioned. Regulators have commented for pivotal trials to request a co-primary endpoint of symptoms and an objective marker that is either endoscopic passability and/or radiology, like MR enterography. What will be important, what learning from the open label extension with this low event rate is that low event rate is a clinically meaningful event for our patients. That can be used, in fact, then to solidify the endpoints for a pivotal trial after the Phase IIb, or even allow the Phase IIb to be the first pivotal trial on the registration process. Overall, biomarkers, if you refer to mucosal biomarkers or systemic biomarkers, have not been sufficiently validated to count as surrogates for fibrostenosing disease. It will be a combination of symptoms, endoscopy, or imaging.
Thanks.
Great. Thank you for the question, Judah. Our next question comes from Anupam Rama at JP Morgan. Please go ahead, Anupam. Anupam, you may now ask your question.
Hey, guys. Yeah. Sorry about that. Thanks so much for taking the question, and congrats on the update. A question for the KOL, Dr. Reider, on the line. I know in your opening comments you said this is a drug that should definitely be further developed. I was wondering if you could expand on that. With the emerging profile of ontunisertib, how would you see a product like this fitting into your treatment paradigm, and how would you think about using it? Thanks so much.
This is an excellent question. In principle, and this is several steps ahead into the future, but in principle, if successfully developed and approved, this is a drug that could be anticipated to be given at diagnosis in combination with an anti-inflammatory drug to prevent stricture formation altogether. That would be an aspirational goal for several steps ahead. Regulators at this point in time require to start at patients with already established tissue damage, radiologically confirmed stricturing disease, to show efficacy. Ultimately, this drug will move, if successfully approved, this drug will move earlier and earlier in the paradigm. This could be either then going to a pre-stricture state in patients that already have established Crohn's disease, and then you prevent stricture formation in the short term, or then ultimately towards diagnosis, like I mentioned in the beginning.
The second aspect that I found quite interesting that was, from a biology perspective, a bit of a surprise, there were initial concerns that blocking TGF-beta may be pro-inflammatory because it has immunoregulatory functions. But the opposite seems to be the case based on the part A of the study. The SES-CD inflammatory components, which is surface area affected by inflammation, ulcer size, surface area affected by ulcers, also all trended towards improvement. This opens the door to test ontunisertib also in the luminal Crohn's disease space, because if it has anti-inflammatory and anti-remodeling properties within the same drug, could be very attractive. In other words, I think the first steps have to be taken in established strictures, but ultimately the market for a drug that has these properties as we see them, if confirmed, the market would be wide open.
Thank you, Anupam, for the question.
Did I answer your question?
Totally. Thanks so much.
Thank you.
Great. Thanks, Anupam Rama. Our next question comes from Thomas Smith at Leerink. Please go ahead, Thomas.
Hey, guys. Congrats on the data, and thanks so much for taking our questions. For Dr. Rieder, obviously quite a remarkably low event rate in this OLE. I am wondering if you could elaborate a bit on how clinically meaningful the signal is to you, and maybe just expand a little bit on how you see these results and this event rate relative to some of the other contemporary publications, specifically the vedolizumab and ustekinumab retrospective studies. Thanks so much.
Yeah. Thanks so much, Thomas. I share with you that this was actually a very exciting finding in these patients. This is not a direct comparison, and it's an open-label extension, so these are two limitations I have to preface my answer with. Having said that, as I mentioned during the talk, I'm not aware of any data set showing this low event rate over this time period in patients with radiologically confirmed stricturing disease. From a radiology perspective, these patients are all comparable. The vedo study, the ustekinumab study, and the standard of care all-comer study we ran in our consortium have all centrally read, confirmed CONSTRICT criteria strictures on imaging. This is very comparable, just like centrally confirmed eligibility in STENOVA. The major drivers of event rates are the presence of symptoms, stricture length, disease duration, and others.
This is hard to match between these two cohorts because one is retrospective, one is prospective. But the delta between the historical cohorts being between 25%-35% over one year, and the 3% in STENOVA, to me is quite remarkable. Compared with this is the low symptom burden at week 48, because going in, we didn't know what we would expect. These are patients that on imaging are obstructed, and at week 48, close to all of the patients are in clinical remission based on CDAI criteria. Even including the obstructive symptoms that we elucidated through the S-PRO, the symptom burden is extremely low. Clinically, this is highly meaningful because these patients change their diet when they come in. They have abdominal pain after eating, and if you treat them, and after one year, they are essentially completely asymptomatic. It's quite remarkable.
But again, I want to also be cautious because open-label extensions have a set of biases that are true for all open-label extensions, not only for STENOVA, but overall, the signs of this trial are very positive. So thank you so much for the question.
Super helpful. Thank you. If I could just sneak in a follow-up for the team. I know you mentioned now that we've established safety, potentially looking at luminal Crohn's disease. Just wondering if you could elaborate a bit on the plans to advance a program in luminal Crohn's, and maybe Dr. Rieder, if you could also opine on the potential role for ontunisertib in luminal disease. Thanks so much.
Thank you for the follow-up question, Tom. We wouldn't have expected otherwise, of course. As discussed, we remain very interested in exploring the potential of ontunisertib in luminal disease. We think that combining a direct anti-fibrotic mechanism of ontunisertib with an anti-inflammatory agent may really help address the therapeutic ceiling that currently still exists in luminal Crohn's. I think OLE is all about safety. Now that we have shown that we can dose chronically in Crohn's patients on top of standard of care, I think that's a major win. On top of the safety profile, we also see a consistent picture where all parameters are trending in the right direction in the most difficult to treat fibrosing Crohn's population. Of course, in essence, STENOVA was already a combination study as well because we treated on top of standard of care.
I think for next step, it's too early to comment on exact timelines or design or combination place, but we will surely keep you updated as our plans mature in the nearby future. Refer to Florian Rieder to discuss the potential positioning of ontunisertib in the larger luminal field in the future.
I agree with what Tim was saying about the unmet need. We are getting better and better with anti-inflammatory drugs, biologics, and small molecules, and there's a huge pipeline in addition to what's already approved. But all the drugs hit the ceiling, and my prediction is even the combo plays that are currently under investigation will hit a ceiling. The big unmet need is really an anti-remodeling approach because multiple factors point towards tissue remodeling being a predictor for negative response to biologics and small molecules. In other words, too much tissue damage gives you a poor response to anti-inflammatories. You need to combine anti-inflammatories with a drug that addresses tissue damage. That would be actually the first time this has been done with ontunisertib, and that would be a very reasonable combination partner for something like this.
You may wonder, Thomas, about Crohn's disease versus ulcerative colitis. Crohn's disease classically is considered the progressive disease with strictures in small bowel strictures, sometimes colonic strictures. But really, ulcerative colitis is emerging also as a progressive fibrotic disease, and we have done multiple studies confirming that there's significant amounts of fibrosis also in UC. Without wanting to expand the opportunities too much, Crohn's disease is probably a reasonable starting point, but in principle, remodeling drugs eventually will enter the space of ulcerative colitis as well, in my opinion, because the ceiling we observe in Crohn's, we also observe in ulcerative colitis, and remodeling may be one reason why we can't break the ceiling.
Great. Thank you so much.
Thank you, Dr. Rieder.
Yeah. Thanks for the questions, Thomas. Our next question comes from Shannon Duffy at Piper Sandler. Please go ahead, Shannon.
Hi, good morning, team. This is Shannon Duffy on for Yasmeen Rahimi from Piper Sandler. Congrats on this awesome data, particularly with the event rates being so low. Our question here is, would you consider powering on that considering how low they are in the upcoming phase IIb NOV-ERA, and how are you thinking about your ideal product profile from that result upcoming? Thank you so much.
Thank you for the question, Shannon. I defer the question to Philippe, if he's still on.
Yeah, sure. Absolutely. Thanks so much for the question. I think indeed, the reduction in the event rate is very striking. I think it has the potential to become a standalone, robust endpoint for registration. I think a reduction in these hard clinical outcomes would be seen favorably by regulators to support NOV-ERA. It is still an open-label extension. We will certainly characterize the event rate very carefully with adjudication in the upcoming phase IIb trial. On this, I think we'll make a decision whether this should be the primary efficacy endpoint for the phase III program or whether we keep working perhaps on a co-primary endpoint. I think this opens a new opportunity, which is very interesting and meaningful. This will be really the objective for the phase IIb, to make a determination.
Great. Thanks for the question, Shannon. Our next question comes from Yanni Souroutzidis at Cantor. Please go ahead, Yanni.
Hi, folks. Congrats on the data. Really speaks for itself. Just a couple of quick ones. I guess, as it relates to obviously the event rate and the S-PRO, it seems like there's an opportunity here to think a bit more critically about endpoint selection. I guess, can you comment on your views in terms of the FDA on the U.S. side versus the European Medicines Agency in Europe, how they're viewing and weighting things like a PRO versus a more hard endpoint, like an event-driven outcome? Additionally to that, you mentioned that imaging, like MRE, might play a role as well. Obviously, there's a few measures there that you're showing, some a bit more indicative of the signal than others. I guess, would MRE be viable as something as a secondary where we'd be looking just at one component of the MRE measures?
Thank you so much for the question, Yanni. I will defer the question to Philippe.
Yeah, I think we have overall a general agreement between FDA and European Medicines Agency. I think they follow the blueprint perhaps for luminal disease, where I think one of the ways to go to market will be to the co-primary endpoint, assessing an objective measure, like perhaps endoscopic passability or an MRE-based endpoint. On the other side of the co-primary endpoint, something that is meaningful to patients, for instance, symptoms reductions. That is one option. I think there is clearly the potential to bring the event rate as a standalone sole endpoint supporting registration.
Both agencies have encouraged us to look at the event rate. I think they would be both open to that, but I would say that with the caveat of needing, requiring further interaction with the agency. I think we have these two major paths for us, either event-based or co-primary. I think we have learned tremendously in STENOVA to support these two paths. I think the phase IIb will provide more definitive data to support the section of the regulatory path.
Good. Got it. Understood. Maybe the second component was just on MRE, how to think about that as kind of an endpoint. Is it the stricture length or the wall thickness? Is there any component there that carries additional weight, or how might that endpoint be structured?
I think it may be suitable for the objective measure of a co-primary endpoint. I think MRE remains the gold standard in practice. It has been also shown to be able to measure clinically meaningful parameters with precision. I think our data also provides some important learnings, perhaps about the impact of stricture size on some of those measurements. The phase IIb will include extensive evaluations of MRE parameters and will give us information about which components or MRE parameters could be selected in terms of how it correlates, perhaps with events or symptoms or other efficacy endpoints. That will be useful to potentially bring an MRE parameter as part of a co-primary efficacy endpoint. Obviously, we have also the opportunity or the option to go for endoscopic passability if confirmed. I think it is nice to have multiple options.
Understood. Thank you so much.
Thanks for the questions, Yanni. Our next question comes from Sushila Hernandez at Kempen. Please go ahead, Sushila. Sushila, you may be on mute. It looks like Sushila is having some tech difficulties. We will go to the next question from Luis Santos at H.C. Wainwright. Please go ahead, Luis.
Hello, everyone. This is Luis in for Patrick. Thank you for taking our questions, and congrats on the progress. Our questions are more looking forward into NOV-ERA, and what supports the further conversion by week 24. From STENOVA, the question that we are having is whether the original passability responders retained a response or whether it was from additional patients that converted. I am trying to translate that idea into NOV-ERA's 24 weeks.
Thank you for the question. Philippe?
Yeah. Here again, we have a very low sample size for endoscopy, as I mentioned. A significant proportion of patients either were not able to enter the Open-Label Extension or dropped out. So very limited numbers. I think it's really difficult to assess either sustained passability or patients newly achieving passability. We try to look at the data, but you end up every time with two, three, four patients. I think it's really difficult to make conclusions. I think we're pleased to have seen the robust data in the placebo-controlled Part A study with a significantly higher proportion of patients achieving passability in the high-dose group compared to placebo in the low dose, and we'll then further explore that in the phase II-B.
Just a very quick follow-up. How will you standardize the scope caliber in NOV-ERA?
Yeah, sure. I think the guideline is to use the same caliber, either pediatric or adult, for all assessment in individual patients. There are some centers that have guidelines to use pediatric scopes for strictures, so we can't impose an adult scope. But certainly, it has to be standardized. Also, we did extensive work to understand the robustness of centrally read passability. We looked at the agreement between two independent readers and also used a third reader in case of disagreement to adjudicate those cases. We also reread all endoscopy videos by four readers to reestablish those measures of performance. Indeed, the narrowing component or the passability score is very high, as high as other components of the SES-CD score or higher. So we are very pleased to see that this is a robust process based on a very strict central reading procedure.
Great. Thank you so much.
Perhaps I can quickly add to Philippe's point. The narrowing subcomponent of the SES-CD was not reliable in moderate to severe Crohn's populations. What Philippe mentioned here is actually new and very important, meaning that in established strictures in Crohn's disease, the reliability of passability versus not is very robust. This is a solid basis to choose this as an endpoint in NOV-ERA.
Thank you, Florian.
Great. Thanks for the questions, Luis. Sushila, you should be able to unmute now.
Yes. Thank you. Sorry about that. Thank you for taking my question again. Also a question for Dr. Rieder, perhaps on disease activity. How should we interpret that 97% of developed patients were in clinical remission in this setting?
Yes, so it's a very good question. My interpretation is this is extremely positive. The CDAI has not been developed for stricturing disease, but all the symptom metrics that were established during STENOVA, which is the S-PRO, CDAI, and others, track with each other fairly well. At baseline, the remission rate for the CDAI was approximately 50%. That means that from these 50% that had symptomatically active disease, close to all of them went into remission at week 48 in a very difficult to treat population. Median disease duration 17 years is the longest disease duration, to my knowledge, that ever went into an RCT in Crohn's disease. They had small bowel disease, which is harder to treat. They had tissue damage as established by stricturing disease, which is harder to treat. And 85% have seen biologics before, which is harder to treat.
Again, with the limitations of an open label extension, this was one of the results that to me stood out almost the most. Not only the CDAI, which is developed for luminal Crohn's disease, but the S-PRO that contains proximal symptoms to stricture, stricturing, food-related items like abdominal pain after eating or dietary changes. At week 48 after open label extension, very low scores on the stricture PRO. This is quite remarkable clinically.
Okay. Thank you for the additional color. Perhaps if I can ask one more question to the team. What is your latest thinking on the enrollment speed in the phase II-B study? Thank you.
Sushila, I am not sure whether we fully comprehended the question. Could you please repeat?
Yes, sure. For the phase II-B study, the upcoming phase II-B study, what is your latest thinking on how fast you can enroll that study?
Philippe?
Yeah. I think we are always cautious about forecasting enrollment. I think certainly there is a very significant medical need, which is a good driver for patients being incentivized to participate. This is something that we saw in STENOVA, with 0.2 patient per site per month, which is significantly greater than a typical IBD study. We now have very positive phase II data in addition to that. We will do our best, and we will provide guidance at a later stage.
Okay. That is clear. Thank you.
Great. Thanks for the question, Sushila. Our next question comes from William Wood at B. Riley. Please go ahead.
Thanks so much for taking our questions and congratulations on the very nice data. Looking at when we are thinking about the phase II-B NOV-ERA study, could you speak to any particular learnings that you may have had from the STENOVA trial that you may be incorporating into the NOV-ERA? Maybe specifically thinking about going into a more severe or longer stricture length, just since you have seen less variability there. Then maybe also for Dr. Rieder, when we are thinking about or possibly also for the team, but when we are thinking about the PROs, whether that is S-PRO or the short IBDQ or the other, how should we sort of interpret the overall improvements across these when thinking about the trial, including the placebo arm, even in the part A, and then continuing to prove throughout the 48-week OLE? Thank you.
Thank you for the question, William. I will defer the first question to Philippe on the learnings from the STENOVA study, including OLE to NOV-ERA, and the second part to Dr. Rieder. Philippe?
Sure. Thanks for the question. I think indeed, we have learned a lot from STENOVA. The phase II-B, NOV-ERA trial, will include somewhat more severe patients. All patients will be required to have a non-passable stricture. We know that these patients typically have somewhat longer strictures and may be more symptomatic. I think overall that will increase the level of symptoms and potentially the event rate in the placebo arm. We have also learned tremendously in terms of how we read endoscopy and MRE in terms of the central reading paradigm, whether it is sequential or scrambled. We are going to publish this in scientific communication later on, but we have learned enormously about how to make these measurements precise. So far, we are not going to require patients with longer strictures.
Our primary efficacy endpoint is endoscopic passability, and we think patients in the phase IIb, as I said, will have somewhat longer strictures, and we will see after phase IIb based on the data, whether we do use MRE-based parameters like stricture length, and in that case, whether we want to adjust the population for the phase III trial.
I can maybe answer the second part of your question. Philippe mentioned already, which I think is important, to avoid the lower effect that you observed in STENOVA with the placebo arm. The symptom burden at inclusion for NOV-ERA is anticipated to be higher for the reasons that Philippe mentioned. I think we will then, in combination with the STENOVA data, learn what could be a meaningful improvement in S-PRO, and if it continues to track with the CDAI. One thing that becomes clear in this work and also work in our consortium is that symptoms do not correlate strongly with morphology of strictures or passability. So we see some correlation, but they are not connected strong enough for regulators, for instance, to favor composite endpoint, which is where the co-primary endpoint is coming from.
You may have raised this point because the S-PRO is not yet fully validated in the eyes of the regulators, and they acknowledge that in the interactions. They are very pleased with how the symptom instrument is being developed, and they indicated that shall the S-PRO not be ready for a pivotal trial by the time the pivotal trial will come along, there are alternative ways to build a symptom endpoint and find acceptance by them by, for instance, choosing symptoms proximal to stricturing disease. So in other words, the S-PRO development speed, while we all wish it will be completed as fast as possible will likely not impede further development of the drug because of other ways around that in the eyes of the regulators.
Thank you, Florian.
Great. Thanks for the questions, William. We had a few questions come over the webcast. This one's from Julian Harrison at BTIG. Are there plans to make a longer-term endoscopy assessment required in the phase II-B study to help further define the long-term profile of ONQ-1202?
Yeah, the phase II-B trial will be a one-year trial, so indeed extending the treatment period. It will be also a much larger study with 80 patients per arm for a 320-patient trial, which will include three doses against placebo going even higher with the dose, [100 mg] BID based on the verifiable safety. We will assess endoscopy at week 24 initially, but potentially also at week 52. There, we will also assess the event rate over a year as well as the radiological progression or regression at week 40. I think we have a very large and long study where indeed we'll be able to fully characterize either imaging, endoscopy, and the event rate. I hope this answered your question.
Great. Thank you. Yes. This concludes our Q&A session for today and also concludes this event. Thank you everyone for joining and you may now disconnect.