PIASKY Solution for injection Ref.[110563] Active ingredients: Crovalimab

Crovalimab-akkz is a monoclonal antibody that specifically binds with high affinity to the complement protein C5, inhibiting its cleavage into C5a and C5b, preventing the formation of the membrane attack complex (MAC). Crovalimab-akkz inhibits terminal complement-mediated intravascular hemolysis in patients with PNH.

Concentration-dependent inhibition of terminal complement activity following treatment with PIASKY was observed in patients with PNH naïve to complement inhibitor therapy and patients switching from another complement C5 inhibitor therapy. Terminal complement activity (CH50 as measured by Liposome Immunoassay [LIA]) inhibition was achieved by the end of the initial PIASKY infusion and was sustained through the duration of PIASKY treatment. Similarly, mean free C5 concentrations declined to low levels (<0.0001 g/L) in comparison to baseline and remained low throughout the treatment period.

Crovalimab-akkz exhibits dose proportional pharmacokinetics over the dose range from 75 to 1500 mg when given as a single intravenous infusion and from 100 to 1020 mg when given as a subcutaneous injection. Following the first intravenous loading dose, crovalimab-akkz concentrations exceeded the target threshold for complete terminal complement inhibition (100 µg/mL). After approximately 12 weeks, with the administration of subsequent subcutaneous doses, crovalimab-akkz attained a steadystate plateau of exposure. Pharmacokinetic exposures in patients with PNH are summarized for the recommended dosage of crovalimab-akkz in Table 6.

Table 6. Mean (%CV) Pharmacokinetic Parameters of Crovalimab-akkz in Subjects with Paroxysmal Nocturnal Hemoglobinuria:

AUC_τ,ss = area under the concentration-time curve for a dosing interval at steady state; C_max,ss = maximum concentration during a dosing interval at steady state; C_trough,ss = trough concentration at steady state.

Absorption

The mean absorption rate constant is 0.126 day-1 [90% CI: 0.105, 0.176]. Following subcutaneous administration, the bioavailability is 83.0% [90% CI: 69.6, 92.0].

Distribution

The mean central and peripheral volume of distribution is 3.23 L [90% CI: 3.16, 3.29] and 2.32 L [90% CI: 2.02, 2.67], respectively.

Elimination

In PNH treatment-naïve patients, the mean clearance is 0.0791 L/day [90% CI: 0.0678, 0.0872]. The mean estimated terminal half-life is 53.1 days [90% CI: 47.7, 58.6].

Metabolism

Crovalimab-akkz is expected to be catabolized by lysosomal proteolysis into small peptides and amino acids.

Excretion

Crovalimab-akkz is not eliminated via renal or hepatic pathways.

Special Populations

After inclusion of body weight, population pharmacokinetic analyses in patients with PNH showed that age (13-85 years of age), gender, and race (Caucasian, Black, and Asian) did not meaningfully influence the pharmacokinetics of PIASKY. No clinically significant differences in the pharmacokinetics of PIASKY were observed based on renal impairment (mild, moderate, and severe) and mild hepatic impairment. PIASKY has not been studied in patients with moderate or severe hepatic impairment.

Pediatric Patients

Data obtained in PNH clinical studies indicates that exposure in pediatric patients weighing ≥40 kg was consistent with that of adult patients.

Patients Switching from Another C5 Inhibitor

In patients switching from another C5 inhibitor (e.g., eculizumab or ravulizumab), a transient increase in clearance is observed due to the formation of transient immune complexes, leading to a faster elimination of PIASKY. However, this transiently different clearance does not require dose adjustment in patients switching from another C5 inhibitor.

Long-term carcinogenicity studies and genotoxicity studies have not been conducted with crovalimabakkz. No effects on female or male reproductive organs were observed in cynomolgus monkeys following repeated administration of crovalimab-akkz for up to 6 months with subcutaneous doses up to 100 mg/kg/week which corresponds to 18- and 16- times for males and females, respectively, the MRHD based on AUC.

14.1 Paroxysmal Nocturnal Hemoglobinuria

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 2upper 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 6.

Table 6. Demographics and Baseline Characteristics for COMMODORE 2 (Randomized Population):

pRBCs = packed red blood cells
¹ Includes medications that were started prior to initiation of study treatment and were either stopped before or were ongoing at time of initiation of study treatment.

Efficacy was based on hemolysis control, as measured by the mean proportion of patients with LDH ≤1.5 x 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 x ULN after prior reduction of LDH to ≤1.5 x 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 7.

Table 7. Efficacy Results from COMMODORE 2 (Primary Analysis Population):

CI = confidence interval
¹ One patient randomized to PIASKY did not have post-baseline LDH and was not included in the primary efficacy analysis
² Difference calculated as PIASKY minus eculizumab
³ Non-inferiority was demonstrated based on the margin pre-specified in the study protocol
⁴ Odds ratio calculated as odds for PIASKY divided by odds for eculizumab

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; 1317 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; 1517 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 x 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 x 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.