During the last five years, Vertex Pharmaceuticals has maintained a stronghold in the cystic fibrosis (CF) market with its two CF transmembrane conductance regulator (CFTR) modulator therapies, Kalydeco (ivacaftor) and Orkambi (ivacaftor/lumacaftor). Vertex is poised to bring yet another blockbuster CFTR modulator therapy, dual combination tezacaftor with ivacaftor, to market in Q3 of 2018. In addition, GlobalData anticipates the launch of PTC Therapeutics’ CFTR modulator Translarna (ataluren) in Q3 of 2018 for the treatment of CF patients with nonsense mutations. Despite the increasing variety of CFTR modulators to correct the function of defective CFTR protein, considerable opportunities for more efficacious therapies still remain.
CF is an inherited, autosomal recessive disorder that causes persistent lung infections and impairs breathing ability over time, and affects more than 70,000 people worldwide. Characterized by a loss of function in the CFTR protein, CF causes abnormally thick, sticky mucus production that can lead to airway obstruction and lung infections, and can eventually lead to pancreatic insufficiencies due to mucous blockage of the pancreatic duct. Currently there are six different classes of CF that categorize more than 2,000 different CFTR mutations. The F508del mutation is the most prevalent CF mutation, a Class II mutation that accounts for approximately two-thirds of CF cases worldwide.
CFTR modulators are drugs designed to correct the function of defective CFTR protein translated from a mutated CF gene. As various CF mutations exist, resulting in different protein defects, the specificity of CFTR modulators dictates which of these drugs is prescribed. Vertex’s Kalydeco was the first CFTR modulator approved in the US and EU, in 2012, and is indicated for CF patients with any one of the following mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, and R117H. According to the Cystic Fibrosis Foundation (CFF) Patient Registry, Kalydeco is approved to treat approximately 8.3 percent of the total CF population in the US.
In 2015, Vertex’s Orkambi became the second CFTR modulator approved in the US and EU. Its target population is CF patients ages six years and older with two copies of the F508del mutation, accounting for 46.5 percent of the total CF population in the US. In addition to Kalydeco and Orkambi, Vertex has another drug in its late-stage pipeline, a combination drug of ivacaftor and tezacaftor, which is expected to target CF patients with one copy of the F508del mutation and another CFTR mutation, a population that makes up 36.2 percent of the total US CF population. Therefore, 5 percent of total US CF patients are left without a CFTR-modulating therapy.
Although 5 percent looks like a low percentage of patients without a CFTR-modulating therapy, there is plenty of room for improvement regarding the marketed modulators as well as late-stage pipeline modulators. According to CF Key Opinion Leaders (KOLs), Kalydeco is regarded as the gold standard to which all CFTR-modulating therapies are benchmarked. On the other hand, Orkambi, while covering a large percentage of CF patients, does not effectively restore CFTR function as readily as Kalydeco. As a result, patients who are on Orkambi report less symptomatic and quality of life improvement compared to those on Kalydeco. In March 2016, the National Institute for Health and Care Excellence (NICE) concluded that it would not be able to recommend Orkambi to NHS England for the treatment of CF, stating that the benefit Orkambi offers does not justify its considerable cost.
There have also been concerns arising for CFTR modulators currently undergoing late-stage clinical trials. PTC Therapeutics’ Translarna has received criticism after Phase III results showed that it was ineffective in patients who were also administered aminoglycoside antibiotics, such as tobramycin, an inhaled antibiotic most commonly used in CF patients for the treatment of Pseudomonas aeruginosa. Vertex’s late-stage pipeline therapy, ivacaftor/tezacaftor, also received criticism after the CFFT Data Safety Monitoring Board (DSMB) halted a Phase III trial. The trial was suspended due to apparent lack of benefit conferred by ivacaftor/tezacaftor in CF patients with one copy of the F508del mutation and a second CFTR mutation resulting in minimal CFTR protein function.
It is clear that more efficacious CFTR-modulating therapies are still warranted. While the CF community awaits the completion of the Translarna and ivacaftor/tezacaftor Phase III trials, Vertex is currently pursuing Phase II trials aimed at improving existing modulator therapies, while also providing a modulator option for those CF patients without one. Specifically, Vertex’s Phase II trials encompass first-in-class triple combination therapy regimens, which combine ivacaftor, tezacaftor, and a third agent. CoNCERT Pharmaceuticals, Nivalis, Novartis, and Bayer also have CFTR-modulator therapies in early-stage clinical trials. Unfortunately, CFTR-modulator therapies can only restore CFTR protein function to a certain extent. Since these modulator therapies do not correct the underlying genetic mutation causing CF, they are not considered curative.
Gene therapy has been highly regarded as the most feasible curative option for CF patients. Imperial College London recently conducted a Phase IIb clinical trial using a monthly application of pGM169/GL67A gene therapy formulation in CF patients of various mutation types. Although the treatment showed modest benefit in forced expiratory volume in one second (FEV1) compared with placebo at one year, further improvements in efficacy and consistency of response are needed before the formulation can progress to clinical use. Most other gene therapy studies for CF are currently in preclinical trials, due to challenges in delivering the therapies to designated cells safely and effectively. GlobalData estimates that gene therapy options will not be available for CF patients until 2030.
Although the near future appears promising for the CF community, considerable opportunity still exists for both CF patients and for companies developing modulator and curative therapies. Kalydeco and Orkambi, as well as the late-stage pipeline CFTR modulators, offer most CF patients a treatment option that restores CFTR protein function to a certain extent. Curative options, such as gene therapy, have the potential to result in marked advantages, but are still in the early stages of development. It will be important for pipeline CFTR modulators to improve upon the efficacy offered by current modulators, while patients await possible curative therapies, in gene therapy trials to be completed.