AP1189 + Methotrexate for Rheumatoid Arthritis

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

Trial Summary

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.

What data supports the effectiveness of the drug AP1189 + Methotrexate for Rheumatoid Arthritis?

The research on etanercept, a drug similar to AP1189, shows that it can improve symptoms in rheumatoid arthritis patients, especially when combined with methotrexate. This suggests that AP1189 might also be effective when used with methotrexate for treating rheumatoid arthritis. ^{1 2 3 4 5}

What is known about the safety of methotrexate in treating rheumatoid arthritis?

Methotrexate is generally considered safe for treating rheumatoid arthritis, with common side effects like stomach upset and liver enzyme changes. Serious side effects, such as lung issues and blood cell problems, are rare and can often be prevented by monitoring for early signs. ^{6 7 8 9 10}

What makes the drug AP1189 + Methotrexate unique for treating rheumatoid arthritis?

AP1189 (Resomelagon) combined with Methotrexate offers a novel approach by potentially enhancing the anti-inflammatory effects of Methotrexate, which is already a well-established treatment for rheumatoid arthritis. This combination could provide improved outcomes for patients who do not respond adequately to Methotrexate alone. ^{7 11 12 13 14}

What is the purpose of this trial?

The study is a randomized, double blind, placebo-controlled, dose response, phase II, 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.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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 (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]

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 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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Etanercept: a review of its use in rheumatoid arthritis. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Comparison between low disease activity or DAS remission as treatment target in patients with early active rheumatoid arthritis. [2022]

3. United States 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. [2022]

4. England 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. [2022]

5. United States 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. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

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

7. Italy pubmed.ncbi.nlm.nih.gov

Methotrexate: its use in the rheumatic diseases. [2017]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy, safety and immunogenicity of etanercept biosimilars versus reference biologics in patients with rheumatoid arthritis: A meta-analysis. [2023]

9. Chile pubmed.ncbi.nlm.nih.gov

[Methotrexate in rheumatoid arthritis]. [2013]

10. England 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. [2022]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Methotrexate in rheumatoid arthritis. An update. [2018]

12. Italy pubmed.ncbi.nlm.nih.gov

[Weekly low-dose methotrexate in rheumatoid arthritis. Review of the literature]. [2016]

13. England pubmed.ncbi.nlm.nih.gov

Does the p38 MAP kinase inhibitor pamapimod have potential for the treatment of rheumatoid arthritis? [2010]

14. Italy pubmed.ncbi.nlm.nih.gov

Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. [2022]