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.

Grant Number: 5R21AR083566-02
NIH Institute/Center: NIH
Principal Investigator: James Andrews