Rilzabrutinib induces rapid, durable response in ITP, may become ‘new standard’
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Key takeaways:
- Patients with immune thrombocytopenia achieved durable platelet count expansion with rilzabrutinib.
- Rilzabrutinib exhibited a safety profile comparable to placebo.
SAN DIEGO — Rilzabrutinib induced “fast” and “persistent” platelet count expansion for heavily treated individuals with immune thrombocytopenia, according to results of the randomized phase 3 LUNA 3 study.
Rilzabrutinib (Sanofi) also significantly improved overall response rate and quality-of-life measures compared with placebo, findings presented at ASH Annual Meeting and Exposition showed.
“In a refractory patient population, rilzabrutinib has worked incredibly well,” David J. Kuter, MD, DPhil, director of clinical hematology at Massachusetts General Hospital and professor at Harvard Medical School, told Healio.
“I say ‘incredibly well’ not just because the platelet counts rose, but for three other reasons, as well. The adverse event rate was remarkably low. This is a very safe drug. Equally important is the fact that the response occurred fast and, when it occurred, it didn’t disappear. It kept being persistent. And finally, a major problem with patients with ITP is not so much they bleed, but they have a poor quality of life. Patients’ fatigue levels dramatically decreased when they responded to the drug.”
Background
Kuter began investigating Bruton tyrosine kinase (BTK) inhibitors in ITP more than a decade ago, when he found the therapy made the disease “disappear” among people with chronic lymphocytic leukemia.
He then tested ibrutinib (Imbruvica; Janssen, Pharmacyclics), a first-generation BTK inhibitor, for three patients with severe ITP but not chronic lymphocytic leukemia. The agent worked, he said.
However, ibrutinib can reduce platelet function and promote bleeding. That prompted an investigation of rilzabrutinib, a covalent, reversible BTK inhibitor.
During the phase 1/2 LUNA 2 study, Kuter and colleagues found rilzabrutinib increased platelet counts in 40% of patients with ITP. Presumed mechanisms of its action included turning off lymphocytes that make the antibodies that attack platelets, as well as inhibiting macrophages that destroy the antibody-coated platelets.
As Healio previously reported, patients responded to treatment within 2 weeks.
Methods
The LUNA 3 study included patients aged 10 years or older with primary persistent/chronic ITP. On average, participants had failed four to five prior therapies, Kuter said.
Eligible participants had to have platelet counts below 30 × 109/L within 2 weeks of the study’s start.
Kuter and colleagues randomly assigned patients 2:1 to 400 mg oral rilzabrutinib twice daily or placebo for up to 24 weeks, followed by rilzabrutinib only for 28 weeks in an open-label portion of the trial.
As of March 14, researchers had randomly assigned 202 adults (median age, 47 years; range 18-80).
Researchers had two categories of platelet response — a platelet count of at least 50 × 109/L, or a platelet count between 30 × 109/L and 50 × 109/L that had doubled from baseline.
Durable platelet response, defined as a platelet count at least 50 × 109/L for at least 8 of the final 12 weeks of the blinded portion of the study, served as the study’s primary endpoint.
Results
Results showed a significantly higher platelet response rate in the rilzabrutinib group than the placebo group (65% vs. 33%).
In addition, 23% of patients in the rilzabrutinib group achieved durable response compared with none assigned placebo (P < .0001).
After combining both the blinded and open-label portions of the study, 29% of participants assigned rilzabrutinib had durable response.
Median time to first response was 36 days in the rilzabrutinib group but had not been reached in the placebo group (HR = 3.1; 95% CI, 1.9-4.9). Participants assigned rilzabrutinib and achieved response had a median time to first response of 15 days (range, 2-99).
Rilzabrutinib decreased use of rescue therapy by 52% compared with placebo (P = .0007).
Rilzabrutinib also conferred improvements in physical fatigue (P = .01) and bleeding (P = .0006).
Researchers reported similar rates of any-grade and serious adverse events between groups. A higher percentage of patients assigned rilzabrutinib experienced diarrhea (23% vs. 4%), nausea (17% vs. 6%), headache (8% vs. 1%) or abdominal pain (6% vs. 1%).
One patient assigned rilzabrutinib developed a treatment-related grade 3 peripheral embolism. However, that individual had multiple risk factors, according to researchers. One person died due to pneumonia deemed unrelated to study treatment.
‘New standard of care’
At this year’s International Society on Thrombosis and Haemostasis Congress, Kuter presented data from LUNA 2 that showed individuals achieved better overall platelet response to rilzabrutinib if they had ITP for 3 years or less (48% vs. 38%), received fewer than four prior therapies (71% vs. 33%), or received the agent as second-line therapy vs. in the third line or later (86% vs. 37%).
Additionally, patients achieved more durable responses if they had ITP for 3 years or less (35% vs. 25%), had fewer than four previous treatments (43% vs. 25%), or received it as a second-line therapy vs. in the third line or above (57% vs. 26%).
The next steps in research include investigating rilzabrutinib in earlier-stage disease, both as part of LUNA 3 data and in future trials.
Kuter said he is “confident” those results will make rilzabrutinib “a new standard of care.”
“ITP is a poster child for autoimmune diseases,” he added. “It’s a disorder in which many other autoimmune disease drugs are being tested. These molecules are not just focused on ITP. They are broad immune modulatory drugs that can be used in a wide range of other diseases.
“Rilzabrutinib is going to have major effects on other disease categories, such as warm antibody hemolysis,” he continued. “It may improve nephritis. It may affect people who have pemphigus. It may affect a wide variety of other autoimmune conditions, and there’s even an abstract that shows that it might be used in sickle cell disease.”
For more information:
David J. Kuter, MD, DPhil, can be reached at dkuter@mgh.harvard.edu.
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Kuter DJ, et al. Abstract 5. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2024; San Diego.
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