#NACFC2022 – Vertex Aiming to Expand Trikafta’s Use, Better Treat CF

Asking FDA to approve therapy for patients ages 2 to 5, new combo in trials

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Vertex Pharmaceuticals recently filed an application with the U.S. Food and Drug Administration (FDA) asking that Trikafta, its triple-combination modulator therapy, be approved for children with cystic fibrosis (CF) ages 2 to 5.

The company is planning to file similar requests in the European Union and U.K. by the end of the year, according to a Vertex spokesperson.

“Treating children with cystic fibrosis early in life is critically important because early intervention has the potential to slow the progression and prevent the irreversible damage of this devastating disease,” the company said in an email response to questions from Cystic Fibrosis News Today.

Vertex also plans to ask the FDA to approve the single-modulator therapy Kalydeco (ivacaftor) for patients as young as 1 month old. The therapy is currently approved for people, ages 4 months and older, who have one of 97 amenable mutation.

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An illustration shows images of lungs flanking an announcement of the North American Cystic Fibrosis Conference.

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“We continue to evaluate all our CF medicines in younger ages to ensure they bring a safe and effective benefit profile to patients,” the spokesperson said.

Applications for Trikafta are based on data from an open-label, Phase 3 clinical trial (NCT04537793) in children with CF, ages 2 to 5, who had at least one copy of F508del, the most common CF-causing mutation.

Results presented earlier this month at the North American Cystic Fibrosis Conference (NACFC) in Philadelphia showed that the therapy helped improve lung function and stabilize nutritional status in these young children. It was also generally well-tolerated, meeting the study’s main goal of demonstrating safety.

“[Trikafta] was generally safe and well-tolerated in children 2 through 5 years of age, with a safety profile consistent with older age groups,” Vertex said.

Trikafta contains a combination of three medications (elexacaftor, tezacaftor, and ivacaftor) that can improve the functionality of the defective CFTR protein in people with CF caused by specific mutations.

In other NACFC presentations, scientists at Vertex and other institutions shared new three-year data from the Phase 3 AURORA studies, which supported the initial FDA approval of Trikafta in patients ages 12 and up in 2019. After the placebo-controlled trials, participants had the option to enroll in an open-label extension study (NCT03525574), where all were treated with Trikafta and followed for long-term efficacy and safety.

“This is the longest study of Trikafta to-date and it has shown that Trikafta has changed standard of care therapy in CF,” Vertex said.

Results showed that gains in lung function and nutritional status were maintained after nearly three years of treatment. Assessments of sweat chloride also indicated maintained improvement of CFTR protein function.

“The 144-week data underscores the remarkable long-term health benefits of treating the underlying cause of disease with Trikafta in people with CF,” Vertex said. “Demonstrating that clinically meaningful improvements of lung function, respiratory symptoms, and CFTR function can be maintained over an extended period, highlights the importance of treating cystic fibrosis with CFTR modulators as early as possible.”

Improvements in the respiratory domain of the Cystic Fibrosis Questionnaire Revised — an instrument of health-related quality of life — were similarly maintained.

“What we are seeing through the data is significant improvements in the patient-reported outcome CFQ-R Respiratory Domain, reflecting a reduction in cough, among other symptoms and the reduction in exacerbations, meaning less time spent in clinic visits and in the hospital,” Vertex said.

Trikafta “continued to be generally safe and well tolerated, with no new safety findings” in the open-label extension study, it added.

Potentially ‘more potent’ CF treatment advancing in trials

In addition to its suite of approved CFTR modulators, Vertex is sponsoring trials of a new triple-combination therapy, vanzacaftor/tezacaftor/deutivacaftor (formerly called VX-121/tezacaftor/VX-561).

“We continue to advance even more effective CFTR modulator therapies aimed at further improving CFTR function in the lung and all organs affected in CF to levels that are not associated with disease,” the company said.

The therapy contains one of the CFTR modulators used in Trikafta (tezacaftor) alongside two more recently developed investigational modulators. In preclinical experiments, it was seen to be more potent at improving CFTR function, Vertex reported.

In a Phase 2 study (NCT03912233) of vanzacaftor/tezacaftor/deutivacaftor in adults with CF who had at least one F508del mutation, the therapy was generally well-tolerated and met the trial’s main goal of improving lung function.

A pair of Phase 3 clinical trials is underway to test the novel combination against Trikafta in CF patients ages 12 and older. One study, SKYLINE 103 (NCT05076149), is open to patients with at least one mutation predicted to be responsive to the treatment, while the other, called SKYLINE 102 (NCT05033080), is enrolling only patients with one copy of F508del and one minimal function mutation

Contact and site information for SYLINE 103 and SYLINE 102 is available; both are actively recruiting participants at dozens of sites across Europe, the U.S., Australia, and New Zealand.

Vertex is also running an open-label clinical trial (NCT05422222) testing vanzacaftor/tezacaftor/deutivacaftor in children with CF, ages 1 to 11, who have at least one responsive mutation. Patients are being enrolled at sites in the U.S.

Through a collaboration with Moderna that was started in 2016, Vertex is also working to advance mRNA therapies for CF. The overarching goal of this treatment strategy is to deliver a genetic template with instructions for making CFTR, which cells can use to generate a working version of the protein.

Notably, these therapies would be expected to work regardless of the underlying disease-causing mutation.

“Our focus for genetic therapies is to target the underlying cause of disease in people with CF who are not responsive to CFTR modulators and therefore continue to have a high unmet medical need,” Vertex said.

The company reports being on track to submit an application asking for FDA permission to begin clinical testing of these treatments by year’s end.

“We … are making rapid progress … to advance our first CFTR mRNA therapy, bringing us closer to our goal of treating all people with CF,” Vertex said. “We have come a long way, but there is still more important work to do.  We won’t stop until we are able to treat all people with CF regardless of genotype or age.”

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