Assessment of Emerging Therapies for Cystic Fibrosis

Cystic fibrosis (CF) is a complex, genetic disease that affects the respiratory system, digestive system, and other organs due to the production of an abnormally thick mucus that causes obstructions in airways, ducts, and passageways throughout the body. While treatment of CF has historically focused on alleviating symptoms and reducing complications, newer therapies that target the cystic fibrosis membrane conductance regulator (CFTR) protein work to treat the underlying cause of disease. In this article, we examine the evolving treatment and reimbursement landscape in CF across the globe.

Disease Background 

Approximately 70,000 to 100,000 people worldwide are living with CF; however, this may represent an underestimate, as those living in countries with underdeveloped healthcare systems may die before diagnosis. Moreover, it is estimated that thousands are treated for symptoms of CF without being diagnosed with the disease itself. The complex management of CF is associated with many physical and social challenges for patients and caregivers, in addition to economic insecurity, which can greatly impact quality of life.

Treatment Landscape

Treatment of CF has historically focused on alleviating symptoms and reducing complications, particularly in the respiratory system, which is the source of significant morbidity and mortality (Figure 1). 

Pharmacologic therapies have been utilized to improve lung function, treat or avoid infection, and address treatment goals with varying degrees of success, including hypertonic saline, dornase alfa (Pulmozyme^®), antibiotics, anti-inflammatory agents, and other chronic therapies (eg, inhaled beta2 adrenergic agonists, leukotriene modifiers, inhaled or oral N-acetylcysteine, inhaled glutathione, inhaled anticholinergics).

The discovery that defects in the CFTR protein were responsible for the clinical manifestations of CF led to development of the CFTR modulator therapies. CFTR modulators are fundamentally different from other CF therapies because they act directly on the CFTR protein defect, targeting the underlying cause of CF, thereby improving and even restoring CFTR protein function for patients with certain CFTR variants. Studies have shown that effective CFTR modulators can improve several important patient outcomes, including lung function, pulmonary exacerbation, inflammatory burden, and presence of CF pathogens. 

CFTR modulators function as either CFTR potentiators or CFTR correctors. CFTR potentiators, such as ivacaftor monotherapy (Kalydeco^®), work to keep the CFTR channel open longer, allowing more ions to move in and out of the cells. CFTR correctors, such as lumacaftor and tezacaftor, bring more CFTR proteins to the cell surface. Two products are currently available that address the flow of ions and increase the number of proteins on the cell surface by combining a CFTR potentiator and a CFTR corrector: Orkambi^® (lumacaftor/ivacaftor) and Symdeko^® (United States)/Symkevi (Europe) (tezacaftor/ivacaftor). 

Emerging Therapies

Numerous CFTR modulators are currently in phase 2 development, and several investigative triple combinations are on the horizon. The triple combinations being developed by Vertex build on the clinical success of the tezacaftor/ivacaftor combination by adding experimental products, VX-659 and VX-445. There is significant interest in these triple-combination therapies within the CF community because they target additional mutations and have the potential to successfully treat up to 90% of all patients with CF. Vertex is expected to file for approval in the United States during the first half of 2019.

Status of Drug Approvals and Reimbursement Landscape

United States

As the first disease-modifying therapy for CF, Kalydeco received initial Food and Drug Administration (FDA) approval in 2012 and has since gained approvals that expand the population in which it is used; it is currently approved for use in patients who are ≥12 months of age and who have 1 mutation in the CFTR gene that is responsive to ivacaftor based on clinical and/or in vitro assay data. Orkambi was initially approved by the FDA as the first combination product in 2015; it is currently indicated for patients who are ≥2 years of age and who are homozygous for the F508del mutation in the CFTR gene. Symdeko (Symkevi EU) was FDA-approved in 2018 for use in patients who are ≥12 years of age and who are homozygous for the F508del mutation, or who have ≥1 mutation in the CFTR gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence. The price tags to acquire these drugs are well over $250,000 per patient per year, creating challenges for healthcare decision makers who are trying to balance clinical benefit and cost.

Institute for Clinical and Economic Review (ICER)

In 2018, ICER evaluated the effectiveness and value of Kalydeco, Orkambi, and Symdeko for use in treating patients with CF. ICER’s economic analyses found that in the 3 populations considered (Table 1), the cost of the drugs, combined with best supportive care, far exceeded commonly accepted thresholds for cost-effectiveness of $100,000 to $150,000 per quality-adjusted life-year (QALY) gained when compared to best supportive care. ICER’s analysis suggested that discounts of up to 77% would be necessary to bring the prices into alignment with the drugs’ clinical value, and a majority of the Council voted that the treatments represent a low long-term value for money.

Vertex, the manufacturer of all 3 products evaluated by ICER, responded to ICER’s report and recommendations in a strongly worded letter to ICER, stating that the methodology of the evaluation was flawed and ICER was attempting to limit patients’ access to life-saving medications. 

Centers for Medicare & Medicaid Services

On the basis of ICER’s evaluation, New York state health officials determined that Orkambi was “not worth its price” and requested steep discounts for the state’s Medicaid program from the Vertex. Specifically, the New York State Department of Health recommended that net rebates should equate to a unit price of $56.94 for Orkambi, which aligned with ICER’s estimate of the unit price required to fall within the $150,000 per QALY limit.

Europe 

Three drugs currently have marketing authorization from the European Medicines Agency for the treatment of CF: Kalydeco (initial approval in 2012), Orkambi (initial approval in 2015), and the most recent entrant, Symkevi (initial approval in 2018; marketed as Symdeko in North America) (Table 2). These approvals paved the way for access of the products across the Europe. Each product is approved in a variety of different populations, and the level of reimbursement varies from one country to the next. 

United Kingdom: National Institute for Health and Care Excellence (NICE)

Although NICE has not conducted an assessment of Kalydeco, the National Health Service (NHS) in England initially funded its use in 2012 for patients aged 6 and older with gating mutations and subsequently expanded use in 2016 to patients aged 2 and older. Conversely, the Scottish Medicines Consortium did not recommend the use of Kalydeco, leaving Scotland to pay for the product using the rare disease fund to ensure patient access to therapy.

Orkambi failed to gain a positive recommendation from NICE on the basis that the benefits were not sufficiently cost-effective in patients aged 12 and older who are homozygous for the F508del mutation to merit routine NHS funding. The analysis estimated incremental costs of £704,645 and an incremental QALY gain of 2.59, with an estimated cost per QALY gained of £272,265 for Orkambi plus standard of care, compared with standard of care alone.

The appraisal for Symkevi in the United Kingdom is currently suspended because Vertex did not provide an evidence submission to NICE for evaluation. 

France: Haute Autorité de Santé (HAS)

In France, the Haute Autorité de Santé (HAS) deemed Kalydeco to have a substantial actual benefit rating (ASMR II), demonstrating substantial clinical added value in patients aged 2 years and older with gating mutations. This rating indicates that Kalydeco offers an important clinical benefit for patients and allows for significant reimbursement. Additionally, HAS recommended inclusion of Kalydeco on the list of reimbursable products for supply by retail pharmacists and for hospital use.

HAS considered Orkambi to have substantial actual benefit and minor added value improvement in actual benefit (ASMR IV) for patients aged 12 years and older with homozygous F508del mutation. Additionally, HAS recommended inclusion of Orkambi on the list of reimbursable products for supply by retail pharmacists and for hospital use.

An evaluation of Symkevi has not yet been conducted by HAS.
 

Canada

Kalydeco, Orkambi, and Symdeko are approved for use in Canada (Table 3). 

The Canadian Agency for Drugs and Technologies in Health (CADTH) recommended reimbursement for Kalydeco in patients aged 18 or older with an R117H mutation and in patients aged 6 years and older with a gating mutation, under the condition that Vertex offer a substantial reduction in price. At the price submitted by Vertex, CADTH estimated an incremental cost per QALY of CAD$850,932 in patients with gating mutations, and CAD$926,776 in patients with the R117H mutation. Both estimates far exceeded commonly accepted cost-effectiveness thresholds, thereby resulting in the determination.

CADTH did not recommend reimbursement for Orkambi in patients aged 6 years or older who are homozygous for the F508del mutation, citing concerns over the clinical effectiveness and cost.

CADTH has not yet conducted a review for Symdeko.

Australia

Kalydeco and Orkambi are approved for use in Australia (Table 4).

The Australian government reached an agreement with Vertex to fund reimbursement for Kalydeco in patients aged 2 years and older who have a G551D or other gating mutation. Vertex received a positive recommendation for the reimbursement of Orkambi to treat patients aged 6 years and older who are homozygous for the for the F508del mutation. No reimbursement decisions related to Symdeko have been announced. 

Innovative Agreements

In the face of challenges to its product pricing, Vertex has entered into innovative agreements with some markets. For example, in Denmark, Amgros, the service for pharmaceutical procurement within the 5 regional authorities, agreed to an innovative access contract with Vertex that provides eligible Danish patients with CF access all current and future CFTR modulator medicines after regulatory approval. Sweden and Ireland have agreed to portfolio agreements in which Vertex sets 1 price for all of its CF treatments that become available over a set number of years.

Key Learnings and Recommendations for Manufacturers

Evaluation of the current CFTR therapies provides a good example of the potential benefits and challenges of introducing a personalized medicine for access and reimbursement in multiple global markets. Despite strong clinical evidence, Vertex faced substantial challenges in justifying a premium price for Orkambi across all markets. Key markets such as the United Kingdom and Scotland did not find sufficient benefit to justify the price, even when evaluated through alternate pathways (eg, orphan, ultra-orphan) and explicitly taking into account patient and clinician perspectives.
Key recommendations for manufacturers to consider include the following: 

The article should be referenced as follows: 

Tennant L, Migliaccio-Walle K. Assessment of emerging therapies for cystic fibrosis. HTA Quarterly. Winter 2019. Feb. 25, 2019.

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