Phase III COMMODORE 2 and 1 Trials: Characterization of Breakthrough Hemolysis Events in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Crovalimab or Eculizumab

Introduction

Crovalimab (crova; PiaSky®), a novel C5 inhibitor (C5i) allowing for maintenance subcutaneous (SC) maintenance dosing (weight-based tiered regimen) every 4 weeks (Q4W) , was assessed vs eculizumab (ecu) in the global, randomized, Phase III COMMODORE 2 and 1 trials (NCT04434092; NCT04432584; primary analysis clinical cutoff date [CCOD]: Nov 16, 2022). In COMMODORE 2, crova showed non-inferior efficacy and a similar safety profile vs ecu in C5i-naive patients (pts; Röth Am J Hematol 2024). In COMMODORE 1, crova was well tolerated in C5i-experienced pts and pts who switched from eculizumab (ecu) to crova had similar efficacy to pts who continued ecu (Scheinberg Am J Hematol 2024). Here, we report a comprehensive characterization of breakthrough hemolysis (BTH) events during the primary treatment periods of COMMODORE 2 and 1 based on data from the updated CCOD.

Methods

In COMMODORE 2 and 1, self-administration of crova was permitted. BTH was defined as the presence of elevated lactate dehydrogenase (LDH) ≥2×upper limit of normal (ULN) after a prior decrease to <1.5×ULN after study start and a concurrent new or worsening symptom of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 g/dL], major adverse vascular event, dysphagia, or erectile dysfunction). BTH events that occurred during the 24-week primary treatment period (baseline to Week 25) were analyzed and categorized as follows:

• being temporally associated with a complement-activating condition (CAC; such as infection, surgery, or pregnancy);

• being temporally associated with suboptimal C5 inhibition (i.e. 50% hemolytic complement (CH50) levels >30 U/mL, crova serum concentration <100 µg/mL). If loss of pharmacodynamics/pharmacokinetics was concurrent with a CAC, BTH was attributed to suboptimal C5 inhibition;

• unrelated to either of the above.

Results

The updated CCOD was Mar 12, 2024. In COMMODORE 2, 134 C5i-naive pts in the crova arm and 69 in the ecu arm were evaluable for efficacy. In COMMODORE 1, 44 and 42 C5i-experienced pts in the crova and ecu arms, respectively, were evaluable for efficacy. BTH events occurred in 10 of 134 pts (7% [95% CI: 4%, 14%]) in the crova arm and 9 of 69 (13% [7%, 24%]) in the ecu arm of COMMODORE 2, and 4 of 44 (9% [3%, 23%]) and 4 of 42 (10% [3%, 24%]), respectively, in COMMODORE 1. Across both studies, 14 of 178 pts (8% [95% CI: 5%, 13%]) in the crova arms and 13 of 111 pts (12% [7%, 20%]) in the ecu arms had BTH.

In COMMODORE 2, 6 pts (4%) had BTH attributed to a CAC, 2 (1%) had BTH attributed to suboptimal C5 inhibition, and 2 (1%) had BTH of unknown cause in the crova arm. The ecu arm had 4 (6%), 3 (4%), and 2 (3%) pts with BTH attributed to a CAC, suboptimal C5 inhibition, and unknown cause, respectively.

In the crova arm of COMMODORE 1, 2 pts (5%) had BTH attributed to a CAC, 1 pt (2%) had BTH attributed to suboptimal C5 inhibition, and 1 (2%) had BTH of unknown cause. In the ecu arm BTH occurring in 0 (0%), 3 (7%), and 1 (2%) pts were attributed to a CAC, suboptimal C5 inhibition, and unknown cause, respectively.

Of all pts in the crova arms of COMMODORE 2 and 1, 8 pts (4%) had BTH attributed to a CAC, 3 (2%) had BTH attributed to suboptimal C5 inhibition (all due to presence of anti-drug antibodies [ADA]), and 3 (2%) had BTH of unknown cause. In the ecu arms of both studies, 4 pts (4%) had BTH attributed to a CAC, 6 (5%) had BTH attributed to suboptimal C5 inhibition, and 3 (3%) had BTH of unknown cause.

Six pts in the crova arm and 2 pts in the ecu arm of COMMODORE 2, and 1 pt in each arm of COMMODORE 1 received red blood cell transfusions.

Conclusions

Incidence and categorization of BTH events were similar between the crova and ecu arms of both COMMODORE 2 and 1.

The majority of BTH cases occurring during the primary treatment periods in the crova arms of COMMODORE 2 and 1 were associated with a CAC while maintaining complete C5 inhibition. A similar trend was seen in the ecu arms.

Overall, updated CCOD results show that BTH was infrequent with crova and further support the favorable benefit-risk profile of crova in both C5i-naive and C5i-experienced pts with PNH.

Kulasekararaj:Akari: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioCryst: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Agios: Honoraria; Apellis: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Achillion: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Silence Therapeutics: Honoraria; Sobi: Consultancy, Honoraria, Speakers Bureau; Samsung: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy. Czyz:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Flynn:Sobi: Consultancy, Honoraria, Speakers Bureau; F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Consultant Haematologist: Current Employment. Gastal:F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Hus:Roche: Other: travel expenses; medical writing support; AbbVie Inc., Amgen, AstraZeneca, BMS/Celgene, Janssen, GSK, MSD, Novartis, Roche, Oncopeptides, Sanofi, Takeda: Honoraria; Janssen: Other: travel expenses. Nur:Novartis: Research Funding; Vertex: Speakers Bureau; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Scheinberg:AstraZeneca: Consultancy, Speakers Bureau; BMS: Consultancy; Alnylam: Research Funding; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy; Roche: Consultancy, Speakers Bureau. Ueda:Sobi: Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ono: Consultancy; Nippon Shinyaku: Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kaken: Honoraria; Incyte: Speakers Bureau; Chugai: Consultancy, Honoraria, Research Funding; Asahi Kasei: Consultancy; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi:.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Vidriales Vicente:F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Viigimaa:F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Buatois:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in private company, Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Chang:F.Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.; Genentech Inc: Current Employment. Chebon:F.Hoffmann-La Roche: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Bena Lim, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.. Röth:Apellis: Consultancy; 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 Scott Battle, PhD, CMPP, of Nucleus Global, an Inizio company, and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Amgen: Consultancy; Kira: Consultancy; Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Biocryst: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria.