Bioteknikbolaget SynAct Pharma har presenterat ytterligare data från sin kliniska fas II-studie EXPAND med resomelagon för behandling av reumatoid artrit. De nya fynden visar en konsekvent responsnivå för läkemedelskandidaten i en subpopulation av patienter med CRP-nivå över 3 mg/L, vilket är en indikation för aktiv systemisk inflammation. De positiva resultaten är viktiga för fortsatt utveckling av resomelagon, enligt bolagets CSO Thomas Jonassen i en intervju. 

SynAct Pharma är ett bioteknikbolag specialiserat på att lösa inflammation genom selektiv aktivering av melanokortinsystemet. Bolagets ledande läkemedelskandidat, resomelagon (AP1189), är en oral selektiv melanokortinagonist som  ger antiinflammatorisk effekt och inflammationsupplösning. 

Under 2022 inledde bolaget två kliniska fas II-studier med resomelagon i reumatoid artrit (RA): EXPAND på nydiagnostiserade RA-patienter med allvarlig sjukdomsaktivitet och RESOLVE på RA-patienter som upplever ofullständigt svar på metotrexat. 

De initiala resultaten var en besvikelse

Den 4 september presenterade SynAct Pharma top-line-data från EXPAND som visade att resomelagon inte uppfyllde det primära effektmåttet, vilket var att visa ett signifikant högre ACR20-svar vid 12 veckor jämfört med placebo. ACR är ett mått som ofta används i kliniska prövningar för att bedöma effekten av läkemedel för reumatiska sjukdomar. För att uppnå ett ACR20-svar måste en patient visa minst 20 procent förbättring av olika kriterier som definierats av American College of Rheumatology, såsom antalet ömma och svullna leder. 

54,7 procent av patienterna som fick resomelagon i EXPAND uppnådde ett ACR20-svar efter 12 veckor, vilket är en lägre procentandel än placebogruppen där 55,7 procent av patienterna som uppnådde ACR20-svar. Bolaget var förvånade över det höga placebosvaret som de tror drevs av variabliteten i de subjektiva utfallsmåtten och den efterföljande svårigheten att visa en tydlig fördel med resomelagon jämfört med placebo. 

Efter dessa nyheter tappade SynActs aktiekurs 80 procent. 

Nya data – konsekvent respons vid systemisk inflammation

En närmare granskning av EXPAND-data visade dock lovande fynd. Bolaget har tittat närmare på patientens nivåer av den inflammatoriska markören CRP och funnit att resomelagon har konsekvent aktivitet på patienter med CRP-nivåer över 3 mg/L. Denna delpopulation representerar 61 procent av hela studiepopulationen. Cirka 70,6 procent av dessa patienter som behandlades med resomelagon uppnådde ett ACR20-svar jämfört med 54,3 procent i placebogruppen. 

CRP är en blodinflammatorisk markör som är förhöjd vid systemisk inflammation. De senaste resultaten tyder på att förhöjt CRP kan vara en viktig selektionsfaktor för att identifiera patienter som är mer benägna att svara på resomelagon, vilket är både relevant och logiskt enligt vd Torbjørn Bjerke: 

»Resultaten i denna patientpopulation är mycket relevanta och intressanta ur en kommersiell synvinkel. Den höga responsnivån stöder vår tro på potentialen för inflammationsupplösning med resomelagon.«

Positiv effekt för alla sekundära effektmått

Men det var inte bara i det primära effektmåttet som man såg positiva effekter. Den gynnsamma trenden kunde detekteras för alla sekundära resultatmått, inklusive förbättringar i individuella ACR-mått och minskning av sjukdomsaktivitet som utvärderades med Clinical Disease Activity Index (CDAI) och Disease Activity Score (DAS28). 

Dessutom rapporterade patienterna som behandlades med resomelagon en signifikant förbättring på 60 procent i Health Assessment Questionnaire (HAQ)-Disability Index, där patienterna själva bedömer sin fysiska förmåga i samband med aktiv RA. HAQ-poängen förbättrades nästan tre gånger mer än den minsta kliniskt meningsfulla skillnaden (MCID), enligt SynAct Pharmas webcast. 

Kanske viktigast av allt är att dessa fördelar uppnåddes med en gynnsam säkerhets- och tolerabilitetsprofil. 

Mer data under 2023

Nästa steg blir att rapportera ytterligare data från en delstudie med MRI för att utvärdera synovial inflammation, samt biomarkörer för att utvärdera substansens behandlingseffekt på synovial inflammation. Dessutom ser bolaget fram emot att presentera top-line-data från RESOLVE-studien med DMARD-IR-patienter i oktober i år. Enligt bolaget har cirka 70 procent av patienterna i RESOLVE del A-studien en CRP-nivå på över 3 mg/L. Vid positiva resultat från RESOLVE-studien planerar bolaget att starta del B av studien. 

Frågor till SynActs CSO Thomas Jonassen

BioStock kontaktade bolagets CSO Thomas Jonassen för att få mer information om de senaste resultaten. 

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.

Prenumerera på BioStocks nyhetsbrev