close
close

Harnessing small molecules to treat chronic inflammatory diseases

Dr. Sheldon Sloan, MBE, Chief Medical Officer, Abivax, shares why the company’s microRNA small molecule treatment could provide long-lasting efficacy for patients with ulcerative colitis, as well as the prospects for using small molecule-based drugs in autoimmune diseases and chronic diseases.

small molecule obefazimodsmall molecule obefazimod

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

Manufacturers of small molecule active pharmaceutical ingredients (APIs) are in fierce competition with drugs such as biologics because “complex compounds offer (a) targeted, effective” approach, a market report states. However, as Dr. Sloan explains, small molecule drugs offer unique advantages, such as more desirable delivery compared to these larger molecules.

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

Most treatments for more severe forms of ulcerative colitis (UC) involve injections, with some oral entrants in the past five years.”

Unlike biologics, small molecules can be taken orally, which many patients prefer to injectable medications. This is due to their ease of use and the ability to travel without having to worry about keeping infused therapies cold. Most treatments for more severe forms of ulcerative colitis (UC) involve injections, with some oral treatments having been used in the past five years. A possible disadvantage of oral therapies is the dosing frequency, usually once or twice a day, while some injectables can be used once every eight weeks. This difference may affect treatment compliance.

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

One of the key challenges in clinical trials for a small molecule, especially in oral therapy, is adherence and confirmation of adherence. Does the participant adhere to the protocol and how is this followed? Managing the number of pills, electronically tracking pill intake through devices, and proper monitoring of patient participation by trial sites are manageable solutions.

Second, small molecules generally have a shorter half-life than biologicals (meaning they are cleared from the body more quickly than biologicals), usually measured in days. For biologics, half-lives are much longer, usually measured in weeks and not days. This makes adherence even more important in small molecule clinical trials – so putting in place the safeguards I mentioned are critical.

Given 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 characterized by inflammation in the gastrointestinal tract, mainly affecting the colon and rectum. The pathogenesis of this condition is complex and involves 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.

Furthermore, many advanced therapies target a single pathway, allowing the immune system to evade the effect, which can lead 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 the patient cycling through medications with different mechanisms of action until they find a drug that works for them.

Enhanced expression of miR-124… stabilizes the dysregulated immune response and reduces inflammation, without causing broader immunosuppression. This approach can lead to more sustainable efficacy in the long term.”

Obefazimod, currently in Phase III clinical trials for the treatment of moderately to severely active ulcerative colitis, is a 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 regulated in patients with ulcerative colitis.

Enhanced expression of miR-124 results in the regulation of multiple inflammatory pathways simultaneously, driving inflammatory cells and proteins to, but not below, their homeostatic levels. This stabilizes the dysregulated immune response and reduces inflammation, without causing broader immunosuppression. This approach may lead to more durable efficacy in the long term, as it is less likely that the immune system will find a way to evade the effect.

Based on the mechanistic concept of obefazimod, we began evaluating potential follow-on drug candidates from Abivax’s proprietary chemical library, which contains additional miR-124 enhancers.

Can you share some important recent data on obefazimod, for example from phase II trials?

The data from our global Phase II clinical trials are very encouraging and demonstrate the potential of obefazimod for durable maintenance efficacy in patients with moderately to severely active ulcerative colitis, at all stages of their disease trajectory.

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

The data also demonstrate a favorable safety profile, with a low incidence of serious adverse events comparable to placebo.

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

Encouraged by the emerging clinical profile, we are 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 to be launched in the second half of 2024 expected.

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

Although small molecules have been used in many therapeutic areas for decades, they are relatively new in the field of autoimmune diseases and chronic diseases, including inflammatory bowel disease.”

Although small molecules have been used in many therapeutic areas for decades, they are relatively new in the field of autoimmune diseases and chronic diseases, including inflammatory bowel disease.

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

About the interviewee

Dr.  Sheldon Sloan, MBE, Chief Medical Officer, AbivaxDr.  Sheldon Sloan, MBE, Chief Medical Officer, AbivaxDr. Sheldon Sloan, MBE, is Chief Medical Officer at Abivax. He has more than 30 years of experience in academia and the biopharmaceutical industry, with an extensive track record in gastroenterology and IBD.

Before joining Abivax, Sheldon worked for Arena Pharmaceuticals and, post-acquisition, Pfizer. He was program leader for Velsipity.

Before joining Arena Pharmaceuticals, Sheldon held various leadership positions at J&J in medical affairs, R&D and science policy. Most recently at J&J, he was Global Medical Affairs Leader for IBD, leading the global launch strategy and execution of Crohn’s disease and ulcerative colitis for Stelara®.

Sheldon holds an MD from Rush Medical College, Chicago, USA, and a Masters in Bioethics from the University of Pennsylvania, USA.

Back To Top