Long-term safety, efficacy profiles of nintedanib characterized in IPF patients
medwireNews: Results of the INPULSIS-ON extension study suggest that nintedanib has a manageable long-term safety profile and may slow the progression of idiopathic pulmonary fibrosis (IPF).
Previously published findings from the two phase III INPULSIS trials, in which patients were randomly assigned to receive nintedanib 150 mg twice daily (with dose reductions to 100 mg twice daily to manage adverse events) or placebo, demonstrated that the tyrosine kinase inhibitor “significantly reduced the annual rate of decline in forced vital capacity (FVC) versus placebo” over 1 year, and had “an adverse event profile that was acceptable for most patients”, say Bruno Crestani (Hôpital Bichat, Paris, France) and co-investigators.
In all, 734 IPF patients who completed the INPULSIS trials – 59% from the nintedanib group and the remainder from the placebo group – enrolled in the INPULSIS-ON extension study (nintedanib continuation and initiation groups, respectively). All participants received open-label nintedanib at a dose of 150 mg or 100 mg twice daily for a median of 31.5 months in the extension study, giving a total median exposure time of 44.7 months.
As reported in The Lancet Respiratory Medicine, 69% of 430 patients in the nintedanib continuation group and 72% of 304 patients in initiation group discontinued the drug during INPULSIS-ON, primarily as a result of adverse events (AEs).
Diarrhoea was the most commonly reported AE, with event rates of 60.1 per 100 patient exposure–years in the nintedanib continuation group and 71.2 per 100 patient exposure–years in the nintedanib initiation group. The AE most frequently leading to permanent treatment discontinuation was progression of IPF, affecting 12% and 14% of patients in the continuation and initiation groups, respectively.
The corresponding event rates of major adverse cardiovascular events were 3.6 and 2.4 per 100 patient exposure–years, which the authors note were similar to the rates observed among placebo-treated patients in the initial INPULSIS trials.
“[T]hese data are reassuring with regard to the cardiovascular safety of nintedanib and suggest that the risk of these events does not increase with continued nintedanib treatment”, they write.
In the efficacy analysis, average FVC declined at an adjusted rate of 135.1 mL/year from baseline to week 192 among all participants in the extension study, and results were “generally consistent” in subgroup analyses by age, race, and FVC % predicted at study enrolment.
Together, these findings suggest that “[l]ong-term use of nintedanib slows disease progression in patients with idiopathic pulmonary fibrosis and has a manageable safety and tolerability profile,” remark the investigators.
Writing in an accompanying commentary, Athol Wells (Royal Brompton Hospital, London, UK) says that the INPULSIS-ON study provides “invaluable safety data”, but cautions that “the situation is less straightforward” with regards to efficacy given the large number of patients that discontinued treatment during follow-up. He also points out that the extension study was limited by the lack of a control group.
“An intention-to treat study design would have provided invaluable long-term efficacy data and should be prioritised in future”, he concludes.
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