BRISBANE, Calif.—Hoping to rise to approved status for the novel lung disease drug pirfenidone, global biotech firm InterMune Inc. has resubmitted its 2010 New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA)—four years after the FDA asked for a more stringent Phase 3 clinical trial.
This time, InterMune says, it was much better prepared. On May 18, 2014, the biotech reported top-line results from ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF), a controlled Phase 3 trial sponsored by InterMune. The randomized, double-blind, placebo-controlled trial enrolled 555 patients.
ASCEND data confirmed observations from other clinical studies that pirfenidone significantly reduced idiopathic pulmonary fibrosis (IPF) disease progression, showed a favorable safety profile and was generally well tolerated. A paper about the Phase 3 trial appeared May 18 in the online version of the New England Journal of Medicine.
Pirfenidone has been developed and even marketed already for the treatment of IPF. But while it has been part of IPF treatment in Europe, Asia and South America, approval of pirfenidone in the United States had been elusive.
“We are pleased to have resubmitted the pirfenidone NDA and look forward to our interactions with the FDA,” Daniel G. Welch, chairman, CEO and president of InterMune, stated in a news release. “The final steps in preparing the resubmission were completed very smoothly and efficiently, allowing us to complete the process somewhat earlier than expected.”
“If the FDA grants approval of our NDA within the six-month review period of an NDA resubmission, we would be ready to launch pirfenidone in the first quarter of 2015,” Welch added.
That’s also good news for the “between 50,000 to 70,000 adults in the U.S. diagnosed with IPF, a chronic, progressive and irreversible lung disease characterized by scarring in the lungs, which hinders a person’s ability to breathe,” according to Jim Goff, vice president of investor relations for InterMune. “Of these, between 30,000 and 50,000 are estimated to have mild to moderate impairment.”
With no cure or effective treatment, the odds for IPF patients are grim.
“The median survival time from diagnosis is two to five years, which makes IPF more rapidly lethal than many malignancies, including breast, ovarian and colorectal cancers, and similar to those with pancreatic cancer and of all the leukemias combined and nearly 30 times that of cystic fibrosis,” Goff says. “Currently, there are no medicines approved to slow the progression of the disease.”
Pirfenidone is approved for marketing in 30 European countries (28 in the European Union plus Norway and Iceland) and Canada under the InterMune trade name Esbriet and in Japan and South Korea, where it is marketed by Shionogi & Co. Ltd. under the trade name Pirespa.
“Under different trade names, pirfenidone is also approved for the treatment of IPF in China, India and Argentina,” Goff says. “Esbriet is the only approved IPF medicine in the EU and Canada.”
In the United States, “the FDA spends the time necessary to ensure drugs are properly approved, and this timing may differ depending on each country’s specific regulatory policies,” Goff adds. “The regulatory process varies from country to country.”
After InterMune originally submitted its NDA for pirfenidone to the FDA in November 2009, the FDA sent a Complete Response Letter (CRL) in May 2010 to the biotech firm recommending an additional Phase 3 clinical trial to further support the efficacy of pirfenidone in IPF.
In January 2011, InterMune reported that, as recommended by the FDA in its CRL, the company would conduct a new Phase 3 clinical study to demonstrate a clinically meaningful effect on forced vital capacity (FVC). The first patient was enrolled in the study, referred to as the ASCEND study, in July of 2011, and enrollment was completed in January 2013, according to InterMune.
InterMune’s NDA resubmission in May included the ASCEND clinical study report, as well as the pooled analyses of efficacy and mortality from the three InterMune Phase 3 trials, according to Goff.
“The magnitude of the treatment effect of pirfenidone was measured by comparing the proportion of patients in the pirfenidone and placebo groups experiencing either a clinically meaningful change in FVC or death,” Goff explains. “A 10-percent decline in FVC in an individual IPF patient is considered clinically meaningful and strongly predicts mortality.
“At week 52, 16.5 percent of patients in the pirfenidone group experienced an FVC decline of 10 percent or more or death, compared with 31.8 percent in the placebo group, representing a 47.9-percent reduction in the proportion of patients who experienced a meaningful change in FVC or death.”
Additionally, at week 52, the ASCEND data demonstrated that 22.7 percent of patients in the pirfenidone group experienced no decline in FVC, compared to 9.7 percent in the placebo group, representing a 132.5-percent increase in the proportion of patients whose FVC did not decrease between baseline and week 52.
“The most common adverse events with higher incidence in the pirfenidone group were gastrointestinal, as in nausea and dyspepsia and a skin rash,” according to Goff. “The gastrointestinal and rash adverse events were generally mild to moderate in severity; they were manageable, reversible and only infrequently led to treatment discontinuations.”
In the ASCEND study, pirfenidone demonstrated “significant reduction in decline in lung function as well as significant treatment effects on both change in six-minute walk distance, a common functional exercise capacity test, and progression-free survival,” Goff reports.
The percentage of patients discontinuing treatment due to an adverse event was 14.4 percent in the pirfenidone group and 10.8 percent in the placebo group.
“Serious adverse events were reported in 19.8 percent of patients in the pirfenidone group and 24.9 percent in the placebo group,” Goff says. “The most common serious adverse event was worsening of idiopathic pulmonary fibrosis (2.5 percent of patients in the pirfenidone group vs. 9.7 percent in the placebo group).”
Dr. Paul W. Noble, chair of the Department of Medicine at Cedars-Sinai Medical Center in Los Angeles and co-chair of the ASCEND protocol steering committee, was impressed with the study’s most recent results.
The ASCEND trial “reinforces the favorable safety and tolerability profile observed in previous studies of pirfenidone and through real-world experience where it is currently marketed,” Noble stated. “As a treating physician, I am pleased that there is such a robust and thorough assessment of the safety and tolerability of pirfenidone, a medicine that may play an important role in managing patients with IPF.”