Cystic fibrosis

Novel triple combo for CF holds promise for better CFTR function

A novel once-daily triple therapy combination for cystic fibrosis has shown promise in mid-stage trials, with data suggesting that it might further enhance CFTR function than the current standard of care and with reduced frequency of administration, researchers report.

In two Phase II clinical trials funded by Vertex, once-daily treatment with the corrector-potentiator combination of vanzacaftor–tezacaftor–deutivacaftor, tested in people with CF who have at least one F508del allele, was found to be safe and well tolerated overall while improving lung function, respiratory symptoms and CFTR function.

Investigators including Prof John Wilson, Head, Cystic Fibrosis Service, Alfred Hospital, Melbourne, published the findings in The Lancet Respiratory Medicine. In an indirect comparison also showed greater reductions in sweat chloride concentrations in patients with F/MF and F/F genotypes given vanzacaftor–tezacaftor–deutivacaftor than in those with F/MF and F/F genotypes who took part in studies with elexacaftor–tezacaftor–ivacaftor, now the standard of care.

In a linked editorial, Canadian respiratory specialists Dr Lucy Perrem and Dr Felix Ratjen commented that favourable benefit–risk profile for vanzacaftor–tezacaftor–deutivacaftor observed in these Phase II studies, along with its potential to be superior to elexacaftor–tezacaftor–ivacaftor in restoring CFTR function, support its further evaluation and direct comparison with the latter in Phase III trials.

“These studies were done before elexacaftor–tezacaftor–ivacaftor became commercially available such that the control groups do not reflect the existing standard of care, and direct comparisons with the treatment effects observed in the Phase 3 studies for elexacaftor–tezacaftor–ivacaftor are problematic given the lower number of participants and higher variability observed in Phase 2 studies,” they noted.

“However, the results do provide sufficient evidence to bring this drug combination forward to Phase 3 studies with elexacaftor–tezacaftor–ivacaftor as the active control; these trials are underway (NCT05033080 and NCT05076149)”.

The Phase II studies

The analysis was based on two Phase 2, randomised trials: VX18-561-101, which assessed the efficacy and safety of deutivacaftor monotherapy in adults with CF and a CFTR gating mutation, who were previously stable on ivacaftor monotherapy; and VX18-121-101, which evaluated the safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with CF with ppFEV1 between 40 and 90 percentage points.

In VX18-561-101, 77 participants with similar demographic and baseline characteristics were randomly assigned to receive either ivacaftor (n=12), deutivacaftor 25 mg (n=6), deutivacaftor 50 mg (n=11), deutivacaftor 150 mg (n=24) and deutivacaftor 250 mg (n=24).

Data showed a mean absolute change in ppFEV1 from baseline at week 12 of 3.1 percentage points for deutivacaftor 150 mg once daily and 2.7 percentage points for deutivacaftor 250 mg once daily, versus –0.8 percentage points for ivacaftor 150 mg every 12 hours.

The mean change in sweat chloride concentration was 3.3 mmol/L for deutivacaftor 150 mg and –6.5 mmol/L  for the 250 mg dose, compared with 0.9 mmol/L for ivacaftor 150 mg, according to the paper.

In part 1 of VX18-121-101, participants with F/MF genotypes were given either 5 mg, 10 mg, or 20 mg vanzacaftor in triple combination with tezacaftor–deutivacaftor or triple placebo for 4 weeks, after which they received tezacaftor–deutivacaftor or a dual placebo.

In part 2 of the trial, following completion of a 4-week run of tezacaftor–ivacaftor, participants with the F/F genotype were treated either with 20 mg vanzacaftor in triple combination with tezacaftor–deutivacaftor or tezacaftor–ivacaftor alone for four weeks, with all participants then receiving tezacaftor–ivacaftor for a further 4 weeks.

Results from the first part of the trial showed that treatment with vanzacaftor 5 mg, 10 mg and 20 mg, combined with tezacaftor and deutivacaftor, in CF patients with F/MF genotypes resulted in mean changes in ppFEV1 from baseline to day 29 of 5 percentage points, 14 percentage points and 10 percentage points, respectively, compared with a mean change of 2 percentage points for those in the placebo arm.

Those for sweat chloride concentration in participants with the F/MF genotypes in the vanzacaftor treatment groups were −43 mmol/L, −46 mmol/L and −50 mmol/L, respectively, versus 2 mmol/L for participants receiving placebo, while for those with the  F/F genotype given vanzacaftor (20 mg)–tezacaftor–deutivacaftor there was a mean change of −46 mmol/L compared with –3 mmol/L in those treated with tezacaftor–ivacaftor.

Safe, effective and once-daily

According to the authors, data from both studies showed that vanzacaftor–tezacaftor–deutivacaftor was effective in adults with cystic fibrosis who have F/MF or F/F genotypes, and that it was safe and well tolerated, with adverse events “mostly mild or moderate in severity and generally consistent with manifestations of cystic fibrosis”.

They also emphasised that the additional convenience of a once-daily dosing regimen could improve adherence to CTFR modulator therapy, particularly among patients taking multiple medicines.

The editorialists added that adherence to CFTR modulators “is already high and better than for other maintenance therapies,” but that “it is possible that decreasing the frequency of administration of modulator treatments from twice to once daily might provide a further boost to adherence rates”.

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