Cystic fibrosis: Market shake-up to come?

This article, a Cortellis Market Insight report, is adapted from the author’s comprehensive Cystic Fibrosis Disease Report. Publication of the report coincides with Cystic Fibrosis Awareness Month in May in the U.S. and Canada, which aims to raise awareness and improve understanding of the disease.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies have transformed the cystic fibrosis (CF) treatment landscape and led to improved life expectancy. Vertex holds a monopoly within the CFTR modulator market: The company’s three approved treatments are the only disease-modifying CF drugs currently available, and are labeled to treat approximately 60% of the patient population.1-6 

Moreover, Vertex is aiming to expand the treatable CF patient population considerably to around 90% through its triple combination CFTR modulator program, with regulatory filings planned for 3Q19 in the U.S. and 4Q19 in the EU.6-9 Proteostasis Therapeutics has been advancing its own CFTR modulator development program in an attempt to seize some of the market share. 


Competition and patient access 

Similar to many rare disease treatments, Vertex’s three approved CFTR modulator therapies are expensive with annual list prices of around $270,000 to $310,000 in the U.S.10, and Vertex’s pricing has come under scrutiny in both the U.S. and Europe. The Institute for Clinical and Economic Review (ICER) has suggested that price discounts of >70% are needed to align prices with clinical benefit and achieve cost-effectiveness, and reimbursement has met with issues in certain countries in the EU, such as France and the UK.3,10-14 

Vertex’s issues with reimbursement may provide opportunities for companies such as Proteostasis to gain market share in certain regions. Although several years behind Vertex, Proteostasis anticipates that competition within the CFTR modulator therapy market will benefit patients with improved access and pricing reimbursement, as well as better tolerability and a greater choice of treatment options.15

The success of Vertex’s innovative CFTR modulator therapies has generated significant revenue growth for the company (see Figure 1).16 Following market entry in January 2012, Kalydeco, which was initially approved for the G551D mutation that affects 4% of CF patients, achieved sales of $371 million in 2013 in its first full year following approval.2 Both regional and label expansion into additional CFTR mutations and younger patient populations have driven further sales increases, and in 2018 sales of $1.008 billion were reported.1 

In comparison, Orkambi, which treats the most common CFTR mutation F508del, surpassed Kalydeco in its first full year on the market in 2016 with sales of $979 million, and in 2017 Orkambi achieved blockbuster status with sales of $1.320 billion.17 Like Orkambi, rapid sales growth is predicted for Symdeko and triplet VX-445/tezacaftor/ivacaftor, with consensus forecast sales of $2.167 billion and $2.226 billion, respectively, anticipated for 2023.


Recent Proteostasis triple combination data suggest caution

Recent data released in March 2019 by Proteostasis for its proprietary triple combination PTI-NC-733 (PTI-428/PTI-801/PTI-808) have cast doubts on whether Proteostasis will challenge Vertex’s hold on the CFTR modulator space.15,18,19 In a phase I trial assessing PTI-NC-733 in patients homozygous for the F508del mutation, 14-day data demonstrated a significant increase in ppFEV1 of 5 percentage points compared with baseline.15,19 Although not directly comparable,  phase III data from Vertex’s triple combinations suggest that the Vertex drugs may have a greater effect.7 However, Proteostasis has noted that improvement in ppFEV1 did not plateau in the phase I study, suggesting that longer-term data may reveal a larger effect for PTI-NC-733.15       

Proteostasis plans to initiate three 28-day phase II studies of PTI-NC-733 in 2019, with phase III trials planned to begin by mid-2020.15,19 Notably, the inclusion criteria for the earlier studies allowed harder-to-treat CF patients predisposed to rapid pulmonary decline and those who were intolerant or non-responders to CFTR modulator therapies.15 For the planned studies, selection criteria have been revised and are consistent with current standard of care – the trials will include patients with respiratory stability for at least 28 days prior to dosing and exclude those with lung colonization associated with a more rapid decline in pulmonary function.15,19

According to Cortellis Analytics – Drug Timeline & Success Rates  (DTSR), the probability of PTI-NC-733 progressing to phase II studies in the U.S. is 89%, with approval predicted for February 2024 (see Figure 2a). The DTSR forecasts a 95% probability of a regulatory filing in the U.S. for Vertex’s triple combination VX-659/tezacaftor/ivacaftor, with a 94% probability of approval in December 2020, if filed (see Figure 2b). For VX-445/tezacaftor/ivacaftor, a 95% probability of a regulatory filing in the U.S. is forecast, with a 94% probability of approval in May 2021 if filed (see Figure 2c). Proteostasis’s triple combination is therefore anticipated to gain approval around three years behind the first Vertex triple combination, allowing Vertex to gain first mover advantage in this market segment.



Although Proteostasis has experienced a setback to challenging Vertex’s monopoly in the CFTR modulator market, the company is moving forward with its proprietary triple combination regimen. By selecting a patient population who are more likely to respond to treatment and by evaluating efficacy over a longer duration, the company is maximizing the likelihood of achieving a positive outcome in the planned studies. If successful, Proteostasis has the potential to significantly disrupt the CFTR modulator therapy market and challenge Vertex.

For more information on the comprehensive Cortellis assessment of the CF disease landscape, including patient survey results and analysis provided by Raremark, the rare disease-focused patient advocacy network, as well as analysis of the role of digital health in the post-approval arena, see the Cystic Fibrosis Disease Report.