Session Title: Muscle Biology, Myositis and Myopathies
Session Type: Abstract Submissions (ACR)
Polymyositis and dermatomyositis (PM/DM) comprise a heterogeneous group of chronic inflammatory muscle diseases where infiltration of lymphocytes in the skeletal muscle plays a key pathogenic role. BAF312 (siponimod), an oral sphingosine-1-phosphate (S1P) receptor 1/5 modulator may be efficacious in inflammatory myopathies by inhibiting lymphocyte trafficking from secondary lymphoid organs to the muscle. A randomized, double–blind, placebo-controlled, multi-centric, partial cross-over Phase IIa Proof of Concept study was conducted to evaluate the safety, tolerability and efficacy of BAF312 in patients with PM/DM.
Eighteen patients with clinically active PM/DM who had responded inadequately to conventional treatment were randomized to receive 10 mg BAF312 or matching placebo (1:1) once daily for 12 weeks. The 10 mg dose was reached by a dose up-titration regimen over 10 days to minimize bradycardia, a common adverse effect of the S1P1 receptor modulator class. Following the placebo-controlled Period 1, all patients received 10 mg BAF312 for an additional 12 weeks in Period 2. No immunosuppressives but oral corticosteroids at a stable dose (max. 20 mg prednisone/day) were allowed as concomitant medication. Key outcomes were safety and efficacy as assessed by the responder rate according to the Definition of Improvement by the IMACS (International Myositis Assessment Study) group. Clinical response was defined as an improvement in the IMACS core set measure of myositis disease global activity by greater than 30% and an improvement in manual muscle testing (MMT8) by 1 -15 %; or an improvement in MMT8 by greater than 15% and in myositis disease global activity by greater than 10%; and in either case, with no more than 2 IMACS measures worsening by 25%.
For safety, in addition to routine assessments, cardiac monitoring for the first 10 days, pulmonary function testing, ocular coherence tomography were performed. Peripheral absolute lymphocyte counts were measured to monitor the pharmacodynamic (PD) effect of BAF312.
Eighteen patients were enrolled into this trial and 16 patients received BAF312 either in Period 1 and/or Period 2. Overall, BAF312 was safe and well tolerated with no significant bradycardia observed. Four serious adverse events occurred in three patients, all in the Placebo group. Fourteen patients were evaluable for the efficacy analysis. The observed responder rates at week 12 were 4/7 (57%) for BAF312 and 1/7 (14%) for placebo using the IMACS definition of improvement. A Bayesian analysis of the IMACS responder status at week 12 yielded a probability of 0.96 that BAF312 is superior to Placebo. The PD effect of BAF312 (i.e. decrease in absolute lymphocyte count) was confirmed in all subjects receiving BAF312, with a mean decrease by >75% after 4 weeks of treatment.
Considering disease heterogeneity and low sample size firm conclusions should not be drawn, but further investigations of BAF312 as a new treatment modality for patients with refractory PM/DM are warranted.
Although disease heterogeneity and low sample size prevent definite conclusions, further investigations of BAF312 as a new treatment modality for patients with refractory PM/DM are warranted.
I. E. Lundberg,
A. A. Amato,
C. V. Oddis,
Novartis Pharmaceutical Corporation,
A. Mallari Moher,
Novartis Pharma AG.,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-selective-sphingosine-1-phosphate-receptor-15-modulator-siponimod-baf312-shows-beneficial-effects-in-patients-with-active-treatment-refractory-polymyositis-and-dermatomyositis-a-phase-iia-pr/