Potential Regulatory Submission for Inebilizumab in Myasthenia Gravis Following Positive Phase 3 MINT Data
Jay Bradner, MD
In a recent company conference call, Amgen announced positive data from its phase 3 MINT trial (NCT04524273) assessing inebilizumab (Uplizna), an FDA-approved therapy for neuromyelitis optica spectrum disorder (NMOSD), in patients with generalized myasthenia gravis (gMG). As a result, the company is planning to initiate regulatory filing activities for inebilizumab as a potentially new treatment for gMG.1
MINT included 238 patients with gMG who were randomly assigned 1:1 to either intravenous ineblizumab 300 mg (n = 119) or placebo (n = 119) for a 12-month period. Change from baseline in Myasthenia Gravis Activities of Daily Living (MD-ADL), the study’s primary end point, was statistically significant for inebilizumab-treated patients, with scores of –4.2 compared with –1.9 for those on placebo (P <.0001). Above all, the therapy showed a safe and well tolerated profile, with no new safety signals observed.
The trial is considered the largest placebo-controlled study testing a biologic therapy in gMG. In addition to enrolling those with anti-acetylcholine receptor antibody positive (AChR-Ab+) positive gMG, the study included the most patients with muscle-specific tyrosine kinase antibody positive (MuSK-Ab+; n = 48) gMG recorded in a therapeutic trial. Coming into the study, patients had an MG-ADL score of 6 or greater and a Quantitative Myasthenia Gravis (QMG) score of 11 or greater.
Presented by Jay Bradner, MD, executive vice president, Research and Development, and chief scientific officer at Amgen, results from the study showed that inebilizumab achieved clinically meaningful and statistically significant benefit in change in MG-ADL score for both AChR+ and MuSK+ cohorts. At week 26, investigators recorded statistically significant QMG score improvement with inebilizumab compared with placebo (inebilizumab: –4.8 overall improvement; placebo: –2.5; P = .0002). These data, as well as additional assessment of efficacy, durability of response, and safety, will be presented at the upcoming American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, held October 15-18, in Savannah, Georgia.
READ MORE: RNS60 Extends Survival and Improves Respiratory Function in ALS, Post-Hoc Analysis Shows
In the company update, Amgen also shared positive data from the MITIGATE trial (NCT0454097), a phase 3 study assessing inebilizumab in patients with immunoglobulin G4-related disease (IgG4-RD). IgG4-RD is a chronic, systemic, immune-mediated, fibroinflammatory disease which can affect numerous and generally multiple organs of the body. MITIGATE, the first global placobo-controlled, randomized trial in IgG4-RD, included 135 patients with the disease who met a robust assessment and central eligibility review.
After a screening period of up to 28 days, participants were randomly assigned 1:1 to either 300 mg intravenous inebilizumab or placebo on Days 1, 15, and week 26 after premedication, and followed for the 52-week randomized controlled period. All participants received an initial tapering dose of glucocorticoids to complete treatment of their active disease. All told, inebilizumab met its primary end point, demonstrating a clinically meaningful and statistically significant 87% reduction in IgG4-RD flare risk at 52 weeks relative to placebo (HR, 0.13; P <.0001).
Statistical significance was also achieved for the 3 key secondary end points: annualized flare rate; flare-free, treatment-free complete remission; and flare-free, corticosteroid-free complete remission. Similar to MINT, there were no new safety signals identified, and regulatory filings are expected to proceed. Inebilizumab, a CD19-targeting agent, provides targeted, rapid, and sustained CD19+ B-cell depletion. In IgG4-RD, CD19+ B cells, including plasmablasts and mature B cells, are thought to be important drivers of the disease, contributing to immune dysregulation and chronic inflammation seen.
"MITIGATE is a landmark study with results that demonstrate an important advance in the treatment of patients with IgG4-RD, a devastating and rare disease that currently has no approved therapy," Brander said in a statement during the release of MITIGATE earlier this summer.2 "We are grateful for the partnership with patients, clinicians and patient advocacy groups critical to a successful study, and we look forward to bringing this therapy to those living with IgG4-RD."
