AP1189 + Methotrexate for Rheumatoid Arthritis

Recruiting at 10 trial locations

Overseen By Thomas Jonassen, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: SynAct Pharma Aps

Must be taking: Methotrexate

Must not be taking: Corticosteroids, Hydroxychloroquine

Disqualifiers: Other autoimmune diseases, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

240 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of a new drug, AP1189 (Resomelagon), in combination with methotrexate for treating early rheumatoid arthritis, a condition that causes painful joint swelling. Participants will receive either varying doses of AP1189 or a placebo for 12 weeks, while continuing methotrexate treatment. The trial aims to assess the effectiveness and safety of AP1189 in reducing joint inflammation and pain. It is suitable for those recently diagnosed with rheumatoid arthritis who have not yet tried disease-modifying drugs and experience active joint inflammation. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to early-stage findings.

Will I have to stop taking my current medications?

The trial requires participants to be naïve to any Disease-modifying anti-rheumatic drugs (DMARDs) and not to have used hydroxychloroquine in the 30 weeks before the Screening Visit. Participants must also not have used systemic or intraarticular corticosteroids within 6 weeks before the Screening Visit. NSAIDs can be used if they have been taken in a stable dose for at least 4 weeks prior to the Screening Visit.

Is there any evidence suggesting that AP1189 in combination with methotrexate is likely to be safe for humans?

Research has shown that AP1189 is under study for its safety and effectiveness in treating rheumatoid arthritis. In earlier studies, most patients tolerated AP1189 well, with no major safety issues identified. Some patients experienced mild side effects, but these were not serious enough to discontinue treatment.

AP1189 targets specific parts of the body, potentially reducing inflammation in conditions like rheumatoid arthritis. The current study tests various doses to determine the safest and most effective amount when combined with methotrexate, a common arthritis medication.

As this trial is in an early stage, researchers continue to gather crucial safety information. The fact that AP1189 is being tested in people indicates it has shown sufficient promise in earlier tests to proceed, providing some reassurance about its safety thus far. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for rheumatoid arthritis?

Researchers are excited about AP1189 for rheumatoid arthritis because it offers a novel approach by working alongside Methotrexate, a standard treatment. Unlike many current treatments that mainly focus on suppressing the immune system, AP1189 targets inflammation more directly, potentially leading to fewer side effects. Additionally, AP1189 is taken orally, which could provide a more convenient option compared to other treatments that require injections or infusions. This combination of a new mechanism of action and ease of use makes AP1189 a promising candidate for improving patient outcomes.

What evidence suggests that AP1189 might be an effective treatment for rheumatoid arthritis?

Studies have shown that AP1189, when combined with methotrexate, may benefit people with rheumatoid arthritis. This trial will test different dosages of AP1189 (40 mg, 70 mg, and 100 mg) and a placebo, all as add-ons to methotrexate. The treatment targets specific body parts to reduce swelling and improve joint function. Early research showed positive results in patients with severe symptoms. Although previous studies noted a strong placebo effect, AP1189 still showed promise in improving symptoms. Overall, AP1189 could be a helpful option for managing early-stage rheumatoid arthritis. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for people who have just been diagnosed with early rheumatoid arthritis and haven't taken any disease-modifying anti-rheumatic drugs (DMARDs) yet. They should be experiencing active inflammation but can't join if they've had certain other treatments or health conditions that the study details exclude.

Inclusion Criteria

Participants with serum high sensitive C-Reactive Protein (hsCRP) ≥3 mg/L at the time of screening

My arthritis is very active, with high scores on specific health tests.

I have rheumatoid arthritis with positive RF or anti-CCP, or my hsCRP levels are ≥6 mg/L.

Exclusion Criteria

I have a joint or muscle condition that affects my rheumatoid arthritis or how drugs work for me.

Functional class IV of Global Functional Status in RA, as defined by the ACR Classification

Serum alkaline-phosphatase, or gamma-glutamyl-transferase greater than 3-fold ULN; alanine aminotransferase, or aspartate aminotransferase, or total bilirubin greater than 2-fold ULN At the Screening Visit

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily treatment of oral AP1189 at doses of 40, 70, or 100 mg in combination with Methotrexate for 12 weeks

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• AP1189

Trial Overview The trial is testing different doses of a new pill, AP1189, to see how well it works and how safe it is when given alongside methotrexate, a common medication for rheumatoid arthritis. Participants will randomly receive either 40 mg, 70 mg, or 100 mg of AP1189 or a placebo without knowing which one they're getting.

How Is the Trial Designed?

Group I: Placebo Experimental Treatment 1 Intervention

12 weeks daily treatment of oral AP1189 matching placebo as add-on to Methotrexate (MTX)

Group II: AP1189 70 mg Experimental Treatment 1 Intervention

12 weeks daily treatment of oral AP1189 70 mg as add-on to Methotrexate (MTX)

Group III: AP1189 40 mg Experimental Treatment 1 Intervention

12 weeks daily treatment of oral AP1189 40 mg as add-on to Methotrexate (MTX)

Group IV: AP1189 100 mg Experimental Treatment 1 Intervention

12 weeks daily treatment of oral AP1189 100 mg as add-on to Methotrexate (MTX)

Who Is Running the Clinical Trial?

SynAct Pharma Aps

Lead Sponsor

Trials

5

Recruited

620+

NBCD A/S

Industry Sponsor

Trials

11

Recruited

2,300+

Published Research Related to This Trial

Low-dose intermittent methotrexate is an effective treatment for refractory psoriatic arthritis, polymyositis, Reiter's disease, and rheumatoid arthritis, demonstrating both immunosuppressive and anti-inflammatory properties.

While methotrexate has fewer short-term side effects compared to other immunosuppressives, it carries a risk of long-term liver toxicity and potential pulmonary complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate: its use in the rheumatic diseases. Bookbinder, SA., Espinoza, LR., Fenske, NA., et al.[2017]

In a study of 6,610 patients with active rheumatoid arthritis, 25% achieved clinical remission while nearly 50% reached minimal disease activity (MDA) after 12 weeks of adalimumab treatment.

The study identified several predictors for achieving remission and MDA, including being male, younger age, and lower baseline disease activity, highlighting factors that may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical remission and/or minimal disease activity in patients receiving adalimumab treatment in a multinational, open-label, twelve-week study. Burmester, GR., Ferraccioli, G., Flipo, RM., et al.[2022]

In a 16-week study involving 315 patients with rheumatoid arthritis who had an unsatisfactory response to methotrexate (MTX), both etanercept (ETN) monotherapy and etanercept combined with methotrexate (ETN+MTX) were found to be effective in improving patient-reported outcomes such as function, pain, and disease activity.

There were no significant differences in the effectiveness of ETN alone versus ETN+MTX, indicating that both treatment strategies can effectively reduce symptoms and improve overall health in patients with active rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported health outcomes in a trial of etanercept monotherapy versus combination therapy with etanercept and methotrexate for rheumatoid arthritis: the ADORE trial. van Riel, PL., Freundlich, B., MacPeek, D., et al.[2022]

Methotrexate shows a success rate of 39% to 88% in treating rheumatoid arthritis patients who do not respond to other treatments, indicating its potential efficacy as a second-line therapy.

While methotrexate can cause mild side effects that often resolve with dose adjustments, it carries a risk of serious reactions like pneumonitis and should be used cautiously in fertile individuals due to possible teratogenic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Methotrexate in rheumatoid arthritis]. Alamo, M., Grisanti, M.[2013]

Pamapimod, a p38α inhibitor, has been evaluated in clinical trials for rheumatoid arthritis but has not shown clear efficacy either alone or in combination with methotrexate, the standard treatment.

The use of pamapimod is associated with adverse effects, leading to the conclusion that it is unlikely to be a beneficial treatment option for rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does the p38 MAP kinase inhibitor pamapimod have potential for the treatment of rheumatoid arthritis? Doggrell, SA., Christensen, AM.[2010]

Methotrexate (MTX) is an effective treatment for Rheumatoid Arthritis (RA), showing significant clinical improvement within 4 weeks and maintaining benefits over long-term use, with a continuation rate of 46-55% over 5 years.

While MTX is effective in managing symptoms and has a steroid-sparing effect, it does not significantly alter disease progression as seen in radiographic assessments, and its use is limited by potential side effects like hepatic toxicity and acute pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Weekly low-dose methotrexate in rheumatoid arthritis. Review of the literature]. Manganelli, P., Troise Rioda, W.[2016]

Methotrexate is an effective treatment for refractory rheumatoid arthritis, showing early symptomatic improvement in most patients and having one of the best efficacy-toxicity ratios among slow-acting antirheumatic agents, based on early placebo-controlled trials and meta-analyses.

The drug acts primarily as an anti-inflammatory agent with immunomodulating properties, although its exact mechanism in rheumatoid arthritis is not fully understood; it is mainly excreted by the kidneys and has significant interindividual variation in bioavailability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate in rheumatoid arthritis. An update. Bannwarth, B., Labat, L., Moride, Y., et al.[2018]

Methotrexate is recognized as the most effective and safest disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis (RA), with over 80% of patients starting treatment with it, indicating its long-term effectiveness.

While biological agents can be more effective for patients with severe RA, the best outcomes are achieved when these agents are combined with methotrexate, reinforcing methotrexate's role as the primary treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. Pincus, T., Yazici, Y., Sokka, T., et al.[2022]

In a study of 308 patients with early active rheumatoid arthritis, targeting a lower disease activity score (DAS <1.6) led to higher rates of remission and drug-free remission compared to targeting a higher score (DAS ≤2.4).

Both treatment strategies resulted in similar improvements in disease activity, functional ability, and radiological damage over five years, but the lower target group had better outcomes in achieving remission at year 1 and drug-free remission at year 5.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison between low disease activity or DAS remission as treatment target in patients with early active rheumatoid arthritis. Akdemir, G., Markusse, IM., Bergstra, SA., et al.[2022]

Lymphoproliferative disease (LPD) was the most common adverse event associated with methotrexate (MTX) therapy, occurring in 36.4% of MTX cases among 3955 reported cases.

Pneumocystis pneumonia (PCP) was strongly linked to combination MTX therapy, with 94.4% of PCP cases involving MTX, highlighting the need for careful monitoring when using MTX in combination with other DMARDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Search of official nationwide database in Japan for adverse events associated with disease-modifying antirheumatic drug therapies: focus on therapies in combination with methotrexate. Inokuma, S.[2022]

Etanercept, an anti-cytokine therapy, significantly reduces disease activity in patients with active rheumatoid arthritis who have not responded to previous treatments, showing improvements in all ACR core set measures within 2 weeks and sustained effects for at least 6 months.

In combination with methotrexate, etanercept led to a higher percentage of patients achieving significant improvement (ACR 20, 50, and 70 criteria) compared to those receiving placebo, indicating its efficacy as a second-line treatment for refractory rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etanercept: a review of its use in rheumatoid arthritis. Jarvis, B., Faulds, D.[2018]

In a study of 1208 rheumatoid arthritis patients over a median follow-up of 2.9 years, infliximab, adalimumab, and etanercept showed comparable effectiveness, with EULAR response rates between 76-79% and low remission rates of 15-23%.

Infliximab had the lowest 5-year drug survival rate at 31%, significantly higher withdrawal rates due to adverse events, and a higher risk of serious infections compared to adalimumab and etanercept, which had survival rates of 43% and 49%, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness and survival of infliximab, adalimumab, and etanercept for rheumatoid arthritis patients in the Hellenic Registry of Biologics: Low rates of remission and 5-year drug survival. Flouri, I., Markatseli, TE., Voulgari, PV., et al.[2022]

Low-dose methotrexate (MTX) is an effective second-line treatment for rheumatoid arthritis (RA) with a good safety and tolerability profile, although its risk-benefit ratio in psoriatic arthritis is less established.

Common side effects include gastrointestinal issues and elevated liver enzymes, but serious complications like severe hemocytopenia and MTX pneumonitis are rare and can often be prevented by monitoring for risk factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose methotrexate in rheumatic diseases--efficacy, side effects, and risk factors for side effects. Schnabel, A., Gross, WL.[2022]

Etanercept biosimilars demonstrated a significantly higher ACR50 response rate at 1 year compared to the reference biologic Enbrel®, indicating improved efficacy in treating rheumatoid arthritis based on a meta-analysis of 6 randomized controlled trials involving 2432 patients.

Overall, the safety and immunogenicity profiles of etanercept biosimilars were comparable to those of the reference biologics, suggesting that these biosimilars are a safe alternative for patients with rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, safety and immunogenicity of etanercept biosimilars versus reference biologics in patients with rheumatoid arthritis: A meta-analysis. Hu, R., Yuan, T., Wang, H., et al.[2023]

Citations

1. acrabstracts.org acrabstracts.org/abstract/efficacy-and-safety-of-the-biased-melanocortin-receptor-agonist-ap1189-resomelagon-in-combination-with-methotrexate-in-dmard-naive-rheumatoid-arthritis-patients-the-expand-trial/

Efficacy and Safety of the Biased Melanocortin Receptor ... AP1189 is a novel, first-in-class, oral, biased melanocortin (MC)1 and MC3 receptor agonist in development for Rheumatoid Arthritis (RA) treatment.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04004429

NCT04004429 | A Study of the Safety, Tolerability and ... The purpose of this study is to determine the safety and efficacy of 2 doses of AP1189 compared with placebo after 4 weeks of treatment. Official Title. A ...

3. synactpharma.com synactpharma.com/en/synact-pharma-presents-positive-clinical-data-on-resomelagon-ap1189-supporting-development-for-the-treatment-of-ra-at-acr-convergence/

SynAct Pharma presents positive clinical data on ... The data we present highlights the treatment potential of resomelagon in a highly relevant group of newly diagnosed RA patients with high disease activity.

4. ctv.veeva.com ctv.veeva.com/study/a-study-of-the-safety-tolerability-and-efficacy-of-treatment-with-ap1189-in-early-ra-patients-with

A Study of the Safety, Tolerability and Efficacy of Treatment ... This is a multicenter, two-part, randomized, double-blind, placebo-kontrolled, 4-week study with repeated doses of AP1189.

5. synactpharma.com synactpharma.com/en/synact-pharma-announces-outcomes-of-the-independent-audit-of-the-4-week-resolve-p2a-clinical-trial-in-rheumatoid-arthritis/

SynAct Pharma announces outcomes of the independent ... However, the study showed a very high placebo effect with ACR20, the primary efficacy readout, around 50% at 1-month and with lower numbers ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04004429

NCT04004429 | A Study of the Safety, Tolerability and ... The purpose of this study is to determine the safety and efficacy of 2 doses of AP1189 compared with placebo after 4 weeks of treatment. Official Title. A ...

7. medchemexpress.com medchemexpress.com/resomelagon.html?srsltid=AfmBOopGpuKfg9Kg73vgWtCcmVBNj9Pjma539EASgwfgmQ8mciPoNPjc

Resomelagon (AP1189) | Melanocortin Receptor Agonist Rheumatoid Arthritis (RA). 2024-10-01, PHASE2. NCT05516979, SynAct Pharma Aps ... SAFETY DATA SHEET (SDS). English - EN (252 KB) Français - FR (252 KB) ...

8. guidetopharmacology.org guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=11292

AP1189 | Ligand page AP1189 has been advanced to clinical investiagtions in rheumatoid arthritis and idiopathic membranous nephropathy. ... A Study of the Safety, Tolerability ...