Summary Basis of Decision for Afstyla

Clinical Pharmacology

Afstyla is a recombinant protein that replaces the missing coagulation Factor VIII (FVIII) needed for effective hemostasis in congenital hemophilia A patients. Afstyla is a single-chain recombinant FVIII construct where most of the B-domain occurring in wild-type, full-length FVIII is removed. After activation, the Afstyla molecule formed has an amino acid sequence identical to Factor VIIIa formed from endogenous, full-length FVIII. Additionally, the single-chain design results in high-binding affinity of Afstyla to von Willebrand Factor.

The clinical pharmacological data support the use of Afstyla for the specified indication. The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic (PK) studies. The PK of Afstyla was first compared to that of Advate then continued to be assessed in adults and adolescent patients 12 to 18 years of age in Study 1001. The PK of previously-treated children <12 years of age was assessed in Study 3002. The expected increased clearance and decreased half-life was found in the <12 years of age groups. Repeat PK evaluation between 3-6 months showed that the PK parameters were maintained over repeated treatments. The FVIII activity levels determined with the one-stage assay were approximately 45% lower than those determined with the chromogenic assay. This difference was consistently reflected in the PK parameters.

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

Clinical Efficacy

The clinical efficacy of Afstyla was evaluated in a Phase I/III study in adults/adolescents (Study 1001) as well as in a Phase III study in children (Study 3002). The studies determined hemostatic efficacy in the control of bleeding events, the prevention of bleeding events in prophylaxis and in the Phase I/III study determined hemostatic efficacy during perioperative management in patients undergoing surgical procedures.

Study 1001 enrolled a total of 175 previously-treated male patients with severe hemophilia A (<1% endogenous FVIII activity). Patients ranged in age from 12 to 65 years, including 14 adolescent subjects (≥12 to <18 years of age). Of the 175 enrolled patients, 174 received at least one dose of Afstyla and 173 (99%) were evaluable for efficacy. A total of 161 patients (92.5%) completed the study. A total of 120 (69.0%) of the patients were treated for at least 50 exposure days (EDs) and 52 (29.9%) of those patients were treated for at least 100 EDs. Patients received a total of 14,592 injections with a median of 67.0 (range 1 to 395 injections per patient).

The primary efficacy endpoints of Study 1001 along with the results are summarized below:

• The rate of treatment success for bleeding episodes defined as a rating of "excellent" or "good" on the investigator's overall clinical assessment of hemostatic efficacy 4-point scale.
  
  A total of 848 bleeding episodes were treated with Afstyla, of which 835 were evaluated for efficacy by the investigator. The median dose per injection used to treat a bleeding episode was 31.7 IU/kg. The majority of the bleeding episodes were localized in joints. Overall, 93.8% (783 of 835) of treated bleeding episodes with available assessments were assessed by the investigator as "excellent" or "good". Overall, 93.5% of bleeding episodes were controlled with 1 or 2 injections of Afstyla. The efficacy was the same across all regions and age groups.
   
• The annualized spontaneous bleeding rate (AsBR).
  
  A total of 146 patients were in the prophylaxis group and 27 patients were in the on-demand group. Routine prophylaxis with Afstyla reduced the AsBR by 92% and the annualized bleeding rate (ABR) by 90% compared to the on-demand regimen. Across all prophylaxis regimens combined, the median (Q1, Q3) AsBR was 0.0 (0.0, 2.4) and the ABR was 1.14 (0.0, 4.2), compared with an AsBR and ABR of 11.73 (2.8, 36.5) and 19.64 (6.2, 46.5), respectively, in the on-demand regimen.
   
• The rate of treatment success during the surgical substudy. The treatment success was defined as an investigator rating of "excellent" or "good" during the operative and specified post-operative periods in non-emergency surgeries. This rating was defined by a 4-point "efficacy evaluation of surgical treatment scale".
  
  Hemostatic efficacy for surgical prophylaxis was rated by the surgeon as "excellent" or "good" for all 16 surgeries in 13 patients of which at least 10 were considered to be major surgeries.

Study 3002, the pediatric study, enrolled 84 previously-treated male patients with severe hemophilia A (35 patients 0 to <6 years of age and 49 patients ≥6 to <12 years of age). Of the 84 enrolled patients, all received at least one dose of Afstyla and 83 (99%) were evaluable for efficacy. A total of 64 (77.4 %) patients were treated for at least 50 EDs and 8 (9.5%) of those patients were treated for at least 100 EDs. Patients received a total of 5,313 injections with a median of 59 (range 4 to 145 injections per patient). A total of 347 bleeding episodes were treated with Afstyla all of which received an efficacy assessment by the investigator. The majority of the bleeding episodes were localized in joints. The median dose per injection used to treat a bleeding episode was 27.3 IU/kg.

In Study 3002, the primary efficacy endpoint was treatment success, defined as a rating of "excellent" or "good" on the investigator's overall clinical assessment of hemostatic efficacy for all treated bleeding episodes. Overall, 96.3% (334 of 347) of treated bleeding episodes with available assessments were assessed by the investigator as "excellent" or "good". The overall investigator's assessment of hemostatic efficacy was similar in the assessed age groups, with treatment success rate of 94.0% in patients 0 to <6 years and 96.6% in patients ≥6 to <12 years. Overall, 95.7% of the bleeding episodes were controlled with 1 or 2 injections of Afstyla.

For patients on prophylaxis with Afstyla, the ABR was low, with a median value of 3.69 bleeding episodes per patient per year for total bleeding episodes, and 0.00 for spontaneous bleeding episodes. The overall median ABR was lower in the 0 to <6 year old group (2.12) than in the ≥6 to <12 year old group (5.11), but the median AsBR was 0.00 in both age groups. The overall median ABR was lower in prophylaxis patients on a 3 times a week regimen (2.30) than in the patients on a 2 times a week regimen (4.37), although the median AsBR was 0.00 in both regimens.

Overall, the submitted studies support Afstyla for adults and children with hemophilia A for control and prevention of bleeding episodes, for routine prophylaxis to prevent or reduce the frequency of bleeding episodes, and for perioperative management of bleeding. The recommended indication is the same as the indication filed with the submission.

Afstyla was an effective FVIII product for treatment of patients with hemophilia A with the expected PK differences seen in children under the age of 12. The difference in the one-stage clotting assay and the chromogenic assay for monitoring treatment is clearly indicated in the Afstyla Product Monograph. The sponsor committed to a specific communication to make health care providers aware of this difference.

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

Clinical Safety

The clinical safety of Afstyla was evaluated in Study 1001 (174 patients 12-64 years old) and in Study 3002 (84 patients 1-11 years old)

The main safety concern with FVIII products is the production of neutralizing antibodies or inhibitors. All patients in the two studies had been previously treated with a FVIII product and the presence of inhibitors was an exclusion criterion for the studies. This was, therefore, a low risk population for inhibitor formation. There was no formation of inhibitors in either study and further follow-up will be needed to know if this occurs over time. The other adverse events which occurred in both clinical studies were not unexpected for FVIII products and did not occur more frequently than expected.

In Study 1001, the safety population included a total of 174 patients who received at least one Afstyla injection. Of the 174 patients, 120 had more than 50 exposure days (EDs) and 52 had more than 100 EDs to Afstyla. There were 292 treatment-emergent adverse events (TEAEs) of which 19 were related to the study drug. Only 1 treatment-emergent serious adverse event (TESAE) of hypersensitivity was related to the study drug. Common TEAEs included fever, chills, arthralgia, dizziness, and injection site pain. There were 3 hypersensitivity reactions, one considered serious but responded to treatment. There were no deaths. The AEs during the surgical substudy were considered related to the surgical procedure. There was no development of inhibitors or antibodies to Chinese hamster ovary (CHO) cells and no thromboembolic events (TEEs). Non-inhibitory anti-drug antibodies were found in some patients and were followed throughout the study but were not associated with adverse events. There was little change in other laboratory parameters throughout the study.

In the pediatric study, Study 3002, the safety population included 84 patients who received at least one dose of Afstyla in the course of the study. Sixty-five patients had ≥50 EDs, of these 8 had ≥100 EDs. Thirty-eight patients, ≥ to <12 years and 27 patients 0 to < 6 years had greater than 50 EDs. There were 183 TEAEs. Only one mild TEAE of hypersensitivity was considered related to Afstyla. No TESAEs were considered related to Afstyla. The most common TEAEs were nasopharyngitis, arthralgia, cough, and headache. There were no deaths, no inhibitor formation, no CHO antibodies and no TEEs. Ten patients had non-inhibitory anti-drug antibodies which were monitored but none led to a TEAE. Other laboratory parameters had little change throughout the clinical study.

Factor VIII plasma activity can be monitored using either a chromogenic substrate assay or a one-stage clotting assay. Study results showed that the chromogenic substrate assay gave values approximately twice that of the one-stage clotting assay which is most often used to monitor FVIII activity in Canada. This issue has been addressed in the Risk Management Plan. Warnings are provided in the Afstyla Product Monograph.

There have been no inhibitory antibodies in previously-treated patients found to date and adverse reactions particularly hypersensitivity reactions have not been increased. These safety factors support Afstyla for the specified indication and recommendations for use. Appropriate warnings and precautions are in place in the Afstyla Product Monograph to address the identified safety concerns.

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