麻豆传媒

SAN DIEGO -- Treatment with an investigational oral inhibitor of Bruton's tyrosine kinase (BTK) was safe and boosted platelet counts in heavily pretreated patients with immune thrombocytopenia (ITP), a phase III trial showed.

In the so-called LUNA 3 study, 23% of patients assigned to rilzabrutinib achieved a durable platelet response at week 25 without the use of rescue therapy versus 0% of those assigned to placebo (95% CI 16-30, P<0.0001), reported David Kuter, MD, DPhil, of Harvard Medical School in Boston.

The study also met all of its secondary endpoints, demonstrating that rilzabrutinib was well-tolerated, reduced fatigue and use of rescue medication, and resulted in fewer bleeding events, he said during a press briefing at the American Society of Hematology annual meeting here.

Durable responders had a clear improvement in measures of fatigue -- a major component of ITP, Kuter noted -- while placebo recipients remained fatigued or worsened.

"To our surprise, those patients who got active therapy but did not have a durable response still had an improvement in their fatigue level, suggesting that rilzabrutinib may affect fatigue or anti-inflammatory properties since BTK inhibition has many different elements to it," he said.

ITP is a rare autoantibody disorder that both prevents platelet production and attacks platelets, resulting in their destruction, Kuter explained. The net result is a platelet count that drops below 100,000/μL, which defines the disease. Symptoms include bleeding, thrombosis, and a marked impairment in quality of life.

Multiple drugs now exist to treat ITP. "We've gone from the generation of ITP therapy of taking your spleen out and killing you with steroids to now having available rituximab, , and TPRAs [thrombopoietin receptor agonists] that treat the platelet count and make the platelet count rise," said Kuter.

But there remains an unmet need for newer therapies, as some patients only have short-term responses with drugs like rituximab and platelet counts can be incredibly unstable with TPRAs, he said.

"We're now entering a third phase where we're hoping that maybe we can cure the disease," said Kuter. "New drugs such as rilzabrutinib raise the platelet count..., but it also may -- and we haven't been able to prove this just yet -- affect the underlying B cells that are making antibody and maybe make the disease disappear, giving a much longer remission. That's a hope."

Rilzabrutinib is a reversible, covalent selective BTK inhibitor designed to simultaneously reduce the production of platelet-targeting autoantibodies and to inhibit B-cell activation and inflammatory pathways. Beyond ITP, the drug has also shown activity in pemphigus and uncontrolled asthma.

Unlike the first-generation BTK inhibitor ibrutinib (Imbruvica), rilzabrutinib does not increase the risks of atrial arrhythmia or platelet dysfunction.

"Many of us have used ibrutinib in [pretreated ITP], but have been plagued by the fact that it affects platelet function ... and affects bleeding," Kuter told 麻豆传媒, adding that rilzabrutinib is "a much safer way" to treat ITP.

Press briefing moderator Charles Abrams, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, remarked that the study included "the hardest of hard patients," with nearly half having already received five prior therapies, and asked if the drug is more active in an earlier setting.

Kuter noted that data pulled from a phase I/II study of rilzabrutinib in ITP showed that patients receiving rilzabrutinib as second-line therapy had durable response rates well over 50%.

"This drug, like all the other ITP drugs that are developed, does much better when given early on ... so I think this is a good first step for treating all patients," he said.

The LUNA 3 study enrolled 202 adults with heavily pretreated ITP and randomized them 2:1 to rilzabrutinib (400 mg, twice daily) or placebo. Patients had to have persistent or chronic primary ITP, a platelet count below 30,000/μL, and were allowed to be on stable doses of other ITP medications such as corticosteroids or TPRAs.

Participants had a median age of 46-47, and 63% were women. Median platelet count at baseline was 15,000/μL in both arms. Participants had a median disease duration of 6 to 8 years; 46% had received five prior therapies, including splenectomy in 28%.

The primary endpoint was durable platelet response at week 25, which was defined as a platelet count of at least 50,000/μL for at least 8 of the last 12 weekly visits in the absence of rescue therapy.

Researchers also evaluated platelet response at week 13, here defined as a platelet count of 50,000/μL on one or more occasion, or 30,000/μL to <50,000/μL but at least twice as high baseline. Rates of platelet response using this less-stringent criteria were twice as high with rilzabrutinib versus placebo (64% vs 32%). Non-responders at week 14 in the placebo arm could exit the trial or go on to receive active therapy in an open-label portion of the study.

Patients who responded to rilzabrutinib did so rapidly -- often within 15 days -- and maintained their response in the open-label phase, said Kuter. Durable platelet responses were achieved by 25% of patients in the open-label part of the trial, while the durable response rate increased from 23% to 29% among those assigned to rilzabrutinib for the entire study timeframe.

In regards to safety, the rates of treatment-related adverse events (AEs) occurred in about 50% of rilzabrutinib-treated patients and 20% of placebo recipients. Rates of grade ≥3 and serious AEs were both lower with the BTK inhibitor. The most common treatment-related AEs of any grade with rilzabrutinib included diarrhea (23%), nausea (17%), headache (8%), and abdominal pain (6%).

Responders in the study will continue to be followed for an additional 28 weeks to further assess the durability of platelet response and safety.

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