David J. Kuter, MD, DPhil
The experimental drug rilzabrutinib was well tolerated and generated an increase in platelet counts among some adults with immune thrombocytopenia (ITP) who had not experienced lasting improvements with other available ITP treatments, according to the results of a phase III trial. These findings were presented by lead author David J. Kuter, MD, DPhil, Program Director of Hematology at Massachusetts General Hospital and Professor of Medicine at Harvard Medical School in Boston, at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 5).
The trial’s primary endpoint of durable platelet response was achieved in about one-quarter of patients taking the drug and none of those taking a placebo and continued to improve with longer follow-up. Even among those who did not meet the threshold for the primary endpoint, many patients taking rilzabrutinib experienced secondary benefits including improvements in platelet count, bleeding, and fatigue.
“The drug is highly active in a highly refractory group of patients,” said Dr. Kuter. “In addition to raising platelet counts, bleeding events decreased significantly and quality of life improved. The drug also worked really fast—within 15 days—and those who responded maintained a durable response for a long time.”
Study Background and Methodology
ITP leads to low levels of platelets. In children, it can resolve on its own, but in adults, it is typically chronic. Several medications are available to help increase platelet counts, but people who cannot tolerate or do not respond to available medications can experience uncontrolled bleeding and chronic fatigue.
Rilzabrutinib is a first-in-class oral Bruton’s tyrosine kinase inhibitor designed to boost platelet counts by simultaneously reducing the production of platelet-targeting autoantibodies, reducing the destruction of platelets by macrophages, and inhibiting B-cell activation and inflammatory pathways. Although other drugs increase the rate of platelet production, the mechanism of action for rilzabrutinib is unique in its multifaceted approach to ITP.
For this phase III trial, researchers enrolled 202 adults with persistent or chronic ITP that was not sufficiently managed with standard-of-care therapies. Participants had seen no lasting benefit from a median of four prior therapies before enrolling in the trial. Two-thirds of the participants were randomly assigned to take rilzabrutinib, and one-third took a placebo for a 24-week double-blind period. After the first 12 weeks, 64% of patients on rilzabrutinib and 32% on placebo achieved a platelet response (platelet count ≥ 50 × 109/L or ≥ 30 to < 50 × 109/L and doubled from baseline) and continued on the blinded study; those with no platelet response had the option of discontinuing the study or taking rilzabrutinib as an open-label treatment. After 24 weeks, all participants had the option to take open-label rilzabrutinib.
Key Findings
The study’s primary endpoint was a durable platelet response, defined as platelet counts of 50 × 109/L or higher for 8 or more of the last 12 weeks of the 24-week blinded period without taking any additional ITP rescue therapies. This endpoint was met in 23% of patients randomly assigned to take rilzabrutinib (29% when including initially nonresponding rilzabrutinib recipients at week 12 who crossed over to open-label rilzabrutinib) and no patients taking placebo. Secondary endpoints revealed that participants treated with rilzabrutinib showed improvements in platelet counts, fatigue, and bleeding, as well as a reduced need for ITP rescue therapies compared with those in the control group.
“The fatigue scores got much better among those taking the drug, and that happened whether the platelet count rose or not,” said Dr. Kuter. “This suggests there are other aspects of ITP that affect fatigue besides platelet count.” For example, he suggested, the anti-inflammatory action of rilzabrutinib may help to reduce fatigue even without improvements in platelet counts.
Dr. Kuter reported that rilzabrutinib was safe and well tolerated, with comparable rates of adverse events among both study arms. The most common treatment-related adverse events were diarrhea, nausea, headache, and abdominal pain, mostly low grade.
The researchers will continue to follow responding patients in the open-label portion of the trial for an additional 28 weeks and long-term extension for at least 1 year to assess the durability of the platelet response and long-term safety profile. In addition, results from a parallel phase III study in children are anticipated to be reported next year. Dr. Kuter added that future studies may help to determine whether rilzabrutinib might be suitable for use earlier in the course of ITP treatment and whether it could be helpful in treating other autoimmune conditions.
Disclosure: This study was funded by Sanofi, maker of rilzabrutinib. Dr. Kuter has served as a consultant for Inmagene Biopharmaceuticals, Ligand, Medscape, Merck Sharp Dohme, New York Blood Center, PeerView, PER, Pfizer, Platelet Disorder Support Association, Regeneron, Seismic, Sobi, Takeda, UCB, Up-To-Date, Verve, AIRx, CRICO, Daiichi Sankyo, Dianthus, Electra Therapeutics, Fuji, Hemopure, Incyte, Immunovant, Hengrui, Chugai, Cellphire, Cellularity, Caremark, Bristol Myers Squibb, Argenx, Apellis, Amgen, Alpine, Alnylam, Alexion, Sanofi, Rigel, Principia, Novartis, Hutchmed, BioCryst, Kezar, Kyowa-Kirin, Momenta, Nuvig, Platelet Biogenesis, Protagonist, and Zafgen; and has received research funding from Takeda, UCB, Alnylam, Sanofi, Rigel, Principia, Novartis, Hutchmed, and BioCryst. For full disclosures of all study authors, visit ash.confex.com.
