Modifying the dose of Esbriet (pirfenidone) can effectively reduce the number of treatment-related adverse events without affecting the drug’s potential to manage idiopathic pulmonary fibrosis (IPF), a new retrospective analysis of data from Phase 3 clinical trials shows.
The findings of this recent post-hoc analysis were published in the journal BMJ Open Respiratory Research in a study titled, “Dose modification and dose intensity during treatment with pirfenidone: analysis of pooled data from three multinational phase III trials.”
Marketed by Genentech, Esbriet is an approved therapy used to manage the symptoms of IPF and prevent its worsening. It is a dual acting agent that modulates the response of fibroblasts — the most common type of connective tissue cell — while reducing inflammation and tissue scarring.
Despite its therapeutic potential, during the trials almost all Esbriet-treated patients experienced at least one treatment-related adverse event. Also, more treated patients discontinued the therapy prematurely due to symptoms of toxicity, such as gastrointestinal and skin-related events.
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As Esbriet’s effects have been reported to be dependent on the dose used, it has been suggested that dose modifications could help manage the number of adverse reactions. Until now, though, it remained unclear if this alternative approach could change the effectiveness of the treatment to manage IPF.
Researchers re-analyzed pooled data of the three pivotal trials, comprising 1,247 IPF patients who were randomized to receive oral Esbriet (2,403 mg per day) or a placebo for up to 72 weeks.
Results showed that about the same proportion of patients in the Esbriet and placebo groups had temporary dose reductions during the trials — 59.7% vs. 60.1%, respectively. But more patients treated with Esbriet had to permanently reduce the dose — 31.5% vs. 20.8% in the placebo group.
Most of the interruptions happened during the first six months of treatment, whereas dose modifications were reported throughout the duration of the trials.
When researchers reviewed the therapy’s efficacy data, they found that regardless of the administrated dose, Esbriet showed a clear benefit in preventing decline of forced vital capacity (FVC, a measure of lung function), exercise capacity, or death at one year compared to placebo.
“Despite dose reductions and interruptions, most patients with IPF maintained relatively high dose intensity on [Esbriet] without compromising its treatment effect compared with placebo,” the researchers wrote.
A safety comparison between groups revealed that those taking a lower dose of the treatment had fewer adverse events, such as nausea, compare to those taking higher doses of Esbriet.
While dose reductions were seen to be a “useful management tool to reduce the risk of treatment discontinuation,” the researchers highlight that the study results still do not set a minimum effective dose of Esbriet that could be used during a treatment adjustment period.
Also, the analysis failed to find any evidence of a relationship between body weight and the effectiveness and safety of Esbriet that could support a weight-based dosing.
Still, the team concluded that “dose modifications are an appropriate strategy to manage adverse events and to help ensure long-term persistence with [Esbriet] treatment.”