Rilzabrutinib Shines in Phase 3 Trial of Tough-to-Treat ITP

Phase 3 data support rilzabrutinib as a potential first-in-class oral Bruton tyrosine kinase (BTK) inhibitor for patients with previously treated immune thrombocytopenia (ITP). 

In the LUNA 3 trial, treatment with rilzabrutinib (Sanofi) led to rapid and durable platelet responses, reduced bleeding and need for rescue therapy, and improved health-related quality of life in patients with persistent or chronic immune thrombocytopenia. 

Notably, rilzabrutinib also “significantly improved fatigue, even among patients who did not have a significant platelet count rise,” said David J. Kuter, MD, DPhil, director of clinical hematology, Massachusetts General Hospital, Boston, who reported the findings during a press briefing here at the American Society of Hematology (ASH) 2024 Annual Meeting.

Briefing moderator Charles Abrams, MD, University of Pennsylvania, Philadelphia, noted that LUNA 3 enrolled a “remarkably tough group of patients, really the hardest of the hard” and showed that rilzabrutinib was “well-tolerated and caused an increase in platelet counts.”

The study, Abrams added, demonstrates “significant progress” in treatment of a disease that has historically been viewed as “benign,” which is “good for our patients.”

Immune thrombocytopenia is a relatively rare autoimmune disease that affects 10 to 23 patients per 100,000 in the United States. For those with the condition, the body’s immune system attacks platelets, causing platelet counts to drop below 100,000/μL of blood. The disease leads to increased bleeding risk and thrombosis, impaired clotting and health-related quality of life, as well as greater fatigue. 

“People living with immune thrombocytopenia who cannot tolerate or do not respond to medications aimed at raising platelet counts are at risk of uncontrolled bleeding and often endure side effects from steroids and other available therapies,” Kuter noted in a Sanofi news release. 

Rilzabrutinib, which received fast-track designation in November 2020 from the US Food and Drug Administration to treat immune thrombocytopenia, is currently under regulatory review and has a target action date of August 29, 2025. 

In the LUNA 3 study, adults with persistent or chronic immune thrombocytopenia and severely low platelet counts (median, 15,000/μL) received oral rilzabrutinib 400 mg twice a day (133 patients) or placebo (69 patients) for up to 24 weeks during a blinded treatment period, followed by a 28-week open-label period.

Platelet response — defined as counts at or above 50,000/μL or counts between 30,000/μL and 50,000/μL but doubled from baseline — was achieved in nearly two thirds of patients taking rilzabrutinib compared with almost one third of patients taking placebo at week 13. 

The primary endpoint was durable platelet response, defined as the proportion of patients able to achieve platelet counts at or above 50,000/μL for at least eight out of the last 12 weeks of the 24-week blinded period, without the need for rescue therapy. 

No patient taking placebo met this endpoint, compared with 23% of patients taking rilzabrutinib (P .0001)

For the combined double-blind and open-label periods, a durable response was achieved in 29% of the 133 patients randomized to rilzabrutinib and 25% of the 193 patients receiving the drug in the open-label period at the data cutoff. 

Rilzabrutinib also led to significant improvements in bleeding (based on the Immune Thrombocytopenic Purpura Bleeding Score), with a mean change from baseline at week 25 of –0.04 with rilzabrutinib versus 0.05 with placebo (P = .0006).

Patients on rilzabrutinib were three times more likely to achieve a platelet response than their peers on placebo (hazard ratio, 3.1; P .0001), with a median time to first platelet response of 36 days (vs median not achieved by patients on placebo). Among patients randomized to rilzabrutinib who achieved a response, the median time to response was 15 days.

Compared with placebo, rilzabrutinib significantly reduced the need for rescue therapy by 52% (P = .0007).

Rilzabrutinib was also associated with significant and sustained improvement in physical fatigue (based on the Immune Thrombocytopenic Purpura Patient Assessment Questionnaire [ITP-PAQ] Item 10 score).

“To our surprise, those patients who got active therapy but did not have a durable response still had an improvement in their fatigue levels and that suggests rilzabrutinib may affect fatigue or have anti-inflammatory properties since BTK inhibition has many different elements to it,” Kuter said during the briefing. 

The most common treatment-related adverse events with rilzabrutinib versus placebo were mild to moderate (grade 1/2) diarrhea (23% vs 4%), nausea (17% vs 6%), headache (8% vs 1%), and abdominal pain (6% vs 1%). Rates of grade 2 or higher gastrointestinal adverse events were comparable between groups: 6% with rilzabrutinib versus 4% with placebo. In the rilzabrutinib group, one patient who had numerous risk factors had a treatment-related grade 3 peripheral embolism and one patient died due to pneumonia unrelated to treatment.

“I’m encouraged by the robust therapeutic effects I’ve seen in patients of the LUNA 3 study across all aspects of the disease, including clinically meaningful and sustained improvements in platelet count, quality of life metrics, reduction in bleeding, and a favorable safety profile,” Kuter said in the Sanofi news release. 

The LUNA 3 study was funded by Sanofi. Kuter has disclosed various relationships with Sanofi and other pharmaceutical companies.