GSK’s mepolizumab (NUCALA®, GlaxoSmithKline plc.) is a humanized monoclonal antibody to IL-5. Mepolizumab binds to IL-5, which decreases IL-5 signaling leading to decreased eosinophils in the blood and tissue. In November 2015, the FDA approved mepolizumab as an add-on treatment of severe eosinophilic asthma for patients aged 12 years and older. Mepolizumab 100 mg must be reconstituted by a healthcare professional and is administered subcutaneously once every 4 weeks in a physician’s office. The European Commission granted a marketing authorization valid throughout the European Union (EU) for mepolizumab on December 2, 2015. Canada also approved mepolizumab in December 2015 and Australia in January 2016.
In addition to the country-specific summaries provided in the table above, the Institute for Clinical and Economic Review (ICER) issued a report on mepolizumab in 2016 which concluded that adding mepolizumab to SOC confers clinical benefits in terms of reduced rates of exacerbations and improved quality of life compared to SOC alone. The ICER report estimated cost-effectiveness ratio for mepolizumab was $385,546 per quality-adjusted life year (QALY) gained, and in order to achieve a cost-effectiveness ratio of $100,000 per QALY gained, a price of $599 per vial (a 76% discount from the $2,500 wholesale acquisition cost [WAC]), or $32,500 per year, would be required. Although the United States (US) is not subjected to formal HTA review for reimbursement, in an Xcenda-sponsored PayerPulse® survey of US payers, the vast majority (96%) agreed the ICER framework has the potential to be more influential in future decision making.11
Reslizumab (CINQAIR®, CINQAERO®)
Teva’s reslizumab (CINQAIR® in the US and Canada, CINQAERO® in Europe) is another monoclonal anti-IL-5 antibody approved as add-on maintenance treatment for patients aged 18 years and older with severe eosinophilic asthma inadequately controlled despite combination therapy with high-dose inhaled corticosteroids. Unlike mepolizumab, reslizumab is dosed according to weight (3 mg/kg every 4 weeks) and is administered intravenously. Reslizumab was approved by the FDA in March 2016, in Canada in July 2016, and by the European Commission for the 28 countries of the EU in addition to Norway, Liechtenstein, and Iceland in August 2016, with pending regulatory approvals in other global markets. At present, it is not approved in Australia.
Reslizumab is an IL-5 antagonist monoclonal antibody (IgG4 kappa) indicated for add-on maintenance treatment of patients with severe asthma aged 18 years and older, and with an eosinophilic phenotype. In Germany, IQWiG reported that Teva did not completely concur with the appropriate comparator therapy as specified by the “Gemeinsamer Bundesausschuss” G-BA (Federal Joint Committee). The Canadian Drug Expert Committee (CDEC), on the other hand, recommended that reslizumab be reimbursed, provided the established clinical criteria and 2 additional conditions are met: 1) patients should be managed by a physician with expertise in treating asthma; and 2) reduction in price of 90%. In the UK, reslizumab was also recommended for reimbursement provided certain patient criteria were met, including: 1) the blood eosinophil count has been recorded as 400 cells per microlitre or more; 2) the person has had 3 or more asthma exacerbations in the past 12 months; and 3) the company provides reslizumab with the discount agreed in the patient access scheme. Additionally, a stopping rule at 12 months was included to limit spending on non-responding patients.
Omalizumab was first approved by the FDA in 2003 to treat adults and children aged 12 years and older with moderate to severe persistent allergic asthma not controlled by inhaled steroids. It is designed to block IgE, which limits the release of mediators in the early and late phases of the allergic inflammatory cascade. Omalizumab is administered subcutaneously every 2 or 4 weeks according to age, treatment frequency, pretreatment IgE levels, and body weight. Approval was first granted in Europe in 2005 for all of its member states for severe persistent asthma. Because its approval pre-dated AMNOG, omalizumab did not have to submit a dossier to IQWiG; however, the G-BA already introduced stricter controls for its use. Additionally, when its label was expanded in 2011 to include children aged 6–12 years, patients were required to keep a daily diary to document that the treatment was being effective.12
In Australia, the PBAC in 2016 recommended a Section 100 (Highly Specialised Drugs Program) listing of omalizumab for treatment of severe allergic asthma in patients aged 6 years to less than 12 years. The recommendation was made on the basis of sufficient evidence to demonstrate the effectiveness of omalizumab when compared to placebo plus optimized asthma therapy. The benefits from using omalizumab to reduce severe asthma exacerbations were considered to be important for the small paediatric population, as there are currently limited options available to treat the proposed group, and long-term oral steroid use is undesirable.13
In Canada, the pharmacoeconomic report from 2005 submitted to Common Drug Review (CDR) by the manufacturer reported an incremental cost per clinically significant exacerbation avoided of $53,000 from a 28-week trial-based evaluation, and $13,000 from a 1-year modeled evaluation. CDR considered this report to be of limited value since it is dated and could not be validated in the absence of the underlying model. CDR noted the 2006 Canadian Expert Drug Advisory Committee (CEDAC) recommendation for omalizumab referred to a different manufacturer-submitted pharmacoeconomic analysis from the 2005 report provided by the manufacturer for the current submission; the reported ICER in the recommendation was $63,000 per QALY (range: $35,000–$219,000 per QALY). At the time, CEDAC noted that the rates of asthma exacerbation in the analysis potentially overstated the benefits of omalizumab and that the true cost-effectiveness of omalizumab was “likely to be much less favourable.” The CDR Clinical Review identified several new studies since the previous review that showed omalizumab may have benefits on key outcomes of interest such as emergency room visits or hospitalizations due to asthma exacerbations, although the consistency and magnitude of the observed effects were uncertain. In the absence of an economic model, CDR was unable to assess the cost-effectiveness of omalizumab in light of the new clinical information.14
In the UK, omalizumab in 2016 was recommended as an option for treating severe persistent confirmed allergic IgE mediated asthma as an add on to optimized standard therapy for people aged 6 years and older who need continuous or frequent oral corticosteroid treatment (defined as 4 or more courses in the previous year) and only if the manufacturer makes omalizumab available with the discount agreed in the patient access scheme. The committee concluded that, with the patient access scheme for omalizumab, the most plausible ICER is £23,200 per QALY gained for the combined population of adults, adolescents, and children on maintenance or frequent courses of oral corticosteroids, defined as 4 or more courses in the year before receiving omalizumab. The committee acknowledged the uncaptured benefits of reducing dependence on oral corticosteroids and was persuaded that these uncaptured benefits were sufficient to justify accepting an ICER of £23,200 per QALY gained.15
Implications for Manufacturers
As more targeted therapies for severe, uncontrolled asthma enter the market and contribute to progression toward personalized medicine, payers will be challenged to identify the optimal treatment pathways that achieve the best outcomes at a sustainable cost. Even within the subgroup of asthma sufferers who have a biomarker profile targeted by new therapies, physicians may have difficulty determining the optimal treatment selection. To help navigate this field, manufacturers preparing to launch treatments for severe asthma should look to NUCALA® and CINQAIR®/CINQAERO® for market access and reimbursement insights. Despite the high unmet need in severe asthma, payer decisions for these products indicate manufacturers will need to meet high clinical and economic evidentiary requirements for reimbursement. Treatment comparator selection, data coming from real-world evidence for further establishing long-term safety and efficacy, population subgroups, proper use and inclusion of biomarkers, and modeling clinical benefits and costs of new treatments are likely to remain critical areas for favorable pricing and access decisions.