Summary Basis of Decision for Piasky

Clinical Pharmacology

The medicinal ingredient in Piasky, crovalimab, is a recombinant humanized immunoglobulin G1 (IgG1)-based monoclonal antibody. It binds specifically and with high affinity to component 5 of the complement system (C5), blocking the C5 cleavage into subunits C5a and C5b and thus preventing the formation of the membrane attack complex, membrane disruption, and cell lysis.

The pharmacokinetics of crovalimab was characterized by population pharmacokinetic analysis methods using pooled data from patients with paroxysmal nocturnal hemoglobinuria (PNH) who had not been previously treated with a complement inhibitor (treatment-naive patients) and patients with PNH who switched to crovalimab treatment from previous treatment with another C5 inhibitor.

Based on the population pharmacokinetic modelling, the clearance and terminal half-life of crovalimab were estimated to be 0.0791 L/day (90% CI: 0.0678 L/day, 0.0872 L/day) and 53.1 days (90% CI: 47.7 days, 58.6 days), respectively. Body weight was a significant covariate on crovalimab clearances and volumes of distribution. Age was found to affect the absorption rate of crovalimab. Taking into consideration the proposed weight-based, two-tiered dosing regimen of crovalimab in PNH patients, the model estimated comparable exposures in patients with a body weight of 40 kg to less than 100 kg and patients with a body weight of 100 kg or more across the age groups (13 to 17 years of age, 18 to 64 years of age, and 65 years of age and above).

Following the recommended dose and dosing regimen of crovalimab in patients with PNH, the serum concentrations exceeded the target threshold for complete terminal complement inhibition (100 µg/mL) after the first loading dose and throughout the treatment period. Steady-state exposure was achieved approximately 12 weeks after the initial dose. At steady state, the exposure was similar between treatment-naive patients and patients who had switched from another C5 inhibitor to crovalimab.

Based on data from clinical studies, crovalimab exposure in pediatric patients weighing at least 40 kg was consistent with that of adult patients.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). Across three Phase III studies of crovalimab, ADAs were detected in 31.4% of treatment-naive patients with PNH and 23.4% of patients with PNH who switched to crovalimab treatment from previous treatment with another C5 inhibitor. Eleven of 375 (2.9%) ADA-positive patients showed reduced crovalimab exposure and pharmacological activity, and six of these patients had a loss of clinical response (i.e., a loss of hemolysis control). There was no clinically meaningful impact of ADA status on the safety of crovalimab.

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

Clinical Efficacy

The efficacy of Piasky in patients with PNH who have not been previously treated with a complement inhibitor was evaluated in a randomized, active-controlled, open-label, non-inferiority Phase III study (COMMODORE 2).

The study randomized 204 adult patients weighing at least 40 kg in a ratio of 2:1 to receive either Piasky (135 patients) or eculizumab (69 patients). Six pediatric patients over 13 years of age and with a body weight of at least 40 kg were additionally enrolled to receive Piasky in a separate non-randomized cohort of the study. Eligible patients had lactate dehydrogenase (LDH) levels greater than or equal to two times the 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 (two times or greater the ULN to four times the ULN or more than four times the ULN) and by transfusion history (0, greater than 0 to less than 6, or greater than 6 packed red blood cell [pRBC] units administered within 6 months prior to randomization). Demographic and baseline characteristics of the randomized study population were generally balanced between the treatment arms. In the Piasky group, the patients’ mean age at baseline was 40.5 years (range: 18 to 76 years) and 57.0% of patients were male. In the eculizumab group, the patients’ mean age at baseline was 41.9 years (range: 17 to 78 years) and 50.7% of patients were male.

Patients received a single intravenous loading dose of Piasky on Day 1 (1,000 mg for patients weighing 40 kg to less than 100 kg or 1,500 mg for patients weighing 100 kg or more), followed by four additional weekly subcutaneous loading doses of 340 mg on Day 2, Day 8, Day 15, and Day 22. Starting on Day 29, maintenance subcutaneous doses were given every 4 weeks (680 mg for patients weighing 40 kg to less than 100 kg or 1,020 mg for patients weighing 100 kg or more). A 24-week primary treatment period was followed by an extension period in which patients either continued treatment with Piasky or switched to receiving Piasky.

The primary objective of the study was to evaluate the efficacy of Piasky compared to eculizumab, based on the non-inferiority assessment of the following co-primary endpoints:

• The proportion of patients who achieved hemolysis control (defined by LDH levels less than or equal to 1.5 times the ULN, as measured at the central laboratory) from Week 5 through Week 25.

• The proportion of patients who achieved transfusion avoidance from baseline through Week 25 (after 24 weeks on treatment). Transfusion avoidance was defined as patients who were pRBC transfusion-free and did not require transfusion per protocol-specified guidelines.

Key secondary 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 levels greater than or equal to two times the ULN after prior reduction of LDH to less than or equal to 1.5 times the ULN during treatment. Hemoglobin stabilization was defined as avoidance of a decrease in hemoglobin level of greater than or equal to 2 g/dL from baseline, in the absence of transfusion.

Piasky was shown to be non-inferior to eculizumab for the two co-primary endpoints and the key secondary endpoints. The mean proportion of patients with hemolysis control from Week 5 through Week 25 was 79.3% (95% confidence interval [CI]: 72.9%, 84.5%) in the Piasky group and 79.0% (95% CI: 69.7%, 86.0%) in the eculizumab group. There were 65.7% (95% CI: 56.9%, 73.5%) of patients in the Piasky group and 68.1% (95% CI: 55.7%, 78.5%) of patients in the eculizumab groups who achieved transfusion avoidance from baseline through Week 25 (after 24 weeks on treatment).

The clinical development program for Piasky included 12 adolescent patients with PNH aged 13 to 17 years and weighing at least 40 kg. Nine pediatric patients were treatment-naive, two patients switched to Piasky treatment from eculizumab treatment, and one patient switched to Piasky treatment from ravulizumab treatment. All pediatric patients received the same dosing as adult patients based on body weight. Hemolysis control from baseline to Week 25 was achieved in seven of the nine patients who were treatment naïve, and the three patients who switched to Piasky treatment from another C5 inhibitor maintained hemolysis control through 24 weeks of Piasky treatment. Nine of the 12 pediatric patients (six of whom were treatment-naive) achieved transfusion avoidance and hemoglobin stabilization, and no patients had a breakthrough hemolysis event during the 24-week treatment period. Overall, clinically meaningful benefit has been demonstrated in adolescent patients treated with Piasky, consistent with the benefit observed in adults with PNH.

Indication

The New Drug Submission for Piasky was filed by the sponsor with the following proposed indication:

Piasky (crovalimab injection) is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria.

Health Canada revised the proposed indication to reflect the studied population in the pivotal trial. Accordingly, Health Canada approved the following indication:

Piasky (crovalimab for injection) is indicated for the treatment of paroxysmal nocturnal hemoglobinuria in adults and adolescents 13 years of age and older with a body weight of at least 40 kg.

For more information, refer to the Product Monograph for Piasky, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Piasky in patients with PNH was evaluated in a non-inferiority Phase III study (COMMODORE 2, described in the Clinical Efficacy section). Two other Phase III studies (COMMODORE 3 and COMMODORE 1) and one Phase I/II study (COMPOSER) provided additional safety data.

Based on a pooled analysis of 393 patients with PNH who were treated with Piasky across the three COMMODORE studies, the median treatment duration for Piasky was 64.0 weeks (range: 0.1 to 136.4 weeks). Of the 393 patients, 192 patients had not been previously treated with a complement inhibitor (treatment-naive patients) and 201 patients switched to Piasky treatment from previous treatment with another C5 inhibitor (herein referred to as switch patients).

Adverse events were reported in 366 of the 393 (96.1%) Piasky-treated patients. The incidences of adverse events were balanced between the treatment-naive patients (184/192 [95.8%]) and the switch patients (182/201 [90.5%]). The most commonly reported treatment-emergent adverse events (occurring in at least 10% of patients) were coronavirus disease 2019 (COVID-19) (33.3%), upper respiratory tract infection (18.6%), pyrexia (13.5%), decreased neutrophil count (11.2%), headache (10.9%), and infusion-related reaction (10.2%).

Serious adverse events were experienced by 89 of the 393 (22.6%) Piasky-treated patients. The most commonly reported serious adverse events (occurring in at least 1% of patients) were COVID-19 (3.3%), type III hypersensitivity (immune complex-mediated) reactions (2.0%), pneumonia (1.5%), breakthrough hemolysis (1.3%), and urinary tract infection (1.0%). Eight deaths occurred in the Piasky-treated population. The causes of death were subdural hematoma, respiratory tract hemorrhage, myocardial infarction, colorectal cancer, COVID-19, COVID-19 pneumonia, and pneumonia aspiration; one death was due to an unknown cause. All deaths were assessed as not related to Piasky treatment.

Twelve pediatric patients (over 13 years of age and weighing at least 40 kg) and 43 geriatric patients (65 years of age and over) were included in the pooled Piasky-treated population. A consistent safety profile was observed across the age groups. In the pivotal Phase III study COMMODORE 2, the safety profile of Piasky was consistent with that of the active comparator eculizumab.

Importantly, based on the mechanism of action, a known risk of treatment with C5 inhibitors is an increased susceptibility to serious infections caused by encapsulated bacteria, such as Neisseria meningitidis (also known as meningococcus). This risk, along with a requirement for relevant vaccinations or prophylactic antibiotic therapy, is highlighted in a Serious Warnings and Precautions box in the Piasky Product Monograph. Furthermore, Piasky is contraindicated in patients with unresolved Neisseria meningitidis infection.

Crovalimab binds to a different C5 epitope than the other approved C5 inhibitors (i.e., eculizumab and ravulizumab). Consequently, when crovalimab is present in circulation along with either eculizumab or ravulizumab, drug-target-drug complexes can form made of crovalimab, eculizumab or ravulizumab, and C5. Hence, a notable risk for patients switching from another C5 inhibitor to Piasky or vice versa is the development of type III hypersensitivity (immune complex-mediated) reactions due to the transient formation of drug-target-drug complexes. This risk has been included in the Warnings and Precautions section of the Piasky Product Monograph.

For more information, refer to the Product Monograph for Piasky, approved by Health Canada and available through the Drug Product Database.

The medicinal ingredient in Piasky, crovalimab, is a recombinant humanized monoclonal antibody based on a human immunoglobulin G1 (IgG1) framework. The antibody binds with high affinity to component 5 of the complement system (C5) and blocks its cleavage into subunits C5a and C5b, thereby preventing the formation of the membrane attack complex and consequent cell lysis.

The pharmacodynamic studies demonstrated effective binding of crovalimab to human C5 and cynomolgus monkey C5 in a concentration-dependent and pH-dependent manner, supporting the cynomolgus monkey as the only pharmacologically relevant species. In vitro data demonstrated that crovalimab led to a concentration-dependent reduction in hemolysis of antibody-sensitized erythrocytes in both human and cynomolgus monkey sera. In in vivo studies, intravenous or subcutaneous administration of crovalimab resulted in dose-dependent decreases in the 50% hemolytic complement (CH50) activity of serum and free C5, with associated dose-related increases in duration of reduction. Reductions in the CH50 activity of serum and free C5 were reversible over the course of the recovery periods.

The toxicity potential of crovalimab was studied in 5-week and 6-month repeat-dose toxicity studies in cynomolgus monkeys with recovery periods of up to 6 months following the final dose. No toxicologically significant findings were observed following doses up to 100 mg/kg/week administered subcutaneously or 160 mg/kg/week administered intravenously, with the exception of incidental arteritis/periarteritis within several organs associated with immune-complex formation.

In an enhanced prenatal and postnatal development toxicity study in cynomolgus monkeys, weekly subcutaneous crovalimab doses of 10 or 100 mg/kg from gestational Day 20 until parturition were not associated with adverse changes in pregnancy outcome and infant development, including T-cell mediated antibody response in weaned infants. The no-adverse-effect level for maternal and developmental toxicity was 100 mg/kg administered subcutaneously. Mean serum crovalimab concentrations in offspring of pregnant monkeys dosed with crovalimab during gestation were approximately 2% to 7% of mean maternal concentrations throughout the post-dosing period ending on postnatal Day 180. The presence of crovalimab in milk was not assessed. However, given that human IgG1 is known to be excreted in human milk, a risk to a breastfed infant cannot be excluded.

Genotoxicity and carcinogenicity studies were not warranted as per relevant guidelines. Specific juvenile toxicity studies were not conducted based on an acceptable scientific rationale provided by the sponsor.

A margin of exposure of approximately 14 or greater was estimated for all repeat-dose and reproductive and developmental toxicity studies when compared to human adult exposure based on the area under concentration-time curve.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Piasky. In view of the intended use of Piasky, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Product Monograph for Piasky, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Crovalimab is a recombinant humanized monoclonal antibody based on a human immunoglobulin G1 (IgG1) framework. The antibody binds with high affinity to component 5 of the complement system (C5) and blocks its cleavage into subunits C5a and C5b, thereby preventing the formation of the membrane attack complex and consequent cell lysis. Crovalimab consists of two heavy chains (451 amino acid residues each) and two light chains (217 amino acid residues each). Its approximate molecular weight is 145 kDa.

Detailed characterization studies were performed to provide assurance that crovalimab consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits. A risk assessment for the presence of nitrosamine impurities was conducted according to the requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risk of the formation or introduction of nitrosamines during the drug substance and drug product manufacturing processes is considered negligible or low; therefore, no confirmatory testing is required.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Crovalimab is manufactured using a genetically engineered Chinese hamster ovary (CHO) cell line. The cell culture process is initiated with the thawing of a single working cell bank. Cells are expanded through a series of steps and transferred into a production bioreactor. After harvest and clarification of the cell culture fluid, the recovery and purification of crovalimab is achieved through a combination of chromatography, viral inactivation, and filtration steps. Following conditioning to reach the final concentration and composition, the drug substance is sterile filtered into single-use bags and stored frozen at or below-30 °C.

The drug product manufacturing process consists of drug substance thawing, optional pooling of multiple drug substance batches and their mixing, bioburden-reduction filtration, in-line sterile filtration, aseptic filling of vials, stoppering, and capping. None of the non-medicinal ingredients (excipients) in Piasky are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of crovalimab with the excipients is supported by the stability data provided.

The manufacturing process control strategy was established based on quality-by-design principles. A risk-based (risk ranking and filtering) approach was applied to identify critical quality attributes. Appropriate testing was put in place for critical quality attributes at risk of exceeding an acceptable range. Acceptable ranges for critical process parameters were established based on the process characterization, design-of-experiments studies, and validation studies.

The drug substance and drug product manufacturing processes were validated using consecutive commercial-scale batches. The process parameters were maintained within defined limits and all batches met the acceptance criteria and release specifications, indicating that the process is capable of consistently producing drug substance and drug product batches of acceptable quality.

Control of the Drug Substance and Drug Product

The release and stability specifications for the drug substance and drug product were set based on a combination of considerations including clinical experience, product-specific knowledge, formulation development studies, current compendia and regulatory guidelines, and storage/process effects. Adequate justifications have been provided for the established specifications.

The in-house analytical procedures used in the release and stability testing of the drug substance and drug product were appropriately validated.

A two-tiered reference standard program has been established for the drug substance. The primary and secondary reference standards are well characterized and an appropriate protocol is in place for the preparation and qualification of future reference materials.

Piasky is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory.

The shelf life of 36 months at 2 °C to 8 °C for the drug product, when protected from light, is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through stability studies and studies of extractables and leachables.

Facilities and Equipment

Based on a risk assessment performed by Health Canada, on-site evaluations of the drug substance and drug product manufacturing sites were not deemed necessary.

Overall, the design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured. The manufacturing sites are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The manufacturing process of the drug substance incorporates adequate control measures to prevent contamination and maintain microbial control.

Master cell banks, working cell banks, and pre-harvest cell culture fluid undergo thorough testing for detectable adventitious agents (bacteria, fungi, mycoplasma, and viruses). The cell culture process includes in-process tests to monitor for bioburden, endotoxins, mycoplasma, and viruses. Scaled-down viral clearance studies demonstrate that the downstream purification process is capable of inactivating or removing model viruses with diverse physicochemical characteristics.

No raw materials of human or animal origin were used during cell bank preparation, drug substance and drug product manufacturing. Materials of animal origin used during cell line development were properly sourced and tested. Accordingly, the risk of contamination of the drug product with bovine spongiform encephalopathy and transmissible spongiform encephalopathy agents is considered negligible.

The excipients used in the drug product formulation are not of animal or human origin.