Summary Basis of Decision for Alhemo

As described above, the New Drug Submission for Alhemo was reviewed as part of the New Active Substance Work Sharing Initiative. Health Canada completed the review of the clinical component of the NDS for Alhemo, with Australia’s Therapeutic Goods Administration reviewing the clinical module independently. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.

Clinical Pharmacology

Concizumab (the medicinal ingredient in Alhemo) is a humanized immunoglobulin G4 (IgG4) monoclonal antibody targeting the human tissue factor pathway inhibitor (TFPI) isoforms TFPIα and TFPIβ. Concizumab binds to the Kunitz-2 domain of TFPI and prevents TFPI from binding to activated Factor X (FXa). The reduced TFPI activity enables FXa to increase thrombin generation and subsequent clot formation, which aids in achieving hemostasis in hemophilia patients.

The clinical pharmacology of concizumab following subcutaneous administration was characterized in multiple Phase I studies evaluating single and multiple doses in healthy subjects and patients with hemophilia A or hemophilia B, and in the main Phase III multiple‑dose study (described in the Clinical Efficacy section) in patients with hemophilia A with inhibitors (HAwI) or hemophilia B with inhibitors (HBwI). Population pharmacokinetic and exposure-response analyses for efficacy were conducted using pooled data from the Phase I, II, and III studies to support the proposed dosing regimen.

Concizumab exhibited non-linear pharmacokinetics, with greater than dose-proportional increases in exposure parameters (the area under the concentration-time curve [AUC] and maximum concentration [C_max]). When concizumab was administered to healthy subjects and patients with hemophilia at doses ranging from 0.05 to 3 mg/kg, the time to maximum concentration (t_max) ranged from 8 to 99 hours. In patients who received a 1 mg/kg loading dose on Day 1 and daily maintenance doses of 0.2 mg/kg starting on Day 2, the population pharmacokinetic analysis indicates that steady state is approximately achieved at Week 4. At Week 24, the geometric mean (coefficient of variation [CV]) steady-state maximum and trough concentrations of concizumab were 1,167.1 (128%) ng/mL and 665.4 (221%) ng/mL, respectively. Exposure levels were slightly lower in adolescents than in adults, and were similar between patients with hemophilia A and B.

The pharmacokinetics of Alhemo has been characterized in patients and healthy volunteers. Following the subcutaneous administration of concizumab at doses ranging from 0.05 mg/kg to 3 mg/kg, the time to maximum plasma concentration (t_max) ranged from 8 hours to 99 hours (4.1 days). Based on population pharmacokinetic modelling, the bioavailability of concizumab was estimated as 77.7%, and the steady-state volume of distribution for a typical subject was 5.92 L. The metabolism of concizumab has not been studied. However, immunoglobulin G antibodies such as concizumab are mainly catabolized by lysosomal proteolysis and then eliminated from or reused by the body. Concizumab is eliminated through both linear and non-linear pathways. Due to its elimination in a non-linear manner, the half-life of concizumab depends on its concentration. Following the subcutaneous administration of concizumab at single doses ranging from 0.25 mg/kg to 3 mg/kg, the terminal half-life ranged from 39 hours (1.6 days) to 195 hours (8.1 days). Following the administration of multiple doses and based on a population pharmacokinetics analysis, the linear clearance of concizumab was approximately 0.192 L/day (0.008 L/h). The estimated half-life at the steady-state trough concentration (C_trough) was approximately 38 hours.

In the main Phase III study, explorer7 (NN7415-4311), the geometric mean (CV%) of free TFPI decreased from 88.3 (20%) ng/mL at baseline to 10.7 (105%) ng/mL at Week 24. The mean thrombin peak increased to normal plasma range.

The exposure-response analysis of annualized bleeding rate indicated near-plateau efficacy at concentrations of approximately 200 ng/mL and above. No covariates were identified in the exposure-response model. Collectively, the pharmacokinetic and pharmacodynamic data, along with the results of pharmacometrics analyses, support the proposed dosing regimen.

No dedicated studies have been conducted to evaluate the effects of hepatic impairment or renal impairment on the pharmacokinetics of concizumab. In the main Phase III study, explorer7, 112 patients were treated with concizumab. Four patients had elevated liver enzymes (defined as alanine transaminase [ALT] or aspartate transaminase [AST] level ≥1.5 × upper limit of normal [ULN]). Five patients had an estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m² at the time when the loading dose was administered. No impact was observed on the exposure of concizumab.

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

Clinical Efficacy

The clinical efficacy of Alhemo was demonstrated in the Phase III study explorer7 (NN7415-4311), which was designed to evaluate the safety and efficacy of Alhemo for routine prophylaxis in hemophilia A patients with inhibitors (HAwI) and hemophilia B patients with inhibitors (HBwI) who were 12 years of age or older. Patients were randomized in a 1:2 ratio to receive either on-demand treatment with bypassing agents (Arm 1, 19 patients) or daily prophylactic treatment with Alhemo (Arm 2, 33 patients). Two additional treatment arms, Arms 3 and 4, enrolled non-randomized patients treated with Alhemo who were included in the overall safety assessment of Alhemo.

Patients randomized to the Alhemo treatment arm (Arm 2) were initially treated with 1 mg/kg Alhemo on Day 1, followed by a daily maintenance dose of 0.25 mg/kg starting on Day 2. However, the study was paused in March 2020 due to thromboembolic events associated with Alhemo. After implementing changes in the protocol, the study resumed in August 2020. Twenty-nine of the 33 patients randomized to Arm 2 continued participation in the study. Following the study pause, patients were treated with the same 1 mg/kg loading dose on Day 1, and a lower daily maintenance dose of 0.2 mg/kg starting on Day 2. Plasma concentrations of concizumab were measured at or around Week 4. For patients with a plasma concentration between 200 and 4,000 ng/mL, the daily maintenance dose remained at 0.20 mg/kg. For patients with plasma concentrations lower than 200 ng/mL, the dose was adjusted to 0.25 mg/kg, and for patients with plasma concentrations greater than 4,000 ng/mL, the dose was adjusted to 0.15 mg/kg.

The efficacy results reported for Alhemo-treated patients were based on data obtained after the study pause with the modified dosing regimen. The primary efficacy outcome measure was the effect of Alhemo prophylaxis compared to no prophylaxis (i.e., on-demand treatment with bypassing agents) in reducing the annualized bleeding rate (ABR) for treated spontaneous and traumatic bleeds in adult and adolescent patients with HAwI or HBwI. An overall benefit was reported for Alhemo prophylaxis versus on-demand treatment. The ABR (for treated spontaneous traumatic bleeds) was 11.8 in patients randomized to on-demand therapy (control) and 1.7 for patients randomized to Alhemo prophylaxis. The observed reductions in the rate of bleeds for Alhemo versus on-demand therapy were statistically significant and clinically meaningful.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Alhemo (concizumab injection) is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages 12 years and older with: hemophilia B (congenital factor IX deficiency) with factor IX inhibitors.	Alhemo (concizumab injection) is indicated for the treatment of adolescent and adult patients (12 years of age or older) with hemophilia B (congenital factor IX [FIX] deficiency) who have FIX inhibitors and require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

In addition to rewording the proposed indication, Health Canada included a caveat statement highlighting the limited experience regarding the use of Alhemo in patients known to have mild or moderate hemophilia B (i.e., in whom the FIX activity is higher than 2% of normal levels).

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

Clinical Safety

The clinical safety of Alhemo was demonstrated in the Phase III study, explorer7, which is described in the Clinical Efficacy section.

The two key adverse reactions identified for Alhemo are thromboembolic events and hypersensitivity reactions. The clinical development of Alhemo was paused from March to August 2020 due to 5 thromboembolic events in 3 patients. The Alhemo Product Monograph therefore highlights the risk of thromboembolic events in a Serious Warnings and Precautions box and includes guidelines regarding when this product should be used and how to monitor for these events. Hypersensitivity reactions were also reported during the clinical development of Alhemo, including one patient requiring hospitalization. Five hypersensitivity reactions were reported across the clinical development, including two from the main study.

Injection site reactions were the most common adverse reactions associated with Alhemo. Most reactions were mild or moderate in severity. In some instances, these led to the more serious and complicated hypersensitivity reactions described above. Other events possibly associated with Alhemo included arthralgia, infections, headaches, and pyrexia; the majority of these events were reported as mild or moderate in severity.

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). A reduction or loss of Alhemo activity was reported in two patients, which is possibly related to neutralizing antibodies against concizumab. This information has been added to the Alhemo Product Monograph.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Alhemo, and to promote its safe and effective use. Overall, the benefit-risk profile of Alhemo is acceptable for the intended patient population. 

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

As described above, the New Drug Submission for Alhemo was reviewed as part of the New Active Substance Work-Sharing Initiative. The Swiss Agency for Therapeutic Product (Swissmedic) completed the review of the non-clinical component of the NDS for Alhemo. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.

Non-clinical safety studies were conducted in cynomolgus monkeys, which were chosen due to the cross-reactivity of concizumab to monkey tissue factor pathway inhibitor (TFPI). Concizumab was administered to male and female cynomolgus monkeys by weekly intravenous injections for up to 26 weeks, and by daily subcutaneous injections for up to 52 weeks. Evaluations of safety pharmacology endpoints (relating to the function of the central nervous system, cardiovascular system, and respiratory system), fertility endpoints (testicular size, sperm functionality, or menstrual cycle duration) and cytokine release were included in the general toxicology studies.

Across the toxicology studies, the pharmacology-mediated formation of thrombi was observed in the lungs, heart, and other organs in the animals at higher doses (≥1 mg/kg/day). These observations are consistent with the risk of thromboembolic events reported in patients treated with Alhemo. In the 52-week toxicology study with subcutaneous administration of 0.5, 1, and 9 mg/kg/day (corresponding to 85-, 310-, and 4,400-fold the human exposure based on the area under the concentration-time curve from 0 to 24 hours [AUC_0-24h]), the no-observed-adverse-effect level (NOAEL) was 0.5 mg/kg/day.

A number of observed findings were consistent with the expected pharmacology of concizumab (i.e., activation of the coagulation system). These included increases in coagulation markers (i.e., D-dimers and thrombin-antithrombin) occurring 24 hours after the first dose and decreases in fibrinogen starting after repeat dosing. At subcutaneous doses of ≥3 mg/kg/day (resulting in exposures ≥630-fold the human exposure based on AUC_0-24h), there were slight and occasional prolongations in clotting time parameters (i.e., activated partial thromboplastin time and prothrombin time), and/or a decrease in platelet counts.

Long-term studies in animals to evaluate the carcinogenic potential of concizumab have not been performed. No studies have been performed to establish the genotoxic potential of concizumab.

No data are available regarding the potential adverse effects of concizumab on embryo-fetal development. This is considered acceptable, as nearly all patients with hemophilia are male. Although no dedicated reproductive and developmental toxicology studies were conducted, no adverse effects were observed on fertility and no changes were detected in male or female reproductive organs in a 26‑week toxicity study in cynomolgus monkeys administered doses up to 9 mg/kg/day.

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

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

As described above, the New Drug Submission (NDS) for Alhemo was reviewed as part of the New Active Substance Work-Sharing Initiative. Health Canada completed the review of the quality component of the NDS for Alhemo. Although the agencies collaborated on the review of the submission, each agency made its regulatory decision independently.

Characterization of the Drug Substance

Concizumab, the drug substance, is a humanized immunoglobulin G (IgG) antibody. Detailed characterization studies were performed to provide assurance that concizumab consistently exhibits the desired characteristic structure and biological activity. The results of the studies indicate that the drug substance has the expected primary and higher order structure, and the observed biological activities are consistent with the proposed mechanism of action.

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

Concizumab, the drug substance, is expressed from Chinese hamster ovary (CHO) cells, which have been engineered to express this protein through recombinant deoxyribonucleic acid (DNA) technology. After the cell culture expansion to commercial scale, concizumab is purified through a series of chromatography, viral inactivation, and filtration steps. The drug substance is partially formulated, and then stored at ‑80 °C ± 10 °C.

Manufacturing of the drug product, Alhemo, involves formulation, sterile filtration, and filling steps. The manufacturing process is the same for all three concentrations of the drug product.

Critical steps in the drug substance and drug product manufacturing processes were identified during development. Criticality was based on the potential to impact product quality and/or process performance. The results of validation studies reflected consistency in both the drug substance and drug product manufacturing processes.

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

Control of the Drug Substance and Drug Product

Alhemo 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. For post-approval monitoring, Alhemo has been assigned to Lot Release Group 4. It is considered a low-risk product, as concizumab is well characterized and any significant issues from the submission have been resolved. The risk level associated with a drug product is determined by factors including the nature of the product, its indication and target patient population, and the manufacturer's production and inspection history.

The results of consistency tests for Alhemo support the suitability of the chosen analytical methods for their intended purpose.

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 at 2 °C to 8 °C for Alhemo is considered acceptable, including an in-use period of up to 28 days during which the drug product must be stored below 30 °C.

Facilities and Equipment

Based on risk assessment scores determined by Health Canada, on-site evaluations (OSEs) were not recommended for either the drug substance or drug product manufacturing sites.

Adventitious Agents Safety Evaluation

The risk of introducing adventitious agents into the manufacturing process of Alhemo is mitigated through the control of raw materials, facilities, and manufacturing processes, viral testing of the cell banks and the unprocessed bulk, and the viral clearance capacity of the purification process.

The concizumab drug substance is manufactured without any materials of human or animal origin. The master and working cell banks were prepared using chemically defined media without any human-derived or animal-derived components. The master and working cell banks were evaluated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and found to be free of viral and non-viral contamination.

Viral clearance studies were performed using scale-down models and model viruses representing a range of physicochemical properties, as recommended in ICH guidelines. Viral inactivation or clearance studies were performed in duplicate, and the worst-case clearance outcome selected as the clearance factor for each step. Based on the results of the viral clearance studies, the proposed strategy was found to be capable of consistently reducing viral contamination to levels below the acceptable limits.