New triple-combo CFTR modulator bests Trikafta in Phase 3 trials

New 'vanza triple' outperformed approved therapy at reducing sweat chloride

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A new triple-combination CFTR modulator therapy for cystic fibrosis (CF) — vanzacaftor, tezacaftor and deutivacaftor — outperformed the approved therapy Trikafta (elexacaftor/tezacaftor/ivacaftor) at reducing sweat chloride levels in Phase 3 trials.

The new “vanza triple” combo was similar to Trikafta at maintaining short-term lung function for eligible CF patients. The findings were announced by Vertex Pharmaceuticals, which markets Trikafta and is developing the new combination therapy.

“We are very pleased with today’s results, which demonstrate the vanza triple is non-inferior to Trikafta in improving lung function and superior to Trikafta in lowering levels of sweat chloride in people living with CF, setting a new standard for the level of CFTR protein function achievable, and raising the very high bar set by Trikafta,” said Carmen Bozic, MD, executive vice president, global medicines development and medical affairs, and chief medical officer at Vertex, in a company press release.

“The efficacy seen with the vanza triple gives me great hope for CF patients in the future,” added Bonnie Ramsey, MD, co-chair of Vertex’s CFTR modulator steering committee and professor emerita at the University of Washington School of Medicine.

Vertex intends to ask regulatory agencies in the U.S. and Europe to approve the vanza triple for eligible CF patients ages 6 and older by mid-year, based on the results. The company said it plans to use a priority review voucher for the U.S. application, which will trim the review time from 10 to six months.

“We look forward to submitting our application to regulators with the aim of bringing this potential medicine to patients as quickly as possible,” Bozic said.

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 Results of SKYLINE studies

CF is caused by mutations that disrupt the CFTR protein’s activity or production. CFTR modulators are a recent class of medicines that can improve the protein’s functionality in patients with specific disease-causing mutations.

“I have been working as a pediatric pulmonologist for more than four decades and have seen firsthand the dramatic impact of CFTR modulators on people with CF, transforming CF from a life-shortening disease to today, where we see the potential for halting the disease before it starts,” Ramsey said.

Trikafta is widely approved for patients with the most common CF-causing mutation, called F508del, aalong with other mutations that respond to it. The vanza triple is a next-generation therapy containing one of the modulators in Trikafta, tezacaftor, alongside two new ones — vanzacaftor (VX-121) and deutivacaftor (VX-561).

Vertext conducted three Phase 3 clinical trials of the vanza triple combination in patients with F508del and other mutations responsive to triple-modulator therapy.

Two of them, SKYLINE 103 (NCT05076149) and SKYLINE 102 (NCT05033080), collectively included more than 1,000 people ages 12 and older with CF. After a run-in period where all were given Trikafta, the patients were randomly assigned to Trikafta or the vanza triple for about six months.

The main goal was to compare the rate of decline in forced expiratory volume in one second (FEV1), a common measure of lung function. FEV1 was largely unchanged throughout the study for those given either therapy, suggesting stable lung function with both.

Changes in sweat chloride levels

A key secondary measure was the level of chloride in patients’ sweat. Chloride is a salt molecule (half of table salt, or sodium chloride). When CFTR is dysfunctional, excess chloride is secreted in sweat, which is why people with CF characteristically have very salty sweat.

In both trials, sweat chloride levels decreased significantly more with the vanza triple than with Trikafta. Since sweat chloride is a marker of CFTR function, this suggests the new combination therapy leads to better function of the protein whose defect is at the heart of the disease.

Across both SKYLINE trials, significantly more participants given the vanza triple than Trikafta had sweat chloride levels below 60 mmol/L (86% vs. 77%) or below 30 mmol/L (31% vs. 23%). For context, sweat chloride levels of 60 mmol/L or higher are the usual diagnostic cutoff for CF and levels below 30 mmol/L are seen in people with one mutated copy of the CFTR gene, but without any manifestation of disease (carriers). People with CF have two mutated CFTR gene copies.

The third Phase 3 trial, called RIDGELINE 105, enrolled 78 children with CF ages 6-11. All were on Trikafta for at least four weeks before switching to the vanza triple.

Throughout the six-month study, FEV1 was unchanged (indicating stable lung function), while sweat chloride levels decreased significantly by an average of 8.6 mmol/L, suggesting better CFTR function with the vanza triple than Trikafta. After six months on the new combo, more than half (53%) the children had sweat chloride levels below 30 mmol/L, and almost all had levels below 60 mmol/L.

“These results were particularly striking in the pediatric study where 95% of children achieved a SwCl [sweat chloride] level below 60 mmol/L, the diagnostic cutoff for a positive test for CF, and more than 50% of children achieved a SwCl level below carrier levels where they may see no symptoms of disease at all,” Ramsey said.

Across all three trials, the vanza triple was generally well tolerated and its safety profile was similar to Trikafta’s in SKYLINE 102 and SKYLINE 103. The most common safety-related issues were infections, including pulmonary exacerbations, COVID-19, cough, and the common cold.