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Abstract Number: 910

The Selective Sphingosine-1- Phosphate Receptor 1/5 Modulator Siponimod (BAF312) Shows Beneficial Effects in Patients with Active, Treatment Refractory Polymyositis and Dermatomyositis: A Phase IIa Proof-of-Concept, Double-Blind, Randomized Trial

Katalin Danko1, Jiri Vencovsky2, Ingrid E. Lundberg3, Anthony A Amato4, Chester V. Oddis5, Maria Molnar6, Antonette Mallari Moher7, Laurence Colin8, Florian Muellershausen9, David Lee10 and Peter Gergely9, 1Institute of Rheumatology, University of Debrecen, Hungary, Debrecen, Hungary, 2Institute of Rheumatology, Charles University, Prague, Czech Republic, 3Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden, 4Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 5Rheum/Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, 6Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, Hungary, 7Translational Medicine, Novartis Institutes for Biomedical Research (former emplyee), Basel, Switzerland, 8Novartis Pharma, Basel, Switzerland, 9Translational Medicine, Novartis Institutes for Biomedical Research, Basel, Switzerland, 10Novartis Pharmaceuticals Corporation, Basel, Switzerland

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: immunology, Multicenter study, myositis and polymyositis/dermatomyositis (PM/DM)

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Session Information

Title: Muscle Biology, Myositis and Myopathies

Session Type: Abstract Submissions (ACR)

Background/Purpose

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.

Methods

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.

Results

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.

Conclusion

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.


Disclosure:

K. Danko,
None;

J. Vencovsky,

Novartis Pharma,

5;

I. E. Lundberg,

Novartis Pharma,

5;

A. A. Amato,
None;

C. V. Oddis,

Novartis Pharmaceutical Corporation,

5;

M. Molnar,
None;

A. Mallari Moher,
None;

L. Colin,

Novartis Pharma,

3,

Novartis Pharma,

3;

F. Muellershausen,

Novartis Pharma AG.,

3;

D. Lee,

Novartis Pharma,

1,

Novartis Pharma,

3;

P. Gergely,

Novartis Pharma,

1,

Novartis Pharma,

3.

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