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BACKGROUND Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcgamma receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of >=50x103 per cubic millimeter and an increase from baseline of >=20x103 per cubic millimeter without the use of rescue medication). RESULTS Sixty patients were enrolled. At baseline, the median platelet count was 15x103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50x103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50x103 per cubic millimeter was 65%. CONCLUSIONS Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400

Introduction: Key characteristics of immune thrombocytopenia (ITP) include immune-mediated platelet destruction/impaired production, with resultant thrombocytopenia and increased bleeding risk. Durable response to current therapies remains an unmet need, particularly in the relapsed/refractory setting. Rilzabrutinib is the first oral, reversible, covalent inhibitor of Bruton tyrosine kinase designed to target immune-mediated pathways in ITP without inhibiting normal platelet aggregation. Initial phase I/II results in ITP demonstrated rapid and durable efficacy with rilzabrutinib that was well-tolerated at all dose levels, including the optimal 400 mg bid dose. Interim results on rilzabrutinib effects in patients with relapsed/refractory ITP were previously reported. Here we present long-term data from a larger group of patients who initiated rilzabrutinib at 400 mg bid and are continuing in the long-term extension (LTE) period. Method(s): This ongoing, global phase I/II study (NCT03395210) enrolled adult patients from 8 countries with relapsed or refractory ITP who previously responded to >=1 prior ITP therapy. Eligible patients with 2 baseline platelet counts of <30x10 9/L no less than 7 days apart in the 15 days before baseline received oral rilzabrutinib at starting doses of 200 or 400 mg QD, 300 or 400 mg bid for 24 weeks; intrapatient dose escalation was permitted to improve efficacy. Stable doses of concomitant corticosteroids and thrombopoietin receptor agonists were allowed for patients with inadequate platelet response. The primary endpoints were safety and achievement of >=2 consecutive platelet counts >=50x10 9/L and increased >=20x10 9/L from baseline without rescue medication. Responding patients could continue in the LTE period with rilzabrutinib at the optimal 400 mg bid dose. Result(s): As of June 1, 2021 in 60 patients, 45 patients initiated rilzabrutinib 400 mg bid and to date, 16 patients with durable, stable response proceeded to LTE at 400 mg bi

Background: Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and high bleeding risk. In a global phase I/II trial (NCT03395210) of heaily pretreated patients with long-standing disease, the Bruton tyrosine kinase inhibitor rilzabrutinib showed a rapid and durable platelet count increase and was well tolerated. We present results for patients initiating rilzabrutinib 400 mg BID who are continuing in the long-term extension (LTE). Aim(s): Assess if the efficacy and safety of rilzabrutinib 400 mg BID continue to be maintained in LTE patients on rilzabrutinib +/- concomitant medication. Method(s): Patients with 2 baseline platelet counts <30x109/L were required to hae responded to >=1 prior ITP therapy but at baseline were unable to maintain an adequate response to prior/concomitant therapies. The main treatment period was 24 weeks; patients who achieed platelet counts >=50x109/L at >=50% of the isits during the last 8 weeks of the main period were permitted to continue 400 mg BID in the LTE. Primary endpoints were safety and efficacy (>=2 consecutie platelet counts >=50x109/L and increased >=20x109/L from baseline without requiring rescue medication). Stable doses of concomitant ITP medication (thrombopoietin-receptor agonists [TPO-RA] and corticosteroids [CS]) were allowed for patients with inadequate platelet response. Patients who receied rescue medication discontinued from the study. All patients proided informed consent. Result(s): At baseline, the 45 patients initiating 400 mg BID in the main period had a median age of 49 years, median duration of ITP of 6.1 years, median platelet count of 15x109/L, and a median of 4 unique prior therapies (24% prior splenectomy). A total of 15 patients (33%) receied rilzabrutinib monotherapy, and 30 had concomitant therapy (TPO-RA n=13 [29%], CS n=12 [27%], TPO-RA + CS n=5 [11%]). Primary platelet resp

Background: Immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired production, triggering thrombocytopenia, and a predisposition to bleeding. Despite recent therapeutic advances, durable remission remains an unmet need for relapsed/refractory ITP patients. Rilzabrutinib is an oral, reversible, covalent inhibitor of BTK that targets immune-mediated ITP activities and has simultaneous rapid anti-inflammatory effects and neutralization and prevention of autoantibody signaling preclinically. The ongoing phase I/II study (NCT03395210) assesses the safety and efficacy of rilzabrutinib in patients with relapsed or refractory ITP who previously responded to >=1 prior ITP therapy and have no available treatment options. Initial results have shown rapid and durable clinical activity and a well-tolerated safety profile in patients responding to rilzabrutinib. Aim(s): Phase II evaluation of rilzabrutinib in the overall study population and patients initiating 400 mg BID rilzabrutinib. Method(s): Eligible patients with 2 baseline platelet counts <30x109/L received oral rilzabrutinib at starting doses of 200 mg QD, 400 mg QD, 300 mg BID, or 400 mg BID; intrapatient dose escalation was allowed to improve efficacy. Rilzabrutinib was given for 24 weeks; additional long-term therapy was administered at the 400 mg BID dose in responders only. Stable doses of concomitant ITP medication (corticosteroids and thrombopoietin-receptor agonists) were permitted for patients without adequate platelet response. The primary endpoints are safety and >=2 consecutive platelet counts >=50x109/L and increased >=20x109/L from baseline without requiring rescue medication. All patients provided informed consent. Result(s): The overall study population comprises 59 patients, of whom 44 had a starting dose of 400 mg BID; data cutoff was 09Nov2020. Overall, patients had a median age 50 years (range, 21-74), median duration of ITP 6.4 years (range, 0.4-52.5), and

Background: For most ITP patients, durable remission remains elusive and their disease becomes refractory to current treatments. Rilzabrutinib, an oral, reversible, covalent BTK inhibitor, targets mechanisms of platelet destruction. Preliminary phase I/II results in ITP showed rilzabrutinib was efficacious and safe at all dose levels, including the optimal 400 mg BID dose (NCT03395210). Aim(s): Assess efficacy/safety of rilzabrutinib with longer follow-up at 400 mg BID and in long-term extension (LTE). Method(s): Eligible patients had 2 baseline platelet counts <30x109/L. Concomitant ITP therapy was permitted at stable doses. Primary endpoints: safety and >=2 consecutive platelet counts >=50x109/L and increased >=20x109/L from baseline without requiring rescue medication. All patients provided informed consent. Result(s): As of 09Nov2020 in 59 patients, 44 initiated rilzabrutinib 400 mg BID and to date, 14 patients with durable, stable response proceeded to LTE at 400 mg BID. For patients initiating rilzabrutinib 400 mg BID, baseline median age was 49 y, median prior therapies: 5.5 (range, 1-53 25% prior splenectomy), and median platelet count: 16x109/L. 39% of patients initiating rilzabrutinib 400 mg BID achieved the primary endpoint at a median of 20.6 weeks (range, 1.4-24.6) on treatment (Table 1) 50% had platelet counts >=30x109/L by day 8. Platelet responses to rilzabrutinib were observed irrespective of prior treatment or responses. LTE patients received rilzabrutinib for a median of 55.9 weeks (range, 13.9-84.3). All LTE patients achieved the primary endpoint response in the main treatment period and maintained platelet counts >=50x109/L for 96% of the LTE (Figure 1). Treatment-related emergent adverse events were all grade 1/2, most commonly diarrhea and nausea, with no related bleeding/thrombotic events. Conclusion(s): Rilzabrutinib 400 mg BID showed rapid and durable responses and was well-tolerated with longer follow-up and in LTE. This ongoing study cont

Background: For most ITP patients, durable remission remains elusive and their disease becomes refractory to current treatments. Rilzabrutinib, an oral, reversible, covalent BTK inhibitor, targets mechanisms of platelet destruction. Preliminary phase I/II results in ITP showed rilzabrutinib was efficacious and safe at all dose levels, including the optimal 400 mg BID dose (NCT03395210). Aims: Assess efficacy/safety of rilzabrutinib with longer follow‐up at 400 mg BID and in long‐term extension (LTE). Methods: Eligible patients had 2 baseline platelet counts <30×109/L. Concomitant ITP therapy was permitted at stable doses. Primary endpoints: safety and ≥2 consecutive platelet counts ≥50×109/L and increased ≥20×109/L from baseline without requiring rescue medication. All patients provided informed consent. Results: As of 09Nov2020 in 59 patients, 44 initiated rilzabrutinib 400 mg BID and to date, 14 patients with durable, stable response proceeded to LTE at 400 mg BID. For patients initiating rilzabrutinib 400 mg BID, baseline median age was 49 y, median prior therapies: 5.5 (range, 1‐53; 25% prior splenectomy), and median platelet count: 16×109/L. 39% of patients initiating rilzabrutinib 400 mg BID achieved the primary endpoint at a median of 20.6 weeks (range, 1.4‐24.6) on treatment (Table 1); 50% had platelet counts ≥30×109/L by day 8. Platelet responses to rilzabrutinib were observed irrespective of prior treatment or responses. LTE patients received rilzabrutinib for a median of 55.9 weeks (range, 13.9‐84.3). All LTE patients achieved the primary endpoint response in the main treatment period and maintained platelet counts ≥50×109/L for 96% of the LTE (Figure 1). Treatment‐related emergent adverse events were all grade 1/2, most commonly diarrhea and nausea, with no related bleeding/thrombotic events. Conclusions: Rilzabrutinib 400 mg BID showed rapid and durable responses and was well‐tolerated with longer follow‐up and in LTE. This ongoing study continues to as