Adverse effects of vanzacaftor-tezacaftor-deutivacaftor in a cystic fibrosis population: A case series

Abstract

Vanazacaftor-Tezacaftor-Deutivacaftor (VTD) is a novel cystic fibrosis transmembrane receptor (CFTR) modulator therapy. This development added another highly effective modulator therapy to the market as an alternative to the standard of care, Elexacaftor-Tezacaftor-Ivacaftor (ETI). Phase III trial data comparing VTD and ETI demonstrated non-inferiority in outcomes and similar adverse effect profile and rates. Here we present a case series demonstrating known and potentially unknown side effects, specific to VTD. From January 2025 to June 2025, 38 out of 400 patients at our adult CF center, were switched from ETI to VTD. Six of those patients experienced potential VTD related adverse events. Liver function testing (LFT) elevations were seen in 2/6 cases, worsening pulmonary symptoms in 3/6 cases, dermatologic manifestations in 2/6 cases, hypertension in 1/6 cases, neuropsychiatric symptoms in 2/6 cases, and gastrointestinal symptoms in 2/6 cases. Notably, one case led to hospitalization, with development of a severe rash, thrombocytopenia, and LFT elevations. In each case, all symptoms and laboratory manifestations resolved within days after switching back to ETI. This case series demonstrates both previously recognized and unrecognized adverse effects of VTD in a “real-world population.” The majority of our patients’ presenting symptoms were described in phase III clinical trials, including LFT elevations, pulmonary exacerbations, rash, and neuropsychiatric symptoms. On the contrary, thrombocytopenia, gastrointestinal manifestations, and hypertension have not been described thus far with VTD. Further research and more robust monitoring are needed to determine the overall incidence and risk of lesser-known side effects of novel CFTR modulators.