Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Clinical Study of Apilimod Mesylate, an Oral IL-12/IL-23 Inhibitor, in Patients with Active Rheumatoid Arthritis.

Krausz3,  Sarah, Boumans3,  Maartje J. H., Gerlag3,  Daniëlle M., Lufkin4,  Joelle, van Kuijk2,  Arno W. R., Bakker3,  Alian A. B., de Boer3,  Maarten

Academic Med Ctr/Univ of Amsterdam, Amsterdam, The Netherlands
Academic Medical Center/University of Amsterdam
Academic Medical Center-University of Amsterdam
Synta Pharmaceuticals Corp

Objective:

Apilimod mesylate (STA-5326) is an oral small-molecule compound. It selectively inhibits production of interleukin (IL)-12 and IL-23, which play an important role in regulating the immune response, and has demonstrated safety and efficacy in a phase I/IIa trial for Crohn's disease. We investigated the efficacy, safety and tolerability of STA-5326 in patients with active rheumatoid arthritis (RA).

Methods:

We performed a phase IIa, single-center, randomized, double-blind, placebo-controlled, proof-of-principle study of STA-5326 in combination with methotrexate (MTX) in 29 patients with active RA (3:1, STA-5326 to placebo). In stage I, 9 patients were treated with STA-5326 100 mg QD and 2 with placebo for 4 weeks. In stage II, 8 patients received STA-5326 100mg QD and 3 placebo for 8 weeks. In stage III, 5 patients received STA-5326 100 mg BID and 2 placebo for 8 weeks, with an optional extension of 4 weeks. Clinical response was assessed according to DAS28 and ACR response criteria. Synovial tissue samples were obtained at baseline and day 29 (stage I/II) or day 57 (stage III), and stained for CD3, CD22, CD55, CD68 and IL-1b by immunohistochemistry, and evaluated by digital image analysis.

Results:

STA-*-treated patients (100mg QD) showed a modest, but statistically significant reduction in DAS28 compared to baseline at day 29 and day 57, but an ACR20 response was reached in only 6% of patients at day 29 and 25% at day 57 (Table). This was similar to the response in placebo treated patients. The increased dosage (100mg BID) did not improve clinical efficacy. Consistent with the clinical results, there were no clear cut changes in expression of synovial biomarkers between baseline and day 29 in stages I/II or day 57 in stage III. While only mild adverse events (mainly gastro-intestinal and dizziness) were observed in stages I/II, in stage III all patients experienced debilitating side-effects (nausea and headache) causing 2 of 5 STA-*-treated patients to withdraw prior to day 57 and only 1 patient to extend the study until day 85.

Table. Changes in DAS28 and ACR responses in RA patients treated with STA-5326 100mg QD, 100mg BID or placebo

Stage I/II, 100mg QDDay 29 (n = 17)Day 57 (n = 8, stage II only) 
DDAS28-0.41 (p = 0.03)-0.61 (p = 0.004) 
ACR201 (6%)2 (25%) 
ACR5000 
ACR7000 
Stage III, 100 mg BIDDay 29 (n = 4)Day 57 (n = 3)Day 85 (n = 1)
DDAS28-0.67 (ns)-0.47 (ns)-0.50
ACR2001 (33%)1 (100%)
ACR501 (25%)00
ACR70000
Placebo (n = 7, pooled)Day 29 (n = 7)Day 57 (n = 4)Day 85 (n = 2)
DDAS28-0.21 (ns)-0.92 (ns)-0.90
ACR2001 (25%)0
ACR50000
ACR70000
In stage III, 1 patient withdrew prior to day 29 and 1 patient prior to day 57 due to side effects. Only 1 out of 5 decided to extend the study until day 85. Changes in DAS28 (p-value) are compared to baseline, ns= not significant

Conclusion:

The results presented here do not support the notion that STA-5326 treatment is able to induce robust clinical improvement of RA.

To cite this abstract, please use the following information:
Krausz, Sarah, Boumans, Maartje J. H., Gerlag, Daniëlle M., Lufkin, Joelle, van Kuijk, Arno W. R., Bakker, Alian A. B., et al; A Phase IIa, Randomized, Double-Blind, Placebo-Controlled Clinical Study of Apilimod Mesylate, an Oral IL-12/IL-23 Inhibitor, in Patients with Active Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1095
DOI: 10.1002/art.28862

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