Ofev, Esbriet Combo Seen to Be Safe for IPF Patients in Phase 4 Trial

Adding Ofev (nintedanib) to Esbriet (pirfenidone) for idiopathic pulmonary fibrosis (IPF) is tolerated by most patients and has a similar safety profile as taking each medication alone, a Phase 4 study evaluating the combo treatment over a six-month period showed.

The study, “Safety of Nintedanib Added to Pirfenidone Treatment for Idiopathic Pulmonary Fibrosis,” was published in the journal European Respiratory Journal.

Although treatment with either Boehringer Ingelheim‘s Ofev or Genentech‘s Esbriet helps preserve lung function in patients with IPF and slows disease progression, it cannot stop or reverse the disease course. So, even at a slower pace, lung fibrosis continues to aggravate while patients are on treatment.

Ofev and Esbriet target different molecules that contribute to fibrosis. While Ofev inhibits a group of enzymes called tyrosine kinases — which are involved in mechanisms leading to collagen production and deposition, and the proliferation of fibroblasts (key cells that mediate the scarring process) — Esbriet inhibits TGF-β (which is responsible for excess collagen production), and reduces the secretion of inflammatory mediators and the proliferation of fibroblasts.

Given their different mechanisms of action, researchers have reasoned that adding both drugs to a therapeutic regimen may combine their anti-fibrotic effects and offer superior clinical benefits compared to each individual medicine.

Two previous trials — a small Phase 2 extension study (NCT01136174) in Japan, and the Phase 4 INJOURNEY trial evaluating the combo treatment for three months (NCT02579603) — have suggested that the combination of Ofev plus Esbriet is as safe and well-tolerated as treatment with each drug alone.

But larger, long-term studies are lacking to understand if the combo’s acceptable tolerability and safety are maintained for prolonged periods.

Researchers conducted a single-arm, open-label, international Phase 4 study (NCT02598193) to evaluate the safety of adding Ofev to a stable regimen of Esbriet, over six months (24 weeks), as a combo treatment for patients with IPF.

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Before starting the study, patients needed to be on a stable dose of Esbriet (1,602 mg/day to 2,403 mg/day) for at least 16 weeks before treatment initiation with Ofev (at 200-300 mg/day). 

In total, 89 patients were enrolled from several centers in the U.S., Canada, Denmark, France, Germany, Italy, the Netherlands, and Spain. From these, 16 discontinued treatment, mostly due to associated adverse events (13 patients), especially with Ofev.

At the end of the study, 69 patients met the primary endpoint, which was completing a six-month treatment period receiving the target doses of Ofev and Esbriet.

Almost all patients (99%) experienced at least one adverse event. This value is in line with results from the INJOURNEY trial, which tested the same combo treatment over a shorter period (three months).

Still, it is considered high for a six-month study, especially if compared with one-year treatment with Ofev (95.3%) or therapy with Esbriet (98.7%) alone.

Of these patients, 74 reported 418 treatment-related adverse events. Diarrhea (49%), nausea (46%), and vomiting (24%) were the most common.

Only two patients had serious adverse events due to treatment, both attributed to Ofev. One patient had a transient ischemic attack (a mini-stroke) but continued with treatment, and the other developed deep vein thrombosis (a blood clot block in one of the body’s deep veins) and withdrew from Ofev treatment.

Most treatment-related adverse events were mild to moderate, and were mostly problems affecting the gastrointestinal system (75%), and most were attributed to Ofev.

Seven patients experienced treatment-related sun allergy (photosensitivity) or rash, and six reported liver side effects due to treatment. However, at the end of the study, the combo treatment was not associated with an increased risk of liver toxicity or photosensitivity when compared with Ofev or Esbriet taken alone.

No fatalities were reported during the study.

Overall, the types and frequency of adverse events experienced by IPF patients was in agreement with the safety profile of either medicine alone. Discontinuation rates were also consistent with single-agent treatments.

A likely explanation for the higher incidence of adverse events attributed to Ofev is that, in this study, patients were already tolerant to a stable dose of Esbriet when they started taking Ofev.

Concerning efficacy, an exploratory analysis suggested that lung function declined very slightly during treatment with the two therapies, though solid conclusions cannot be made given the small sample size and the lack of a control group.

“Results of the current study suggest that combination treatment with pirfenidone [Esbriet] and nintedanib [Ofev] could provide a viable future option for patients with IPF,” the researchers wrote.

The findings “encourage further study to determine the efficacy and safety of pirfenidone and nintedanib taken as combination treatment versus monotherapy in patients with IPF,” they added.

Researchers, however, caution that such a combo therapy might not be suitable for all patients, and emphasize that more research is needed to clarify its long-term benefits and risks.

The team also highlighted the need to develop effective strategies to help reduce the burden of gastrointestinal adverse events with this treatment.