Orkambi is the first therapy addressing the underlying cause of the disease in cystic fibrosis (CF) patients with two copies of the F508del mutation. Orkambi launched in the United States in July 2015 and in Europe starting in November 2015, for CF patients aged 12 and older with the homozygous F508del mutation. Based on Vertex’s most recent earnings report, Orkambi captured $223 million in sales in the first quarter of 2016, of which over 95% came from the United States—only $9 million of sales were from outside of the United States. Despite longer availability in the U.S. market, the discrepancy in earnings for Orkambi compared with Europe results from the customary delay in continent-wide market access following launch. Moreover, a U.K. rejection in March 2016 may signal a turbulent market access road ahead for Orkambi, where Vertex’s previous disease-modifying therapy for CF, Kalydeco, was more swiftly accepted. Further, on June 1, 2016 regulators in Ireland came to the same conclusion and rejected Orkambi due to lack of cost effectiveness.

What is Cystic Fibrosis? CF is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR protein is a channel for the transport of chloride ions across the epithelium. CFTR mutations can result in reduced levels or complete lack of CFTR protein at the cell surface, or the CFTR protein may be correctly localized but dysfunctional and thus impair chloride transport across the cell membrane. In CF, the results of CFTR protein deficiencies are most pronounced in the lungs and pancreas, where water is excessively expelled of the lumen (the organ cavity) to maintain the necessary salt balance, resulting in the accumulation of thick mucus. Consequently, CF patients suffer from chronic bronchiectasis, recurrent pulmonary infections and inflammation, and pancreatic insufficiency.

What is Orkambi? What is Kalydeco? Orkambi is a combination therapy of lumacaftor and ivacaftor. The CFTR corrector lumacaftor is designed to increase traffic of the misfolded CFTR protein to the plasma membrane. Ivacaftor is a CFTR potentiator that can help in channel opening of mutant CFTR proteins to resume chloride ion flow. Ivacaftor monotherapy, also from Vertex and marketed under the brand name Kalydeco, has experienced a strong uptake in CF patients who have at least one copy of a CFTR gating mutation, e.g., the G551D mutation. (In patients with gating mutations levels of CFTR protein at the plasma membrane are normal, but the protein is dysfunctional.) In clinical trials, Orkambi’s clinical benefit in CF patients with two copies of the F508del mutation—approximately 40% of the CF population—was more modest compared with that observed for Kalydeco in CF patients with the G551D mutation (~4% of the CF population).

How were Orkambi and Kalydeco received in the United Kingdom? In March 2016, Orkambi failed to gain a positive recommendation from the National Institute for Health and Care Excellence (NICE) in the United Kingdom. NICE’s draft guidance noted that the benefit Orkambi offered was not sufficiently cost effective to merit a recommendation for routine National Health Service (NHS) funding. According to NICE, Orkambi is priced at £104,000 ($152, 000) per patient per year in the United Kingdom, a nearly 40% discount of Orkambi’s U.S. price ($259,000 per patient per year). In comparison, Kalydeco, with better clinical profile and a much smaller patient population, was recommended by NHS England back in 2012. The basic annual NHS price for Kalydeco is £182,625 ($267,000). Even with the discounted price agreed upon for a Patient Access Scheme (PAS), the incremental cost effectiveness ratio (ICER) for Kalydeco reached £285,000 ($417,000) per quality-adjusted life-year (QALY), greatly exceeding the £30,000 ($44,000) per QALY threshold usually used by the NHS to determine cost-effectiveness.

What are the next steps for Orkambi? Orkambi is currently available in Germany, where the most of $9 million non-US Q1 sales came from, but the eventual reimbursed price hinges on the pending assessment of the drug’s additional benefit. It is currently undergoing price and reimbursement assessments in many European markets, such as Italy and Spain, while at the same time, early access to the agent is possible in France under the temporary authorization for use (ATU) program. However, an increasingly challenging market access environment due to constrained healthcare budgets in Europe appears set to become one of the biggest obstacles to funding this premium-priced therapy, even though Orkambi addresses a high unmet need and is the first disease-modifying therapy for a large segment of the CF population. European payers have to balance the significant unmet need with their finite funding resources—and thus tough pricing and reimbursement negotiations are expected across the markets, as signaled by NICE’s initial rejection of Orkambi. Vertex will therefore have to be creative and flexible while negotiating for reimbursement of Orkambi with a multitude of national, state, and/or local payers.

For a more in-depth analysis of market access dynamics for orphan drugs in Europe, please see our recent content European Payer Perceptions of Reimbursement for Orphan Drugs.

For a more in-depth analysis of the therapeutic market, please see our recent content on Cystic Fibrosis.


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