The efficacy of PIASKY in patients with PNH was evaluated in COMMODORE 2 (NCT04434092), an active-controlled, open-label, non-inferiority study that randomized 204 patients (body weight ≥ 40 kg) with PNH not previously treated with a complement inhibitor in a 2:1 ratio to receive either PIASKY (n=135) or eculizumab (n=69). The study additionally enrolled 6 pediatric patients (aged >12 years and body weight ≥ 40 kg) to receive PIASKY in a separate non-randomized cohort.

Patients were required to be vaccinated against Neisseria meningitidis, either within 3 years prior to the start of treatment or within 7 days after starting treatment with PIASKY. Patients vaccinated within 2 weeks prior to initiating PIASKY or after the start of study treatment received prophylactic antibiotics until at least 2 weeks after the vaccination.

A single intravenous loading dose of PIASKY was given on Day 1 (1,000 mg for patients weighing ≥40 kg to <100 kg, or 1,500 mg for patients 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 patients weighing ≥40 kg to <100 kg, or 1,020 mg for patients weighing ≥100 kg).

The study consisted of a primary treatment period of 24 weeks, after which patients had the option to continue or switch to PIASKY in an extension period.

Eligible patients 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 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). In the PIASKY and eculizumab arms, the median PNH clone size was 90.9% and 95.1% for monocytes, 91.4% and 93.6% for granulocytes and 25.3% and 44.6% for erythrocytes, respectively.

Demographics and baseline characteristics of the randomized study population were generally balanced between the treatment arms and are presented in Table 7.

Efficacy was based on hemolysis control, as measured by the mean proportion of patients with LDH ≤ 1.5× ULN from Week 5 to Week 25; and the proportion of patients who achieved transfusion avoidance, defined as patients who were pRBC transfusion-free, from baseline through Week 25. Other efficacy endpoints included the proportion of patients with breakthrough hemolysis and the proportion of patients with stabilized hemoglobin. Breakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥ 2 × ULN after prior reduction of LDH to ≤ 1.5 × ULN on treatment. Hemoglobin stabilization was defined as avoidance of a ≥ 2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion.

Efficacy results for these endpoints are shown in Table 8.

Pediatric Population with PNH Treated with PIASKY

Efficacy was evaluated in 12 pediatric patients (with body weight ≥ 40 kg) treated with PIASKY in COMMODORE 2 (n=7; 13–17 years old), COMMODORE 1 (n=2, 13 – 16 years old) and in a single arm study in patients who were complement-inhibitor naïve, COMMODORE 3 (NCT04654468; n=3; 15–17 years old).

Nine pediatric patients were treatment-naïve, two patients switched from standard dose eculizumab and one patient switched from ravulizumab. Six pediatric patients were females and six were males. Nine patients were Asian, two were White and for one pediatric patient the race was unknown. The proportion of patients with a history of transfusions in the prior 12 months was 58%, with a median number of 1.3 pRBC units (range: 0-40.5) transfused, and a baseline median LDH of 6.4 × ULN (range 1.1-26.6). Aplastic anemia was reported in 50% of patients. All pediatric patients received the same dosing as adult patients based on body weight [see Dosage and Administration (2.2)]. Hemolysis control (defined as LDH ≤1.5 × ULN) from baseline to Week 25 was achieved in 7 of the 9 patients who were treatment-naïve, and the 3 patients switching from eculizumab or ravulizumab to PIASKY maintained hemolysis control through 24 weeks of PIASKY treatment. Nine (six patients who were treatment-naïve and three patients who switched from eculizumab or ravulizumab) out of the 12 pediatric patients achieved transfusion avoidance and hemoglobin stabilization, and no patients had a breakthrough hemolysis event during the 24-week treatment period.

Overall, the treatment effect of PIASKY in pediatric patients with PNH was consistent with that observed in adults with PNH.