Summary Basis of Decision for Nuwiq

 

Clinical Pharmacology

Hemophilia A is a rare congenital bleeding disorder occurring predominantly in males, characterized by a deficiency of factor VIII (FVIII), which results in abnormal clot formation, causing prolonged and abnormal bleeding. Bleeding may be life-threatening or result in significant morbidity. Nuwiq is a recombinant human coagulation FVIII product that has been modified to delete the B domain of the protein, which is antigenic but does not contribute to coagulant activity. Nuwiq is used as replacement therapy to increase plasma levels of FVIII, thereby enabling a temporary correction of the factor deficiency and bleeding tendency.

When exogenous FVIII is given to persons lacking FVIII they often develop inhibitory antibodies which neutralize the coagulant activity of both exogenous and intrinsic factors. This may produce a state of resistance to FVIII that can lead to very high dose requirements. Nuwiq was developed to attempt to reduce inhibitor development by modifying intrinsic human FVIII to retain only those sections of the protein molecule essential to the clotting process and by producing the protein in human cell culture.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The incremental in vivo recovery (IVR) for Nuwiq was measured as part of the pharmacokinetics profile and in all clinical studies. The IVR is a measure of the relative increase in plasma FVIII per administered dose. The IVR for Nuwiq was over 2%/IU/kg for adults and remained relatively stable at 3 and 6 months. The clinical pharmacological data support the use of Nuwiq for the specified indication.

Nuwiq has been shown to have pharmacokinetic parameters comparable to other FVIII products and as with other products these parameters may vary with age and body mass index. In particular, the half-life can be shorter in children and doses required to achieve therapeutic target levels may be higher than in adults. Treatment regimens must be designed and monitored with this in mind.

Together, the clinical and pharmacological data support the use of Nuwiq for the treatment and prophylaxis of bleeding in patients of all ages suffering with hemophilia A (congenital factor VIII deficiency).

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

Clinical Efficacy

The clinical efficacy of Nuwiq was assessed primarily in three pivotal multicentre, multinational studies (GENA-08, GENA-01 and GENA-03). All studies assessed the efficacy of Nuwiq in on-demand/breakthrough bleeding episodes (BEs) and surgical prophylaxis, and all studies except GENA-01 assessed efficacy in prophylaxis. Study GENA-03 was a pediatric study in children aged 2 to 12 years. The planned duration of each study was at least 50 exposure days (ED) and at least 6 months. Detailed dosing information for all three studies may be found in the Nuwiq Product Monograph.

Study GENA-08 was a Phase III, open-label, international, multicentre study comprised of 32 previously treated patients (18-75 years of age) with severe hemophilia A. The primary objective of the study was to determine the efficacy of Nuwiq during prophylactic treatment, in the treatment of bleeding episodes (BEs) and in surgical prophylaxis. All patients received prophylactic treatment and five patients had surgery during the study.

Study GENA-01 was a Phase II, randomized, actively controlled, cross-over, open-label, multicentre study comprised of 22 previously treated patients (12-65 years of age) with severe hemophilia A. The primary objective of the study was to determine the pharmacokinetics (PK) of Nuwiq in terms of the FVIII concentrate and to compare it with a licensed full length recombinant FVIII concentrate. This study also assessed efficacy of Nuwiq in the on-demand treatment of BEs and in surgical prophylaxis in previously treated patients (PTPs) with severe hemophilia A.

The GENA-01 study, which evaluated PK as the primary objective, started with a randomized cross-over phase to compare the PK parameters for Nuwiq with those of a comparator product, that of Kogenate FS. In the following efficacy assessment phase, efficacy was analyzed for on-demand treatment and surgical prophylaxis. After three months, all patients underwent an IVR assessment and after six months a second full PK assessment for Nuwiq only. GENA-01 required patients to be followed up for 50 EDs.

Study GENA-03 was a Phase III non-controlled, open-label, multinational, multicentre study comprised of 59 previously treated patients (2-12 years of age) with severe hemophilia A. The primary objective of the study was to determine the efficacy of Nuwiq in terms of prevention and treatment of BEs. The efficacy of Nuwiq in surgical prophylaxis was also assessed in five pediatric patients with severe hemophilia A, who underwent one major surgery each.

The efficacy assessments were based on defined classification criteria for prophylaxis, treatment and surgical prophylaxis, respectively, and were consistent across studies. The efficacy of prophylactic treatment was assessed according to pre-defined objective ranges of the frequency of breakthrough BEs per month:

• Excellent: Less than 0.75 BEs/month;
• Good: 0.75 to 1.0 BEs/month;
• Moderate: 1.0 to 1.5 BEs/month;
• Poor: More than 1.5 BEs/month.

The efficacy for on-demand treatment of BEs was assessed at the end of each BE according to pre-defined criteria, including the number of infusions and improvement in signs of bleeding and pain. Efficacy was rated as follows:

• Excellent: Abrupt pain relief and/or improvement in objective signs of bleeding within approximately 8 hours after a single infusion;
• Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after infusion requiring up to 2 infusions for complete resolution;
• Moderate: Probable or slight beneficial effect within approximately 12 hours after the first infusion requiring more than two infusions for complete resolution;
• None: No improvement within 12 hours, or worsening of symptoms, requiring more than 2 infusions for complete resolution.

The efficacy for surgical prophylaxis was assessed at the end of each surgery and at the end of postoperative prophylaxis, by the surgeon and the haematologist as excellent, good, moderate, or none, according to pre-defined objective criteria for intra-operative and post-operative efficacy, respectively:

Intra-operative efficacy:

• Excellent: Intra-operative blood loss was lower than or equal to the average expected blood loss for the type of procedure performed in a patient with normal haemostasis and of the same sex, age, and stature;
• Good: Intra-operative blood loss was higher than average expected blood loss but lower or equal to the maximal expected blood loss for the type of procedure in a patient with normal haemostasis;
• Moderate: Intra-operative blood loss was higher than maximal expected blood loss for the type of procedure performed in a patient with normal haemostasis, but haemostasis was controlled;
• None: Haemostasis was uncontrolled necessitating a change in clotting factor replacement regimen.

Post-operative efficacy:

• Excellent: No post-operative bleeding or oozing that was not due to complications of surgery. All post-operative bleeding (due to complications of surgery) was controlled with Nuwiq as anticipated for the type of procedure;
• Good: No post-operative bleeding or oozing that was not due to complications of surgery. Control of post-operative bleeding due to complications of surgery required increased dosing with Nuwiq or additional infusions, not originally anticipated for the type of procedure;
• Moderate: Some post-operative bleeding and oozing that was not due to complications of surgery; control of post-operative bleeding required increased dosing with Nuwiq or additional infusions, not originally anticipated for the type of procedure;
• None: Extensive uncontrolled post-operative bleeding and oozing. Control of Post-operative bleeding required use of an alternate FVIII concentrate.

All efficacy data was then assessed by an Independent Data Monitoring Committee (IDMC).

Efficacy in Routine Prophylaxis Treatment

In the pivotal study GENA-08, 32 patients received prophylactic treatment with Nuwiq. Of the 32 patients, 24 had at least 50 EDs and were followed for at least 6 months. Thirty-one patients accumulated more than 50 EDs and the same 31 patients stayed in the study for at least 176 days. The mean prophylactic dose was 32.8 IU/kg and was administered every other day. The overall efficacy of prophylactic treatment was evaluated based on the rate of BEs.

A total of 44 BEs occurred during the study at any time between the start of treatment and the completion visit. Half of the patients (16/32) did not experience any BEs, and more than one third (11/32 patients; 34.4%) experienced only one BE during the study.

In all 32 patients, the overall efficacy of Nuwiq prophylaxis for spontaneous BEs was excellent (<0.75 BEs/month); for all types of BEs, it was excellent in 29 (90.6%) and good (0.75-1.0 BEs/month) in 2 (6.3%) patients. The mean annualized bleeding rate was 2.28 (median 0.9).

One patient had a moderate efficacy for all types of BEs. This patient experienced 7 BEs during the prophylactic treatment period and his overall monthly bleeding rate was 1.2; however, his historical rate before study entry had been 4.0. Moreover, 4 BEs were spontaneous, and the efficacy of prophylactic treatment for spontaneous BEs was rated as excellent.

Efficacy in Control of Bleeding (On-Demand Treatment)

Efficacy of Nuwiq in the on-demand treatment of BEs was assessed in 22 adult and adolescent PTPs with severe hemophilia A (study GENA-01). Of the 22 patients, 17 of these had at least 50 EDs. All patients had at least 150 previous EDs to a FVIII concentrate.

A total of 986 BEs were treated with Nuwiq in this study. The mean on-demand treatment dose was 32.3 IU/kg. Of the BEs treated, 642/986 (65.1%) were spontaneous, 341/986 (34.6%) were traumatic, and 3/986 (0.3%) were due to other causes. In total, 416/986 (42.2%) were minor, 566/986 (57.4%) were moderate to major and 3/986 (0.3%) were major to life-threatening. The severity for one BE was not recorded.

The overall efficacy of on-demand treatment was evaluated based on the criteria noted above which include improvement of objective signs of bleeding, number of infusions required to control the bleeding, and the time until bleeding improvement. Overall, the proportion of BEs with successful treatment (rated as "good" or "excellent") was 94.4% (931/986 BEs) with a 95% Confidence Interval (CI) of 92.8, 95.8. Efficacy was judged as moderate in 5.5% of BEs. In no BE was Nuwiq treatment efficacy judged as "none". The rate of BEs successfully treated with just 1 or 2 infusions was 96.8% (954/986 BEs; CI: 95.4, 97.8). Consequently, as the lower CI for the rate of successfully treated BEs was >70%, on-demand treatment can be claimed efficient. This threshold for efficacy was agreed upon in negotiations between the sponsor and the United States Food and Drug Administration (FDA), and accepted by the EMA and Health Canada.

The efficacy of Nuwiq in the treatment of breakthrough BEs during prophylaxis was assessed in a total of 32 previously treated adults with severe hemophilia A (GENA-08). Of the BEs experienced by patients, a total of 30 BEs were treated with Nuwiq. The mean dose of Nuwiq per infusion for the treatment of breakthrough BEs was 33.3 IU/kg. Efficacy was rated excellent or good in 100% of these BEs and 88.9% were treated with one or two infusions.

Efficacy in Perioperative Management

Across the 2 studies with adults and adolescents (GENA-01 and GENA-08), the efficacy of Nuwiq as surgical prophylaxis was assessed in a total of 7 surgical procedures in 7 adult patients with severe hemophilia A; 5 procedures were classified as major. Efficacy was assessed as excellent in 6/7 (85.7 %) and moderate in 1/7 (14.3%) surgery.

Pediatric Previously Treated Patients

Efficacy of Nuwiq was assessed in a pediatric study (GENA-03) that enrolled 59 children aged 2 to 12 years. Fifty-seven (57) of these patients had at least 50 EDs. All patients had at least 50 previous EDs to a FVIII concentrate. The mean prophylactic dose was 38.9 IU/kg, administrated every other day or 3 times per week. A total of 45.8% (27/59) of the patients did not experience any bleeding while receiving Nuwiq prophylaxis. The annualized median (range) rate of all BEs was 1.9 (0-20.7), with spontaneous BE rates of 0 (0-13.8) and traumatic BE rates of 1.57 (0-18.6). Prophylaxis with Nuwiq was assessed to be excellent or good for spontaneous BEs in 96.6% of the patients, for traumatic in 98.3% and for all BEs 91.5% of the patients.

Efficacy of Nuwiq in the treatment of breakthrough bleeding was rated excellent or good for 82.4% of BEs. One or two infusions were sufficient to treat 81.3% of BEs and the median (range) number of infusions required to stop a BE was 1.0 (range 1-22). The mean dose for breakthrough bleeding treatment was 45.1 IU/kg.

Efficacy of Nuwiq was assessed in 5 pediatric patients with severe hemophilia A, who underwent one major surgery each. Hemostatic efficacy of Nuwiq was rated excellent for all surgeries.

Supportive Studies

Two additional supportive studies, GENA-09 and GENA-04, were provided. These studies were conducted in Russia in a very different population (more severely affected, less well managed) and the results were not felt to be applicable to Canadian medical practice.

Overall Analysis of Efficacy

Nuwiq has been studied in previously treated adults and children (2-75 years). The pivotal studies presented in the submission have been sufficient to comply with the EMA guidance document that was in effect at the time (2009). The studies are small but the nature of the disorder makes this inevitable. The data support the view that the product is as safe and as effective as similar available products currently authorized in Canada for the specified indication.

During the original filing of this New Drug Submission, the sponsor initially sought approval for use in children less than 2 years of age, including newborns, and in hemophilia A patients with known allergic reactions to mouse or hamster protein. Health Canada requested additional information to support the safety and efficacy of Nuwiq in these groups of patients. In response to this request, the sponsor suggested revisions to the indication and Product Monograph to clarify the scope of the data provided. The indication authorized by Health Canada was revised to exclude reference to newborns and patients with demonstrated allergy to mouse or hamster protein because the clinical data provided did not include these groups of patients. The Product Monograph was revised to clarify that clinical studies of Nuwiq did not include children less than 2 years of age, newborns, or patients not previously treated with a FVIII replacement preparation.

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

Clinical Safety

The safety profile of Nuwiq was established based on safety data from the pivotal studies, GENA-08, GENA-01 and GENA-03 (described in the Clinical Efficacy section) in addition to data derived from two supportive studies (GENA-09 and GEN-04). Details of the two supportive studies shall not be presented in this Summary Basis of Decision, given these two studies did not factor heavily in the final decision for the approval of Nuwiq (see Supportive Studies in the Clinical Efficacy section). Nonetheless, safety results obtained from these supportive studies were included as part of the safety profile.

Across these five clinical studies, a total of 135 patients were enrolled and received at least one dose of Nuwiq. Enrolled patients within these studies included previously treated children (2-11 years, n = 58), adolescents (12-17 years, n = 3) and adults (n = 74) with severe hemophilia A. The patients (n = 135) received a total of 32,650,787 IU (549,033 IU/kg) of Nuwiq via 16,134 infusions over 15,950 exposure days (EDs).

A total of 272 adverse events (AEs) in 79 patients were reported. All of these events occurred in patients while receiving treatment with Nuwiq. The most commonly reported AEs was that of infections and infestations, which were recorded for 57 patients.

Twelve of the AEs in 9 patients were classified as serious adverse events (SAEs), one of which resulted in death. For the SAE which resulted in death, this event was a consequence of a pre-existing disorder (epilepsy) unrelated to hemophilia A and deemed not related to Nuwiq. It occurred 48 days after the last administration of Nuwiq. The other 11 SAEs were all unrelated to the treatment, and with the exception of one case of hepatic cirrhosis, all resolved without sequelae.

There were eight ADRs that were classified as possibly or probably related to Nuwiq. These eight ADRs included paresthesia, headache, injection site inflammation, injection site pain, back pain, vertigo, dry mouth, and the development of persistent non-neutralizing anti-FVIII antibodies (only detectable if the sample was tested undiluted). The frequency of each ADR was estimated as uncommon, meaning between 1/100 and 1/1,000.

During conduct of the clinical studies, there was specific monitoring for possible development of neutralizing antibodies (inhibitors) to FVIII, a known complication of the management of individuals with Hemophilia A. These antibodies inhibit the action of the infused FVIII, which results in insufficient clinical response. Inhibitor development is greatest in previously untreated patients (PUPs) during the first 20-50 exposure days (EDs). Across all five studies, a non-neutralizing anti-FVIII antibody was detected transiently in 3/135 patients at any point during treatment, and in one adult patient at the completion visit. The antibodies detected at the completion visit were assumed to be persistent in the absence of data to the contrary. No inhibitory activity was detected in this patient and clinical efficacy of Nuwiq was not affected. Though these antibodies do not bind to coagulant activity sites, they could accelerate degradation/elimination and reduce the effective half-life. At present, this remains a hypothetical concern and there was no evidence for functional impairment of infused FVIIII. As such, as specified in the Nuwiq Product Monograph, all patients treated with Nuwiq should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected FVIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for FVIII inhibitor presence (Bethesda test) should be performed. In patients with high levels of inhibitor, FVIII therapy may not be effective and other therapeutic options, such as immune tolerance induction (ITI), should be considered. Management of such patients should be directed by physicians with experience in the care of hemophilia and FVIII inhibitors.

The immunogenicity of Nuwiq was evaluated in clinical trials in 135 previously treated patients with severe hemophilia A (74 adult and 61 pediatric patients). None of the patients developed inhibitors during the trial period.

As with any intravenous protein product, allergic-type hypersensitivity reactions are possible. Patients must be closely monitored for any suggestive symptoms throughout the infusion period. Hypersensitivity or allergic reactions may include angioedema, burning and stinging at the infusion site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, and wheezing. While these reactions are often rare, in some cases a reaction may progress to severe anaphylaxis (including shock).

Special Populations

Animal reproduction studies have not been conducted with Nuwiq and it has not been used in women. Nuwiq should be used during pregnancy and lactation only if clearly indicated. Hemophilia A is an X-linked genetic condition and as a result FVIII deficiency is very rare in women.

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