What are the conditions for reimbursement?

Enspryng should only be reimbursed if the price is reduced by 80% to 89%.

Which patients are eligible for coverage?

Enspryng should only be covered to treat patients who are aged 12 years and older and have NMOSD that is anti–aquaporin 4 (AQP4) positive. Patients must have had at least 1 relapse of NMOSD in the 12 months before initiation despite an adequate trial of other accessible preventive treatments for NMOSD, or the patient cannot tolerate other preventive treatments for NMOSD. Patients must have an Expanded Disability Status Scale (EDSS) score of 6.5 points or less.

Why did CADTH make this recommendation?

Evidence from 2 clinical trials demonstrated that Enspryng, alone or in combination with immunosuppressants, reduces the frequency of NMOSD relapses compared with placebo. Enspryng is not cost-effective at the submitted price.

What is NMOSD?

NMOSD is a rare, debilitating, immune-related disorder of the central nervous system. People with NMOSD experience acute attacks or relapses that cause damage to the optic nerves and spinal cord, which can result in limited mobility, paralysis, blindness, or death. The incidence of NMOSD ranges from 0.053 to 0.40 per 100,000 people, and the prevalence ranges from 0.51 to 4.4 per 100,000 people.

What is Enspryng?

Enspryng is approved by Health Canada for use alone or in combination with immunosuppressive therapy for the treatment of NMOSD in adolescent and adult patients who are anti-AQP4 positive. It is a medication (antibody) that blocks the effects of interleukin, a protein that plays a key role in the inflammation in the nervous system of people with NMOSD.

How much does Enspryng cost?

Treatment with Enspryng is expected to cost approximately $132,300 per patient in the first year and $122,850 per patient in subsequent years.

What other treatments are available for NMOSD?

Immunosuppressants, immunomodulators, and corticosteroids are available for the prevention of NMOSD relapses.

Unmet needs in NMOSD

Most of the currently available medications for the prevention of NMOSD relapses are not specifically approved for this use and are associated with numerous adverse effects that patients with NMOSD find difficult to tolerate. Despite several available medications, there remains a need for drugs that are effective in preventing relapses of NMOSD and have minimal adverse effects.

How much do other treatments cost?

Soliris, Rituxan, Actemra, azathioprine, and mycophenolate mofetil cost $701,168, $10,173, $184,262, $246 to $369, and $541 to $6,805, respectively, per patient per year.

Summary of Patient Input

The Multiple Sclerosis Society of Canada provided input for this submission. Patient perspectives were obtained from an online survey that received responses from 37 people, including 25 respondents (68%) who had been diagnosed with NMOSD. The following is a summary of key input from the perspective of the patient group:

• NMOSD is a severe and debilitating autoimmune disease characterized by relapses that may result in permanent and life-changing neurological deficits. Patients with NMOSD report experiencing pain, muscle weakness, paralysis, loss of vision, and bladder or bowel control problems caused by relapses. The accrued disability leads to employment instability or loss, increased need for assistance or caregiving, loss of independence, isolation, cognitive decline, and increased mobility challenges.
• There is a need for safe and effective relapse-prevention treatments for patients with NMOSD, as early intervention to eliminate relapses is key to averting disability and improving longer-term outcomes for patients.
• Patients hope that satralizumab will reduce attacks and disability and allow patients to self-administer their therapy at home. Treatment with satralizumab has the potential to allow people living with NMOSD to remain in the workforce, sustain family and social roles and responsibilities longer, improve their quality of life, and decrease the need for family or paid caregivers.

Clinical Trials

The systematic review included 2 double-blind RCTs of patients with neuromyelitis optica (NMO) or NMOSD (Study 898 and Study 900). Patients were randomized to placebo or satralizumab 120 mg subcutaneous injection at weeks 0, 2, and 4 and every 4 weeks thereafter.

Study 898 enrolled 83 adults and adolescents (12 years to 74 years of age), of whom 55 (66%) were AQP4 antibody positive (i.e., the indicated population). The patients enrolled had at least 2 relapses in the past year (1 of which occurred in the last 12 months) and all received background immunosuppressant treatment of azathioprine, mycophenolate mofetil, or corticosteroids during the trial. Study 900 enrolled 95 adults, aged 18 to 74 years, who had at least 1 relapse in the past year, including a first attack. The AQP4 antibody–positive subgroup included 64 patients (67%). Both were event-driven trials that were designed to stop once 26 primary outcome relapse events were reported (in Study 898) or when 44 primary outcome relapse events had occurred or 1.5 years after the last patient was randomized (in Study 900). The median treatment duration was 33 weeks and 107 weeks for Study 898, and 55 weeks and 92 weeks in Study 900, for the placebo and satralizumab groups, respectively.

The review of the evidence focused on the results in the AQP4 antibody–positive subgroup because this is the indicated population in Canada.

Outcomes

Outcomes were defined a priori in CADTH’s systematic review protocol. Of these, the committee discussed the following:

• Occurrence of relapses of NMOSD, measured in the studies as time to first protocol-defined or clinical relapse. A protocol-defined relapse was any new or worsening neurological symptom attributable to NMO or NMOSD that persisted for a minimum of 24 hours that was not attributable to confounding clinical factors and met the predefined criteria for a change in EDSS or Functional System Score (FSS) score. All events were confirmed by a blinded, independent adjudication committee. A clinical relapse was defined as any relapse reported by the investigator without adjudication.
• Changes in pain measured using a VAS.
• Changes in fatigue symptoms based on FACIT-F scores. The FACIT-F scale is a 13-item questionnaire that measures a patient’s level of daily fatigue over the past week. The total ranges from 0 to 52, where 0 is the worst possible score and 52 the best score (less fatigue).
• Changes in disability measured with the EDSS and the modified Rankin Scale. The EDSS is a quantitative measure of disability that is based on a standard neurological examination. It is an ordinal scale that ranges from 0 points (normal neurological examination) to 10 points (death) which increases in half-point increments once an EDSS of 1.0 has been reached. EDSS steps 1.0 to 4.5 refer to people who are fully ambulatory, and steps 5.0 to 9.5 are defined by impairment to ambulation. The modified Rankin Scale is a clinician-reported scale for measuring the degree of disability or dependence in the daily activities of people who have suffered from a neurological disability. The scale ranges from 0 (no disability) to 6 (death).
• Changes in health-related quality of life measured using the Short-Form (36) Health Survey (SF-36) and the EuroQol 5-Dimension (EQ-5D) instruments.
• Harms.

The primary outcome in both trials was the time to first adjudicated, protocol-defined relapse for the intention-to-treat (ITT) population.

Efficacy

For the AQP4 antibody–positive subgroup in Study 898, 43% of patients in the placebo plus immunosuppressant group and 11% in the satralizumab plus immunosuppressant group experienced an adjudicated, protocol-defined relapse, with an HR of 0.21 (95% CI, 0.06 to 0.75; P = 0.0086 not controlled for type I error). In the AQP4 antibody–positive subgroup of Study 900, 57% of patients in the placebo group and 22% in the satralizumab group experienced a protocol-defined relapse, with an HR of 0.26 (95% CI, 0.11 to 0.63; P = 0.0014 not controlled for type I error). These differences were considered clinically meaningful based on clinical expert input.

In the AQP4 antibody–positive subgroup of Study 898, 68% of patients in the placebo group and 41% in the satralizumab group had a clinical relapse (HR = 0.53, 95% CI, 0.25 to 1.12; P = 0.092 not controlled for type I error). For this subgroup in Study 900, 61% and 46% of patients in the placebo and satralizumab groups, respectively, experienced a clinical relapse, with an HR of 0.51 (95% CI, 0.25 to 1.03; P = 0.056 not controlled for type I error).

Results suggest a reduction in the annualized relapse rate (ARR) for satralizumab versus placebo in Study 898 (ARR ratio = 0.3, 95% CI, 0.1 to 0.8; P = 0.018 not adjusted for type I error), but not for Study 900 (ARR ratio = 0.3; 95% CI, 0.1 to 1.1; P = 0.067 not adjusted for type I error rate). These results were only considered supportive of the effects of satralizumab on relapses because the ARR was reported for the full ITT population only and not for the AQP4 antibody–positive subgroup, and patients were censored at the time of their first relapse and subsequent relapses were not captured, thereby likely underestimating the ARR.

No statistically significant differences were detected between groups for the change from baseline to week 24 in pain VAS score or FACIT-F scores for the full ITT populations in both studies (key secondary outcomes). Pain and fatigue data for the AQP4 antibody–positive subgroup were similar to the results in the overall study populations.

The trials did not report health-related quality of life or disability outcomes for the AQP4 antibody–positive subgroup. No differences were found between groups based on the ITT population in either study for the change from baseline in EDSS score, modified Rankin Scale score, visual acuity, EQ-5D, or SF-36.

Harms (Safety)

The percentage of patients who experienced an adverse event ranged from 75% to 95% in the placebo groups and from 90% to 92% in the satralizumab groups. After adjusting for follow-up time, the rate of adverse events was 495 events to 514 events per 100 person-years (PY) among those assigned to the placebo, and from 474 events to 485 events per 100 PY for those who received satralizumab.

The most common adverse events were urinary tract infections, upper respiratory tract infections, headache, nasopharyngitis, and injection-related reactions. The rate of infections ranged from 150 events to 163 events per 100 PY among those randomized to the placebo, and from 100 events to 133 events per 100 PY to those who received satralizumab.

Serious adverse events were reported in 16% to 21% of patients assigned to the placebo and 17% to 19% of patients who received satralizumab, with a serious adverse event rate of 15 events to 20 events per 100 PY and 12 events to 17 events per 100 PY in the placebo and satralizumab groups, respectively. More patients stopped treatment due to adverse events in the add-on therapy trial (Study 898: placebo = 12%; satralizumab = 7%) than in the monotherapy trial (Study 900: placebo = 3%; satralizumab = 2%).

No deaths, hepatotoxicity, or anaphylaxis events were reported in either study.

Indirect Evidence

The sponsor submitted an ITC that estimated the relative treatment effects and safety of satralizumab versus eculizumab or inebilizumab; the latter is not currently available in Canada. Bayesian network meta-analysis (NMA) methods were used to combine data from 4 RCTs, including a subgroup analysis in patients who were AQP4 antibody positive. The NMA results for the time to first protocol-defined relapse did not differentiate between satralizumab and eculizumab, or between satralizumab and placebo, and showed wide 95% credible intervals indicating limited precision around the treatment effect estimates. A similar pattern of results was observed for the analyses of ARR, proportion of relapse-free patients at 48 weeks, change in EDSS score at 48 weeks, withdrawals due to adverse events, and rate of serious infections.

Although the NMA was conducted using accepted statistical methods, there were many differences between study populations, study designs, effect modifiers, and end point definitions in the trials that were not adequately addressed. Combined with the sparse network for the analyses, the results of the NMA are highly uncertain and no conclusions can be drawn on the comparative efficacy and safety of satralizumab versus eculizumab in patients who have NMOSD and are AQP4 antibody positive.

Cost and Cost-Effectiveness

At a submitted price of $9,450 per pre-filled syringe, the annual per patient cost of satralizumab in the first year is $132,300 and $122,850 in subsequent years.

The sponsor submitted 2 cost-utility analyses assessing satralizumab, with or without maintenance immunosuppressants, for the treatment of adolescents and adults with NMOSD who are AQP4 seropositive. Satralizumab as monotherapy was compared with no treatment in 1 model and in combination with maintenance immunosuppressants (i.e., azathioprine, mycophenolate mofetil or corticosteroids) compared with maintenance immunosuppressants alone in the second model. The economic analysis was conducted from the perspective of the public health care payer over a lifetime time horizon (defined as 50 years). The cost-utility models shared a common Markov structure in which health states were defined by the EDSS to reflect the impact of relapses on disease severity and health-related quality of life. The model consisted of 10 EDSS health states (i.e., EDSS 0 to 9) along with an absorbing death health state. At the start of the model, patients had a range of EDSS scores and could either remain in the same EDSS state (reflecting stable disease), experience a relapse (i.e., move to a higher EDSS state), or die after each cycle. Patients could not improve (i.e., move to lower EDSS scores) following recovery from a relapse and were assumed to remain on satralizumab until discontinuation. Treatment efficacy was measured as time to first adjudicated protocol-defined relapse taking data from studies 900 and 898 for satralizumab compared with no treatment and satralizumab plus immunosuppressants compared with immunosuppressants alone, respectively. Health state and caregiver utility values were derived from Study 898, Study 900, and the published literature. The frequency of adverse events was based on data from Study 898 and Study 900.

CADTH identified several key limitations with the submitted analysis:

• The submitted cost-utility analyses do not fully reflect the expected place in therapy for satralizumab. Given the absence of comparative clinical evidence for satralizumab alone compared with immunosuppressants alone, the cost-effectiveness of satralizumab versus immunosuppressants remains unknown.
• The relapse definition used by the sponsor in the model was based on adjudication by an independent committee, which does not reflect Canadian practice.
• Natural history was modelled based on EDSS; however, the validity and reliability of this approach in patients with NMOSD is unknown. Concerns were also raised by the clinical experts consulted by CADTH with the database selected to inform natural history estimates because expected life-years were likely overestimated in both the treatment and comparator arms.
• Caregiver disutilities were applied, which misaligns with the public health care payer perspective.
• Frequency of adverse events were based on the respective clinical studies. Although fewer adverse events were observed in the satralizumab plus immunosuppressant group compared with immunosuppressants alone in Study 898, these observed differences were likely due to chance and may not be observed in clinical practice.

CADTH attempted to address the identified limitations in both economic models by changing the relapse definition and removing caregiver disutilities. In addition, for the economic model for satralizumab plus immunosuppressants compared with immunosuppressants alone, CADTH assumed no differences in the frequency of adverse events between groups. In the CADTH base case, the ICER for satralizumab was $337,535 per QALY compared to no treatment and the ICER for satralizumab plus immunosuppressants was $752,179 per QALY compared to immunosuppressants. An 80% price reduction is required for satralizumab monotherapy and an 89% price reduction is required for satralizumab combination therapy for the drug to be considered cost-effective at $50,000 per QALY threshold.

CADTH was unable to address inherent limitations with the economic model and the uncertainties resulting from the overestimation of life-years. Importantly, the economic analyses do not address the cost-effectiveness of satralizumab versus immunosuppressants.