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A three-drug combination for a certain form of cystic fibrosis (CF) not addressed with other therapies met its efficacy and safety endpoints in a phase III trial, researchers said.

Elexacaftor, tezacaftor, and ivacaftor (Trikafta) together improved forced expiratory volume in one second (FEV₁) and lowered chloride levels in sweat in CF patients with Phe508del-gating or Phe508del-residual function genotypes, relative to a control regimen of ivacaftor either alone (Kalydeco) or with tezacaftor (Symdeko), reported Peter J. Barry, MD, of Manchester University NHS Foundation Trust in England, and colleagues in the .

Adverse events were similar in character and prevalence to those seen in previous studies of the three-drug combo, which the for a related but separate CF subtype, in which patients have one copy of the Phe508 deletion plus another non-Phe508 mutation on a separate allele that results in no functional CFTR protein expression. Patients in the current study could still have some CFTR activity, though at a level low enough to cause substantial CF symptoms.

"Most patients with gating or residual function CFTR mutations are heterozygous for the Phe508del mutation," Barry and colleagues explained.

For the code-named VX18-445-104, the researchers enrolled 258 patients and randomized them 1:1 to the three-drug combo or one of the two active control regimens. All patients initially began with a 4-week run-in period in which they received ivacaftor alone at 150 mg twice a day, or ivacaftor at that dosage plus 100 mg/day of tezacaftor. These regimens were chosen on the basis of patients' specific genotypes and approvals in the trial sites' countries.

In the 8-week, double-blind, randomized phase, patients either remained on their run-in regimens (control) or received the three-drug combination that included elexacaftor at 200 mg/day.

Baseline characteristics included the following:

• Close to 50% each men and women
• Mean age about 38
• About 90% white
• 38% in North America, 52% in Europe, 10% in Australia
• 37% Phe508del-gating, the rest with Phe508del-residual function
• Mean FEV₁ 67%-68%, with about half in the 40%-70% range and most of the rest at 70%-90%
• Mean sweat chloride level 58 mmol/L
• Mean Cystic Fibrosis Questionnaire Revised respiratory domain score 77

Mean change in FEV₁ was 0.2 percentage points in the combined control groups versus 3.7 points with the three-drug combination, for a between-group difference of 3.5 points (95% CI 2.2-4.7).

Similarly, sweat chloride increased by 0.7 mmol/L with the control treatments compared with a decrease of 22.3 mmol/L with triple therapy, for a difference of 23.1 mmol/L (95% CI 20.1-26.1).

Changes in CFQ-R respiratory domain score, a patient-reported measure of breathing function, followed the same pattern.

About two-thirds of patients experienced some type of adverse event, though only about 4% were rated as severe and none were life-threatening. Of 16 events deemed serious, nine were CF-related lung infections, seven of which were in the control group. Two control patients and one assigned to triple therapy stopped treatment because of side effects.

The only class of adverse event seen predominantly with the three-drug combination was liver enzyme elevation, specifically alanine and aspartate aminotransferase. Most of these events involved elevations of at least three times but less than five times the upper limit of normal (ULN). One patient on triple therapy experienced elevations more than eight times ULN, but none of these events was classed as serious.

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