A dramatic increase in the number of cystic fibrosis patients eligible for highly-priced disease-modifying therapies

In July, Vertex Pharmaceutical announced positive topline Phase II data for two triple-combination therapies for cystic fibrosis (CF): ivacaftor/tezacaftor/VX-440 and ivacaftor/tezacaftor/VX-152. With the successful development of these new agents, the Boston-based biotechnology company will be poised to dominate the CF market by offering a disease-modifying therapy (DMT) to most CF patients well ahead of the competition (Figure 1).

Until just a few years ago, the absence of a functional cystic fibrosis transmembrane conductance regulator (CFTR) protein in CF patients was merely managed with a combination of symptomatic therapies such as mucolytic agents, antibiotics and pancreatic enzyme replacement therapies. However, in the last five years, Vertex Pharmaceuticals gained regulatory approval for two first-in class DMTs, Kalydeco (ivacaftor) and Orkambi (ivacaftor/lumacaftor), both of which have revolutionized treatment for CF patients with eligible CFTR mutations.

The first-ever DMT for CF, Kalydeco, a potentiator designed to address the deficiencies of residual function mutations of the chloride channel, was initially approved by the FDA in 2012 based on clinical trial data showing a dramatic improvement in lung function. However, despite several label extensions based on its mechanism of action and age limits, Kalydeco is indicated for less than 10% of CF patients in the U.S (Figure 1).


Figure 1


In 2015, Vertex launched their second DMT: Orkambi. This regimen consists of a fixed-dose combination of ivacaftor with lumacaftor, a corrector designed to improve CFTR protein folding and trafficking to the cell surface. Orkambi’s clinical trial performance was less impressive than Kalydeco, demonstrating only a modest improvement of pulmonary function and a less-than-ideal safety profile. Nevertheless, Orkambi is currently approved in the U.S. for patients homozygous of the F508del mutation of the CFTR gene older than 6 years, a patient population four times the size of those eligible for Kalydeco. Between Kalydeco and Orkambi, Vertex can currently offer a DMT to almost 50% of the entire U.S. CF patient population (Figure 1).

Vertex has continued to showcase its dominance of the CF pipeline and its commitment to bringing additional treatment options to market. Last March, the company released positive Phase III clinical data for a second combination therapy for CF, a fixed-dose combination of ivacaftor/tezacaftor. And although ivacaftor/tezacaftor offers only a modest improvement in pulmonary function compared with Kalydeco and Orkambi (based on EVOLVE and EXPAND clinical trials – Figure 2), Vertex announced their intention to submit an NDA to the FDA and a Marketing Authorization Application (MAA) to the EMA in Q3 2017. If approved, the ivacaftor/tezacaftor combination is likely to be indicated for patients homozygous for the F508del mutation and patients with the F508del mutation in heterozygosis with a second residual function mutation clinically responsive to ivacaftor.

In July, Vertex released top-line phase II results for two triple combination therapies showing impressive lung function improvements (Figure 2). What is notable about the triple-combination therapies is that their clinical trials are designed to establish efficacy in the F508del heterozygous patients. This patient group has a high remaining unmet need for DMTs as only a little over 15% of patients with this genotype are eligible for treatment with either Kalydeco or ivacaftor/tezacaftor, and none of them are eligible for treatment with Orkambi. Therefore, successful development of the triple therapies would allow Vertex to expand the CF patient pools eligible for at least one of their therapies. If the triple therapies are approved, Vertex will have an arsenal of DMTs offering treatment to roughly 80% of the entire CF patient population in the U.S.


Figure 2


Although Vertex will likely have a DMT for nearly all CF patients, the company’s pricing strategy for their next-generation CF drugs will dictate patient access. In fact, while Kalydeco was rapidly adopted despite its high price point (~$300,000/year in the U.S.), Orkambi initially faced significant payer pushbacks both in the U.S. and in European markets, resulting in sluggish adoption. Payers’ concerns mostly stemmed from Orkambi’s high price point (~$275,000/year in the U.S.) and relatively large eligible patient population, resulting in a significant budget impact, and the less than impressive efficacy and safety profile.

For the ivacaftor/tezacaftor combination, a pricing strategy in-line with Kalydeco, which could be supported by efficacy data showing a modest improvement in performance, will likely result in payer pushback comparable to what was seen for Orkambi, particularly since it’s still unclear how a modest improvement in pulmonary function over Orkambi or Kalydeco translates into improvements in real-life benefits, such as fewer pulmonary exacerbations or extended life expectancy. Whatever price Vertex sets for ivacaftor/tezacaftor, it is clear that it will be fundamental in establishing a price point for Vertex’s follow-on triple combinations, which are likely to rekindle the debate over budget impact and cost effectiveness of high-priced orphan drugs. Assuming that the triple therapies are priced in-line with or even slightly above Kalydeco, the expansion in treatment-eligible patients will unavoidably have a significant impact on payers’ budgets. However, considering the impressive efficacy data, the potential for cost-effectiveness could tip the balance in favor of positive coverage for the new triple therapies.  Health economic analysis of total medical cost, as well as outcome analysis assessing how improvement in lung functions translate into outcomes such as pulmonary exacerbations and overall survival, could aid in this debate, supporting positive coverage decisions for the Vertex products.


For more insights on forecast and adoption of current CF treatments, please consult DRG’s 2016 Cystic Fibrosis disease landscape & forecast report, and stay tuned for the 2017 update, coming in September 2017.

For more insights on market access and reimbursement of current CF therapies, please consult DRG’s 2017 Orphan Drugs and Rare Diseases | Access & Reimbursement.

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