Authors:
Marie Scully, Javier de la Rubia, Katerina Pavenski, Ara Metjian, Paul Knoebl, Flora Peyvandi, Flora Peyvandi, Spero R. Cataland, Paul Coppo, Johanna A. Kremer Hovinga Strebel, Jessica Minkue Mi Edou, Rui de Passos Sousa, Filip Callewaert, Sriya Guna (...)
Marie Scully, Javier de la Rubia, Katerina Pavenski, Ara Metjian, Paul Knoebl, Flora Peyvandi, Flora Peyvandi, Spero R. Cataland, Paul Coppo, Johanna A. Kremer Hovinga Strebel, Jessica Minkue Mi Edou, Rui de Passos Sousa, Filip Callewaert, Sriya Gunawardena, Julie Lin
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Abstract:
Abstract Background: The post-HERCULES trial (NCT02878603) evaluated long-term safety and efficacy of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura (aTTP; also known as immune-mediated TTP), and efficacy of repeated use of caplacizumab for aTTP recurrence. Methods: Patients who completed the HERCULES trial were invited to participate in the post-HERCULES study and attend twice-yearly visits for 3 years. In case (...)
Abstract Background: The post-HERCULES trial (NCT02878603) evaluated long-term safety and efficacy of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura (aTTP; also known as immune-mediated TTP), and efficacy of repeated use of caplacizumab for aTTP recurrence. Methods: Patients who completed the HERCULES trial were invited to participate in the post-HERCULES study and attend twice-yearly visits for 3 years. In case of aTTP recurrence, patients could receive open-label (OL) caplacizumab with therapeutic plasma exchange (TPE) and immunosuppression (IST). Safety was assessed during the overall study period (intention-to-observe [ITO] population) and during recurrences. TTP-related events (recurrence, mortality, or major thromboembolic events) were assessed in the efficacy ITO population. The ITO population (n=104) included all enrolled patients, grouped by whether they received caplacizumab during HERCULES (randomized or switched to OL after exacerbation). The efficacy ITO population (n=78) included those without aTTP recurrence during HERCULES or prior to the beginning of post-HERCULES. The recurrence population (n=19) included patients with ≥1 recurrence during post-HERCULES; the repeat-use population (n=9) was a subset treated at least twice with caplacizumab (received caplacizumab in HERCULES or treated twice in post-HERCULES). Pharmacodynamics and immunogenicity were assessed in the ITO population. The study was conducted in accordance with the Declaration of Helsinki. Results: Of 104 patients enrolled in post-HERCULES, 75 were treated with caplacizumab along with TPE+IST during HERCULES (caplacizumab group) and 29 were treated with TPE+IST only (placebo group). During the overall post-HERCULES study period, incidence of adverse events (AEs) and serious AEs was similar between the groups. In the ITO population, recurrence occurred in 11/75 patients (15%) in the caplacizumab group and 8/29 patients (28%) in the placebo group. In the efficacy ITO population, TTP-related events occurred in 8% of patients (4/49) randomized to caplacizumab versus 38% (11/29) randomized to placebo (Table 1). Prior rituximab use during HERCULES was similar in both groups (21/49 patients [43%] randomized to caplacizumab and 12/29 [41%] randomized to placebo). Incidence of recurrence by prior rituximab use (with vs without) was 10% (2/21) versus 7% (2/28) among patients randomized to caplacizumab, and 17% (2/12) versus 35% (6/17) among patients randomized to placebo. Of 19 patients with ≥1 recurrence, 13 were treated with caplacizumab and 6/13 received concomitant rituximab. Recurrences were resolved (12/13) or resolving (1/13) for all patients treated with caplacizumab, including 9 patients with repeat caplacizumab use. One patient who did not receive caplacizumab in either HERCULES or post-HERCULES died as an outcome of recurrence. Safety profile of caplacizumab for treatment of recurrence was consistent with that observed in HERCULES (Table 2) . The most common treatment-emergent AEs (TEAEs) with caplacizumab during the first recurrence (n=13) were headache and constipation (n=3 each). In the repeat-use population (n=9), bleeding events were reported in 5/9 patients (56%) for the first recurrence; 2 patients had a serious treatment-related TEAE of genitourinary or gastrointestinal bleeding; 2 patients had treatment-emergent anti-drug antibodies (ADAs) positive in a functional neutralizing antibody assay. No apparent impact of treatment-emergent ADAs on RICO activity or change from baseline in von Willebrand factor antigen concentration was found. Conclusions: The long-term safety profile of patients exposed to caplacizumab together with TPE+IST was similar to those who received IST+TPE only, with no observed increases in recurrence of aTTP. Repeat caplacizumab use was efficacious, with no evidence of safety concerns or boosting of ADA response. Funding: This research was funded by Ablynx, a Sanofi company. Figure 1 Figure 1. Disclosures Scully: Shire: Research Funding; Novartis: Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octopharma: Speakers Bureau. de la Rubia: Ablynx/Sanofi: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; Celgene, Takeda, Janssen, Sanofi: Honoraria; Celgene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; GSK: Consultancy. Pavenski: Alexion: Honoraria, Research Funding; Bioverativ: Research Funding; Ablynx: Honoraria, Research Funding; Octapharma: Research Funding; Shire: Honoraria. Metjian: Momenta/Johnson & Johnson, Sanofi Aventis, Takeda: Research Funding; Ablynx/Sanofi: Consultancy; Sanofi Aventis, Takeda: Other: Advisory. Knoebl: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Peyvandi: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. Cataland: Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Sanofi Genzyme: Consultancy. Coppo: Alexion Pharmaceuticals, Sanofi Aventis, Octapharma AG: Consultancy, Other: Advisory; Alexion Pharmaceuticals, Sandoz, Sanofi Aventis, Takeda: Other: Speakers Bureau; Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremer Hovinga Strebel: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Speaker at symposia; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Other: Speaker at symposia; Roche: Other: Speaker at symposia; Siemens: Other: Speaker at symposia. Minkue Mi Edou: Sanofi: Current Employment, Other: May hold shares and/or stock options. de Passos Sousa: Sanofi: Current Employment, Other: May hold shares and/or stock options. Callewaert: Sanofi: Current Employment, Other: May hold shares and/or stock options. Gunawardena: Sanofi: Current Employment, Other: May hold shares and/or stock options. Lin: Sanofi: Current Employment, Other: May hold shares and/or stock options.
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