Regulatory Decision Summary for Piasky

The purpose of this submission is to seek market authorization for Piasky (crovalimab) for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH).

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

After evaluation of the submitted data package, Health Canada authorized Piasky (crovalimab) for the following indication: Piasky of paroxysmal nocturnal hemoglobinuria (PNH) in adults and (crovalimab for injection) is indicated for the treatment adolescents 13 years of age and older with a body weight of at least 40 kg.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening acquired hematopoietic stem cell disorder. The clinical manifestations of PNH can lead to severe clinical sequelae that have a negative impact on patients’ life.

The benefits of Piasky (crovalimab) in adults with PNH who weigh at least 40 kg was assessed in one pivotal Phase 3 clinical study demonstrating non-inferiority to another C-5 inhibitor treatment authorized for this indication in Canada, based on the analysis of the co-primary endpoints, hemolysis control and transfusion avoidance. Results for the proportion with breakthrough hemolysis and proportion of patients with stabilized hemoglobin, that were assessed as key secondary endpoints, were also supportive of treatment benefit. The recommended dose of Piasky is based on body weight (≥40 kg to <100 kg and ≥100 kg).

The safety profile of Piasky in adult and adolescent PNH patients was informed from a pooled safety analysis of 393 patients consisting of 192 Piasky naïve patients and 201 patients switched from another Complement C5 inhibitor with a median dosing time of 64 weeks. The most common treatment emergent adverse events (TEAEs) reported (³10%) were COVID-19, upper respiratory tract infection, pyrexia, neutrophil count decreased, headache, and infusion-related reaction. A total of 89/393 (22.6%) of Piasky patients experienced serious adverse events (SAEs) with the most common (≥1%) being COVID-19, Type III hypersensitivity reactions, pneumonia, breakthrough hemolysis and urinary tract infection. A total of eight deaths occurred in Piasky-treated patients in the pooled safety data, which were not deemed related to Piasky treatment.

A total of 12 pediatric patients (>13 years of age and weighing ≥40 kg) were included in the pooled Piasky dataset, and the efficacy and safety profile for Piasky in adolescent PNH patients was consistent with that observed in adult patients.

Adverse event incidence rates and severity were consistent between the Piasky naïve and switch PNH patient population apart from the incidence of Type III hypersensitivity reactions. Events of Type III hypersensitivity reactions, resulting from the formation of Drug-Target-Drug Complexes, were more frequently reported in patients treated with Piasky who switched treatment from another Complement C5 inhibitor vs. naïve patients.

An additional known risk for Complement C5 inhibitors based on their mechanism of action is an increased susceptibility to serious meningococcal infections, especially Neisseria meningitidis. While no incidences of meningococcal infection were observed in the PNH population, all patients must be vaccinated against meningococcal infections prior to, or at the time of, initiating Piasky treatment. The risks associated with Piasky treatment have been labelled and properly mitigated in the product monograph through statements in a serious Warning and Precautions box, and in the Warnings and Precautions section.

An updated Risk Management Plan (RMP) for Piasky was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for Piasky has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

Overall, based on the data evaluated as part of this submission, the benefit-risk profile of Piasky for the treatment of paroxysmal nocturnal hemoglobinuria in adult and adolescent patients 13 years of age and older with a body weight of at least 40 kg, is considered favourable.

For further details about Piasky, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.