Amgen Launches Novel Rare Disease Trial With New Organ-Specific Flare Definitions

A Q&A with Daniel Cimbora, Sr. Scientific Director (Rare Disease), Amgen

People with immunoglobulin G4-related disease (IgG4-RD) experience inflammation and associated pain in “almost any organ in the body, often involving multiple organs at a time.” Also, according to Amgen, maker of UPLIZNA (inebilizumab-cdon), for which it’s evaluating safety and efficacy for IgG4-RD patients, the long-term effects include irreversible organ damage.

Until now, the standard treatment for patients with this chronic, immune-mediated disease involves glucocorticoids, which can lead to steroid toxicity. In the pursuit of this new therapy, which is already approved for the treatment of Neuromyelitis Optica Spectrum Disorder (NMOSD), clinical researchers developed a novel clinical trial design that included a new set of organ-specific flare definitions to help them better evaluate the efficacy of UPLIZNA.

Amgen’s Sr. Scientific Director of Rare Disease, Daniel Cimbora, discusses the importance of the new definitions and how they were evaluated by a central adjudication review committee, as well as the effort to ensure the long-term safety and efficacy of this therapy via an open-label extension (OLE).

Clinical Leader: The MITIGATE trial was the first to use a new set of organ-specific flare definitions for 14+ organs developed by medical experts across the world. How were these experts chosen and how did you convene them to create these definitions?

Cimbora: The clinical development team, with the input of our lead investigator Dr. John Stone (Harvard/Mass General Hospital), and other experts, selected advisors based on a number of attributes, including:

• Expertise in IgG4-RD based on their medical practice, publications, and other contributions to the field.
• Geographic diversity, to ensure global applicability of the flare criteria given the regional difference in the approach to management of this disease.
• Diverse medical specialties representing those that most commonly manage IgG4-RD patients, to ensure appropriate representation of all manifestations of the disease in the flare criteria.

Given the diverse locations and time zones, we convened the experts in a series of virtual meetings to have robust discussions that led to draft definitions and online reviews. The MITIGATE trial represents a groundbreaking effort to determine the safety and efficacy of a treatment for IgG4-RD. Experts were eager to collaborate to ensure the trial design addressed gaps in knowledge for this complex, devastating disease.

Why were these definitions needed? How do they better assess therapeutic success than existing methods?

IgG4-RD flares represent perhaps the most important IgG4-RD-related event in patients with this disease and were selected for the primary endpoint because of this. Flares are periods of organ inflammation and dysfunction, accumulation of fibrosis and organ damage, impaired quality of life, and the need to initiate treatment (typically glucocorticoids) to regain remission.

At the time the study was designed (and even today) there is no widely accepted definition for diagnosis of an IgG4-RD flare in the public domain. Thus, we enlisted the help of global experts to develop objective criteria that consider current clinical practices and make use of data typically collected in the monitoring of patients with IgG4-RD. This ensured consistency across regions and between practitioners from different specialties and with varying degrees of familiarity with the many manifestations of the disease.

What is “central flare adjudication,” and why was it chosen for this trial?

Given the importance of flare determination in this study, and in light of the potential variability of flare manifestation per organ, we elected to utilize an expert, blinded, independent central review of all potential flares to ensure consistency and accuracy for the primary and other endpoints.

A central adjudication committee was formed to ensure uniformity in the application of the flare diagnostic criteria. This committee is composed of physicians with expertise in the care and treatment of patients with IgG4-RD. The committee members, trained on the study flare criteria, review all suspected flares evaluated by investigators during the trial. The adjudication committee received all data available to the investigator and operated independently. This committee was blinded to the treatment group of the participant experiencing the potential flare, the investigator’s decision about whether to treat the event and the participant’s response to any treatment administered. (See Perugino C, Culver EL, Khosroshahi A, Zhang W, Della-Torre E, Okazaki K, Tanaka Y, Löhr M, Schleinitz N, Falloon J, She D, Cimbora D, Stone JH. Efficacy and Safety of Inebilizumab in IgG4-Related Disease: Protocol for a Randomized Controlled Trial. Rheumatol Ther. 2023 Dec;10(6):1795-1808)

And since this was a new step in the process, what were some of the challenges and successes with its implementation?

We are very pleased with the process of central adjudication and the thoughtful consideration given to each event by the adjudicators. Full details of the adjudication committee process and performance in the MITIGATE trial will be provided in the future.

Lastly, the MITIGATE trial design includes a three-year open-label treatment option as well as a two-year safety follow-up period after participants stop using UPLIZNA. What is the importance of these offerings, and how do they contribute to improving post-trial participant care?

IgG4-RD is a chronic systemic disease, with devastating consequences, and is characterized by remissions and repeated flares. Maintaining remission and preventing flares over time is an important therapeutic goal. Therefore, it is critical to understand the efficacy and safety of IgG4-RD treatments over time.

Together, the open-label and safety follow-up periods are intended to provide important information on the long-term treatment with UPLIZNA in IgG4-RD patients. The three-year open-label period will provide an opportunity to understand the long-term benefits and risks, as both safety and efficacy assessments (including central adjudication of flares) continue during this period. Similarly, the two-year safety follow-up period will provide insight into the safety and other measures after patients discontinue UPLIZNA treatment. Data from these phases of the study will more fully inform practitioners on the potential use of inebilizumab in their patients.

About The Expert:

Daniel Cimbora, PhD has 24 years of experience in the pharmaceutical industry, having participated in numerous early- and late-stage development programs in inflammation, autoimmunity, and oncology.  Dr. Cimbora has devoted the last 10 years to the clinical development of inebilizumab for rare autoimmune diseases, resulting in the approval of UPLIZNA for NMOSD and the successful completion of the MITIGATE trial in IgG4-RD. Dr. Cimbora’s education and training include a Doctorate in Human Genetics from the University of Utah and post-doctoral training at the Fred Hutchinson Cancer Research Center in Seattle, WA.