Background/Purpose:  Pomalidomide (POM) is an IMiD compound, structurally similar to thalidomide. POM binds to cereblon and facilitates Ikaros and Aiolos degradation, resulting in immunomodulation of myeloid and lymphocyte cell responses. POM exhibits anti-fibrotic activity in preclinical models of dermal fibrosis. To examine the effect of POM on systemic sclerosis with interstitial lung disease [SSC-ILD], the safety and efficacy of POM on forced vital capacity (FVC), modified Rodnan Skin Score (mRSS), and gastrointestinal  symptomatology as measured by the University of California, Los Angeles (UCLA) Scleroderma Clinical Trial Consortium Gastrointestinal Tract (SCTC GIT) 2.0 instrument total score compared to placebo in subjects with SSC-ILD was assessed over 52 weeks of treatment (NCT01559129).

Methods:  23 SSC-ILD adult subjects were randomized 1:1 POM:placebo (PBO) with 22 subjects dosed. Subjects were required to have a diagnosis of SSc based on the American College of Rheumatology (ACR) 1980 criteria with onset of the first non‑Raynaud’s manifestation of SSc within 7 years of screening. Diffusion lung capacity for carbon monoxide (DLco) ≥ 35% and ≤ 80% was required at screening along with abnormalities on high resolution computed tomography (HRCT) consistent with SSc lung involvement. Subjects were required to meet at least one of the following 2 pulmonary-related criteria to be eligible: (1)FVC readings ≥ 45% and < 70% at Screening and Baseline (Visit 2); or (2) FVC readings ≥ 70% and ≤ 80% at Screening and Baseline with a documented history of either or both: (a) A ≥ 5% decrease in FVC in the 24-month period prior to Baseline; (b) An HRCT fibrosis score > 20%. Subjects received either 1 mg POM capsule PO QD or placebo.

Results: The mean change from Baseline in predicted FVC% at Week 52 was -5.2 and -2.8 in the POM and PBO arms, respectively; for the mRSS at Week 52 was -2.7 and -3.7 in the POM and PBO arms, respectively; and for the UCLA SCTC GIT 2.0 instrument total score at Week 52 was 0.1 and 0.0 in the POM and PBO arms, respectively. In  both  groups  there  was  deterioration in FVC  and  improvement  in  mRSS,  and the observed changes in all three co-primary efficacy endpoints favored placebo. Overall treatment emergent adverse events (TEAEs) were comparable across both treatment arms. The most frequently reported TEAEs (in ≥ 3 subjects) in the POM arm were constipation and arthralgia. There were no deaths in the study. Severe, serious, or TEAEs leading to discontinuation in the POM arm occurred in four (40%) of the 10 subjects each. In the PBO arm, severe and serious TEAEs were each reported in one (8.3%) of the 12 subjects.

Conclusion:  In this study, POM was well tolerated with an AE profile consistent with the known safety for POM use in other diseases. The study did not meet its primary endpoints of improvement in FVC, mRSS, nor for the UCLA SCTC GIT 2.0 total score at Week 52. The study was terminated for lack of efficacy.