Clinical Benefits of ABX464 for Ulcerative Colitis Revealed in Review Study

Clinical Benefits of ABX464 for Ulcerative Colitis Revealed in Review Study

Abivax has published a review study summarizing the mechanisms, as well as the previously undisclosed clinical benefits of ABX464, its treatment candidate for people with inflammatory diseases, including ulcerative colitis (UC).

ABX464, undergoing clinical testing for several inflammatory diseases, will soon be evaluated in a Phase 2/3 trial for Crohn’s disease, the company announced.

The review, “Specific and selective induction of miR-124 in immune cells by the quinoline ABX464: a transformative therapy for inflammatory diseases,” was published in the journal Drug Discovery Today.

“Our recent publication in Drug Discovery Today once again demonstrates the unique mechanism of action and transformative potential of our lead drug candidate ABX464 to effectively and durably treat chronic inflammatory diseases,” Hartmut J. Ehrlich, MD, CEO of Abivax, said in a press release.

Over the past decades, scientists have investigated the role of microRNAs as key players in regulating immune responses. MicroRNAs are tiny RNA molecules that regulate gene activity within cells. They bind to a gene’s messenger RNA (mRNA) — the molecule generated from DNA and used as the template for protein production — to prevent the generation of that protein. Depending on their target mRNA, microRNAs might either promote or suppress inflammation, making them attractive targets for potential therapies.

The levels of a particular microRNA called miR-124, which has the ability to dampen inflammation, were previously found to be reduced in patients with certain autoimmune diseases. Importantly, increasing levels of miR-124 were found to inhibit intestinal inflammation by suppressing the activity of a main regulator of the inflammatory response, called STAT3.

ABX464, an oral medicine originally developed as an inhibitor of HIV replication, was shown to promote the production of miR-124 in immune cells.

In studies with a mouse model of IBD — wherein colon inflammation (colitis) is induced by adding a chemical called dextran sodium sulfate (DSS) in the animals’ drinking water — ABX464 was shown to potently attenuate DSS-induced colitis and had a long-term protective effect even after treatment stopped.

The therapy helped preserve the intestinal epithelium architecture and prevented its infiltration by inflammatory cells, with a significant drop in the levels of inflammatory molecules (such as the monocyte chemoattractant protein-1, MCP-1, and the tumor necrosis factor alpha or TNF-alpha) in the colon. These effects were consistent with increasing levels of miR-124.

In lab tests with human immune cells, treatment with ABX464 lowered the levels of several pro-inflammatory molecules (cytokines), including TNF-alpha and MCP-1, among others. Also, previously unpublished data from Abivax showed that ABX464 significantly reduced two subpopulations of proinflammatory immune T-cells, called Th17 and Th1. Th17-secreting molecules are often increased in the intestinal epithelium of patients with UC and Crohn’s disease.

“By increasing the expression of miR-124 in the immune system cells, ABX464 inhibits the excessive inflammatory response that causes inflammatory diseases, such as ulcerative colitis,” said Jamal Tazi, PhD, vice president of research at Abivax. “The scientific publication shows that miR-124 acts as an endogenous regulator of inflammation that limits the activation of the signalling pathways which are responsible for the expression of pro-inflammatory cytokines.”

Moreover, in DSS-exposed mice, treatment with ABX464 prevented the rise of Th17 cells, while the therapy exerted no effect in Tregs — cells responsible for keeping the immune system in check.

Following Phase 1 clinical studies that assessed the therapy’s safety at different doses, ABX464 moved to a proof-of-concept Phase 2 study with UC patients.

The ABX464-101 (NCT03093259) Phase 2 trial assessed the safety and efficacy of a 50 mg dose given once daily, versus a placebo, in people with moderate-to-severe active UC who failed or were intolerant to immunomodulators, TNF-alpha inhibitors, Entyvio (vedolizumab), or corticosteroids. Participants were treated for eight weeks.

Top-line results showed that ABX464 was well-tolerated and led to clinical remission (according to the total Mayo score) in 35% of the patients, compared with 11% of those on placebo.

Colorectal mucosal healing was also significantly higher in the ABX464-treated group — 50% – compared to 11% in the placebo group. ABX464’s effects were detected within two weeks of treatment. Overall, a clinical response was reached by 70% of treated patients, compared with 30% of controls.

After this initial trial, all participants were able to enroll in an open-label extension study, called ABX464-102 (NCT03368118), in which all were given ABX464 for 12 months.

Data from the 16 enrolled patients who underwent an endoscopy showed that all of them had an endoscopic score of zero or one, which is indicative of healing, and 12 (75%) achieved clinical remission. The clinical benefits seen with ABX464 correlated with sustained increase of the levels of miR-124.

The company recently completed patient enrollment for its ABX464-103 Phase 2b trial (NCT03760003), which will continue to evaluate ABX464 as a treatment candidate for people with moderate-to-severe UC.

The therapy is also being investigated for patients with COVID-19 in a Phase 2b/3 clinical trial (NCT04393038), and for people with rheumatoid arthritis in a Phase 2a trial (NCT03813199). Top-line results from both trials are expected this year. A Phase 2b/3 clinical study for Crohn’s disease is also being prepared.

Abivax is “very much looking forward to seeing the results of our ongoing clinical trials which are expected in Q2 2021, namely the Phase 2b trial in UC, the Phase 2a trial in rheumatoid arthritis as well as the Phase 2b/3 study in Covid-19 disease with the objective to prevent hyper-inflammation in high-risk patients,” Ehrlich said. “We are also keen to initiate the pivotal Phase 2b/3 clinical study in Crohn’s disease in the course of this year.”