InterMune ASCENDs on new Phase III pirfenidone data
This article was originally published in Scrip
InterMune will resubmit its new drug application (NDA) to the US FDA early in the third quarter of this year now that the company has positive data in hand from the Phase III ASCEND clinical trial for pirfenidone in the treatment of idiopathic pulmonary fibrosis (IPF).
Brisbane, California-based InterMune's stock soared 170.8% higher on 25 February to close at $37.80 per share with a $3bn market cap after the company said pirfenidone cut the percentage of IPF patients who died or experienced a 10% decrease in lung function by 47.9% versus placebo. More than three years after the FDA rejected pirfenidone and required a third Phase III study for approval, InterMune added nearly $2bn to its market cap in one day.
"This is a special moment for us and, more importantly, for patients who have no approved therapies in the United States," InterMune executive vice president of research and development Jonathan Leff told Scrip.
Pirfenidone is approved to treat adults with mild-to-moderate IPF in the EU and Canada, where it is sold as Esbriet. Shionogi sells the oral drug as Pirespa in Japan and South Korea. Pirfenidone also is approved to treat IPF in China, India, Argentina and Mexico.
The FDA required the ASCEND clinical trial for US approval since InterMune's Phase III CAPACITY-1 clinical trial missed its primary endpoint, but the Phase III CAPACITY-2 trial showed statistically significant efficacy. At the time, Jefferies analyst Eun Yang said she would not be surprised if the company ended its pirfenidone program in IPF based on the mixed CAPACITY results and the FDA rejection (scripintelligence.com, 5 May 2010).
Now, Dr Yang says FDA approval for pirfenidone is likely and she projects peak sales of $650m in the US and $300m in the EU.
Phase III success
InterMune stayed its course and pirfenidone generated a third set of Phase III data that Dr Leff described as a complete and unambiguous success "with p-values you very rarely see."
The ASCEND study's primary endpoint was the proportion of IPF patients treated with pirfenidone and placebo who died or experienced a 10% or greater decline in lung function as measured by forced vital capacity (FVC) at 52 weeks of treatment.
InterMune reported that 16.5% pirfenidone-treated patients had a 10% FVC decline or died compared with 31.8% of placebo patients (p=0.000001), which was a 47.9% reduction in the incidence of clinically meaningful lung function decline or death. Also, 22.7% of patients in the pirfenidone arm of the ASCEND study had no FVC decline versus 9.7% in the placebo arm – a 132.5% difference.
There were also statistically significant differences between pirfenidone and placebo in terms of certain secondary endpoints – the proportion of patients with a 50-meter or greater decline on six-minute walk distances (p=0.0360) and the risk of disease progression or death (p=0.0001). However, pirfenidone's effect on dyspnea, or shortness of breath, was not statistically significant (HR=0.57; p=0.1577).
Mortality benefit
ASCEND was not powered to show differences in all-cause or treatment-emergent mortality, but a pre-specified analysis of data from 1,247 patients in ASCEND and the CAPACITY studies showed a 48% reduction in all-cause mortality for pirfenidone versus placebo (HR=0.52; p=0.0107) and a 68% reduction in treatment-emergent mortality (HR=0.32; p=0.0061).
Dr Leff said the mortality data trumps all other results, because "no one would ever debate the importance of a mortality benefit."
Based on the full ASCEND and CAPACITY data package, and especially the mortality results, William Blair analyst Katherine Xu said in a 25 February report that: "We believe such an unequivocal data package should pave the way for a smooth approval in the United States."
IPF patients usually die within two to five years of diagnosis, but some patients who were treated in InterMune's early pirfenidone studies are still taking the drug in extension studies and are alive eight years after beginning treatment.
"Pirfenidone continues to be well-tolerated over the long haul," Dr Leff said.
More detailed efficacy and safety data from ASCEND will be presented at the American Thoracic Society (ATS) International Conference in May in San Diego.
Safety profile
InterMune's drug was described at well-tolerated in ASCEND, but 14.4% of patients in the pirfenidone arm of the study discontinued treatment due to adverse events compared with 10.8% in the placebo group.
However, serious adverse events were observed in 19.8% of pirfenidone-treated patients versus 24.9% in the placebo group. Only 3.6% of pirfenidone patients were hospitalized for serious respiratory, thoracic and mediastinal events versus 11.2% of placebo patients.
Gastrointestinal side effects, including nausea and indigestion, and rash were the most frequent adverse events that were more common with pirfenidone than placebo. Aminotransferase levels were three times the upper limit of normal for 2.9% of pirfenidone-treated patients versus 0.7% in the placebo group.
Sagient Research's BioMedTracker noted in a 25 February analysis that there was one case of elevated liver function test results under Hy's law, but the patient recovered.
BioMedTracker still raised the likelihood of FDA approval by 1% to 72%, which is 5% above average for drugs in similar stages of development, since "given other benefits of the drug and lack of other treatment, we tend to think that will not stop it from being approved, depending on how the FDA views the supportive data, like mortality."
Since InterMune's NDA will be a resubmission rather than a new application, the FDA is expected to reconsider the pirfenidone NDA within six months of the re-filed application.
Boehringer's competing drug
Boehringer Ingelheim apparently also has Phase III results for its IPF drug nintedanib, but the German company is saving the data for the ATS conference in May.
BioMedTracker noted that nintedanib could be close on pirfenidone's heels in the US market if the FDA approves InterMune's drug six months after the company's NDA resubmission and if the regulator approves the Boehringer NDA after an eight-month priority review.
Dr Leff said there is no publicly available Phase III data for nintedanib to compare the two drugs, but added: "What's really important is not the competition, but what we have to offer patients, and that's hope. If more drugs are available, even better. The hope is to turn IPF into a chronic, manageable disease versus the fatal disease it is currently."
InterMune also has a preclinical compound for IPF that is known as a pirfenidone analog. Dr Leff said the early-stage drug candidate has shown better pharmacokinetics in animal studies with the potential for once-daily dosing, better efficacy and improved safety.