Pos1207 efficacy and safety of anti-ifnβ-specific monoclonal antibody, pf-06823859, on myositis: phase 2 study in patients with moderate-to-severe dermatomyositis

Background Interferon (IFN) dysregulation is a key feature in the pathogenesis of dermatomyositis (DM). PF-06823859 is a potent, selective, humanised immunoglobulin 1-neutralising monoclonal antibody (mAb) directed against human IFNβ. Objectives To examine the efficacy and safety of IFNβ blockade with PF-06823859 in adult patients with muscle-predominant moderate-to-severe DM. Methods This DM cohort within the Phase 2 study randomised patients with DM with moderate-to-severe muscle disease activity to PF-06823859 600 mg or placebo (1:1) for 12 weeks. Patients were required to meet one of the following inclusion criteria: (1) Manual Muscle Testing (MMT-8) ≤136/150 and Physician Global Assessment (PhGA) ≥3 cm on a 0–10 cm visual analogue scale (VAS) or (2) the sum of PhGA, Patient Global Assessment (PtGA), extramuscular global assessment ≥10 cm (using 0–10 cm VAS for each), with refractory disease, defined as failure of at least two or more adequate courses of an immunosuppressive or immunomodulatory agent, including intravenous immunoglobulin. Endpoints included clinical efficacy assessments (mean Total Improvement Score [TIS], mean change from baseline [CFB] in MMT-8, and mean CFB in PhGA), patient-reported outcomes (mean CFB in PtGA and mean CFB in Health Assessment Questionnaire Disability Index [HAQ-DI]), muscle enzyme levels (mean CFB in creatine kinase [CK]), mean CFB in extra muscular activity, and safety and tolerability at Week 12. Results All 18 randomised patients completed the 12-week treatment. The least squares mean (LSM) TIS showed numerical advantage of PF-06823859 600 mg versus placebo with increasing trends over time (4–12 weeks) and no plateau at Week 12. The LSM (90% confidence interval [CI]) TIS at Week 12 for PF-06823859 600 mg and placebo were 56.4 (41.4, 71.4) and 36.9 (22.0, 52.0), respectively, with a placebo-adjusted difference of 19.4 (-1.8, 40.7). Sensitivity analyses, excluding a single efficacy observation for a placebo recipient who received prohibited concomitant medications, reached nominal statistical significance (p=0.0497). At Week 12, PF-06823859 600 mg had numerically better efficacy scores than placebo across other key muscle function endpoints (estimated mean [90% CI] CFB in MMT-8 21.2 [11.9, 30.6] for PF-06823859 600 mg and 11.7 [2.3, 21.0] for placebo; in PhGA -3.40 [-4.9, -1.9] for PF-06823859 600 mg and -2.05 [-3.56, -0.55] for placebo; in PtGA -4.6 [-5.9, -3.4] for PF-06823859 600 mg and -1.2 [-2.4, 0.1] for placebo; in HAQ-DI -0.54 [-0.87, -0.22] for PF-06823859 600 mg and -0.03 [-0.38, 0.32] for placebo; in CK -185.8 [-273.9, -97.6] for PF-06823859 600 mg and -39.9 [-125.7, 46.0] for placebo; in extra muscular activity -2.81 [-3.87, -1.76] for PF-06823859 600 mg and -1.62 [-2.68, -0.56] for placebo. The mean (90% CI) placebo-adjusted differences in CFB for MMT-8, PtGA and CK were 9.6 (-3.8, 23.0), -34.5 (-52.7, -16.2) and -145.9 (-269.4, -22.4), respectively, with nominal statistical significance for PtGA (p=0.0046) and CK (p=0.0282). Treatment-emergent adverse events (TEAEs) were similar between the PF-06823859 and placebo groups, and mostly mild in severity. The most common TEAEs were gastrointestinal disorders. There were no cases of herpes zoster or herpes simplex. Conclusion Anti-IFNβ mAb PF-06823859 was generally safe and well tolerated, improved clinical parameters (TIS, MMT-8, PhGA), patient-reported outcomes (PtGA, HAQ-DI), extra muscular activity and significantly decreased muscle enzyme levels (CK) in patients with muscle-predominant refractory moderate-to-severe DM. Acknowledgements Study sponsor was Pfizer. The sponsor greatly appreciates the International Myositis Assessment and Clinical Studies (IMACS) group for allowing the myositis assessment tools to be used in this clinical trial. Medical writing support, under direction of the authors, was provided by Macarena Ramos, PhD, CMC Connect, a division of IPG Health Medical Communications, and funded by Pfizer, New York, NY, USA, in accordance with Good Publication Practice guidelines (Ann Intern Med 2022; 175: 1298-1304). Disclosure of Interests Rohit Aggarwal Consultant of: Mallinckrodt, Octapharma, CSL Behring, Bristol Myers-Squibb, EMD Serono, Kezar, Pfizer Inc, AstraZeneca, Alexion, Argenx, Boehringer Ingelheim, Corbus, Janssen, Kyverna, Roivant, Merck, Galapagos, Actigraph, Abbvie, Scipher, Horizontal Therapeutics, Teva, Biogen, Beigene, ANI Pharmaceutical, Nuvig, Capella, CabalettaBio, Grant/research support from: Mallinckrodt, Pfizer Inc, Bristol Myers-Squibb, Q32, EMD Serono, Janssen, Boehringer Ingelheim, Izabela Domyslawska: None declared, Patricia Carreira Consultant of: Janssen, Lilly, VivaCell, Emerald Health Pharmaceuticals, Gesynta Pharma, Boehringer Ingelheim, Abbvie, Sanofi Genzyme, Mitsubishi Tanabe, Grant/research support from: Boehringer Ingelheim, Iltoo, Corbus, Galapagos, Idorsia, Mitsubishi Tanabe, Certa, Prometheus, Pfizer Inc, Alexion, Horizon, Argenx, Genentech, David Fiorentino Consultant of: Pfizer Inc, UCB Biopharma, Johnson & Johnson, Corbus, Concert, Kyverna, Grant/research support from: Pfizer Inc, EMD Serono Inc, Jason Sluzevich Consultant of: Novartis, GSK, Abbvie, Grant/research support from: Regeneron, Merck, Novartis, Victoria Werth Consultant of: AstraZeneca, Pfizer Inc, Biogen, Celgene, Resolve, Janssen, Gilead, Lilly, BMS, Nektar, Abbvie, Viela, GSK, EMD Serona, Sanofi, Anaptysbio, Amgen, Merck, Kyowa Kirin, Rome Therapeutics, Xencor, Janssen, Neovacs, Idera, Octapharma, CSL Behring, Corbus, 1Galderma, Novartis, Rome, Principia, Genentech, Regeneron, viDA, Janssen, Immune Pharmaceuticals, Cabaletta, Argenx, ONO Pharmaceutical Inc, Grant/research support from: Celgene, Amgen, Janssen, Biogen, Gilead, Viela, Horizon therapeutics, Ventus, Pfizer Inc, Corbus, CSL Behring, Genentech/Roche PI, Argenx, Syntimmune, Regeneron, Anindita Banerjee Employee of: Pfizer Inc, Myron Chu Employee of: Pfizer Inc, Barry Oemar Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Mikhail Salganik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Abigail Sloan Employee of: Pfizer Inc, Michael Vincent Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Elena Peeva Employee of: Pfizer Inc.