InterMune's (ITMN) sole product pirfenidone (brand name Esbriet) is an orally active, small molecule drug currently seeking approval from the FDA for the treatment of idiopathic pulmonary fibrosis, a progressive and fatal lung disease. Esbriet is already approved and marketed in 29 European Countries and in Canada. The drug is also marketed under the trade name Pirespa in Japan and South Korea by Shionogi & Co.
Pirfenidone is not yet approved in the United States but hopes are running high that the additional Phase III ASCEND study InterMune is currently conducting will satisfy FDA demands and the drug may finally reach US shores by as soon as mid-2015.
In Brief: Esbriet has demonstrated solidly good efficacy results in previous clinical trials. With zero drugs treating the chronic and fatal IPF on the market, the benefit Esbriet provides to patients is an automatic improvement over the current situation, giving ITMN an almost sure chance of commercial success upon approval. The only threat faced by Esbriet is from other drugs currently in development. Esbriet's only late-stage competitor is Boehringer Ingelheim's (BI) nintedanib, which completed its latest Phase III clinical trials in October 2013 but has yet to report results. In Phase II trials nintedanib failed to demonstrate a statistically significant clinical benefit over placebo across several endpoints, and the company has recently registered new Phase III trials with altogether new endpoints. As a private company, BI is not obliged to publish nintedanib's PhIII study results, but, despite the company's covert behavior, rumors have circulated that nintedanib performed well in the pivotal INPULSIS-1 and INPULSIS-2 Phase III trials and is en route to FDA approval by mid-2015.
Even if nintedanib is approved by the FDA, the orphan IPF market is large enough to accommodate both pirfenidone and nintedanib without significant hindrance to each other. Considering the anticipated price of Esbriet and the size of the IPF market in the U.S., even in the pessimistic scenario in which Esbriet secures only a quarter of the potential IPF market, its US sales will still exceed $500 million annually.
Idiopathic Pulmonary Fibrosis ((IPF)) is a chronic disease characterized by progressive and ultimately fatal decline in lung function due to inflammation and scarring of the lung interstitium (the tissue surrounding the lungs). Exact causes of IPF are not fully understood, however an excess of inflammatory cells and cytokines (signaling molecules) have been identified in IPF interstitial scars. Two cytokines found in abundance in IPF and linked to the propagation of scarring, are transforming growth factor beta (TGF-β) and the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α).
Pirfenidone (Esbriet) is an orally active, small molecule drug that inhibits the synthesis of the cytokines TGF-β and TNF-α. Pirfenidone has demonstrated activity in multiple fibrotic conditions, including those of the lung, kidney and liver.
Pirfenidone is already approved and marketed in 29 European countries and Canada under the trade name Esbriet. The drug is also marketed under the trade name Pirespa in Japan and South Korea. In Europe, the drug has been granted Orphan Drug status.
In the US, Pirfenidone has been grated Orphan Drug and Fast Track designation by the FDA, but as of yet remains unapproved. Despite a 9-3 FDA Advisory Committee vote in favor of pirfenidone approval, on May 4, 2010 the FDA responded with a Complete Response Letter to the drug's NDA, requesting that the company perform an additional Phase III trial in order to better support efficacy of pirfenidone in IPF. The company is now performing another Phase III trial, the results of which are due to be released in early Q2 2014.
Pirfenidone Clinical Trials
Pirfenidone has been tested in multiple IPF clinical trials, including a Phase II trial which was completed in 2003, two Phase III CAPACITY trials conducted by InterMune, completed in 2009, and a Phase III SP3 trial conducted by Shionogi.
Pirfenidone is intended for the treatment of mild-to-moderate IPF, and all of InterMune's trials are aimed at this patient category. The CAPACITY safety & efficacy program consisted of two concurrent 72-week trials which enrolled a total of 779 patients. Both trials were multinational, randomized, double-blind, and placebo-controlled.
InterMune is currently running the Phase III "ASCEND" study, which is a multinational, randomized, double-blind, placebo controlled trial of 555 patients designed to evaluate the safety and efficacy of pirfenidone in IPF patients with mild-to-moderate impairment in lung function over 52 weeks.
Phase III CAPACITY Trial
The CAPACITY program consisted of two concurrent studies - CAPACITY 004 and CAPACITY 006. In study 004, patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in study 006, patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo.
The primary endpoint was Forced Vital Capacity (FVC), defined as the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible - an important measure of lung function. The secondary endpoint was a Six-Minute Walk Test (6MWT), a performance-based test of functional exercise capacity which measures the distance an individual is able to walk over a total of six minutes. Persons with better lung function will naturally be able to perform longer walks in the 6MWT.
At week 72, study 004 demonstrated statistically significant positive effect of pirfenidone on FVC function (Table 1). Study 006 failed to show a significant improvement, with a 0.6% (p=0.501) difference between the pirfenidone and placebo group, however a consistent pirfenidone effect was apparent until week 48 (p=0.005).
Table 1. FVC results from pirfenidone CAPACITY studies 004 and 006
2:1:2 pirf. 2403 mg/day, pirf. 1197 mg/day,
1:1 pirf. 2403 mg/day, placebo
In the pooled patient population from both studies, the mean change in FVC in the pirfenidone patient group was -8.5% in comparison with -11.0% in the placebo group - a difference of 4.0%, with a p value of 0.005.
In the 6MWT, an overall 31% difference in distance decline was observed between pirfenidone and placebo groups at week 72 (p<0.001). There were fewer overall IPF-related deaths (3% vs 7%) in the pirfenidone group than in the placebo group (p<0.03). A 26% increase in progression-free survival was also reported.
Pirfenidone was found to be generally well tolerated at a daily dose of 2403mg. Adverse effects were observed in 31% of placebo patients and in 33% of pirfenidone patients. The most common side effects were nausea (32.8% vs. 13.3%), rash (28.7% vs. 8.6%), fatigue (22.3% vs. 13.3%), diarrhea (21.7% vs. 13.5%), dyspepsia (16.8% vs. 5.5%) and photosensitivity reaction (12.2% vs. 1.7%). [Link to full study]
New "ASCEND" Phase III Study
The FDA issued a Complete Response Letter to InterMune in January 2011, stating that the results of the CAPACITY trial were inconclusive in demonstrating pirfenidone efficacy. The agency recommended the company to perform an additional Phase III trial in order to produce more evidence to demonstrate benefit.
The currently running Phase III ASCEND trial was initiated in July 2011, with enrollment of 555 patients completed in 2013. The results are due to be published in April 2014 and will be presented in full at the May 2014 International Conference of the American Thoracic Society in San Diego. InterMune intends to file the New Drug Application (NDA) with the FDA in Q2 2014.
Like CAPACITY, ASCEND is a multinational, randomized, double-blind, placebo controlled trial. The Pirfenidone dosage and study endpoints remained unchanged, however InterMune has introduced four new changes to the trial protocol in ASCEND in comparison with CAPACITY.
The first change was a reduction in trial length - from 72 weeks down to 52 weeks. This reduction time is significant: throughout the CAPACITY trials, a more consistent effect was noted across all endpoints, which became less apparent after week 48 of treatment (Lancet). Furthermore, previous SP3 Phase III studies conducted by Shionogi in Japan, which ran over 52 weeks, demonstrated a 43.8% difference in Vital Capacity (similar to FVC) between placebo and pirfenidone groups, and a 55% reduction in risk of death over 52 weeks [Link]. Although differences between CAPACITY and SP3 protocols exist, it appears that pirfenidone demonstrated a much higher efficacy during the shorter 52-week setup.
Another change introduced in ASCEND was some tweaking to the patient eligibility criteria, with the patient contingent in ASCEND now more progressed in terms of disease, but still in mild-to-moderate area. The purpose of these changes was to ensure that the study consisted of patients more likely to undergo decline in lung function and increase in disease progression over 52 weeks.
In ASCEND, the magnitude of effect will be presented as a categorical measure of the proportion of patients with decrements of less than 0% or greater than 10% at Week 52, rather than standard mean change.
Positive results in previous trials, combined with the rich patient data InterMune has been collecting throughout the countries where Esbriet is already marketed, make it very likely that it will demonstrate statistical significance in ASCEND trials, and will be approved by the FDA next year.
Competition from Boehringer Ingelheim's nintedanib (BIBF 1120)
Pirfenidone's only late-stage competitor is BI's nintedanib (a triple tyrosine kinase inhibitor), which completed a Phase III program (two parallel studies) in October 2013. The results of the two studies will likely not be available until the American Thoracic Society (ATS) Conference in Sag Diego on May 16-21 2014.
In Phase IIb TOMORROW trials run by BI, nintedanib's efficacy was tested in a double-blind, randomized, dose-ranging placebo-controlled study on 432 patients. FVC decline at 1 year was used as primary endpoint, and changes in total lung capacity, total lung diffusion capacity for carbon monoxide (DLCO), 6MWT, acute exacerbation rate, quality of life were used as secondary endpoints. The results demonstrated only a borderline improvement in FVC between nintedanib and placebo groups, with a p value of 0.06 for primary endpoints between the group of subjects receiving the highest dose of nintedanib (150 mg twice daily) and the placebo.
Despite the fact that Phase II trials did not demonstrate a strong clinical benefit of nintedanib, BI proceeded with Phase III INPULSIS trials, with patients fully enrolled in September 2012, and trials completed in October 2013. The primary endpoint was the annual rate of decline in forced vital capacity (FVC) over a treatment period of 52 weeks in approximately 1,000 enrolled patients. Secondary endpoints included change from baseline in quality of life, time to first acute exacerbation, respiratory mortality, overall survival and on-treatment survival.
Despite finishing the INPULSIS trials in October of 2013, BI has not disclosed any trial results, instead registering a new Phase III trial with a completely different primary endpoint: the relative change from baseline in HRCT Quantitative Lung Fibrosis (QLF) score.
Speculation of nintedanib's INPULSIS trial success
On January 31 2014, citing an unidentified source, BioPharm Insight released intelligence suggesting that nintedanib, "has produced two positive Phase III idiopathic pulmonary fibrosis (IPF) trials, said a source close to the situation. The results are due to be presented in May at the American Thoracic Society (ATS) meeting in San Diego, and will also likely be published in the New England Journal of Medicine (NEJM) at the same time". The news plunged ITMN by 20% within a few hours, but the information has not been confirmed or denied by either BI or any other source.
IPF is classified as an orphan condition with large patient population for its class. InterMune estimates that there are 120,000 to 160,000 IPF patients in the US and North America, and about 30,000 more diagnosed every year. About 30,000 to 50,000 patients in the US suffer from the mild-to-moderate form of the disease.
In Europe, InterMune has negotiated prices ranging from $33,000 to $47,000 per full year of treatment. In the US, where drug prices are commonly much higher, this number is likely to increase up to $60,000.
Considering the mid-range of anticipated patient numbers in the US (40,000) and taking a conservative estimate of the price of Esbriet in the US as ~$50,000 per full year of treatment, Esbriet could generate at least $2 billion a year for InterMune if nintedanib does not reach the market. If both drugs are approved by the FDA, even a quarter of the American IPF market would secure revenue of at least $500 million from Esbriet for InterMune.
If approved, nintedanib's price range is likely to be similar to that of pirfenidone. It is improbable that the two drugs will compete on price, thus the chances of insurance coverage/reimbursement are equal for both, provided they offer roughly equal benefit. Co-administration is unlikely.
The large orphan IPF market in the US is worth at least $2 billion a year, with zero drugs addressing the disease currently on the market. Considering the performance of Esbriet in previous studies, and the experience with patients which InterMune has gathered throughout Esbriet's marketing history in the EU, Japan and South Korea, Esbriet has a very high chance of succeeding in its Phase III ASCEND studies and of reaching the market in mid-2015. Less is known about BI's nintedanib, given the lack of news from the company, but recent speculation seems to suggest that the latest Phase III INPULSIS trials of nintedanib may have been a success. Even if both pirfenidone and nintedanib reach the market in the US, both drugs could enjoy profits of $500 million - $1.5 billion annually. Esbriet's sales, therefore, are thus unlikely to gravely suffer in case of approval of nintedanib in the US.