Biotech SynAct Pharma has unveiled additional data from its EXPAND phase II clinical trial with resomelagon for rheumatoid arthritis. The new findings indicate consistent responsiveness to the drug candidate in a sub-population of patients with c-reactive protein level exceeding 3 mg/L, which is an indicative for active systemic inflammation. These encouraging findings are important for further development of resomelagon, according to the company’s CSO Thomas Jonassen in an interview. 

SynAct Pharma is a biotechnology company specialising in resolving inflammation through the selective activation of the melanocortin system. The company’s lead drug candidate, resomelagon (AP1189), is a once-daily oral selective melanocortin agonist, providing anti-inflammatory and immune resolution effects.

In 2022, the company initiated two phase II trials with resomelagon in rheumatoid arthritis (RA): EXPAND in newly diagnosed RA patients with severe disease activity, and RESOLVE in RA patients experiencing an incomplete response to methotrexate.

Initial results were disappointing

On September 4, SynAct Pharma announced top-line data from EXPAND showing that resomelagon did not meet the primary endpoint, which was to show a significantly higher ACR20 response at 12 weeks compared to placebo. ACR is measure commonly used in clinical trials to assess the effectiveness of drugs in rheumatic diseases. To achieve an ACR20 response, a patient must show at least a 20 per cent improvement in various criteria defined by the American College of Rheumatology, such as number of tender and swollen joints.

54.7 per cent of the full study population in EXPAND achieved an ACR20 response at 12-weeks, which is a lower percentage than the placebo group having 55.7 per cent of patients achieving ACR20 response. The company were surprised by the high placebo response and in the early weeks that they believe was driven by variability in the subjective outcome measures and the subsequent difficulty in showing a clear benefit of resomelagon over placebo.

Following these news, SynAct’s stock price shed 80 per cent.

New data – consistent responsiveness in systemic inflammation

However, a closer examination of the EXPAND data revealed a promising revelation. The company has been looking more in detail into the patient’s levels of the inflammatory marker CRP and found that resomelagon demonstrated consistent activity in patients with CRP levels exceeding 3 mg/L. This sub population represents 61 per cent of the full study population. Approximately 70.6 per cent of these patients treated with resomelagon achieved an ACR20 response compared to 54.3 per cent in the placebo group.

CRP is a blood inflammatory marker that is elevated in cases of systemic inflammation. The recent results suggest that elevated CRP may be a positive selection factor for identifying patients more likely to respond to resomelagon, which is both relevant and logical according to CEO Torbjørn Bjerke:

»The results in this patient population are highly relevant and interesting from a commercial point of view. The high rate of responsiveness supports our belief in the potential of inflammation resolution with resomelagon.«

Positive effects across all secondary measures

The positive impact of resomelagon extended beyond the primary endpoint. The favourable trend was detectable across all secondary outcome measures, including improvements in individual ACR component scores and reduction in disease activity assessed using the Clinical Disease Activity Index (CDAI) and the Disease Activity Score (DAS28).

Additionally, patients on resomelagon reported a significant 60 per cent improvement in the Health Assessment Questionnaire (HAQ)-Disability Index, where the patient assesses their own physical limitations associated with having active RA. The HAQ score improved by almost three times the minimum clinically important difference (MCID), according to SynAct Pharma’s webcast.

Importantly, these benefits were achieved with a favourable safety and tolerability profile.

More data to come in 2023

The high level of response seen in these patients is an important finding, allowing SynAct Pharma to better understand the EXPAND results and to effectively identify patients who are more likely to respond positively to resomelagon in the future.

The next step will be to report additional data from a Magnetic Resonance Imaging (MRI) sub-study of EXPAND assessing synovial inflammation as well as biomarkers to evaluate the compounds treatment effect on synovial inflammation. Additionally, the company is eagerly anticipating the presentation of top-line data from the RESOLVE study involving DMARD-IR patients, scheduled for October this year. According to the company, about 70 per cent of the patients in the RESOLVE part A study have an CRP > 3 mg/L. In the event of positive results from the RESOLVE study, SynAct Pharma look forward to initiate part B of the study.

Questions to SynAct’s CSO Thomas Jonassen

BioStock reached out to SynAct Pharma’s Thomas Jonassen for additional details regarding the recent results.

You have reported that patients with systemic inflammation show a better response rate on resomelagon compared to the total study population treated with the compound with the percentage of patients reaching the primary read out (ACR20) going from 54 to 71 per cent in patients with elevated CRP. What does systemic inflammation mean and why should resomelagon have better treatment effects in these patients?

– Circulating levels of CRP above 3 is an indication of systemic inflammation. The plan with EXPAND was to evaluate the potential of resomelagon in RA treatment-naïve patients with early severe RA with the aim to test coadministration with the first line compound Methotrexate.  In our post-hoc assessments, we identified that about 40 per cent of the patients in the EXPAND study had no signs of systemic inflammation at baseline based on CRP measurement. This in contrast to the majority of patients where elevated CRP levels showed evidence of systemic inflammation and thereby a more advanced degree of RA.

– What we have learned from the EXPAND study is that resomelagon treatment may work better in patients with an indication of systemic inflammation that very easily can be determined by measuring circulating levels of CRP.

»What we have learned from the EXPAND study is that resomelagon treatment may work better in patients with an indication of systemic inflammation that very easily can be determined by measuring circulating levels of CRP. This makes biologic sense as resomelagon and CRP may work in complimentary ways.«

– This makes biologic sense as resomelagon and CRP may work in complimentary ways as one of CRP’s functions is to opsonize or coat dead or dying cells as a means improve their efferocytosis or removal from the site of inflammation by macrophages and other cells.  While resomelagon has been shown to have anti-inflammatory activity it differentiates itself from the traditional anti-inflammatory agents by its ability to induce resolution, ie stimulate existing resolution pathways, and help re-balance the immune system. This process includes a shift in the phenotype of the macrophages bringing them from being pro-inflammatory to having pro-resolving properties like increasing the rate and efficiency of efferocytosis.  Given that both CRP and resomelagon can work at least in part to increase efferocytosis of dead or dying cells at sites of inflammation they could be working in conjunction.  The fact that resomelagon may have a higher likelihood of inducing a response in an RA patient with systemic inflammation may mean that there needs to be inflammation that has reached a certain level where resolution is needed. We believe that resomelagon serves its major function by helping the body’s natural resolution mechanisms like CRP resolve the ongoing inflammation.

–  In the BEGIN study the fraction of patients with CPR below 3 mg/L was only 21 per cent in the active dose group and 27 per cent in the placebo group. In other words, in the BEGIN study, a larger fraction of the patients had signs of systemic inflammation compared to the patients in the EXPAND study, which may help explain why the compound showed better treatment effect in the BEGIN study. When we went back to look at the elevated CRP population in the BEGIN study, we also see a relative higher rate of response with 65.0 per cent of the 100mg treated group exhibiting an ACR20 response at 4 weeks compared to 60.6 per cent in the overall 100 mg group.

»In the BEGIN study, a larger fraction of the patients had signs of systemic inflammation compared to the patients in the EXPAND study, which may help explain why the compound showed better treatment effect in the BEGIN study.«

– Moving forward with development of resomelagon we intended to select diagnosed RA patients with elevated CRP as a means of better patient selection. This makes patient selection more precise and has the double benefit of both selecting a population that we feel is more likely to respond to resomelagon as well as limit the exposure in patients who are unlikely benefit from therapy.

There seems to be a big discrepancy between the 4-week results in the BEGIN study and the 4-week results reported from the EXPAND study. In the BEGIN study you had statistically significant treatment effects when compared to placebo evaluated both on ACR20 and CDAI- this is not the case in the EXPAND study where there is much lower treatment effects after 4 weeks and no difference to placebo – do you have any explanation for this?

– The ACR scoring system is comprised of both objective measures like the number of tender and swollen joints and circulating CRP levels and subjective measures like patient and physician subjective scoring of disease activity, patient subjective assessment of pain and the HAQ-DI a patient survey of limitations in daily living associated with active RA.  In the BEGIN study both the objective and the subjective were aligned meaning that they moved in the same direction, and in the highest dose group statistically significant treatment effects were seen on the primary read out of mean change in CDAI as well as on the ACR20 score.  Improvements in tender or swollen joint counts were supported by improvements in the subjective measures. Further, the agreement in objective and subjective scores in BEGIN was also dose-responsive in nature with differences in scoring between the two active dose groups observed as exemplified by the investigator evaluation of reduction in disease activity that reached statistical significance in the 100mg dose group.

– When looking at the average reduction in swollen joint counts (SJ28, ie reduction in 28 predefined joints used in the CDAI and DAS28 scoring systems) at 4 weeks in the EXPAND study we were able to see data resembling what was seen in the BEGIN study with an average reduction of 6.4 joints in the resomelagon group vs 4.6 joints in the placebo group. For the EXPAND group of patients with >3 mg/L CRP, baseline numbers were 6.7 and 4.5 respectively. In other words, we were able to see comparable findings from the BEGIN and EXPAND studies on the objective readout of mean reduction in the number of swollen joints at 4 weeks.

»We were able to see comparable findings from the BEGIN and EXPAND studies on the objective readout of mean reduction in the number of swollen joints at 4 weeks. However, the very clear signal on the subjective scores demonstrated in the BEGIN study is not present after 4 weeks treatment in EXPAND. […] When we look further into the data, we see an unexpected level of variability between sites in their scoring of the subjective measures«

– However, the very clear signal on the subjective scores demonstrated in the BEGIN study is not present after 4 weeks treatment in EXPAND. In EXPAND we saw that objective and subjective measures did not move in parallel as they did in BEGIN and were not in alignment. However, in the whole EXPAND study population, alignment between objective and subjective measures improved over time and with measures more in alignment at 12 weeks.  When we look further into the data, we see an unexpected level of variability between sites in their scoring of the subjective measures that decreased in magnitude over the time of the study but that caused a spike in the placebo rate particularly in the early weeks of the study.

– We have examined several possible causes for the non-aligned objective and subjective measures and site variability seen in EXPAND.  We looked at the safety and tolerability data but as there was no increased safety risk or overall signal that could explain the site variability in scoring.  One possibility to consider is the short interval between RA diagnosis and study entry (median time <4months) as patients with limited experience with their RA may be less able to accurately gauge their own disease activity. The EXPAND sites and investigators also had a range of experience in conducting trials in RA. Clinical trials in RA are complex with many assessments and tests that need to be conducted at every study visit. The combination of recently diagnosed patients without longer-term experience in how their disease affects them combined with some sites that were not as experienced with clinical trials in RA may have contributed to the subjective variability seen in EXPAND.

»Patients with limited experience with their RA may be less able to accurately gauge their own disease activity. The EXPAND sites and investigators also had a range of experience in conducting trials in RA. Clinical trials in RA are complex with many assessments and tests that need to be conducted at every study visit.«

– When we look at the subjective measures in the greater than 3 mg/L CRP group we see this ‘disagreement’ between objective and subjective measures improve starting at week 4.  By week 12, the elevated CRP population reached an ACR20 response rate that, while on the lower end of the range, was more in line with our expectations.  In essence, the activity seen in the elevated CRP population was able to rise above the noise seen with the subjective measures which we believe prevented the trial from demonstrating more pronounced results at the earlier timepoints including week 4.

At the web cast where key results were presented it was stated that the average time from diagnosis to inclusion in the study was 42 weeks in the resomelagon group compared to 19 weeks in the placebo group.  There has been a lot of speculation about this so it would be good if you could explain?

– While the mean time from diagnosis indicated a possible imbalance between the active and placebo groups, the median time from diagnosis was much more aligned between the groups. Six patients were identified in the study who has a much longer time from diagnosis to study entry without ever been treated with methotrexate with majority of the patients included in Active group. While it was not the intention to include such patients in the study, these patients are not considered protocol violations as they were treatment naïve.

How does your further assessment of the EXPAND study influence your thoughts of the ongoing P2a portion of the RESOLVE study?

– While it was a painful lesson to learn, the finding of elevated CRP as a positive selection factor for resomelagon response will be very valuable to the program moving forward. There are key differences in the RESOLVE study including a confirmed lack of response to methotrexate (lower placebo responses are typically seen in this population), longer standing disease duration and the inclusion of US sites that account for about a quarter of the overall recruited patients. While this study is designed to enable dose selection for the P2b portion of the study we feel that the patient population being studied (methotrexate failures) along with the longer disease duration and sites in the US should help mitigate the issues seen with the subjective measures in the EXPAND study.

»While it was a painful lesson to learn, the finding of elevated CRP as a positive selection factor for resomelagon response will be very valuable to the program moving forward. There are key differences in the RESOLVE study including a confirmed lack of response to methotrexate (lower placebo responses are typically seen in this population), longer standing disease duration and the inclusion of US sites«

– Assuming success in the P2a portion, we intend to explore amending the approved RESOLVE 2b design to include elevated CRP as an entry criterion.  While the safety profile of resomelagon remains intact, the ability of elevated CRP to serve as a positive selection factor for patients more likely to respond to therapy adds a level of precision to patient selection that we think will be appreciated by regulatory agencies.

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