Initiation criteria

1. Patients with severe hemophilia A (intrinsic FVIII level < 1%) who are candidates for routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes.

Prescribing conditions

1. The patients must be under the care of a hematologist with experience in the diagnosis and management of hemophilia A.

Pricing conditions

1. The public payer cost of emicizumab should not exceed the public payer cost of treatment with the least costly FVIII replacement that is being reimbursed for the prophylactic treatment of patients with hemophilia A without FVIII inhibitors.

Summary of Patient Input

One patient group, the Canadian Hemophilia Society (CHS), provided input for this submission. Patient perspectives were obtained from personal meetings, conferences, and an online survey conducted between May 31, 2019, and June 15, 2019, for patients with hemophilia A and their caregivers. The following is a summary of key input from the perspective of the CHS:

• Patient input from the CHS highlighted that hemophilia A negatively affects the lives of patients on a physical, psychological, and financial level. The key concerns raised by patients are breakthrough bleeds despite FVIII prophylaxis, damage to joints, venous access challenges, time lost from school and work, and adherence difficulties due to the complex treatment regimen.
• According to the patient input from the CHS, although most patients recognized current treatments as quite effective, most patients and caregivers expressed a clear desire for longer-lasting treatment, more reliable efficacy (i.e., lower risk of breakthrough bleeds), and an easier mode of administration, such as subcutaneous injections instead of IV infusions.
• The CHS suggested that patients with severe hemophilia and those with mild and moderate disease who have a severe phenotype would benefit most from treatment with emicizumab. As well, the CHS believes that the new treatment would greatly benefit infants and children for whom venous access is most difficult, patients who suffer from frequent breakthrough bleeds and joint disease despite FVIII prophylaxis, and patients who have difficulties adhering to the current treatment regimen, which requires frequent IV infusions.

Clinical Trials

The CADTH systematic review included two phase III trials (HAVEN 3, N = 152; HAVEN 4, N = 41).

HAVEN 3 was a 24-week open-label, multi-centre, randomized controlled clinical trial that aimed to evaluate the efficacy of prophylactic emicizumab compared with no prophylaxis in patients with severe hemophilia A without FVIII inhibitors who received prior treatment with episodic or prophylactic factor VIII. Patients who received episodic treatment with FVIII before study entry were randomized in a 2:2:1 ratio to the following emicizumab maintenance dose groups: emicizumab prophylaxis at 1.5 mg/kg weekly, emicizumab prophylaxis at 3 mg/kg every two weeks, and no prophylaxis (control arm). All patients randomized to either of the emicizumab prophylaxis arms received a 3 mg/kg weekly loading dose for four weeks. Patients who received FVIII prophylaxis before study entry (derived from a previous study: the Non-Interventional Study) were enrolled in a separate, non-randomized arm in which they received treatment with emicizumab prophylaxis at 3 mg/kg every week for four weeks, followed by the maintenance dose of 1.5 mg/kg weekly. In HAVEN 3, the primary outcome was the annual bleeding rate ratio for treated bleeds. Secondary outcomes pre-specified in the statistical testing hierarchy included additional bleeding outcomes (annual bleeding rate ratio for all bleeds, treated joint bleeds, treated spontaneous bleeds, treated target joint bleeds) and health-related quality of life (HRQoL) measured with the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) Physical Health.

HAVEN 4 was 24-week open-label, non-randomized, single-arm trial that aimed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab prophylaxis in patients with severe congenital hemophilia A without inhibitors or congenital hemophilia A with FVIII inhibitors. Patients in HAVEN 4 received treatment with emicizumab prophylaxis at 3 mg/kg weekly for four weeks, followed by 6 mg/kg every four weeks. No formal hypothesis testing was performed, and no primary efficacy end point was identified. Analyses for all outcomes (e.g., bleeding outcomes, productivity, and HRQoL) were descriptive.

The key limitations of the body of evidence related to the open-label study design; absence of randomized, direct comparative evidence between emicizumab and FVIII prophylaxis; and generalizability to the Canadian patient population.

Outcomes

Outcomes were defined a priori in CADTH’s systematic review protocol.

Outcomes of HAVEN 3 and HAVEN 4 discussed by the committee included bleeding events, productivity, HRQoL, and patient satisfaction.

Efficacy

Harms (Safety)

In HAVEN 3, adverse events (AEs) occurred in 94.4% of patients in the emicizumab at 1.5 mg/kg weekly group, 85.7% in the emicizumab at 3 mg/kg every two weeks group, 50.0% in the no prophylaxis arm, and 87.3% in the previous FVIII prophylaxis (emicizumab at 1.5 mg/kg weekly) arm. In HAVEN 4, 73.2% of patients treated with emicizumab at 6 mg/kg every four weeks experienced an AE. In both studies, the most common AEs were attributed to injection site reactions. Notable harms identified in the protocol for this review included thrombotic events, injection site reaction, hypersensitivity reactions, inhibitor development, and blood-borne infections. The only notable harms reported in HAVEN 3 and HAVEN 4 were injection site reactions, which occurred in 25.0% of patients in the emicizumab at 1.5 mg/kg weekly group, emicizumab at 20.0% in the 3 mg/kg every two weeks group, 12.5% in the no prophylaxis arm, and 31.7% in the previous FVIII prophylaxis (emicizumab at 1.5 mg/kg weekly) arm. In HAVEN 4, 22.0% of patients treated with emicizumab at 6 mg/kg every four weeks experienced an injection site reaction.

Throughout HAVEN 3 and HAVEN 4, there were no instances of de novo inhibitor development detected in patients who tested negative for inhibitors (titer < 0.6 chromogenic Bethesda unit/mL) at baseline.

In HAVEN 3, serious AEs (SAEs) occurred in 2.8% of patients in the emicizumab at 1.5 mg/kg weekly group, 8.6% in the emicizumab at 3 mg/kg every two weeks group, 0% in the no prophylaxis arm, and 12.7% in the previous FVIII prophylaxis (emicizumab at 1.5 mg/kg weekly) arm. In HAVEN 4, 2.4% of patients treated with emicizumab at 6 mg/kg every four weeks experienced an SAE. No SAEs occurred in more than one patient per arm. No patients died in the studies.

Indirect Treatment Comparisons

In the absence of direct evidence comparing emicizumab and rFVIII prophylaxis, the sponsor conducted an NMA in patients with severe hemophilia A without inhibitors. The NMA compared the efficacy of emicizumab (1.5 mg/kg weekly and 3.0 mg/kg every two weeks) with rFVIIIFc (Elocta/Eloctate), rFVIII (Kovaltry), rFVIII-FS (Kogenate), and rFVIII (Advate) for prophylactic treatment of patients with hemophilia A without inhibitors. The only outcome analyzed was total treated bleeds. The NMA was conducted using a Bayesian framework. Random effects models were chosen as the base case for the total treated bleed outcomes because of various heterogeneity across the five included trials. The between-study variance could not be accurately estimated due to the small number of studies available; therefore, informative priors were used. Total treated bleeds were modelled as a bleed rate and fitted using a generalized linear model with a log link Poisson likelihood. Model inputs included total treatment exposure in person-years and number of bleeding events.

In terms of total treated bleeds, results of the NMA suggest that both emicizumab prophylaxis regimens (1.5 mg/kg weekly and 3.0 mg/kg every two weeks) were associated with a reduction (64% and 69% reduction, respectively) compared with rFVIII prophylaxis in patients with severe hemophilia A without inhibitors.

The NMA was limited by the small number of trials included in the analysis (N= 4 for the base-case analysis). There was a high degree of heterogeneity across the included studies, including the variable severity of hemophilia A, different comparator FVIII products (e.g., long-acting vs. short-acting FVIII) used in different trials. inconsistent or unclear definitions of the bleed outcomes (i.e., the treated bleed), variable outcome estimation time points across trials, and differences in the study design (e.g., randomization vs. partial randomization, blind vs. open label, parallel vs. crossover). In addition, no NMA was performed for safety outcomes, and no evidence for children younger than 7 years old was included in the NMA.

In conclusion, the sponsor-submitted NMA suggested that emicizumab prophylaxis was associated with a reduction of bleed rates compared with FVIII products prophylaxis in the treatment of patients with severe hemophilia A without inhibitors. These results were aligned with those observed in patients previously treated with FVIII prophylaxis (Arm D) in the HAVEN 3 trial. However, due to various methodological limitations, no robust conclusions on the comparative clinical efficacy and safety profile of emicizumab prophylaxis regimens versus rFVIII prophylaxis in patients with hemophilia without inhibitors can be drawn.

Cost and Cost-Effectiveness

The sponsor’s submitted price for emicizumab is $3,661.52 per 30 mg/mL vial, $7,323.04 per 60 mg/0.4 mL vial, $12,815.31 per 105 mg/0.7 mL vial, and, $18,307.59 per 150 mg/mL vial. The recommended regimen is a loading dose of 3 mg/kg for the first four weeks, followed by maintenance treatment with dosage based on the patient’s weight and age. Adolescent and adult patients 40 kg or more can receive 1.5 mg/kg weekly, 3 mg/kg every two weeks, or 6 mg/kg every four weeks; pediatric patients can receive 1.5 mg/kg once weekly or 3 mg/kg every two weeks. At the sponsor’s submitted price, for patients weighing 80 kg, the annual cost of emicizumab is $822,272 in the first year and $763,688 thereafter.

The sponsor submitted a cost-utility analysis comparing emicizumab with FVIII prophylaxis and on-demand use of FVIII prophylaxis in patients with severe hemophilia A without inhibitors. The analysis was conducted from the perspective of the Canadian publicly funded health care system over a lifetime time horizon (98 years; starting age two years). A Markov state-transition model was submitted based on two health states (alive with hemophilia A and death), with a one-year model cycle length. Patients had the risk of dying during each model cycle, dependent on their treatment and their age. Patients alive could experience zero, one, two, or three or more bleeds per year. Annualized bleed rates were sourced from the HAVEN 3 trial. Health state utilities were derived from a de novo time trade-off vignette study conducted on the Canadian general public. Drug acquisition costs for the comparators were sourced from the Patented Medicine Prices Review Board (PMPRB). Other costs (i.e., hospitalization, AEs) were taken from a variety of sources. In the sponsor’s base case, emicizumab was more costly and more effective than FVIII prophylaxis and on-demand FVIII therapy; the ICER of emicizumab was $1.66 million per QALY gained compared to on-demand therapy.

CADTH identified several key limitations with the submitted analysis:

• The model structure does not accurately capture the clinical disease pathway and the effects of treatments appropriately. For instance, rather than employing transition probabilities to describe how patients move between different bleeding strata over time, a fixed proportion was assumed to apply across all time periods.
• The target population of the model (patients with severe hemophilia A without inhibitors) does not reflect the Health Canada indication (i.e., hemophilia A patients of all disease severities) nor the sponsor’s reimbursement requested population (i.e., severe patients, and mild or moderate patients who meet specific eligibility criteria). Furthermore, although HAVEN 3 did not recruit patients younger than 12 years, the sponsor’s base case assumed patients entered the model at the age of two years.
• Comparative treatment efficacy for FVIII prophylaxis was sourced from a non-randomized arm of the NIS trial and, therefore, reflects a naïve clinical comparison.
• Dispensing of treatment was assumed to be at the closest milligram. This does not reflect clinical practice in which treatment is dispensed to the nearest vial size to minimize wastage.
• Treatment-specific utility estimates were applied, which double-counted the utility decrement associated with FVIII prophylaxis.
• The sponsor included the disutility associated with arthroplasty.
• Average patient weight in the model was underestimated, resulting in lower costs of treatment.

CADTH attempted to address some of the identified limitations: changing the patient starting age in the model to reflect HAVEN 3, adjusting dispensing to the nearest vial size, setting the baseline patient utility equal across treatments, attaching a disutility to arthroplasties, and revising patients’ weight to reflect what was observed in HAVEN 3. In the CADTH base case, emicizumab was found to have an ICER of $5.53 million per QALY gained compared to FVIII prophylaxis. A price reduction of at least 89% is required for emicizumab to be considered cost-effective at a willingness-to-pay threshold of $50,000 per QALY. However, a greater price reduction may be required if the price of FVIII products are lower than the PMPRB published values. CADTH was unable to address several of the limitations, including that the evidence directly comparing emicizumab to prophylactic FVIII was limited due to the absence of clinical evidence, and the limitations associated with the model structure. Because the Health Canada indication for emicizumab and the sponsor’s reimbursement request do not align with the modelled population, uncertainty remains to the cost-effectiveness of emicizumab in either population.