Summary Basis of Decision for Altuviiio

Clinical Pharmacology

Altuviiio (antihemophilic factor VIII [FVIII] [recombinant, B-domain deleted], Fc-VWF-XTEN fusion protein) is a recombinant fusion protein that temporarily replaces the missing coagulation FVIII needed for effective hemostasis.

The terminal plasma half-life of Altuviiio following a single intravenous injection is approximately 3- to 4-fold longer than standard and extended half-life FVIII products, respectively, that are currently authorized and marketed in Canada. Dose proportionality was observed in the tested range of 25 IU/kg to 65 IU/kg with a proposed marketing dose of 50 IU/kg administered once weekly. It was demonstrated that the majority of patients treated with 50 IU/kg retained FVIII activity in the blood at or above 40 IU for 2 to 3 days (approximately 40% of normal FVIII levels) and the mean FVIII activity remained above 10 IU for 6 to 7 days (approximately 10% of normal FVIII levels).

The majority of patients in clinical studies were treated with 50 IU/kg Altuviiio. The Product Monograph for Altuviiio captures a slightly decreased exposure in younger patients; however, it also demonstrates that effective bleeding control is achieved regardless of age. Overall, the clinical pharmacology and pharmacometric analyses identified that the 50 IU/kg dose was appropriate across the age range of patients enrolled in clinical studies.

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

Clinical Efficacy

The efficacy of Altuviiio was evaluated in Study EFC16293, a pivotal Phase III, open-label, multicentre study (see Clinical Safety section). In Arm A, 133 previously treated hemophilia A adolescent (12 to 17 years of age) and adult (18 years of age and older) patients with severe disease (less than 1% of normal FVIII activity) received a 50 IU/kg once-weekly intravenous injection of Altuviiio as a prophylaxis treatment regimen for up to 52 weeks. Supportive data were provided from Study EFC16295, a Phase III, open-label, multicentre study in 74 previously treated male patients less than 12 years of age.

In Arm A, four geographic regions were represented: Europe (67 [50.4%] patients), Asia/Pacific (33 [24.8%] patients), North America (26 [19.5%] patients), and South America (7 [5.3%]). The mean age was 33.9 years (range: 12 to 72 years); 132 were male and 1 was female; 29 (21.8%) were Asian, 3 (2.3%) were Black or African American, 71 (53.4%) were White, 26 (19.5%) were not reported, and 4 (3.0%) were Other. Twelve (9.1%) patients were Hispanic or Latino.

One hundred and twenty-eight patients in Arm A had at least 26 weeks of exposure to Altuviiio and were included in the primary efficacy evaluation set. The primary endpoint was the mean annualized bleeding rate (ABR; estimated from the negative binomial model) for treated bleeds compared to historical treated bleed data. Based on currently marketed FVIII products, mean ABRs during clinical trials typically range from approximately 2 to 5 bleeds per year but can be as high as 6 bleeds per year. Accounting for this variability in clinical bleeding phenotype, adequate protection against bleeds and a clinically meaningful treatment effect was claimed if the upper limit of the one-sided 97.5% confidence interval (CI) of the estimated mean ABR was less than or equal to 6. The key secondary endpoint was an intra-patient comparative analysis for a subset of 78 patients with documented ABRs based on treated bleeds on prior factor IX prophylaxis compared to the ABRs reported following prophylaxis treatment with Altuviiio.

In the primary efficacy evaluation set, routine prophylaxis resulted in a mean ABR of 0.71 (95% CI: 0.52, 0.97) and a median ABR of 0.00 (95% CI: 0.00; 1.04). The upper limit of the one-sided 97.5% CI was 0.97, which was substantially less than the pre-specified value of 6, demonstrating that the weekly prophylaxis treatment regimen with Altuviiio provided highly effective protection against bleeds and clinically meaningful treatment effects. Eighty-two patients experienced no bleeding episodes and 92 patients experienced no joint bleeds. For the key secondary endpoint, an intra-patient comparison demonstrated a 77% reduction in the ABR for treated bleeds (95% CI: 58%, 87%) during routine prophylaxis with Altuviiio compared to pre-study prophylaxis treatment with FVIII.

A similar benefit was reported for previously treated males less than 12 years of age in the supportive Study EFC16295, which included 38 patients less than 6 years of age and 35 patients from 6 to less than 12 years of age. The mean ABR for treated bleeds was 0.5 (95% CI: 0.3, 0.8) in patients less than 6 years of age and 0.8 (95% CI: 0.4, 1.4) in patients 6 to less than 12 years of age. The ABRs were consistent with the results reported for adults and adolescents and support a full indication of Altuviiio in children, adolescents, and adults.

Indication

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

Altuviiio (efanesoctocog alfa), a long-acting recombinant antihemophilic factor (coagulation FVIII) with high sustained FVIII activity, indicated in adults and children with hemophilia A (congenital FVIII deficiency) for:

• Routine prophylaxis to reduce the frequency of bleeding episodes

• On-demand treatment and control of bleeding episodes

• Perioperative management of bleeding.

To support safe and effective use of the product, Health Canada approved the following indication:

Altuviiio (antihemophilic factor VIII [recombinant, B-domain deleted], Fc-VWF-XTEN fusion protein) is indicated in adults, adolescents and children with hemophilia A (congenital factor VIII [FVIII] deficiency) for:

• Routine prophylaxis to prevent or reduce the frequency of bleeding episodes

• Treatment and control of bleeding episodes

• Perioperative management of bleeding (surgical prophylaxis).

Altuviiio is not indicated for the treatment of von Willebrand’s disease

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

Clinical Safety

The clinical safety of Altuviiio in patients with severe hemophilia A disease was primarily evaluated in Arms A and B of the pivotal Phase III, open-label, multicentre Study EFC16293. Supportive data were provided from Study EFC16295, a Phase III, open-label, multicentre study in 74 previously treated male patients less than 12 years of age.

Study EFC16293 enrolled 159 adolescent (12 to 17 years of age) and adult (18 years of age and older) patients with severe hemophilia A disease (less than 1% of normal FVIII activity). In total, 154 (96.9%) patients were treated for at least 26 weeks and 98 (61.6%) patients were treated for at least 52 weeks. Additionally, 152 (95.6%) patients achieved at least 25 exposure days and 115 (72.3%) patients achieved at least 50 exposure days with a median of 53 (range: 2 to 63) for both exposure days and injections per patient. Adverse events were monitored for a total of 151.5 patient-years.

The safety population of Study EFC16293 was represented by four geographic regions: Europe (81 [50.9%] patients), Asia/Pacific (33 [20.8%] patients), North America (26 [16.4%] patients), and South America (19 [11.9%]). Of the 159 patients evaluated, 134 (84.3%) were adults (18 years of age and older) and 25 (15.7%) were adolescents (12 to less than 18 years of age), with a mean age of 35.4 years (range: 12 to 72 years). Additionally, 158 were male and 1 was female; 29 (18.2%) were Asian, 3 (1.9%) were Black or African American, 97 (61.0%) were White, 26 (16.4%) were not reported, and 4 (2.5%) were Other. Twelve (9.1%) patients were Hispanic or Latino.

The most frequently reported (greater than 3% of patients overall) treatment-emergent adverse events (TEAEs) were headache (32 [20.1%] patients); arthralgia (26 [16.4%] patients); fall (10 [6.3%] patients); back pain (9 [5.7%] patients); coronavirus disease 2019 (COVID-19) and fatigue (7 [4.4%] patients each); contusion, haemophilic arthropathy, and nasopharyngitis (6 [3.8%] patients each); and joint injury, pain in extremity, and toothache (5 [3.1%] patients each). The majority of TEAEs were assessed by the investigator as mild in severity and not related to Altuviiio. Subgroup analyses of TEAEs by predefined intrinsic and extrinsic factors were generally consistent with TEAEs in the overall population. No unique patterns or trends were identified in any subgroup.

The results from a supportive Phase III, open-label, multicentre study in 74 previously treated male patients less than 12 years of age were consistent with the safety results observed for Altuviiio in adolescents and adults.

There is the risk of inhibitor development in patients with hemophilia A who are treated with FVIII replacement therapies. However, all patients enrolled in the clinical studies were previously treated patients and therefore had been effectively screened out as patients who were likely to develop inhibitors. An accurate assessment of the risk of inhibitor development with Altuviiio will require future studies in previously untreated patients with newly diagnosed disease. Therefore, the frequency of inhibitor development for this novel FVIII replacement therapy is not known at this time and this is reflected in the Product Monograph for Altuviiio.

Overall, the safety of Altuviiio is consistent with other FVIII replacement therapies. As with other FVIII replacement therapies, the main risks include hypersensitivity reactions during and following intravenous injection, the potential for thromboembolic events, and the loss of efficacy due to the development of alloantibodies (inhibitors) against the infused FVIII product.

Appropriate warnings and precautions are in place in the approved Product Monograph for Altuviiio to address the identified safety concerns.

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

The non-clinical repeat-dose toxicology studies evaluated the intravenous administration of Altuviiio every 3 days in rats and every 4 days in monkeys. Systemic exposure of the test article was confirmed on Day 1 in both species. In the monkey study, increased activated partial thromboplastin time (aPTT) values were observed, likely due to acquired hemophilia resulting from the development of anti-drug antibodies to Altuviiio which cross-reacted to endogenous factor VIII (FVIII) and decreased endogenous FVIII activity. Anti-drug antibody-induced acquired hemophilia resulted in the death of one monkey on Day 30 due to excess bleeding following blood sample collection. Greater group mean aPTT values persisted in females given 750 IU/kg per dose after the recovery period. Although other changes in hematology and clinical chemistry observed at the end of the main and recovery phases occurred sporadically, were of minor magnitude, and lacked histological or organ weight correlates, the possibility of a relationship to Altuviiio could not be ruled out. Based on the adverse findings in the group administered 750 IU/kg per dose, the no-observed-adverse-effect level is considered to be 250 IU/kg per dose. There were no other adverse findings directly attributed to the pharmacologic activity/intended mechanism of action of Altuviiio. Altuviiio was well tolerated and there were no treatment-related changes (macroscopic or microscopic) observed at the site of intravenous administration in any study.

The results of a hemocompatibility study did not show any potential for hemolysis or plasma flocculation following in vitro treatment of human whole blood with Altuviiio.

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

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

Characterization of the Drug Substance

Antihemophilic factor VIII (recombinant, B-domain deleted), Fc-VWF-XTEN fusion protein is a recombinant fusion protein consisting of a single-chain, B-domain deleted human factor VIII covalently linked to the D’D3 domain of human von Willebrand factor via the Fc domain of human immunoglobulin G1 and 2 XTEN unstructured hydrophilic polypeptides (Fc-VWF-XTEN).

Detailed characterization studies were performed to provide assurance that the drug substance 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.

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

The drug substance is manufactured from human embryonic kidney cell line using recombinant deoxyribonucleic acid (DNA) technology. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

The manufacturing process of the drug substance consists of a series of stages which include cell culture, product recovery, purification (including viral inactivation/removal steps). The purification process includes the isolation of inclusion bodies and a combination of chromatographic steps. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

Altuviiio is formulated and aseptically filled into vials, lyophilized, capped, and labelled using conventional pharmaceutical equipment and facilities.

Altuviiio is supplied in 250, 500, 1,000, 2,000, 3,000, or 4,000 IU/vial as a lyophilized powder for reconstitution with 3 mL sterile water for injection in a pre-filled syringe via a sterile vial adapter reconstitution device.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

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 the medicinal ingredient with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines.

Each lot of Altuviiio drug product is tested for appearance, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

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).

Altuviiio 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 proposed 48 month shelf life at 5±3 °C for Altuviiio is considered acceptable, with a short-term sequential storage of up to 6 months at up to 30 °C.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of all facilities and equipment involved in the production are considered suitable.

An on-site evaluation of the facilities involved in the manufacture and testing of the drug substance or drug product was not conducted as it was not considered necessary based on mitigation factors identified as part of a risk assessment conducted by Health Canada.

Adventitious Agents Safety Evaluation

The manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure absence of adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

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