The MIGHT Trial - An Exploratory Clinical Trial of IVIG in anti-HMGCR ImmuneMediated Necrotizing Myopathy

PROJECT SUMMARY Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) immune mediated necrotizing myopathy (IMNM) is an increasingly recognized, severe subset of autoimmune myopathy that causes significant muscle weakness, morbidity, and often permanent physical disability. Randomized, placebo-controlled trial (RCT) data

on anti-HMGCR IMNM treatment are highly limited, and no treatment trials specifically of anti-HMGCR IMNM have been completed to date. This lack of placebo-controlled interventional trial data is a critical barrier to improving outcomes for anti-HMGCR IMNM patients and represents an increasingly urgent research gap as

the number of anti-HMGCR IMNM patients increases. Recent observational evidence strongly suggests that intravenously administered pooled human immunoglobulin (IVIG) may be particularly effective in treating anti- HMGCR IMNM. Corroboration of these data via a placebo-controlled trial is a fundamental next step towards

establishing the role of IVIG as an effective treatment for anti-HMGCR IMNM. In addition, understanding of anti- HMGCR IMNM immuno-pathogenesis and its response to immunomodulatory therapy, such as IVIG, is limited. Overcoming this second knowledge gap would also facilitate identification of effective therapies. Our group’s

data suggest that HMGCR-specific CD4+ T cells may play an important role in anti-HMGCR IMNM disease propagation. Our overarching goal is to conduct a pilot, exploratory clinical trial to test the central hypothesis that IVIG is an effective treatment for HMGCR myopathy in improving both key clinical outcomes and immunologic

markers of disease pathogenesis. Our multidisciplinary team will innovatively combine clinical and translational approaches to generate urgently needed placebo-controlled data on the initial clinical efficacy of IVIG in anti- HMGCR IMNM and to determine the relationships of HMGCR-specific CD4+ T cells with disease activity and

response to immunomodulatory therapy. This proposal is responsive to PAR-21-045 which calls for exploratory clinical trials in autoimmune and musculoskeletal conditions. There are two Aims. The goal of Aim 1 (RCT) is to demonstrate the safety, tolerability, and initial efficacy of IVIG for anti-HMGCR IMNM in a phase 2, double-blinded, placebo-controlled trial that will provide critical pilot

data towards a future phase 3 trial. The goal of Aim 2 (T cell immunology) is to determine whether immunologic features of HMGCR-specific CD4+ T cells (prevalence, effector function, and epitope specificity) 1) are biomarkers of disease activity and 2) are affected by IVIG in anti-HMGCR IMNM.