Crovalimab-akkz (PiaSky) is a C5 inhibitor that is recycled within the bloodstream and binds with high affinity to the complement protein C5, inhibiting its cleavage into C5a and C5b and preventing the formation of the membrane attack complex (MAC). This action inhibits terminal complement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH), delivering rapid and sustained complement inhibition. The US Food and Drug Administration (FDA) accepted a biologics license application for crovalimab-akkz (PiaSky) in September 2023, leading to its approval in June 2024 for the treatment of PNH in adult and adolescent individuals aged 13 years and older.
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
PNH is a rare condition caused by genetic mutation in the production of red blood cells (RBCs). The mutation causes RBCs to form without terminal complement inhibitors. The absence of complement inhibitors leads to the constant premature destruction and loss of RBCs (hemolysis) by the individual’s own immune system. The premature loss of RBCs can result in anemia, fatigue, difficulty in functioning, dark urine, pain, shortness of breath, and blood clots. Crovalimab-akkz (PiaSky) inhibits RBC mutation and prevents intravascular hemolysis.
RISK EVALUATION AND MITIGATION STRATEGY
Crovalimab-akkz (PiaSky) was approved by the FDA with a risk evaluation and mitigation strategy (REMS) due to the risk of meningococcal infections. Under the REMS, prescribers must enroll in the program, counsel individuals about the risk of meningococcal infection, provide individuals with the REMS educational materials, and ensure that individuals are vaccinated with a meningococcal vaccine.
OFF-LABEL INDICATIONS
There may be additional indications contained in the policy section of this document due to evaluation of criteria highlighted in the company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
PEER REVIEWED LITERATURE
The efficacy of crovalimab-akkz (PiaSky) was evaluated in an active-controlled, open-label, non-inferiority study COMMODORE 2 (NCT04434092) in individuals with PNH. A total of 204 individuals (body weight ≥40 kg) with PNH not previously treated with a complement inhibitor in a 2:1 ratio were randomly assigned to receive either crovalimab-akkz (PiaSky) (n=135) or eculizumab (Soliris) (n=69). The study additionally enrolled six pediatric individuals (aged >12 years and body weight ≥40 kg) to receive crovalimab-akkz (PiaSky) in a separate nonrandomized cohort. The primary efficacy objective of the study was to assess the noninferiority of crovalimab-akkz (PiaSky) compared with eculizumab (Soliris) with respect to the co-primary endpoints of hemolysis control and transfusion avoidance. Secondary endpoints were the proportion of individuals with breakthrough hemolysis (BTH) from baseline through week 25, the proportion of individuals with stabilized hemoglobin from baseline through week 25, and mean change from baseline to week 25 in fatigue assessed in adult individuals aged 18 years or older.
A single intravenous loading dose of crovalimab-akkz (PiaSky) was given on Day 1 (1000 mg for individuals weighing ≥40 kg to <100 kg, or 1500 mg for individuals weighing >100 kg), followed by four additional weekly subcutaneous loading doses of 340 mg on Days 2, 8, 15, and 22. Starting at Day 29, maintenance subcutaneous doses were given every 4 weeks (680 mg for individuals weighing ≥40 kg to <100 kg, or 1020 mg for individuals weighing ≥100 kg). The study consisted of a primary treatment period of 24 weeks, after which individuals had the option to continue or switch to crovalimab-akkz (PiaSky) in an extension period. Eligible individuals had LDH level 2 upper limit of normal (ULN) and at least one or more PNH-related signs or symptoms in the past 3 months. Randomization was stratified by the most recent lactate dehydrogenase (LDH) value (≥2 to ≤4 × ULN, or >4 × ULN) and by the transfusion history (0, >0 to ≤6, or >6 packed red blood cell [pRBC] units administered within 6 months prior to randomization). Crovalimab-akkz (PiaSky) was noninferior to eculizumab (Soliris) for both co-primary endpoints of hemolysis control and transfusion avoidance. The mean proportion of individuals with hemolysis control was 79.3% with crovalimab-akkz (PiaSky) and 79.0% with eculizumab (Soliris). Crovalimab-akkz (PiaSky) was also non-inferior to eculizumab (Soliris) for the secondary endpoints of break-through hemolysis (BTH) and hemoglobin stabilization.The most common infusion-related reaction symptoms were headache (13.3%) and abdominal pain (1.5%) for crovalimab-akkz (PiaSky), and headache (8.7%) for eculizumab (Soliris).
