Q&A: ABX464 for treatment of UC seen as ‘novel mechanism of action’
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Abivax announced updates on ABX464 for the management of moderate to severe ulcerative colitis, according to a company press release.
Healio Gastroenterology spoke with Bruce E. Sands, MD, MS, the Dr. Burrill B. Crohn professor of medicine at the Icahn School of Medicine at Mount Sinai, about key results from the phase 2b trial of ABX464.
Healio: Can you discuss the design of the study?
Sands: The phase 2b clinical trial in patients with moderate to severe UC consists of two parts: a 16-week induction phase (primary endpoint at week 8), where three different daily doses (25 mg, 50 mg or 100 mg) of ABX464 and placebo were tested to evaluate the time to onset of action and the short-term safety and efficacy of the compound. Subsequently, all patients who completed the induction phase had the possibility to roll over into an open-label extension study during which they may be treated for several years to evaluate the long-term efficacy effect and safety profile of daily administrations of 50 mg of ABX464.
The clinical phase 2b study had been set up according to good clinical practice and state-of-the-art methodology, including central blinded reading of the endoscopies and e-diaries. It is a randomized (1:1:1:1), double-blind and placebo-controlled trial conducted at 130 study sites in 15 European countries, Canada and the United States.
A total of 254 patients with moderately to severely active UC were enrolled. They all suffered from long-standing UC and most of the patients (< 70%) had severely active disease (modified Mayo score, 7-9). Further, 50% of these patients had an inadequate response, loss of response or intolerance to currently available treatments such as biologics and/or janus kinase (JAK) inhibitors, while the other 50% were refractory to conventional therapies. The key characteristics of the patients, such as gender as well as clinical, biologic and endoscopic parameters, were well distributed across placebo and treatment arms at the time of enrollment, so the obtained results are representative across all groups.
The endoscopies were blinded and read centrally by independent reviewers to avoid any potential bias. Additionally, the study employed electronic patient diaries in which the study participants provided information on their disease symptoms and overall well-being. Although general well-being is not a part of the modified Mayo score, it does inform as to whether the overall state of health of the patients improves.
Healio: What are the key results?
Sands: From an efficacy point of view, the primary endpoint of the phase 2b induction study was the reduction of the modified Mayo score after 8 weeks. A statistically highly significant difference from placebo was observed for all active treatment groups for all patients (placebo: –1.9; 25 mg: –3.1; 50 mg: –3.2; 100 mg: –2.9), as well as for the subgroup of patients’ refractory to treatment with biologics and/or JAK inhibitors (placebo: –1; 25 mg: –2.8; 50 mg: –2.9; 100 mg: –2.8). The modified Mayo score takes into account the severity of key disease symptoms (stool frequency and rectal bleeding), as well as the endoscopic subscore, which is based on the endoscopic appearance of the mucosa.
Further, key secondary endpoints of this trial, including endoscopic improvement, clinical remission, clinical response and reduction of fecal calprotectin, also showed a significant difference in patients dosed with ABX464 compared with the placebo group, again for all patients and for the subgroup of patients’ refractory to treatment with biologics and/or JAK inhibitors.
As UC is a lifelong chronic disease, we would hope that our treatments would have durable efficacy. The data so far for ABX464 from the ongoing phase 2a and 2b open-label maintenance studies are encouraging, in this regard. During these open-label extension studies, patients take one capsule of 50 mg ABX464 once daily. Overall, 217 of the 222 patients (97.7%) who completed the phase 2b induction study, irrespective of previous treatments or treatment outcome during the induction phase, enrolled into the phase 2b maintenance study. Preliminary results of the open-label maintenance study in the first 51 patients after 48 weeks of treatment showed that 53% of patients were in clinical remission and 59% had an endoscopic improvement.
Within the phase 2a maintenance trial, 15 of the 22 patients who were initially enrolled into the study completed the 3-year efficacy assessment. Among the 13 patients who underwent an endoscopy at the completion of the third year, 11 patients were still in clinical remission (intention to treat [ITT]: 50%; per-protocol [PP]: 85%). Of these, 11 patients had endoscopic improvement and seven patients (ITT: 32%; PP: 54%) had endoscopic remission.
In terms of safety, ABX464 was well tolerated at all dose levels during the induction as well as the maintenance phase. Similarly low rates of infections were observed in the active treatment groups compared with placebo. No deaths or malignancies were reported in the study and the percentage of serious adverse events that occurred in the active treatment arms are lower or at the same level as in the placebo group.
This favorable safety profile may also have contributed to the low overall drop-out rate of patients: 9% within the first 8 weeks (primary endpoint) of the phase 2b induction study — remarkable, given the COVID-19 context. These results are encouraging, suggest that ABX464 may be able to maintain initial response and to further improve clinical remission rates over time, including among the subset of patients who were previously refractory to biologic treatments and/or JAK inhibitors. These data suggest that the molecule has the potential to treat patients suffering from severe UC effectively and durably while being well tolerated.
Healio: What is the take-home message?
Sands: We need to interpret these observations with caution, as the clinical study program with ABX464 in UC is ongoing, and a phase 3 program is under preparation. We will need the results of the phase 3 study to have conclusive evidence of the safety and efficacy of ABX464.
However, I am impressed by the rapid onset of action of the compound and the efficacy in severe patients who previously failed other first-, second- or third-line treatments. Additionally, I am encouraged by the durability of response during maintenance treatment. If ABX464 performs in phase 3 studies in a fashion similar to what we have seen in phase 2, it could provide a novel means of treatment that could have long-term efficacy.
ABX464 is a novel mechanism of action. It is based on the upregulation of a single, specific micro-RNA with anti-inflammatory properties, called miR-124. This new mechanism could provide a completely novel means of treating inflammatory bowel disease. ABX464 is administered once daily, providing convenience, and likely some advantages in compliance with treatment.
Healio: What is the next step in research?
Sands: The manufacturer of ABX464 (Abivax) is currently interacting with the regulatory authorities in the U.S. and Europe to get approval for the launch of a global phase 3 clinical program in UC that will consist of an induction and subsequent maintenance phase. With approximately 1,400 patients to be included in this study, the results will be decisive. We will ultimately see if this program confirms the encouraging phase 2a and phase 2b results in terms of short- and long-term safety and efficacy. Subject to positive feedback from the regulatory authorities, Abivax will launch the program and proceed to the inclusion of patients into these phase 3 trials.
Healio: How do you hope this will change patient care?
Sands: Although progress has been made in the past years, it remains challenging to find a suitable treatment for the majority of patients. Currently available drugs only lead to clinical remission in 10% to 20% of all moderate to severe patients and many of these patients stop responding to their therapies within the first year of treatment, leaving them in a situation where they may have no option other than colectomy. Therefore, the medical need for new treatment modalities to control IBD durably and effectively remains very high.
I think gastroenterologists and their patients would be very happy to have a medication that is efficacious over a long period of time, safe and well tolerated, and easy to administer at the same time.
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Abivax provides an update on the ABX464 clinical data and development strategy in ulcerative colitis. https://abivax.gcs-web.com/news-releases/news-release-details/abivax-provides-update-abx464-clinical-data-and-development. Published Sept. 14, 2021. Accessed Sept. 29, 2021.
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