Phase II data underpin potential of novel triplet for cystic fibrosis

Two phase II studies showed favourable signals for vanzacaftor, tezacaftor, and deutivacaftor (VX-121/TEZ/D-IVA) – a novel triplet regimen for cystic fibrosis (CF) – which could be an alternative to elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA).

 

“ELX/TEZ/IVA is the standard of care (SoC) treatment for CF,” said the researchers. However, only a few patients taking ELX/TEZ/IVA achieve sweat chloride concentrations similar to those observed in individuals with a single copy of a CF-causing mutation who are usually asymptomatic. “This suggests that it might be possible to develop more efficacious CFTR* modulators that could further enhance CFTR function in patients with CF.”

 

The team sought to identify a novel CFTR modulator combination that can further increase CFTR-mediated chloride transport to correct the basic defect causing CF, with the potential for once-daily (QD) dosing to improve adherence. [Lancet Respir Med 2023;11:550-562]

 

In VX18-561-101 (study A), after a 4-week IVA monotherapy run-in period, 77 patients were randomized 1:1:2:2:2 to IVA 150 mg Q12H or D-IVA 25, 50, 150, or 250 mg QD for 12 weeks. In VX18-121-101 (study B), participants with F/MF** genotypes (n=58) were randomized 1:2:2:1 to TEZ/D-IVA with VX-121 5, 10, or 20 mg or a triple placebo for 4 weeks. Those with the F/F** genotype (n=28) were randomized 2:1 to TEZ/D-IVA with or without VX-121 20 mg for 4 weeks, after completing a 4-week TEZ/IVA run-in period.

 

Improved lung function

VX-121/TEZ/D-IVA conferred clinically meaningful improvements in both ppFEV₁*** and CFQ-R^# respiratory domain score.

 

In study A, week 12 saw greater mean absolute changes in ppFEV₁ from baseline with D-IVA 150 and 250 mg vs IVA (3.1 and 2.7 vs –0.8 percentage points). The lower D-IVA doses were discontinued after five patients had ppFEV₁ reductions, which correlated with the inadequate CFTR modulation tied to lower D-IVA doses, the researchers noted.

 

In the F/MF subgroup of study B, mean changes in ppFEV₁ relative to baseline were greater with the VX-121-based regimen (4.6, 14.2, and 9.8 percentage points for the respective 5-, 10-, and 20-mg doses) vs placebo (1.9 percentage points) at day 29. A similar trend was seen in terms of CFQ-R respiratory domain score improvements (17.6, 21.2, and 29.8 vs 3.3 points).

 

In the F/F subgroup, an increase in ppFEV₁ from baseline through day 29 was seen among those receiving add-on VX-121 vs those on TEZ/IVA alone (15.9 vs –0.1 percentage points). The VX-121-based regimen also trumped TEZ/IVA alone in terms of improvement in CFQ-R respiratory domain score (19.4 vs −5.0 points).

 

The ppFEV₁ and CFQ-R improvements with VX-121 10 or 20 mg combined with TEZ/D-IVA were consistent with (or better than) those previously reported with ELX/TEZ/IVA, the researchers noted.

 

Sweat chloride concentration

In study A, mean changes in sweat chloride concentration from baseline were 3.3 and –6.5 mmol/L for D-IVA 150 and 250 mg and 0.9 mmol/L for IVA.

 

In study B, mean changes in sweat chloride concentration were greater with the VX-121-based regimen vs placebo (−42.8, −45.8, and −49.5 mmol/L [5, 10, and 20 mg] vs 2.3 mmol/L; p<0.0001 for all comparisons) in the F/MF subgroup at day 29. Similarly, the VX-121-based regimen trumped TEZ/IVA in the F/F subgroup (−45.5 vs −2.6 mmol/L; p<0.0001).

 

Lower sweat chloride concentrations are tied to reduced mortality and improved clinical outcomes (eg, reduced rates of lung function decline and lung transplantations; better growth and nutritional parameters). [J Cyst Fibros 2015;14:580-586; J Cyst Fibros 2017;16:41-44] “Thus, lifelong improvement of sweat chloride concentrations to amounts closer to those seen in asymptomatic carriers is anticipated to further improve short- and long-term outcomes,” they explained.

 

Safety profile

Overall, the most common adverse events (AEs) were cough, increased sputum, and headache. One participant on VX-121/TEZ/D-IVA had a serious AE of infective pulmonary exacerbation; another discontinued treatment due to a serious rash event. “For most participants, AEs were mild or moderate in severity and were generally consistent with CF manifestations,” the researchers said.

 

More effective than SoC?

The current findings show that VX-121/TEZ/D-IVA led to improved lung function, respiratory symptoms, and CFTR function, and was safe and well tolerated, said the researchers.

 

“Based on the ppFEV₁ and CFQ-R results, together with the changes in sweat chloride concentrations, VX-121/TEZ/D-IVA has the potential to be more efficacious than ELX/TEZ/IVA,” they concluded. Moreover, the QD dosing may reduce barriers to successful treatment and increase adherence, especially among patients on multiple medications.

 

“The favourable benefit-risk profile, along with the potential superiority to ELX/TEZ/IVA in restoring CFTR function, support further investigation of VX-121/TEZ/D-IVA in phase III trials against ELX/TEZ/IVA,” they said.