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A first-in-class investigational agent offered symptom relief to patients with active moderate-to-severe ulcerative colitis (UC), according to a phase IIb randomized trial.

Among over 200 patients, those who received three different doses of obefazimod (ABX464) had a significantly greater improvement in modified Mayo score (MMS) -- a measurement of disease activity, marked by a change in the least squares mean (LSM) from baseline -- at 8 weeks compared with placebo, reported Severine Vermeire, MD, of the University Hospitals Leuven in Belgium, and colleagues in :

• 25 mg: LSM -3.1 (95% CI -3.6 to -2.6)
• 50 mg: LSM -3.2 (95% CI -3.7 to -2.7)
• 100 mg: LSM -2.9 (95% CI -3.4 to -2.5)
• Placebo: LSM -1.9 (95% CI -2.4 to -1.5)

At all doses of obefazimod, more patients achieved clinical response (50-62% with obefazimod vs 34% with placebo), clinical remission (18-26% vs 13%), and endoscopic improvement (35-44% vs 14%) at 8 weeks, with similar results at 16 weeks.

During the 48-week open-label extension period using only 50-mg obefazimod (n=217), 84% of patients achieved new or sustained clinical response, while 65% were in clinical remission, 58% had endoscopic improvement, and 33% were in endoscopic remission.

Treatment options for UC are based on the pattern of disease involvement and severity of clinical activity, Vermeire and team said. Patients with moderate-to-severe UC who do not respond to the usual 5-aminosalicylic acids (5-ASA) may require additional therapeutics.

Obefazimod is a small molecule that induces the selective upregulation of microRNA-124 (miR-124) -- "a modulator of inflammation and innate immunity that has the potential to provide therapeutic restitution of physiological pathways impaired by inflammatory diseases" -- in immune cells, the authors explained.

"There was no apparent dose effect across the ABX464 100 mg, 50 mg, and 25 mg dose groups for the primary or secondary efficacy endpoints," noted Raja Atreya, MD, and Markus Neurath, MD, both of Erlangen University Hospital in Germany, in an . "This result might be attributable to the proposed mode of action of ABX464, in which optimal STAT3 inhibition might not require the highest ABX464 dose."

"It would be interesting to examine in how much miR-124 and phosphorylated STAT3 mucosal expression levels were influenced by each dose and whether they could serve as biomarkers for treatment outcomes before and during ABX464 treatment," they added.

Vermeire told 名媛直播 that "obefazimod was well tolerated up to 56 weeks of exposure. The outcome of this phase IIb induction and maintenance study validates the safety and efficacy data generated with obefazimod in the initial in patients suffering from UC, including in a patient population refractory to biologics and/or JAK inhibitor treatments."

But Atreya and Neurath noted that the findings showing "late therapeutic responders after the 16-week double-blind induction period ... should be interpreted with caution and be adequately analyzed in subsequent studies to identify the optimal induction treatment phase regarding likelihood of response."

This double-blind trial consisted of an induction period occurring over 16 weeks, followed by a 48-week open-label extension period for up to 96 weeks. Vermeire and colleagues enrolled 254 patients with moderate-to-severe UC who were randomized to receive once-daily oral obefazimod at three different doses or to placebo. The study was conducted at 95 centers in 16 countries, including France, Germany, Ukraine, Canada, and the U.S., from August 2019 to April 2021. Inclusion criteria for the trial included an MMS of at least 5 points, a Mayo endoscopic subscore of at least 2, and intolerance or non-response to prior treatment.

Mean patient age was 40-42, and 43-66% were men. Disease duration was 7-9 years. Nearly half of patients were refractory to at least one second-line therapy, including tumor necrosis factor inhibitors (43%), vedolizumab (Entyvio; 32%), or JAK inhibitors (19%). Over 90% were refractory to at least two prior therapies. Patients continued concomitant medications, such as 5-ASA (73-81%), corticosteroids (45-58%), and immunosuppressants (9-16%). Notably, 71% had severe baseline disease activity (mean MMS 7-9).

The most common adverse event (AE) was headache (ranging from 21% to 42% at various doses vs 8% with placebo). Grade 3 severe headache followed a similar pattern with increasing obefazimod dose, but did not affect placebo patients (2% to 5% vs 0%). Worsening UC was the only serious AE, and that occurred in one patient in the 50-mg obefazimod group and one in the 100-mg group versus three on placebo. No deaths occurred. One patient experienced myocardial infarction that was deemed unrelated to the 100-mg treatment received.

Study limitations included the small sample size and the fact that the authors did not test for a dose-response effect. A is in the works, according to obefazimod developer Abivax.

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