Disease Background
Rheumatoid arthritis (RA) is an autoimmune/chronic inflammatory disorder that typically affects more than just the joints. RA is an autoimmune disorder, a disease where the immune system mistakenly attacks your body’s own tissues. RA affects the lining of the joints, causing a painful swelling that can result in cartilage and bone erosion and joint deformity. RA is often associated with symptoms involving other parts of the body including skin, eyes, lungs, heart, and blood vessels. Initial symptoms are in most cases joint pain, arthralgia, but without the cardinal arthritis symptoms of tender and swollen joints. Symptoms of arthritis gradually develop over time. Sometimes over weeks in other cases over months to years. According to guidelines (EULAR and FDA in Europe and US respectively) the treatment of these patients is not initiated before the diagnosis of RA. The diagnosis can due to lack of access to a rheumatologist be significantly delayed and often patients, while waiting to be evaluated by a rheumatologist, are insufficiently treated with pain-killers including NSAID (non steroid anti-inflammatory drugs) and even with glucocorticoids.
Following the RA diagnosis, patients with moderate to high disease activity will as first line treatment in most cases be treated with the conventional disease modulating anti-rheumatic drug (cDMARD) methotrexate (MTX). MTX has a slow onset of action and a reduction in symptoms cannot be expected in the first weeks of treatment. The MTX treatment is therefore often combined with dosing of glucocorticoids, resulting in very fast reduction of symptoms, but glucocorticoids are associated with unwanted side-effects. The guidelines states that the use should be restricted to short term, and the dose of glucocorticoids should be tapered as fast as possible and be redrawn completely within 3 months. However, many RA patients are treated chronically with glucocorticoids.
The goal for first line treatment is to get disease control within 3- 6 months from start of treatment. Disease control is defined as low disease activity or disease remission. Many patients are responding inadequately to the first line treatment and will not experience disease control in the expected time period. In such cases an alternative treatment, such as a biological DMARD, e.g. a TNF-inhibitor, which can induce a higher degree of immunosuppression, can be added to or can be replacing the MTX treatment. Some patients will not respond well to this treatment either or stop responding over time, in which case a third treatment option, such as an alternative bDMARD or the so-called targeted synthetic DMARDs, such as the JAK inhibitors, should be offered to the RA patients.
While new types of medications have improved treatment options, significant unmet needs still exist. For patients not in disease control, RA still progresses, and damage accumulates. Patients often cycle through therapies and classes of therapies and must deal with periods of acute disease activity called flares, which can occur several times per year, and drive the need to adjust the dose of current drugs or to change to a new therapy to maintain control of the disease. The treatment of glucocorticoids is often prolonged for an extended period of time with the risk of severe side effects. Ill controlled RA causes more patient interaction with the health care system and reduces the well-being of the patient.
A patient-friendly and safe treatment option as an add on to first line treatment, that would induce disease control in a glucocorticoid sparing fashion, with the further potential to reduce and/or delay the introduction of second line treatments, might fulfill some of the unmet needs of the RA patients.
Clinical development of resomelagon (AP1189) in RA
In November 2021, SynAct announced results from the Phase 2a study of resomelagon (AP1189) in newly diagnosed and previously untreated RA patients presenting with severe disease activity. The study, called BEGIN, was a randomized, double-blind, placebo controlled multicenter study in previous treatment naïve RA patients where either 50 mg or 100 mg of resomelagon (AP1189) or placebo was administered in addition to MTX.
Resomelagon (AP1189) given once daily for four weeks was safe and well tolerated in the applied patient population. 100 mg of resomelagon (AP1189) demonstrated a statistically significant mean reduction in the clinical disease activity index (CDAI), the primary study endpoint, from baseline to four weeks that was more than 65% higher than the effect seen in the placebo-treated control group (mean reduction in CDAI: resomelagon (AP1189) 100 mg (n=33): 15.5 points compared with placebo (n=30): 9.3%, p = 0.0394). The 100 mg resomelagon (AP1189) group also demonstrated a significantly higher fraction of patients achieving ACR20 than placebo treated patients (ACR20: resomelagon (AP1189) (n=33) 100 mg: 60,6%; Placebo (n=30): 33.3%, P=0.0437) within the 4 weeks.
Continued Development
Based upon the results of the BEGIN RA study, the company has conducted two additional Phase 2 clinical studies in RA with resomelagon (AP1189).
EXPAND – A 12-week Phase 2b study of daily resomelagon (AP1189) in MTX-naïve patients with severe disease activity
The EXPAND study was designed to test the treatment effect of 12-weeks of resomelagon (AP1189) on disease activity as measured by the ACR20 response rate as well as other RA disease measures and to confirm the safety profile of the molecule. The figure below provides an overview of the design of EXPAND.
127 patients presenting with high disease activity (CDAI > 22) were randomized 1:1 for treatment with once daily 100 mg resomelagon or placebo added to a background of MTX therapy. 54.7% of patients treated with 100mg of once-daily oral resomelagon achieved an ACR20 response at 12-weeks as compared to 55.7% of patients receiving placebo.
Resomelagon continued to demonstrate a favorable safety profile in this high activity patient population. The overall rate of treatment emergent serious adverse events (SAEs) was 1.6% (n=2), with 1 SAE in each group. The overall rate of patients experiencing treatment emergent adverse events (AEs) was 44.4% and 42.2% for resomelagon and placebo treated patients respectively (all patients received MTX). There were no observed signs of immunosuppression seen in the resomelagon group over that associated with background methotrexate therapy.
A post-hoc analysis was conducted of treatment naïve rheumatoid arthritis patients who had an elevated baseline level of C-reactive protein (CRP> 3mg/L), marker of systemic inflammation, and who were enrolled within 6 months of their diagnosis of rheumatoid arthritis (RA). In this subpopulation of patients, 100mg of daily resomelagon demonstrated a consistent and statistically significant response to therapy over placebo across assessed outcome measures.
At 12 weeks in EXPAND patients with elevated baseline CRP, the 100mg resomelagon group had an ACR20 attainment of 71% as compared to 54% of placebo patients. At 12 weeks in the subpopulation of patients with elevated CRP who were enrolled and had treatment initiated within 6mo of their RA diagnosis, 23 out of 28 (82%) of patients treated with 100mg resomelagon attained an ACR20 compared to 14 out of 27 (52%) of placebo patients (P<0.05).
A significant difference favoring resomelagon was also seen across the secondary outcome measures including the reduction in CDAI (resomelagon 24.6 vs placebo 14.7 points, p<0.01), reduction in DAS28-CRP (resomelagon 1.9 vs placebo 1.2 points, p<0.01), and reduction in HAQ disability index (0.69 vs placebo 0.31 points, p<0.05).
Safety in the elevated CRP population with treatment within 6 months of was comparable to what has been previously reported for the full EXPAND study population.
RESOLVE – 4/12-week Phase 2a/b study of daily resomelagon (AP1189) in patients with an incomplete response to first-line disease modifying anti-rheumatic drugs (DMARD-IR) who are experiencing moderate to severe disease activity.
A large percentage of patients treated with DMARDs never achieve the full desired effect, have a diminishing treatment effect, or suffer from side effects that can prevent further treatment. These patients who experience an inadequate response to DMARDs are referred to as DMARD-IR (inadequate responder).
RESOLVE part A was conducted under a US Investigational New Drug application as a four arms, multi site, study with treatment of 60 mg, 80 mg, 100 mg resomelagon (AP1189) or placebo once daily for 4 weeks.
In total 125 patients were included, of which 107 completed Resolve Part A per protocol with daily doses of placebo, 60mg, 80mg or 100 mg resomelagon for 4 weeks in addition to a stable dose of MTX.
Resomelagon continued to be generally safe and well tolerated relative to placebo. One serious adverse event (SAE) was reported in the study in a placebo treated patient that was hospitalized due to severe exacerbation in joint pain. The total number of treatment emergent adverse events (TEAEs) reported was 56 in the 125 recruited patients with 16 in the placebo group and 10, 12 and 18 in the 60mg, 80mg and 100mg resomelagon groups, respectively.
A large degree of heterogeneity in the recruited patient population was identified upon analysis of the study. Two-thirds of the patients had been on methotrexate (MTX) treatment for more than one year at the time of recruitment, with most patients being treated for over 2 years with only 5 completed patients having a medical history of initiation of MTX treatment within 6 months of RA diagnosis. In addition, medical history, as reported, did not support treatment with maximal tolerable dose of methotrexate in a fraction of the recruited patients.
Development of resomelagon (AP1189) for the treatment of DMARD-IR patients remains an opportunity, but the patient population needs to be carefully selected in view of the compounds mode of action, and the benefit for the patients to be treated.
ADVANCE – A randomized, double blind, placebo-controlled, dose response, phase 2, multicentre trial to evaluate the efficacy and safety of oral AP1189 administered at the doses of 40, 70, or 100 mg for 12 weeks in combination with methotrexate, in DMARD-naïve participants with early rheumatoid arthritis and active inflammation.
Based on the post-hoc analysis of the outcome of EXPAND, the ADVANCE study was set up as four cohorts of RA patients, diagnosed within 6 months and showing signs of severe RA (DAS28-CRP >5.1; CDAI >22) including signs of systemic inflammation, defined as hsCRP to be above normal range (>3 mg/L) are given either placebo or one of three doses of resomelagon (40, 70, 100 mg) once daily for 12 weeks in combination with MTX treatment. The study is designed to randomize 240 patients using treatment induced reduction in DAS28-CRP as the primary efficacy readout in line with the current guidelines from FDA and EMA. Patients are being recruited at sites in the US and Europe.
