SynAct Pharma has presented negative top-line data from the 12-week Phase IIb clinical study EXPAND. The study is evaluating the drug candidate resomelagon in newly diagnosed patients with severe rheumatoid arthritis. The results showed a high placebo effect and that resomelagon did not achieve the primary endpoint – a statistically greater proportion achieving a 20 percent improvement in ACR compared to the placebo group. BioStock spoke with CEO Torbjørn Bjerke about the results.
SynAct Pharma is a clinical-stage biotechnology company focused on treating inflammation by selectively activating 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
In recent months, the company has conducted two parallel clinical studies 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 study in patients with an incomplete response to first-line disease-modifying antirheumatic drugs (DMARD-IR).
Disappointing top-line results
SynAct Pharma initiated the EXPAND study as an extension of the successful Phase IIa BEGIN study. In this study, resomelagon and first-line treatment methotrexate showed a clinically meaningful reduction in disease activity after just 4 weeks of treatment in newly diagnosed patients with severe RA.
EXPAND was conducted on the same patient population, but with a 12-week treatment period in the hope that this would further improve the results. However, this was not the case. Top-line data show that resomelagon did not meet the primary efficacy endpoint, that significantly more patients would achieve an improvement of at least 20 percent according to American College of Rheumatology score (ACR20), compared to those who received placebo. After 12 weeks, 54,7 percent of patients treated with resomelagon had achieved an ACR20 improvement, while the corresponding figure for patients who received placebo was 55,7 percent.
The negative study results caused the company's stock to drop about 80 percent on September 4.
Subjective measures not in line with expectations
The subjective measures in the ACR scoring system led to high placebo responses, making it difficult to distinguish between active and placebo groups and demonstrate a clear benefit of resomelagon over placebo. However, the objective measures in the EXPAND study, such as improvement in the number of tender and swollen joints, were in line with expectations and with the results of the BEGIN study.
Confirmed favorable safety profile
Although resomelagon did not demonstrate a clear clinical benefit with respect to the primary endpoint, it maintained a favorable safety profile throughout the study. The incidence of serious adverse events (SAEs) was low in both the active and placebo groups. Furthermore, no evidence of immunosuppression associated with resomelagon was observed compared to methotrexate.
In a previous interview highlighted SynAct Pharma's CEO Torbjorn Bjerke the need for new and safe treatment options for RA:
»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 with the outcome of the EXPAND study, SynAct Pharma remains confident in the potential of resomelagon as a resolution treatment for RA. The company plans to carefully evaluate the top-line data and the full dataset to gain a deeper understanding of the results.
The management team also highlights the upcoming results from the RESOLVE study in patients with incomplete response to MTX therapy (DMARD-IR). Although this is a difficult-to-treat patient population, it represents a major commercial potential for resomelagon in the RA market. Top-line data from the RESOLVE study are expected in October. The RESOLVE study is being conducted under an IND with multiple clinics in the US, where approximately 25 percent of patients have been recruited.
Interview with CEO
BioStock contacted Torbjørn Bjerke to get more information and insights about the results from EXPAND.
- 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 percent 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«