SynAct Pharma has announced disappointing top-line data from its 12-week EXPAND phase IIb clinical trial. The study is evaluating the drug candidate resomelagon in newly diagnosed rheumatoid arthritis patients with severe disease. Results show a high placebo effect thus not achieving the primary endpoint – a statistically higher rate of 20 improvement in the American College of Rheumatology score compared to placebo. BioStock spoke to CEO Torbjørn Bjerke about the results.  

SynAct Pharma is a clinical-stage biotechnology company focused on resolving inflammation through selective activation of the melanocortin system. The company’s lead candidate, resomelagon (AP1189) selectively activates melanocortin receptors 1 and 3, which are directly involved in inflammation.

Two clinical trials in RA

During the last couple of months, the company has conducted two parallel clinical trials with resomelagon in rheumatoid arthritis (RA) – EXPAND and RESOLVE. EXPAND is a phase IIb study in newly diagnosed, treatment-naïve patients with highly active RA, while RESOLVE is a phase IIa/b clinical trial in patients with incomplete response to first-line disease-modifying antirheumatic drugs (DMARD-IR).

Disappointing top-line results

SynAct Pharma initiated the EXPAND study as a continuation of the successful BEGIN phase IIa study. In this study, resomelagon and first-line treatment methotrexate induced a meaningful clinical reduction in disease activity compared to placebo after only 4 weeks treatment in newly diagnosed, severe RA patients.

EXPAND was conducted on the same patient population, but with a 12-week treatment period, which some anticipated to improve the results even further.  However, this was not the case. The top-line data revealed that resomelagon did not meet the primary endpoint of achieving a statistically higher rate of 20 per cent improvement in the American College of Rheumatology score (ACR20). 54.7 per cent of patients treated with resomelagon achieved an ACR20 response at 12-weeks as compared to 55.7 per cent of patients receiving placebo.

The negative study results caused the company’s stock to drop about 80 per cent on September 4.

Subjective measures out of line with expectations

The subjective measures used in the ACR scoring system led to high placebo responses, making it challenging to discern between active and placebo groups and show a clear benefit of resomelagon over placebo. However, the study’s objective measures, such as improvements in the number of tender and swollen joint, were in line with expectations and in line with the BEGIN study.

Confirmed favourable safety profile

Despite not demonstrating a clear clinical benefit in terms of the primary endpoint, resomelagon maintained a favourable safety profile throughout the study. The occurrence of serious adverse events (SAEs) was low in both the active group and the placebo group. Moreover, there were no indications of immunosuppression associated with resomelagon when used in conjunction with MTX therapy.

In a previous interview, Synact’s CEO Torbjørn Bjerke commented on the need for new and safe RA treatments:

»The current treatments have also demonstrated the risks that can come with suppressing the immune system. With resomelagon, we seek to go beyond suppression by stimulating the body to resolve inflammation. The efficacy and safety challenges with key classes of RA therapeutics clearly shows the tremendous need for new treatments with improved risk benefit profiles.«

Further analysis and data from RESOLVE

Despite the disappointment in the EXPAND trial outcomes, the company remains committed to the potential of resomelagon as a resolution therapy for RA. SynAct Pharma plans to thoroughly assess the top-line data and the complete study dataset to gain a deeper understanding of the results.

The management team also highlights the upcoming results from the RESOLVE study on patients with incomplete response to MTX therapy (DMARD-IR). While this is a difficult-to-treat patient population, it represents a higher commercial potential for resomelagon in the RA space. Top-line data from the RESOLVE study are expected in October. The RESOLVE study is conducted under an IND with several clinical sites in the US recruiting approximately 25 per cent of patients.

Interview with CEO

BioStock contacted Torbjørn Bjerke for more details and insights from the EXPAND top line data.

Can you give some background to the EXPAND study data released this week?

– The study was designed for new patients with severe RA. Unfortunately, we did not see a difference between the placebo and the active group. The goal was to show a 20 per cent difference after 12 weeks of treatment. We believe there was an unexpectedly high placebo effect, especially in the subjective measures, but in the objective measure we saw similar activity as in the previous 4-week BEGIN study, which showed a significant difference between the placebo and the 100mg dose we tested in EXPAND. Due to the high placebo we just did not reach the delta or difference we expected. Let us not forget about the safety profile, which showed a very good profile after three months of treatment.

»We believe there was an unexpectedly high placebo effect, especially in the subjective measures, but in the objective measure we saw similar activity as in the previous 4-week BEGIN study, which showed a significant difference between the placebo and the 100mg dose we tested in EXPAND.«

The ongoing phase II study RESOLVE is expected to be released in October. What are your expectations for that trial given the results in EXPAND?

– We believe the DMARD-IR patient population in the RESOLVE study as they have failed MTX therapy and represent a large population of patients who have not gotten the support they really need. This group has a clear commercial potential for resomelagon. We are now waiting for the patient data and plan to present top-line data in October.

What do the EXPAND results mean for the future of SynAct?

– The EXPAND results were not positive, but what is positive is that we also saw activity that was similar to the previous BEGIN study. There is absolutely hope for the resomelagon compound, and I know the board and management team are committed. We believe in inflammation resolution and the mode of action in resomelagon. EXPAND was a hiccup, but we need to continue the development because this is so exciting.

»The EXPAND results were not positive, but what is positive is that we also saw activity that was similar to the previous BEGIN study. There is absolutely hope for the resomelagon compound, and I know the board and management team are committed«

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