Rilzabrutinib versus placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study

Abstract

Background: Immune thrombocytopenia (ITP) is characterized by primarily autoantibody-mediated platelet destruction and impaired platelet production resulting in thrombocytopenia and an increased risk of bleeding. Other manifestations include increased risk of thrombosis and diminished quality of life. Current treatment approaches are directed toward lowering the rate of platelet destruction or stimulating platelet production to prevent bleeding. Rilzabrutinib is an oral, reversible, potent Bruton tyrosine kinase inhibitor that was specifically designed to treat immune-mediated diseases and mediates its therapeutic effect through a dual mechanism of action: (1) inhibiting B-cell activation and (2) interrupting antibody-coated cell phagocytosis by Fc gamma receptor in spleen and liver. A 24-week dose-finding phase I/II study of rilzabrutinib in patients with ITP showed a 40% platelet response (⩾2 consecutive platelet counts of ⩾50 × 10⁹/L and increase from baseline ⩾20 × 10⁹/L without rescue medication use) and a well-tolerated safety profile with only grade 1/2 transient adverse events across dose levels.

Objectives: Assess the efficacy and safety of oral rilzabrutinib in adult and adolescent patients with persistent or chronic ITP.

Design: Rilzabrutinib 400 mg BID is being evaluated in the ongoing LUNA 3 multicenter, double-blind, placebo-controlled phase III study.

Methods and analysis: The primary endpoint is durable platelet response, defined as achieving platelet counts of ⩾50 × 10⁹/L for at least two-thirds of ⩾8 available weekly scheduled platelet measurements during the last 12 weeks (including ⩾2 available measurements within the last 6 weeks) of the 24-week blinded treatment period in the absence of rescue therapy.

Ethics: Ethical guidelines and informed consent are followed.

Discussion: The LUNA 3 trial will further investigate rilzabrutinib's safety and efficacy in adult and adolescent patients, with the primary goal of addressing a major objective in treating patients with ITP: durability of platelet response.

Trail registration: ClinicalTrials.gov NCT04562766: https://clinicaltrials.gov/ct2/show/NCT04562766; EU Clinical Trials Register EudraCT 2020-002063-60: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-002063-60.

Keywords: B cells; BTK inhibition; autoimmunity; bleeding; immune thrombocytopenia; platelets; rilzabrutinib.

Figure 1.

Rilzabrutinib mechanism of action in ITP. BTK regulates both B-cell receptor signaling upon antigen binding in B lymphocytes and FcγR signaling through binding of immune complexes in macrophages. By concerted action of the LYN and SYK tyrosine kinases, the PI3K/AKT signaling pathway is activated, leading to the generation of PIP3, which, in turn, results in the recruitment and activation of BTK. Through its noncovalent/reversible covalent binding sites, rilzabrutinib inhibits BTK and blocks its downstream effects. AKT, Ak strain transforming kinase; serine-threonine kinase; BTK, Bruton tyrosine kinase; FcγR, Fc gamma receptor; ITP, immune thrombocytopenia; PI3K, phosphatidylinositol-3 kinase; PIP3, phosphatidylinositol-3,4,5-triphosphate kinase.

Figure 2.

LUNA 3 recruiting countries.

Figure 3.

Study schema flow chart. LUNA 3 is registered as NCT04562766 and EudraCT 2020-002063-60. *Week 25 is the last visit of the blinded treatment period and the start of the open-label period. ^†Following long-term extension completion, patients will undergo the last day of study drug and end of study assessments. BID, twice daily; CS, corticosteroids; EU, European Union; ITP, immune thrombocytopenia; TPO-RA, thrombopoietin receptor agonist.

Figure 4.

Decision flow for assessing response at week 13. After enrollment, patients will start a blinded treatment period for up to 24 weeks (rilzabrutinib or placebo treatment) followed by an open-label period of 28 weeks (where all patients receive rilzabrutinib), and then a 4-week safety follow-up period or long-term extension. Patients who do not complete the initial 12 weeks of treatment are not eligible to proceed to the open-label period. At the end of 12 weeks of treatment, participants will be assessed for platelet response (⩾50 × 10⁹/L or between ⩾30 × 10⁹/L and <50 × 10⁹/L and at least doubled from baseline at any time) and the presence or absence of rescue medication in the 4 weeks before elevated platelet counts meeting the platelet response criteria. Responders with no rescue medication use after week 8 will continue to be evaluated for eligibility to proceed to the blinded treatment period for a total of 24 weeks before entering the open-label period. Non-responders or those who did receive rescue medication after week 8 may discontinue the study or enter the 28-week open-label period at the end of week 12 and receive rilzabrutinib 400 mg BID.