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Publication Number
US-12303489-B2
Publication Date
2025-05-20
Expiration Date
Abstract
The present invention relates to a composition comprising, separately or together, methotrexate (MTX) and (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate (AP1189), or pharmaceutically acceptable derivatives thereof, for use in a method of treating an arthritis disease, such as rheumatoid arthritis.
Core Innovation
The invention provides a method of treating rheumatoid arthritis in a subject in need thereof using methotrexate (MTX) and an acetate salt of a compound of formula (II) or a tautomeric form thereof. The subject receives MTX once per week together with the acetate salt once daily, twice daily, or three times daily. The approach is positioned to address MTX non-responders using defined clinical and model-based criteria.
The compound of formula (II) includes (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium acetate (AP1189) and related formula (I)/(Ia)/(II) compounds, together with pharmaceutically acceptable derivatives and salts. The document links the compound to the melanocortin system, including MC1R/MC3R, and describes the combination as showing superior anti-arthritic effects versus either agent alone. The rationale includes potential reduction of MTX toxicity and enrichment of MTX non-responders.
The document further describes using clinical disease activity indices and response frameworks to evaluate treatment effects, including DAS28, CDAI, and ACR response rates (ACR20/50/70). Arthritis outcomes include reduction of joint inflammation, tender and swollen joint counts, and reduction of c-reactive protein (CRP) in the blood, together with patient-reported physical function and fatigue-related function as determined by HAQ-DI and FACIT-Fatigue. Reported frameworks also include thresholds for disease activity categories and selection of MTX non-responders, including factors and model criteria described by Sergeant et al. 2018.
Claims Coverage
The independent claims cover three complementary ways to treat rheumatoid arthritis using methotrexate (MTX) and an acetate salt of a compound of formula (II) (or a tautomer). Across the independent claims, the inventive features are the combination therapy pairing MTX with an acetate salt of formula (II), the defined MTX/acetate salt dosing schedules and amounts, and the requirement that the dosing is simultaneous for MTX and the acetate salt. Dependent claims further narrow the patient population and add dosing refinements and outcome-based limitations.
Acetate salt of compound of formula (II) with weekly methotrexate
Treating rheumatoid arthritis by administering methotrexate (MTX) and an acetate salt of a compound of formula (II) or a tautomeric form thereof to a subject in need thereof.
Weekly methotrexate and daily/twice daily/three times daily acetate dosing amounts
Administering methotrexate (MTX) once per week in an amount of about 1 to about 30 mg, and administering the acetate salt of the compound of formula (II) once daily, twice daily, or three times daily in an amount of about 1 mg to about 1000 mg per day.
Simultaneous administration of methotrexate and acetate salt of formula (II)
Treating rheumatoid arthritis by administering methotrexate (MTX) and an acetate salt of a compound of formula (II) or a tautomeric form thereof, wherein the acetate salt of the compound of formula (II) is administered simultaneously with the administration of the MTX.
Overall, the independent claim set is focused on combination treatment of rheumatoid arthritis using MTX together with an acetate salt of a compound of formula (II) (or a tautomer), with claim-defined dosing schedules and amounts, and simultaneous administration of MTX and the acetate salt.
Stated Advantages
Superior anti-arthritic effects versus either alone.
Potentially reducing MTX toxicity.
Aiding MTX non-responders.
Reducing joint inflammation.
Reducing the number of tender joints and/or reducing the number of swollen joints.
Reducing c-reactive protein (CRP) in the blood.
Producing partial or complete remission of one or more arthritis symptoms.
Improving physical function as determined by HAQ-DI.
Improving function as determined by FACIT-Fatigue.
Reducing DAS28 score to moderate disease activity, low disease activity, or remission ranges and/or achieving specified DAS28 score reductions.
Reducing CDAI score to moderate disease activity, low disease activity, or remission ranges and/or achieving specified CDAI score reductions.
Reducing CDAI score by 10 points or more, reducing CDAI score of 15 points or more, or reducing CDAI score by 5 points or more.
Improvement in ACR response rates by ≥20%, ≥50% or ≥70%.
Documented Applications
Treating rheumatoid arthritis in a subject in need thereof using MTX and an acetate salt of a compound of formula (II) (including AP1189) and tautomeric forms.
Patient evaluation and selection for MTX non-responders using DAS28/CDAI/ACR frameworks and model-based and biomarker-based criteria described in the document (RF and/or anti-CCP IgG positivity and specified non-response selection factors).
Preclinical mouse arthritis assessment using a K/BxN serum transfer model in which combination MTX and AP1189 prevents severe arthritis.
Clinical evaluation of AP1189 in healthy volunteers including pharmacokinetic/safety outcomes, and an outlined rheumatoid arthritis trial design with efficacy endpoints including CDAI change, joint counts, DAS28, HAQ-DI, FACIT-Fatigue, and ACR responses.
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