Phase III Randomized COMMODORE 1 Trial: 2-Year Safety and Efficacy of Crovalimab in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Switched from Eculizumab

Introduction

Crovalimab (crova; PiaSky®) is a novel C5 inhibitor (C5i) allowing for maintenance subcutaneous (SC) injection every 4 wks (Q4W). Results from the 24-wk primary treatment period of the global, randomized, Phase III COMMODORE 1 trial (NCT04432584) showed that crova was well tolerated and had similar efficacy in patients (pts) who switched from eculizumab (ecu) to crova vs pts who continued ecu (Scheinberg Am J Hematol 2024). These data, in conjunction with the COMMODORE 2 trial (NCT04434092) that demonstrated non-inferior efficacy of crova vs ecu in C5i-naive pts (Röth Am J Hematol 2024), highlight the overall favorable benefit-risk profile of crova. Here, we report 2-y COMMODORE 1 data.

Methods

Adult pts with PNH receiving ecu for ≥24 wks at study start with lactate dehydrogenase (LDH) ≤1.5×upper limit of normal (ULN) were randomized 1:1 to switch to crova (Arm A) or continue ecu (Arm B) for a 24-wk primary treatment period. Crova was given as a weight-based tiered dosing regimen that included loading doses followed by SC Q4W maintenance. Ecu was given via IV infusion at 900 mg every 2 wks. After primary treatment, pts in Arm A continued crova, and pts in Arm B switched from ecu to crova if continuing in the extension period (Arm B switch). In the COMMODORE trials, crova self-administration by pts was permitted from Wk (W)9, after training and confirmation of proficiency by a healthcare provider.

Long-term data were only reported in Arm A and Arm B switch pts who received crova. Long-term safety was evaluated from after the 1^st crova dose up to the clinical cutoff date (CCOD) pooled across both arms. Long-term efficacy was evaluated up to W97 in the extension period in each arm, as the majority of pts had reached this visit. Efficacy endpoints included the proportion of pts with hemolysis control (LDH≤1.5×ULN) at each visit from W25-97, and proportions of pts with transfusion avoidance (TA), breakthrough hemolysis (BTH), and hemoglobin stabilization; data were reported over consecutive 24-wk intervals in the extension period from W25-49, W49-73, and W73-97. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score was assessed at scheduled visits.

Results

All 44 pts from Arm A (crova) continued crova and 40 of 42 pts from Arm B (ecu) switched to crova in the extension period after W25. At CCOD (Mar 12, 2024), 42 pts in Arm A and 32 in Arm B switch were receiving crova. Median treatment duration was 106.2 wks (range, 3.1-180.0).

Across Arm A and Arm B switch, 84 pts (173.4 pt years [PY]) were evaluated for the long-term safety of crova. Incidence of adverse events (AEs) per 100 PY (95% CI) was 362.8 (335.0, 392.3) for all AEs, 50.8 (40.7, 62.5) for treatment-related AEs, 45.6 (36.1, 56.8) for Grade ≥3 AEs, and 29.4 (21.9, 38.7) for serious AEs. The rate of fatal AEs was 0.58 (0.01, 3.21) per 100 PY; the 1 death was unrelated to treatment per the investigator.

Transient immune complex reactions (TICRs; one-time events that some pts may have when switching between crova and another C5i) occurred in 18% of pts (15/84). The reported signs and symptoms of TICRs were mainly skin and joint abnormalities (rash and arthralgia), with no renal manifestations. Most TICRs were mild/moderate, with no life-threatening or fatal events, and resolved with no change in crova treatment. No meningococcal infections occurred.

Mean normalized LDH was maintained at ≤1.5xULN in both arms, with 77%-94% of pts in Arm A and 89%-100% in Arm B switch having LDH≤1.5×ULN at each visit from W25-97. Over consecutive 24-wk intervals in the extension, TA was achieved by 76%-84% of pts in Arm A and 75%-81% in Arm B switch; hemoglobin stabilization was achieved in 68%-73% and 60%-70% of pts, respectively. Proportion of pts with a BTH event remained low and generally stable (7%-11% in Arm A and 3%-18% in Arm B switch). Mean FACIT-Fatigue scores remained stable from W25-97, ranging from 40.8-42.9 in Arm A and 38.2-40.8 in Arm B switch.

Conclusions

In COMMODORE 1, crova was well tolerated and disease control was maintained over a 2-y median treatment duration in pts who switched from ecu to crova, showing a durable and consistent efficacy profile. The overall safety profile of crova was consistent with that of other C5is, except for the identified risk of usually mild/moderate and manageable TICRs in pts when switching between crova and another C5i. Overall, results support the long-term favorable benefit-risk profile of crova.

Scheinberg:Janssen: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Astellas: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Alnylam: Research Funding; Roche: Consultancy, Speakers Bureau; BMS: Consultancy; Novartis: Consultancy, Speakers Bureau. Cle:Alexion: Consultancy, Speakers Bureau; F.Hoffmann-La Roche: Consultancy, Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Pint Pharma: Consultancy; Takeda: Consultancy, Speakers Bureau; Adjum: Consultancy; Telios Pharma: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSK: Consultancy; Janssen: Consultancy, Speakers Bureau; Lilly: Speakers Bureau. Devalet:F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Giai:Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Barrenetxea Lekue:F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Lin:F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Nagy:F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Nishimura:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; BioCryst: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland., Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Received grants, Research Funding. Panse:Swiss Biopharma: Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland., Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Current equity holder in publicly-traded company; Apellis: Consultancy, Current equity holder in publicly-traded company, Honoraria; Samsung Bioepis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Swedish Orphan Biovitrum AB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria; MSD: Consultancy, Current equity holder in publicly-traded company, Honoraria; Bristol Myers Squibb: Consultancy, Current equity holder in publicly-traded company, Honoraria; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Piekarska:Sobi: Speakers Bureau; Astellas: Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Schubert:Roche: Honoraria, Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Sanofi: Consultancy, Speakers Bureau. Sunami:Bristol-Myers Squibb: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding; AbbVie Inc.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline (GSK): Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Janssen Pharmaceuticals, Inc.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Incyte Corporation: Research Funding; F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Beigene: Research Funding; Mitsubishi: Research Funding; Tanabe Pharma: Research Funding. Yenerel:Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Appius:F.Hoffmann-La Roche: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Gentile:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Iwase:F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Patel:F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Genentech Inc: Current Employment. Sreckovic:Genentech Inc: Current Employment; F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Kulasekararaj:Silence Therapeutics: Honoraria; Sobi: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Samsung: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Agios: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioCryst: Consultancy, Honoraria, Speakers Bureau.