Summary Basis of Decision for Winrevair

Clinical Pharmacology

Sotatercept, the medicinal ingredient in Winrevair, is an activin signalling inhibitor that binds to activin A and other transforming growth factor-beta (TGF-β) superfamily ligands. As a result, sotatercept improves the balance between the pro- and antiproliferative signalling to modulate vascular proliferation.

The clinical pharmacology data submitted in support of sotatercept include two pharmacokinetic studies in healthy postmenopausal women and a population pharmacokinetic modelling analysis. The population pharmacokinetic analysis used pooled serum concentration data from the two studies in healthy postmenopausal women and multiple studies in patients with pulmonary arterial hypertension (PAH), including the pivotal Phase III study, STELLAR.

In healthy postmenopausal women, sotatercept exposure increased proportionally with dose following single intravenous doses of 0.01 to 3 mg/kg or single subcutaneous doses of 0.03 to 1 mg/kg. The median time to peak plasma concentration of sotatercept was approximately 7 days after subcutaneous administration. Based on population pharmacokinetic modelling analysis, the pharmacokinetics of sotatercept in healthy participants and patients with PAH was described by a two-compartment model with first-order absorption for subcutaneous dosing. The pharmacokinetic variability of sotatercept was moderate, with a coefficient variation (CV) of approximately 34%. The model-estimated mean clearance was 0.18 L/d, the mean half-life (t_1/2) was 22.5 days, and the mean volume of distribution was 5.3 L (28% CV). The absolute bioavailability of sotatercept following subcutaneous administration was approximately 66%. In patients with PAH following the proposed subcutaneous dose regimen (i.e., a starting dose of 0.3 mg/kg followed by 0.7 mg/kg every 3 weeks [Q3W]), the estimated time to steady state was approximately 15 weeks and the accumulation ratio was approximately 2.2. Despite body weight being identified as a significant covariate for sotatercept pharmacokinetics, sotatercept exposure (as measured by the area under the concentration-time curve [AUC] and the maximum concentration [C_max] at steady state) was not significantly affected by body weight following the proposed body weight-based dosing. Other factors, including age, race, sex, baseline albumin, and renal functions, were not found to have clinically meaningful effects on the exposure of sotatercept. No dose adjustment is deemed necessary.

The pharmacokinetics of sotatercept in patients with PAH with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ranging from 30 to 89 mL/min/1.73m²) was comparable to those in participants with normal renal function (eGFR ≥90 mL/min/1.73m²). Sotatercept has not been studied in patients with severe renal impairment (eGFR <30 mL/min/1.73m²). Studies in non-PAH patients with end-stage kidney disease did not reveal significant impacts of severe renal impairment on the pharmacokinetics of sotatercept. Sotatercept is not dialyzable during hemodialysis.

Sotatercept has not been studied in patients with PAH with hepatic impairment (Child-Pugh Classification A to C).

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

Clinical Efficacy

Data from two Phase II studies and one Phase III study were submitted to support the efficacy of Winrevair in adults with PAH. The Phase III study, STELLAR, evaluated the efficacy of Winrevair versus placebo when added to background PAH therapy for the treatment of PAH. STELLAR was considered pivotal and included a 24-week double-blind placebo-controlled period followed by a long-term double-blind treatment period.

The main study period was the 24-week double-blind placebo-controlled treatment period, during which the primary endpoint was assessed. Eligible patients were adults aged 18 years and older with confirmed World Health Organization (WHO) Group 1 PAH of the following subtypes: idiopathic (iPAH), heritable (hPAH), drug- and toxin-induced (dPAH), PAH associated with connective tissue disorders (CTD), or PAH after pulmonary shunt correction. All enrolled patients had PAH classified as WHO Functional Class II or III. Patients were randomized 1:1 to receive either sotatercept or placebo every 21 days in addition to background therapy. Randomization was stratified by baseline WHO Functional Class (Class II or III) and background therapy (monotherapy, double or triple therapy). The starting dose at Visit 1 was 0.3 mg/kg Winrevair or placebo, followed by 0.7 mg/kg thereafter, subject to the dose modification guidelines contained in the protocol.

Patients had mean age of 47.9 years (range: 18 to 82 years); 13.6% of patients were within the age group of 65 to under 75 years of age and 3.1% were 75 years of age or older. The majority (79.3%) of patients were female, 89.2% were White, 2.2% were Black or African American, and 2.2% were Asian. The median time since PAH diagnosis was approximately 7 years (range: 0.08 to 40.21 years). At baseline, there were 48.6% of patients with WHO Functional Class II PAH and 51.4% with WHO Functional Class III PAH. With respect to the background PAH therapy, four percent (4.0%) of patients were receiving monotherapy (5.5% Winrevair, 2.5% placebo), 34.4% were receiving double therapy (in each arm), and 61.6% were receiving triple therapy (60.1% Winrevair, 63.1% placebo).

In total, 323 patients were randomized (163 to Winrevair, 160 to placebo) and treated with study drug. Eight percent (8.0%) of patients (4.9% in the Winrevair group and 11.3% in the placebo group) withdrew from the study, and 15.5% of patients (6.1% in the Winrevair group and 25.0% in the placebo group) discontinued study treatment. However, 95% of patients completed Visit 9 (at Week 24), at the end of the double-blind, placebo-controlled treatment period.

The median estimate of change in the 6-minute walk distance (6MWD) from baseline to Week 24 was +34.4 m in the Winrevair arm (range: +32.5 to +35.5 m) and +1.0 m in the placebo arm (range: -1 to +5 m). Using the primary analysis method of Hodges-Lehmann location shift, treatment difference (Winrevair vs. placebo) was +40.8 m (95% confidence interval [CI]: 27.53, 54.14; p<0.001) Therefore, a statistically significant improvement in the primary efficacy endpoint was demonstrated in the Winrevair arm as compared with the placebo arm. All sensitivity analyses were consistent with the primary analysis.

Results for the key secondary endpoints supported the primary endpoint analysis. Statistically significant improvements were observed with Winrevair over placebo for Week 24 multicomponent improvement (including prespecified improvements in 6MWD, N-terminal prohormone for brain natriuretic peptide [NT-proBNP], and WHO Functional Classes), change from baseline pulmonary vascular resistance, change from baseline NT-proBNP, proportion of patients with improved WHO Functional Class from baseline, time to death or clinical worsening, proportion of patients maintaining or achieving low-risk French Risk score, and selected disease-specific patient-reported outcomes.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Winrevair (sotatercept) is indicated for the treatment of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to increase exercise capacity, provide clinical improvement, improve WHO functional class, and delay disease progression, including to reduce the risk of death and hospitalization for PAH.	Winrevair (sotatercept) is indicated, in combination with standard pulmonary arterial hypertension (PAH) therapy, for the treatment of adults with World Health Organization (WHO) Group 1 PAH and Functional Class (FC) II or III.

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

Clinical Safety

Based on the results of non-clinical studies and the mechanism of action of sotatercept, thrombocytopenia, thrombotic/thromboembolic events, increased hemoglobin, bleeding events, renal and hepatic toxicity, and embryofetal toxicity were prespecified as adverse events of interest (AEOI) or adverse events of special interest (AESI).

In the pivotal Phase III study, STELLAR, approximately 93% of patients in both the Winrevair arm and the placebo arm experienced treatment-emergent adverse events (TEAEs). However, there were more patients in the Winrevair arm than in the placebo arm that reported adverse drug reactions (50.9% vs. 28.1%), AEOIs (59.5% vs. 44.4%), and AESIs (16.6% vs. 4.4%).

Fewer patients in the Winrevair arm experienced adverse events leading to discontinuation or death, severe adverse events, and serious adverse events. In the safety pool of 321 treated patients, there were two deaths in patients treated with Winrevair related to serious bleeding events (intracranial hemorrhage, gastrointestinal hemorrhage).

Treatment-emergent adverse events reported in more than 5% of patients treated with Winrevair, and which were more common in patients treated with Winrevair than with placebo during the double-blind, placebo-controlled treatment period included epistaxis, telangiectasia, thrombocytopenia, increased hemoglobin, nasal congestion, headache, diarrhea, fatigue, dizziness, hypokalemia, rash, urinary tract infection, and flushing. Cumulative results from the double-blind, placebo-controlled and longer-term periods were generally consistent with those in the 24-week, double-blind, placebo-controlled period.

Treatment with Winrevair should not be initiated in patients with high hemoglobin or low platelet levels. Levels of hemoglobin and platelets should be monitored during treatment and the dosing of Winrevair must be held or reduced if necessary. The Winrevair Product Monograph also includes warnings about the potential for serious bleeding events, particularly in patients receiving concomitant prostacyclin therapy, and about the need for use of contraception due to risk of fetal toxicity.

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

In vitro, sotatercept was demonstrated to bind to and inhibit pathway activation by activin A and many other members of the transforming growth factor-beta (TGF-β) superfamily. In vivo, the murine surrogate for sotatercept produced cardioprotective effects in mouse models of pulmonary arterial hypertension (PAH) disease.

Repeat-dose toxicity studies were conducted in rats and monkeys. The studies with the longest duration, using subcutaneous administration of sotatercept, lasted 3 months in rats and 9 months in monkeys.

Sotatercept was administered to rats once weekly at doses of 0.3, 3, and 30 mg/kg for 3 months, which produce exposures that are 0.4-, 2-, or 18-fold the clinical exposure at the maximum recommended human dose (MRHD), as measured by the area under the concentration-time curve (AUC). Adverse findings included efferent duct/testicular degeneration, adrenal gland congestion/necrosis, and membranoproliferative glomerulonephritis and tubulointerstitial nephritis in the kidneys. The adrenal changes were reversible following a 1-month recovery period. A no-observed-adverse-effect level (NOAEL) could not be determined for this study, as adverse effects were observed at all doses. In a subsequent 3-month toxicity study in rats, with a 1-month recovery period that investigated the same dosing regimen, sotatercept-mediated renal toxicity (occurring at doses of 0.3 mg/kg or higher once per week [Q1W]) was non-reversible and led to chronic progressive nephropathy.

Sotatercept was administered to monkeys at doses of 1, 2.6, and 10 mg/kg once every 4 weeks and 10 mg/kg once every 2 weeks for 9 months. The monkeys developed glomerulonephropathy, interstitial inflammation/fibrosis, and tubular degeneration/atrophy in the kidneys, which were not reversible. One monkey in the high-dose group was moved into the recovery group due to deteriorating clinical condition that was attributed to renal toxicity. Additionally, inflammatory infiltrates were observed in the choroid plexus of the brain. The changes in the brain and kidneys were not associated with immune complex formation/deposition, they occur due to the direct effects of sotatercept. Based on the renal toxicity observed at higher doses, the NOAEL was determined to be 1 mg/kg, which produced exposure equal to the exposure at MRHD based on the AUC.

In a separate study, sotatercept was administered to monkeys at doses of 10, 30, or 50 mg/kg once every 2 weeks for 6 months. Two animals from the mid-dose group (in which sotatercept exposure based on the AUC was 32-fold higher than the exposure at the MRHD) were euthanized following clinical signs of renal failure, with similar renal toxicity confirmed at necropsy. Findings from this study were consistent with those from the 9-month study.

Fertility and early embryonic development studies were conducted in female rats, in which sotatercept was administered subcutaneously at doses of 5, 15, or 50 mg/kg once per week, beginning 2 weeks prior to mating and through gestation Day 7. Two female rats that received the high dose were euthanized during gestation due to hind limb swelling and/or limb impairment. Enlarged and discoloured adrenal glands were observed in females at doses of 15 mg/kg or higher (doses leading to exposures equal to or greater than 9-fold the exposure at the MRHD based on estimated AUC). At these dose levels, female rats also had decreased pregnancy rates, increased preimplantation and postimplantation loss, and reduced live litter size. Increased estrous cycle duration was observed at 50 mg/kg only (exposure equal to 21-fold the exposure at the MRHD, based on estimated AUC). The NOAEL for female fertility and early embryonic development was determined to be 5 mg/kg.

A fertility study was conducted in male rats, in which sotatercept was administered subcutaneously at doses of 0.3, 3, or 30 mg/kg over a 13-week period beginning 10 weeks prior to mating. A subset of animals was examined after a 13-week recovery period. At doses of 0.3 mg/kg or higher (doses leading to exposures equal to or greater than 0.5-fold the exposure at the MRHD based on AUC), non-reversible histologic changes were observed in the efferent ducts, testes, and epididymides. At 30 mg/kg (exposure equal to 20-fold the exposure at the MRHD) a reduction or lack of sperm was observed in the epididymides, along with reversible decreases in fertility. A NOAEL was not determined for this study.

In embryo-fetal developmental toxicity studies, sotatercept was subcutaneously administered to pregnant animals during the period of organogenesis. Sotatercept was administered to rats on gestation days 6 and 13 at doses of 5, 15, or 50 mg/kg (producing exposures equal to 2, 4, and 15-fold the exposure at the MRHD based on AUC, respectively) and to rabbits on gestation days 7 and 14 at doses of 0.5, 1.5, or 5 mg/kg (producing exposures equal to 0.4, 0.6, and 4-fold the exposure at the MRHD based on AUC, respectively). Sotatercept was detected in fetal rabbit plasma, confirming that sotatercept crosses the placenta. Effects observed in both species included reductions in numbers of live fetuses and fetal body weights, delays in ossification, and increases in resorptions and post-implantation losses. In rats only, skeletal variations (increased number of supernumerary ribs and changes in the number of thoracic or lumbar vertebrae) occurred at an exposure 15-fold the human exposure at the MRHD. In rats and rabbits, the NOAELs for developmental toxicity were 5 mg/kg and 0.5 mg/kg, which provided exposures 2-fold and 0.4-fold the exposure at the MRHD based on AUC, respectively.

A pre- and postnatal development study was conducted in rats. Sotatercept was administered subcutaneously at doses of 1.5 or 5 mg/kg on gestation days 6 and 13, or at doses of 1.5, 5, or 10 mg/kg (equal to exposures 0.6-, 2-, and 4-fold the exposure at the MRHD based on AUC, respectively) during lactation days 1, 8, and 15. The maternal NOAEL was 5 mg/kg when administered during gestation, and 10 mg/kg when administered during lactation. No adverse effects were observed in the first filial generation (F1) pups from dams dosed during gestation (the NOAEL was 5 mg/kg, leading to an exposure 2-fold the exposure at the MRHD based on AUC). In F1 pups from dams dosed during lactation, decreases in pup weight correlated with delays in sexual maturation (the NOAEL was 1.5 mg/kg, leading to an exposure 0.6-fold the exposure at the MRHD based on AUC).

No dedicated carcinogenicity, mutagenicity, or genotoxicity studies have been conducted with sotatercept.

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

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

Characterization of the Drug Substance

Sotatercept, the medicinal ingredient in Winrevair, is a recombinant activin receptor type IIA (ActRIIA) fusion protein linked to the human immunoglobulin G1 (IgG1)-Fc domain. The protein functions as a soluble form of ActRIIA to trap transforming growth factor-beta (TGF-β) superfamily ligands. Sotatercept prevents the binding of these ligands to ActRIIA and the induction of Smad2/3 signalling, thereby restoring the balance between the pro- and antiproliferative signalling pathways that lead to pulmonary vascular remodelling and pulmonary arterial hypertension (PAH).

Comprehensive characterization studies were carried out to verify that sotatercept consistently exhibits the expected structure and biological activity essential to its function. The physicochemical, biological and immunological properties, purity, and stability of sotatercept were examined using appropriate analytical procedures and found to be satisfactory.

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

Drug Substance

Sotatercept, the drug substance, is manufactured using recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary (CHO) cells. The cell culture is initiated from a single working cell bank (WCB) vial and expanded to reach commercial scale before the drug substance is harvested. The downstream manufacturing process includes chromatography purification, viral inactivation, multiple filtration steps, filling, and storage at temperatures of -80 °C ± 10 °C.

The sotatercept manufacturing process was validated by the production of consecutive commercial scale drug substance batches within defined process parameter ranges. The process performance qualification (PPQ) study demonstrates that the manufacturing process is capable of consistently manufacturing drug substance of the desired quality.

Drug Product

The drug product manufacturing process consists of drug product formulation, bioburden reduction filtration, sterile filtration, and filling into vials prior to lyophilization, capping, visual inspection, and storage at 2 °C to 8 °C. Labelling and secondary packaging of the vial and/or the co-packaged drug/device combination kit are performed at a different facility.

Process development and validation studies were conducted, and adequate controls are in place for the commercial process. Changes to the drug substance and drug product manufacturing processes and formulation made throughout the process development are considered acceptable upon review.

The prefilled syringe containing sterile water for injection, used to reconstitute the drug product, is prepared by distillation of purified water, filtration for bioburden reduction, in-line filtration, and filling into syringes before terminal sterilization (steam sterilization) and visual inspection. The prefilled syringe sub-assemblies are then assembled, labelled and placed into the co-packaged drug-device combination carton during the packaging process.

The process was validated and found to consistently produce sterile water for injection of the desired quality. The prefilled syringe final assembly process was also validated and it was demonstrated that the fully assembled syringes function as intended. The specifications and methods for sterile water for injection comply with the European Pharmacopeia and ensure the safety of the drug product. All batches met the release acceptance criteria.

Reconstitution and administration of the sotatercept drug product is facilitated by the following components provided in the co-packaged kit: vial(s) of lyophilized sotatercept drug product, vial adaptor(s), prefilled syringe(s) of sterile water for injection, alcohol wipes, a syringe for administration, a safety needle for injection, package insert, and instructions for use. The vial adaptor, syringe for administration, safety needle, and alcohol wipes are commercially available and unaltered when assembled into the kits. The packaging design and configuration were informed by iterative human factors and usability engineering activities throughout development. Functional verification was performed to evaluate the performance of the co-packaged drug-device, and the results indicate that the intended dose can be prepared using the components of the kit.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of sotatercept with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

Winrevair 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.

The drug substance release specifications were established based on product and process understanding, clinical experience, patient safety, stability of the drug substance, and analytical method and process variability considerations. The acceptance criteria are based on statistical assessment of the analytical release and stability data for sotatercept drug substance lots manufactured according to the commercial process. These criteria were suitably justified to ensure safety, identity, strength, potency, and purity of the drug substance. The in-house analytical methods were validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and compendial methods complied with pharmacopeia standards. Analytical bridging data were provided to support comparability of the commercial functional cell-based assay with the cell-based assays used during development. All drug substance batches met the release acceptance criteria.

The process control strategy and control of critical steps were established during manufacturing development and were based on risk assessment, internal quality standards, manufacturing experience and process characterization studies. The PPQ strategy supports validation of the 45 mg and 60 mg drug product manufacturing processes, batch scale range, and equipment. The commercial manufacturing process is consistently controlled by the process parameters within specified ranges and produces drug product that meets the predefined acceptance criteria.

The drug product release and stability specifications were established based on ICH guidelines, product and process knowledge, clinical experience, stability data, and analytical and process variability. All drug product batches met the release and stability acceptance criteria.

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 proposed 36-month shelf life is acceptable when Winrevair is stored between 2 °C to 8 °C and protected from light. The compatibility studies support the proposed in-use shelf life of 4 hours at room temperature for reconstituted sotatercept solution.

Stability studies of the prefilled syringe containing sterile water for injection support the proposed shelf life of 60 months when stored at 2 °C to 32 °C.

Facilities and Equipment

The Swiss Agency for Therapeutic Products (Swissmedic) and Singapore’s Health Sciences Authority (HSA) served as the primary review agencies for this submission, as part of the Access Consortium: New Active Substance Work-Sharing Initiative (NASWSI). Following a peer review of the review reports prepared by Swissmedic and the HSA, an on-site evaluation (OSE) was not recommended to support the review of the New Drug Submission (NDS) for Winrevair, as the additional value of an OSE was determined to be limited.

Adventitious Agents Safety Evaluation

The drug substance and drug product manufacturing processes incorporate adequate control measures to prevent contamination and maintain microbial control.

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