A first-in-class oral miR-124 enhancer significantly improved clinical remission and endoscopic outcomes for patients with moderately to severely active ulcerative colitis (UC) who had failed multiple prior therapies, results from two phase III trials showed.
In the ABTECT-1 trial, both 25-mg and 50-mg once-daily doses of obefazimod met the primary endpoint of clinical remission at 8 weeks, with rates of 23.8% and 21.7%, respectively, compared with 2.5% on placebo (both P<0.0001), reported Bruce Sands, MD, of the Icahn School of Medicine at Mount Sinai in New York City.
Both doses met the symptomatic remission and endoscopic endpoints about equally well in that trial, Sands said in presenting the results at the American College of Gastroenterology annual meeting.
In ABTECT-2, the 50-mg dose again met the primary clinical remission endpoint (20% vs 6.3%, P=0.0001), while the 25-mg dose (11%) did not reach statistical significance (P=0.10). Across both trials, the 50-mg dose also met all key secondary endpoints, including endoscopic improvement (33% vs 5.7% in ABTECT-1; 36% vs 10% in ABTECT-2), clinical response, and histo-endoscopic mucosal improvement. The 25-mg dose showed variable efficacy between trials.
No deaths or safety signals were reported in the pooled analysis, where adverse event rates were comparable to placebo. Serious adverse events occurred in 3.1% of patients on 50 mg versus 3.2% in those on placebo. Headache was the most common side effect (24% at 50 mg vs 6% on placebo), but events were mild, with a median duration of 2 days and a low discontinuation rate (1.1%).
"The safety data also looked quite good," Sands said. While miR-124 is abundantly expressed in the brain and immune system, "there was not any important signal of serious infections. That really suggests that this is not an immune-suppressing medication."
Obefazimod enhances expression of microRNA-124, a regulatory RNA that modulates inflammatory cytokines and helps restore mucosal homeostasis. The drug works by binding to the cap-binding complex in the cell nucleus -- a distinct mechanism compared with biologics, JAK inhibitors, or S1P modulators.
The results, while encouraging, warrant further research, Alan Moss, MBChB, PhD, chief scientific officer of the Crohn's & Colitis Foundation, told MedPage Today.
"Obefazimod represents a potential therapy with a new mechanism of action for patients with moderate-severe ulcerative colitis who have failed other treatments," said Moss, who was not involved in the studies. "This short-term study confirms its ability to induce clinical remission and improve colonic inflammation in these patients. However, further studies will be crucial to confirm these benefits over a longer period and in more diverse patient groups."
Obefazimod is also being studied as a Crohn's disease treatment. Sands described the evaluation as "ongoing" with results not yet available. Phase II data for obefazimod as a rheumatoid arthritis therapy have been "positive as well," he added.
The ABTECT-1 and ABTECT-2 trials each enrolled 636 highly refractory patients with mean ages of 41.4 to 42.3 and mean baseline Mayo scores of 6.8 to 7.0. Nearly half had failed at least one advanced therapy. Roughly 21% previously failed a JAK inhibitor.
A 52-week maintenance trial (ABTECT-3) and a long-term extension study are ongoing to evaluate durability of response and long-term safety.
Disclosures
The trials were funded by Abivax.
Sands reported relationships with AbbVie, Abivax, Adiso Therapeutics, AgomAb, Alimentiv, Amgen, AnaptysBio, Arena, Artugen Therapeutics, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Bristol Meyer Squibb, Celltrion, Enthera, Enveda Biosciences, Equillium, Evommune, Ferring, Fzata, Galapagos, Genentech-Roche, Gilead, Gossamer Bio, GSK, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Janssen, Kaleido, Kallyope, Lilly, Merck, Microba, Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, OSE Immunotherapeutics, Palisade Bio, Pfizer, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Takeda, Target RWE, Teva, TLL Pharmaceutical, Tr1X, TRex Bio, Union Therapeutics, and Ventyx Biosciences.
Co-authors reported relationships with AbbVie, Abivax, AbolerIS Pharma, Adacyte, Adiso, AgomAb, Alimentiv, Alpha Sigma, Allergan, AltruBio, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, AstraZeneca, Athos Therapeutics, Avaxia, Banook, Biogen, BMS, Boehringer Ingelheim, Boston Scientific Corporation, Bristol Meyer Squibb, Celgene, Celltrion, Connect Biopharma, CVasThera, Cytoki Pharma, Dr Falk Pharma, EA pharma, Endpoint Health, Enthera, Eurogenerics, Ferring, F. Hoffmann-La Roche Ltd, Fresenius Kabi, Galapagos, Genentech, Geneoscopy, Gilead, Giuliani, Gossamer Bio, GSK, Hospira, IAC Image Analysis, IMIDomics, Index Pharmaceuticals, Inotrem, Iterative Health, Janssen, JIMRO Co. Ltd, Johnson & Johnson, Kissei Pharmaceutical, Kyorin Pharmaceutical, Landos, Lilly, Lionhealth, Materia Prima, Medac, Merck, Microbiotica, MiroBio, Mitsubishi Tanabe, Mochida Pharmaceutical, Mopac, Morphic, MRM Health, MSD, Mundipharma, Nestlé, Nippon Kayaku, Nordic Pharma, Novartis, Odyssey Therapeutics, Oncodesign, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par' Immune, Pfizer Inc., Predictimmune, ProDigest, Progenity, Prometheus, Protagonist, Spyre, Takeda, Thabor Therapeutics, TiGenix, UCB Pharma, Roche, Robarts Clinical Trials, Samsung, Sandoz, Sanofi, Satisfy, Second Genome, Shire, Surrozen, Takeda, Telavant, Teva, Theravance, Thermo Fischer, TiGenix, Tillotts, VectivBio, Vedanta Biosciences, Ventyx, Viatris, Vifor, Ysopia, Zealand Pharma, and Zeria Pharmaceutical.
Moss reported no financial relationships.
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