Abstract Introduction Vanzacaftor-Tezacaftor-Deutivacaftor (VTD) is a novel cystic fibrosis transmembrane receptor (CFTR) modulator therapy approved in December 2024. This development added another highly effective modulator therapy to the market as an alternative to the standard of care, Elexacaftor-Tezacaftor-Ivacaftor (ETI), which was approved in 2019. The advent of ETI was a major step forward in the revolution of cystic fibrosis (CF) management, providing patients with a therapy that led to less frequent exacerbations, improved lung function, and positively impacted quality of life. As with any new medication, adverse effect monitoring is a critical component of post-market research in the years following FDA approval. Phase III trial data comparing VTD and ETI demonstrated non-inferiority in outcomes and had similar adverse effect profiles and rates. Here we present a case series demonstrating known and potentially unknown side effects specific to VTD, along with their clinical course following discontinuation and ETI reinitiation. Case Descriptions From January 2025 to June 2025, 38 of roughly 400 patients seen at our adult center were switched from ETI to VTD due to intolerable side effects or desire to reduce pill burden. Six of those patients experienced potential VTD related adverse events. Detailed information regarding each individual case is presented in Table 1. 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. Discussion This case series demonstrates both previously recognized and unrecognized adverse effects of VTD in a “real-world population,” all of which led to discontinuation of VTD and reinitiation of ETI. The majority of our patients’ 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 incidence and risk of these lesser-known side effects, which seem to be specific to VTD when compared to ETI. Clinicians should develop a framework for monitoring and discontinuation of novel CFTR modulators such as VTD when adverse effects occur, especially within the initiation or transition period. This abstract is funded by: None
Saag et al. (Fri,) studied this question.