Vertex Pharmaceuticals has taken a major step toward treating 90% of all people with cystic fibrosis (CF), its long-stated goal, with the U.S. Food and Drug Administration’s approval of Trikafta (elexacaftor, tezacaftor, and ivacaftor) as a next-generation, triple combination treatment for CF.
This triple combination treats people with the most common CF-causing mutation, that of at least one F508del defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, found in an estimated 90% of all CF patients.
Trikafta, whose approval was based on two Phase 3 trials in the AURORA program, was specifically approved for use in patients, 12 and older, with one F508del and one minimal function mutation, or with two F508del mutations, which reflects the patient groups in each trial — NCT03525444 for one F508del mutation, and NCT03525548 for two mutations.
The triple therapy is a CFTR modulator, as it helps the defective CFTR protein (produced from a mutated CFTR gene) to work more effectively. The combo was developed to benefit people with one or two F508del mutations in CFTR who don’t respond or respond poorly to already approved Vertex therapies for CF — namely Kalydeco (ivacaftor), a CFTR potentiator, or the potentiator-corrector combinations of Orkambi (lumacaftor/ivacaftor), and Symdeko (tezacaftor/ivacaftor, ivacaftor).
“In the past few years, we have seen remarkable breakthroughs in therapies to treat cystic fibrosis and improve patients’ quality of life, yet many subgroups of cystic fibrosis patients did not have approved treatment options,” Ned Sharpless, MD, the FDA’s acting commissioner, said in an agency release.
“Today’s landmark approval is a testament to … making a novel treatment available to most cystic fibrosis patients, including adolescents, who previously had no options, and giving others in the cystic fibrosis community access to an additional effective therapy,” Sharpless added.
The FDA’s decision came five months ahead of its expected “accelerated” approval date of March 2020.
Trikafta will likely carry a list price of $311,000 when it arrives shortly on the U.S. market, according to several news reports. As such, its price would be comparable to Kalydeco, Vertex’s most effective CF treatment.
“Today marks a milestone for CF patients, their families and Vertex. After a 20-year journey together, we have received FDA approval of Trikafta: a single breakthrough medicine with the potential to treat up to 90% of all people with CF in the future,” Jeffrey Leiden, MD, PhD, Vertex’s president and CEO, said in a news release. “For approximately 6,000 people with CF in the U.S., Trikafta is the first medicine that can treat the underlying cause of their disease.”
For the estimated 6,000 people in the U.S., 12 and older, who have one F508del plus one minimal function CFTR mutation, Trikafta represents a first disease-modifying treatment (DMT). An estimated 12,000 U.S. residents have one or two F508del mutations and could be treated with the other approved Vertex DMTs, but may now also use Trikafta, the release stated.
Both elexacaftor and tezacaftor work as correctors to increase the amount of CFTR functional protein at the cell surface by “correcting” the F508del mutated protein, while Kalydeco — a potentiator — increases how well CFTR works in a cell.
The two Phase 3 AURORA trials tested the triple combo therapy in more than 500 CF patients.
AURORA F/MF (NCT03525444) included 403 people with CF caused by one F508del and one minimal function mutation, who were treated with either Trikafta or a placebo for up to 24 weeks. AURORA F/F (NCT03525548) enrolled 107 patients with two F508del mutations, who were treated with 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-treated patients in AURORA F/MF also showed improvements in all of its secondary goals, including a lower annual rate of pulmonary exacerbations (worsening respiratory symptoms), and reduced levels of chloride in their sweat.
The treatment was generally well-tolerated in both studies.
Kalydeco was approved by the FDA in 2012, Orkambi in 2015, and Symdeko in 2018 — bringing a triple combo treatment that addresses the underlying cause of CF (CFTR mutation) to a near majority of patients worldwide. But Vertex’s goal has long been to treat all patients with CF.
“Since 90% — that’s nine-zero! — of all patients with CF have [at least] one copy of F508 … this has the potential to [be effective in] 90% of people with CF,” David Altshuler, Vertex’s chief scientific officer, said in a September 2018 interview with Cystic Fibrosis News Today about data from two Phase 2 studies that tested the triple combo therapies VX-445 (elexacaftor) and another next-generation corrector called VX-659.
Edith Zemanick, MD, a pediatric pulmonologist at Children’s Hospital Colorado who served as an investigator for several Vertex trials, said in the same interview: “It’s really a shift in how we’re treating CF. We want our patients to have access.”
Given Trikafta’s benefit to the CF community, the FDA said it reviewed and approved the therapy in about three months; therapies marked for accelerated approval by the agency typically undergo a six-month review.
“The incredible speed of this approval underscores our shared sense of urgency with the FDA and the CF community for bringing this medicine to eligible people with CF, particularly those without a medicine targeting the underlying cause of their disease,” said Reshma Kewalramani, MD, Vertex’s executive vice president of global medicines development and medical affairs, and chief medical officer.
The company has also submitted a Marketing Authorization Application to the European Medicines Agency for the elexacaftor/tezacaftor/ivacaftor combination, and is pursuing its plans to test this therapy in children 6 to 11, and in those younger than 6.
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. The program provides information about the therapies, insurance benefits, and available resources.