Harnessing small molecules to treat chronic inflammatory diseases

According to Biotech Abivax SA, obefazimod is the only small molecule drug candidate in clinical development with a mechanism of action that induces production of microRNA, or miRNA (miR-124), a potent anti-inflammatory agent. As a potential differentiated oral treatment option, this drug could facilitate greater durability of efficacy results long-term, Phase II data shows.

Small molecule active pharmaceutical ingredient (API) manufacturers are in fierce competition with medicines such as biologics, since “complex compounds offer [a] targeted, effective” approach a market report states. However, as Dr Sloan elucidates, small molecule-based drugs offer unique advantages such as more desirable administration compared to these larger molecules.

What are the main benefits and limitations of small molecule-based drugs?

Unlike biologics, small molecules can be taken orally which many patients prefer when compared to injectables. This is due to their ease of use and ability to travel without having to worry about keeping infused therapies cold. Most of the treatments for more severe forms of ulcerative colitis (UC) are injectables with a few oral entrants over the past five years. One potential drawback of oral therapies is the frequency of dosing, usually once or twice daily whereas some injectables can be used once every eight weeks—this difference may have an impact on adherence to their medicine.

Compared to other drug modalities, what are two of the major challenges of designing clinical trials for small molecule-based drugs? What are the solutions?

Among the more significant challenges in clinical trials for a small molecule, specifically with an oral therapy, is compliance and compliance confirmation. Is the participant adhering to protocol and how is it being tracked? Managing pill counts, electronic device tracking of pill intake, and proper oversight of patient participation by trial sites are manageable solutions.

Secondly, small molecules typically have shorter half-lives than biologics—that means they are cleared from the body more quickly than biologics—usually measured in days. For biologics, the half-lives are much longer, usually measured in weeks, not days. This makes adherence even more important in clinical trials for small molecules—so putting the safeguards I mentioned are key.

Considering its novel mechanism of action, why does obefazimod have potential in chronic inflammatory diseases such as ulcerative colitis?

Ulcerative colitis is a chronic inflammatory bowel disease characterised by inflammation in the gastrointestinal tract, primarily affecting the colon and rectum. The pathogenesis of this condition is complex, involving dysregulation of multiple inflammatory pathways. Many currently available treatments broadly target patients’ immune systems, which can result in a range of systemic side effects such as infections and malignancies.​

Additionally, many advanced therapies target a single pathway, which can create an opportunity for the immune system to circumvent the effect, leading to loss of response over time. Despite the availability of numerous treatments, many patients do not respond or lose response over time. This results in patient cycling through medications with different modes of action until they get to one that works for them.

Obefazimod, currently in Phase III clinical trials for the treatment of moderately to severely active ulcerative colitis, is small molecule that selectively enhances the expression of a single micro-RNA, specifically miR-124. This is known to act as a natural regulator of the immune response that happens to be downregulated in patients with ulcerative colitis.

Enhanced expression of miR-124 results in regulation of multiple inflammatory pathways simultaneously, bringing inflammatory cells and proteins down to their homeostatic levels, but not below them. This stabilises the dysregulated immune response and reduces inflammation, without causing broader immunosuppression. This approach may lead to more durable efficacy over the long-term because the immune system may be less likely to find a way to circumvent the effect.

Based on the mechanistic concept of obefazimod, we have begun to evaluate potential follow-on drug candidates from Abivax’s proprietary chemical library that includes additional miR-124 enhancers.

Can you share some key recent data for obefazimod, for instance from Phase II trials?

The data from our global Phase II clinical trials is very encouraging and demonstrate obefazimod’s potential for durable maintenance efficacy in patients with moderately to severely active ulcerative colitis, across all stages of their disease journey.

The data show statistically significant improvements in the primary endpoint of the change from baseline of the Modified Mayo Score for all three doses tested (25, 50, 100mg) vs. placebo at Week 8. In addition, there was separation from placebo for key secondary endpoints including clinical remission, clinical response, and endoscopic improvement at Week 8. For those patients who entered the long-term extension study on 50mg/day for up to two years, clinical remission, clinical response, and endoscopic improvement continued to increase by Week 48, and were maintained through Week 96. The increased response rates were seen in both bio/JAK-naïve and experienced subgroups through Week 96.

The data also demonstrate a favourable safety profile, with serious adverse events occurring at low rates similar to placebo.

With the positive safety and efficacy data from the Phase II trials we have initiated a pivotal global Phase III programme for obefazimod in ulcerative colitis and we expect initiation of a Phase IIb clinical trial in moderately to severely active Crohn’s disease later this year.

Since we are encouraged by the emerging clinical profile, we are in the process of evaluating combination therapy of oral and injectable drug candidates with obefazimod in ulcerative colitis with preclinical data to support decision-making on a combination agent expected in the second half of 2024.

How do you see small molecule drug development evolving over the next five years?

While small molecules have been used across many therapeutic areas for decades, they are relatively new in the autoimmune, chronic disease space including inflammatory bowel diseases.

In inflammatory bowel disease (IBD) there are four newer entrants – two S1P receptor modulators and two JAK inhibitors – approved since 2018. And there are several more in development. Since many patients prefer oral medications, some of the mechanisms of action targeted by injectable therapies are now being studied with oral drug candidates. There are also some new mechanism of action approaches on the horizon—like obefazimod. I expect there will be an increasing number of oral therapies available over the coming years to meet the needs and preferences of inflammatory bowel disease patients.