When Vertex Pharmaceuticals’ cystic fibrosis (CF) therapy Trikafta was approved recently by the U.S. Food and Drug Administration, it was a dream come true for Jeffrey Leiden, Vertex’s chairman, president, and CEO.
The therapy, which treats the most common mutation in CF patients (the F508del mutation in the CFTR gene), was considered a dream 20 years ago — a dream “that you could make a small molecule that would actually correct the function of a mutant protein. No one thought that was possible. People laughed at that at the beginning,” Leiden, MD, PhD, said in a recent interview with Cystic Fibrosis News Today.
Accomplishing this dream was possible only because so many played a part and worked together, Leiden said: “It never would have happened without the engagement of the entire CF community, the patients and parents who were brave enough to take part in the trials and support us all along, the CF Foundation that also provided encouragement and support, … and scientists here [at Vertex] who worked on it.”
“This was just an entire community effort that was unlike anything I’ve almost ever seen. I just want to thank all the people who played such an important role in it,” he added.
Trikafta is Vertex’s first triple combination therapy — elexacaftor (VX-445), plus tezacaftor, and ivacaftor (Kalydeco) — approved for use in CF patients, age 12 and older, with one F508del and one minimal function mutation, or with two F508del mutations.
The “combination of all three,” and “not one component or one versus the other” is what underlies the benefits seen in CF patients taking Trikafta, Leiden said.
The therapy was developed for patients who fail to respond or respond poorly to already approved Vertex CF therapies — namely Kalydeco (ivacaftor), a CFTR potentiator, or the potentiator-corrector combinations of Orkambi (lumacaftor/ivacaftor), and Symdeko (tezacaftor/ivacaftor, ivacaftor, and known as Symkevi in the European Union).
In CF patients with a F508del mutation, “the underlying biochemical problem … is twofold,” Leiden said. “One, the protein [CFTR] is misfolded in the cytoplasm so it never gets to the cell surface, and two, even if you can fold it and get it to the cell surface, it’s still defective in its gating function.” This calls for “a very complex mix of molecules or medicines that improves the folding of the protein and gets it to the cell surface and then, once it gets there, increases the opening probability,” he said. That’s a job for the two different correctors — Symdeko and elexacaftor.
“When you put them both together, you get synergistic folding; that gets the protein folded and to the cell surface, and then you need to add ivacaftor, or Kalydeco, which binds to the protein on the cell surface and increases the opening frequency,” he explained. “It’s really the unique combination of these three as opposed to one or the other.”
After granting Trikafta priority review in August, the FDA’s October decision to approve the therapy came in record time — five months ahead of the expected deadline of March 2020.
The “accelerated approval” was not a surprise to Vertex, however. “Were we surprised? No,” said Leiden, who attributes the decision to a “combination of the strength of the clinical data in the Phase 3 trials and the large, unmet need in this patient population that drove the speed of the FDA.”
Kalydeco, in 2012, also was “approved in about three months’ time,” Leiden noted.
Trikafta’s approval was based on data from two Phase 3 clinical trials in the AURORA program: the AURORA F/MF (NCT03525444) with patients who have one F508del mutation; and the AURORA F/F (NCT03525548) with those who have two F508del mutations.
The AURORA F/MF included 403 CF patients who were treated with Trikafta or placebo for up to 24 weeks. In the AURORA F/F, 107 patients with two F508del mutations received either Trikafta or Symdeko for four weeks.
Data from both studies showed significant improvements in lung function in people given Trikafta, as assessed by the percent predicted forced expiratory volume in one second (ppFEV1, a widely used measure of lung function), which was the primary goal of these two studies. The ppFEV1 increased by an average of 13.8 percentage points in the 24-week trial, and by 10 percentage points in the four-week trial.
Trikafta’s impact on patients’ health-related quality of life (HRQoL) was evaluated with the Cystic Fibrosis Questionnaire-Revised (CFQ-R), which incorporates general assessments — vitality, health perceptions, and physical, emotional, social and role functioning — as well as domains specific to CF (body image, eating, treatment burden, and respiratory and digestive symptoms).
“CFQ-R is a validated patient satisfaction score, essentially, how they score the difference in their lives. We look at that in all of these trials,” Leiden said.
“In our Phase 3 trial of Trikafta, we saw a 20-point improvement in CFQ-R, which is really unprecedented in these medical trials. So, that’s telling us that the patients’ own assessment of their lives has changed dramatically,” he said.
The benefits of Trikafta also were seen in the rate of pulmonary exacerbations, which often require patients to be hospitalized and risk losing lung function.
“We saw a 63% reduction in pulmonary exacerbations, so that’s a dramatic clinically and statistically significant reduction in the major complications,” Leiden said. “In addition, we hear lots of stories from patients about how their daily life functions have been fundamentally changed by the medicine.”
Patients using Symdeko and Orkambi have voiced strong interest in trying Trikafta, and “the reason for that is straightforward,” he said. “The clinical trials included a head-to-head comparison of Trikafta versus Symdeko in the F508del homozygous population [with two F508del mutations], and we saw a very significant incremental improvement with Trikafta over Symdeko — a 10-point increase in FEV1 — so that alone will drive a lot of patients to switch.”
However, this is a decision between patients and doctors, and whether patients are satisfied with their current treatment with Symdeko or Orkambi, Leiden emphasized.
“I’m sure there will be some patients who are very happy with the way they are doing on Symdeko or Orkambi and won’t switch, and of course, that’s up to them and their doctors,” he said.
Trikafta is expected to arrive shortly to the U.S. market. “Our teams have been working very hard to make sure we are ready and product is shipping to specialty pharmacies this week,” according to a Vertex spokeswoman who responded via email to questions from CF News Today.
The combo therapy will carry a list price of $311,000 a year, according to Vertex. As such, its price would be comparable to Kalydeco — about $311,000 — but higher than that of Symdeko, which carries a list price of $292,000 per patient per year, and Orkambi $272,000.
“The price reflects reflects a combination of factors, including efficacy of the medicine and its benefit to patients; the value of treating the underlying cause of CF, and our commitment to invest in the discovery and development of new medicines for those still waiting for a cure – and the resources needed to develop these medicines,” Vertex states.
Vertex has a patient assistance program, called Vertex GPS, that offers help to eligible patients in the U.S. who have been prescribed the company’s medications.
There are “assistance programs in place for eligible patients who need additional help, including providing free medicine to patients who meet certain income and other eligibility criteria,” Vertex stated.
“Most commercially insured patients have a monthly out-of-pocket cost for Symdeko, Kalydeco, or Orkambi of $15, and while it is difficult to speculate, we expect out-of-pocket costs for patients on Trikafta who have commercial insurance to be similar,” according to Vertex.
Vertex has submitted a marketing authorization application to the European Medicines Agency for Trikafta. If approved, further negotiations with national health services, like England’s National Health Service (NHS) and the Scottish Medicines Consortium (SMC), will take place. The company also is in discussions with various countries about early access to the therapy.
Vertex recently reached an agreement with England’s NHS, allowing access to all its CF treatments currently approved in Europe at low or no out-of-pocket cost. SMC also granted patients in Scotland access to Orkambi and Symkevi through the national health system in September after initially rejecting them, citing concerns with the cost relative to each treatment’s health benefits.
“Vertex’s CF medicines are now reimbursed in 17 countries around the world including Austria, Australia, Denmark, Germany, the Republic of Ireland, Italy, the Netherlands, Sweden, and the U.S. which underscores the value they bring to patients around the world,” according to the company.
About 10% of CF patients, however, remain without an available therapy, since they don’t make any CFTR protein. So, “there’s no combination of corrector therapies that will actually treat their disease because there’s no protein to treat,” Leiden said.
These patients require a different approach, likely an RNA-based or gene-editing therapies.
Vertex has a partnership with Moderna Therapeutics, and more recently with Ribometrix, to develop potential RNA-targeted therapies. RNA is a blueprint copy of DNA, essential to convert messages contained in genes.
Gene therapies, such as those using the CRISPR gene-editing tool, have shown success in certain genetic diseases. Vertex recently bought Exonics Therapeutics, a gene-editing company that started to use the technology to correct up to 80% of the 3,000 mutations linked with Duchenne muscular dystrophy.
It likely will be a while before that dream comes true, however.
“I don’t think it’s around the corner; I think it’s 10, 15, 20 years down the road. But we are working on it and we’re not going to stop until we get those patients [the 10% without a therapy] something as well,” Leiden concluded.