Disparate Geographical Data from Rigel Anemia Trial "Confound" Investigator

Blood cells

South San Francisco-based Rigel Pharmaceuticals reported its Phase III Forward trial of fostamatinib did not show statistical significance in warm autoimmune hemolytic anemia.

A major peculiarity was how the results varied so much from region to region. The company expects to continue analyzing the data to understand why there were different responses related to the countries and regions where the trial was conducted.

In a posthoc analysis of the study results in the U.S., Canada, Australia and Western Europe, patients receiving fostamatinib had a favorable durable hemoglobin response compared to placebo. But in the Eastern European trial sites, Rigel missed the clinical endpoint.

The study included 90 patients in three detailed geographic regions. There were 14 sites in the U.S., Canada and Australia; 16 in Western Europe, including Austria, Germany, Spain, France, Italy, Belgium, UK, Netherlands and Norway; and 16 sites in Eastern Europe, including Bulgaria, Czech Republic, Russia, Ukraine, Georgia, Belarus and Serbia.

Patients were split 50/50 to receive either fostamatinib or a placebo twice a day for 24 weeks. The primary efficacy endpoint was durable hemoglobin response defined as Hgb greater than or equal to 10 g/dL with an increase from baseline of 2 or more g/dL on three consecutive available visits during the 24 weeks.

Autoimmune hemolytic anemia is a rare but serious blood disease where the immune system manufactures antibodies that destroy the body’s red blood cells. The most common is warm antibody AIHA (wAIHA), marked by antibodies that react with the red blood cell surface at body temperature. The disease affects about 36,000 adults in the U.S. It can be both severe and debilitating. No disease-targeting therapies are approved.

Fostamatinib is approved in the U.S. under the brand name Tavalisse for thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have an insufficient response to previous treatment. The drug is an SYK inhibitor.

“There are currently no approved therapies specifically indicated for wAIHA and the treatments that are currently used have shortcomings related to efficacy, safety, and quality of life,” said Dr. David Kuter, M.D., D.Phil., director of Clinical Hematology at Massachusetts General Hospital, professor of medicine at Harvard Medical School and lead investigator.

He went on to say, “On balance, the findings from the U.S., Canadian, Australian and Western European trial sites are supportive of fostamatinib for the treatment of wAIHA, however, the confounding results from the Eastern European trial sites require further analysis of the data from the trial. I look forward to working with Rigel to better understand these data.”

Paul Rodriguez, president and chief executive officer of Rigel, said that there was a large and unexpected placebo response rate from the Eastern European sites and that, “We continue to believe fostamatinib has the potential to benefit patients with wAIHA, a population with serious unmet medical need.”

In its first-quarter report on May 3, Rigel reported it had delivered 1,836 bottles of Tavalisse to patients and clinics, an increase of 15% compared to the same period a year before. The drug accounts for this increase, with an expanded salesforce and more in-person physician interactions, as well as expanded market access that includes broad commercial coverage and preferred status on three key national formularies.

Unfortunately, Rigel also reported at that time that if the Phase III Forward trial was positive, it planned to proceed with regulatory filings. It may still plan to do so but will have to reconcile the odd geographic differences in the trial outcomes.

The company also reported that it had enrolled 268 patients out of a targeted 308 as of May 2 for a pivotal Phase III trial of fostamatinib in high-risk hospitalized COVID-19 patients. Rigel noted it was evaluating strategies to complete enrollment and report data before the end of the year, possibly completing the trial with fewer patients than originally planned.

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