Inebilizumab Improved Outcomes Over Placebo in Phase 3 Trials for IgG4-RD, Myasthenia Gravis

John Stone, MD, MPH

Credit: Massachusetts General Hospital

Inebilizumab-cdon has demonstrated efficacy in treating IgG4-related disease (IgG4-RD) and generalized myasthenia gravis (gMG) in phase 3 trials.¹

“IgG4-RD is a lifelong systemic inflammatory condition that can affect nearly any organ in the body and typically impacts multiple organs. IgG4 is characterized by CD19+ B cells that overproduce IgG4 creating a massive influx of IgG4+ B cells into organs. This results in tumor like inflammatory masses and associated tissue fibrosis that can cause permanent organ damage. In fact, 60% of patients may have irreversible organ damage at diagnosis. Currently there are no US FDA approved therapies for IgG4-RD, which is primarily managed by moderate to high dose therapies and off label therapies. Those steroids can produce remission, but patients are challenged by chronic steroid requirements and often steroids fail to prevent relapse,” Jay Bradner, MD, executive vice president, research and development, Amgen, said in a conference call about the new data.¹

Inebilizumab-cdon is currently approved under the name Uplizna for treating AQP4+ neuromyelitis optica spectrum disorder in the US and internationally. It is being evaluated in the phase 3 MITIGATE trial (NCT04540497), which is the first global placebo controlled, randomized controlled trial in IgG4-RD. The trial met its primary endpoint, with inebilizumab-cdon demonstrating a clinically meaningful, statistically significant 87% reduction in IgG4-RD flare risk at 52-weeks compared to placebo (hazard rate [HR], 0.13; P <.0001)). Key secondary endpoints also met statistical significance after adjusting for multiplicity.¹

"IgG4-RD is a devastating, chronic, immune-mediated disease that has just begun to be fully understood over the last few decades," John Stone, MD, MPH, principal investigator, and a professor of medicine at Harvard Medical School and the Edward A. Fox Chair in Medicine at Massachusetts General Hospital, said in a statement when topline data from MITIGATE were first announced in June 2024.² "These data mark a major milestone for the IgG4-RD community and provide substantial insight into not only how inebilizumab can help manage IgG4-RD, but also key insights into the nature of this condition."

Inebilizumab-cdon is also being evaluated in the ongoing phase 3 MINT trial (NCT04524273) in participants with gMG. In this trial, the therapy demonstrated a clinically meaningful and statistically significant improvement in MG Activities of Daily Living (MG-ADL) after 2 compared to placebo at Week 26 (-4.2 improvement; -1.9 placebo adjusted improvement (P <.0001), the trial’s primary endpoint. AcHR+ and MuSK+ cohorts also achieved a clinically meaningful and statistically significant benefit in change in MG-ADL scores. The therapy also improved quantitative MG score compared to placebo at week 26 (-4.8 overall improvement; -2.5 placebo adjusted; P = .0002), the trial’s secondary endpoint.¹

“We’re excited about these data and the potential to address continued unmet need in mg. this excitement rests in the novel mechanism of targeting the b cell compartment durably and deeply versus a transient inhibition of complement or FcRn, rapid and consistent efficacy achieved after only 2 doses of drug maintained after 24 weeks after that second dose irrespective of acetylcholine receptor (AChR) or MuSK status, and best in class dosing. Twice annual dosing [has] the opportunity to reduce patient exposure, steroid burden, and toxicity [comprising] a major advantage,” Bradner said.¹

In both potential indications, no new safety signals with inebilizumab-cdon were identified and Amgen is initiating regulatory filing activities. Further data from the phase 3 trials will be presented at the American Association of Neuromuscular & Electrodiagnostic Medicine annual meeting, set for October 15-18 in Savannah, Georgia.

REFERENCES

1. Amgen Conference Call to Discuss New Topline Data in Inflammation and Rare Disease. Webcast. Amgen. September 24, 2024. https://investors.amgen.com/events/event-details/amgen-conference-call-discuss-new-topline-data-inflammation-and-rare-disease

2. Amgen announces positive results for phase 3 registrational trial evaluating UPLIZNA® (inebilizumab-CDON) for treatment of immunoglobulin G4-related disease (igg4-RD). Amgen. June 5, 2024. Accessed June 5, 2024. https://wwwext.amgen.com/newsroom/press-releases/2024/06/amgen-announces-positive-results-for-phase-3-registrational-trial-evaluating-uplizna-inebilizumabcdon-for-treatment-of-immunoglobulin-g4related-disease-igg4rd.