Citizens of Canada’s largest province afflicted by idiopathic pulmonary fibrosis (IPF) have finally been given access to a key IPF therapy after a protracted two-year fight. IPF patients in Canada’s other provinces hope publicly-funded access to first and only treatment isn’t far behind.
Ontario’s Executive Officer has announced that Esbriet (pirfenidone), the only medicine available in Canada to treat mild to moderate IPF in adults, will be funded effective August 19, 2014 through the province’s Exceptional Access Program (EAP), which facilitates patient access to drugs not funded on the Ontario Drug Benefit (ODB) Formulary, or where no listed alternative is available. This funding decision will allow patients who meet certain criteria (which have yet to be published) and who rely on the Ontario Public Drug Programs to finally have access to the only medication currently available for the treatment of the disease.
Esbriet (pirfenidone) is a novel anti-fibrotic agent, proven to slow disease progression in patients with IPF. The efficacy and safety of pirfenidone in IPF are claimed to be particularly well characterized based on three large, Phase 3 trials, with efficacy results out to 1.5 years and two ongoing extension studies that provide safety data for up to eight years. In clinical studies, Esbriet reduced the rate of disease progression by approximately 30 percent, comparable to or exceeding the effectiveness of treatments for similarly lethal diseases, such as lung cancer. Esbriet is an orally active drug that inhibits the synthesis of TGF-beta, a chemical mediator that controls many cell functions including proliferation and differentiation, and plays a key role in fibrosis. Esbriet’s primary anti-fibrotic activity is supplemented by additional anti-inflammatory properties.
Esbriet’s maker InterMune is a biotechnology company specializing in research, development and commercialization of innovative therapies in pulmonology and orphan fibrotic diseases. In pulmonology, InterMune is focused on therapies for the treatment of IPF, and pirfenidone (Esbriet) is the only medicine approved for IPF anywhere in the world, is approved for marketing by InterMune in the EU and Canada as and is currently in a Phase 3 clinical trial in the United States. Pirfenidone is also approved in multiple countries in Asia and Latin America. InterMune’s research programs are focused on the discovery of targeted, small-molecule therapeutics and biomarkers to treat and monitor serious pulmonary and fibrotic diseases.
Idiopathic Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis (IPF) is a rare, progressive, irreversible, unpredictable and ultimately fatal disease characterized by progressive scarring (fibrosis) in the lung. It is a specific type of interstitial lung disease in which the small air sacs of the lung, known as alveoli, gradually become replaced by fibrotic (scar) tissue. The abnormal fibrosis and scar formation typically begins in the terminal areas of the pulmonary tree lining the air sacs where gas exchange occurs. Normally, this tissue is a thin layer consisting of a few, easily permeable cells. With IPF, progressive scarring causes the normally thin and pliable tissue to thicken and become stiff, making it more difficult for the lungs to expand, preventing oxygen from readily getting into the bloodstream.
IPF inevitably leads to worsening lung function and exercise tolerance, and shortness of breath. There is a corresponding increase in respiratory symptoms with dyspnea, air hunger and a non-productive cough. Every IPF patient follows a different and unpredictable course and it is not possible to predict if a patient will progress slowly or rapidly, or when the rate of decline may change. Periods of transient clinical stability in IPF, should they occur, inevitably give way to continued disease progression. IPF is a uniformly fatal disease, with the median estimated survival time from diagnosis two to five years, with a five-year survival rate of approximately 20-40 percent, which makes IPF more rapidly lethal than many cancers, including breast, ovarian, colorectal, pancreatic, lung, and liver cancers. IPF typically occurs in patients over the age of 50, and is more common in men than in women.
The incidence of IPF is greater than that of ovarian cancer, similar to those of pancreatic cancer and of all leukemias combined, and nearly 30 times that of cystic fibrosis.
Of idiopathic (unknown) cause, IPF is not thought to be related to any other disease or condition, such as cancer or asthma. However, the disease is typically found in people between the ages of 40 and 80, and affects more men than women. Cigarette smoking may increase risk of developing IPF. Some cases of IPF occur in patients who have family members with the disease, which suggests genetic factors may contribute to risk of developing IPF in certain individuals.
Although these risk factors are associated with IPF, it is important to remember that they have not been shown to cause IPF — the cause of IPF is still unknown.
Once considered a relatively rare disease, IPF is now recognized as the most common interstitial lung disease (interstitial refers to the tissue surrounding the alveoli). An estimated 50,000-70,000 people are living with IPF in the United States, and approximately 15,000-20,000 new cases are diagnosed annually.It is estimated that between 80,000 and 110,000 patients living with IPF in all of Europe and between 5,000 to 8,000 patients living with IPF in Canada.
Regulatory Status In U.S. And Elsewhere
Pirfenidone has been granted Orphan Drug and Fast Track designation by the FDA, and also has been granted Orphan Drug status in Europe.
On November 4, 2009, InterMune submitted a New Drug Application (NDA) for pirfenidone to the U.S. FDA, seeking approval to market pirfenidone for the treatment of patients with IPF to reduce the rate of decline in lung function. On January 4, 2010, InterMune announced that the FDA had granted Priority Review designation to the pirfenidone NDA. Priority Review designation may be granted by the FDA to an NDA for drugs that have the potential to offer major advances in treatment, or provide a treatment where no adequate therapy exists. Based on the Prescription Drug User Fee Act (PDUFA), the FDA set an action date for the NDA of May 4, 2010. On May 4, 2010, the FDA issued a complete response letter with regard to the pirfenidone NDA, requesting an additional clinical trial to support the efficacy of pirfenidone in IPF. In January 2011 InterMune reported that, as recommended by the FDA in its complete response letter, the company would conduct a new Phase 3 clinical study that would demonstrate a clinically meaningful effect on forced vital capacity. 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. Top-line results from ASCEND were reported in February 2014, as noted above. InterMune currently intends to resubmit the pirfenidone NDA to the FDA early in the third quarter of 2014.
On March 2, 2010, InterMune announced that it had submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA), seeking approval to market pirfenidone for the treatment of IPF patients in the European Union. On March 3, 2011, InterMune announced that the European Commission (EC) had granted marketing authorization for Esbriet (pirfenidone). Esbriet is indicated in adults for the treatment of mild to moderate idiopathic pulmonary fibrosis.
In 2013, the Pharmaceutical Pricing Board of Finland (HILA) agreed to pricing and reimbursement for Esbriet in that country, effective June 1, 2013. The pharmacy purchase price of Esbriet in Finland was at the time equivalent to approximately $33,900 per patient, per year. An estimated 500 to 800 patients are estimated to be living with mild to moderate IPF in Finland.
On October 1, 2012, Health Canada approved Esbriet for the treatment of mild to moderate IPF in adult patients. Health Canada designated Esbriet for Priority Review and completed the accelerated review according to target guidelines of 180 days. However, initial elation felt by Canadian patients at hearing that Esbriet had been approved by Health Canada in October 2012, quickly turned to acute dismay once they learned that the Common Drug Review (CDR) recommended provinces not publicly fund the drug, leaving many patients without access to the only treatment available. Hope had been dashed, and, as a result, the issue of access to Esbriet has caused patients, caregivers, physicians and other healthcare professionals to relentlessly advocate to provincial governments for public funding. The entire IPF community desperately hopes the Ontario government will act on their commitment and begin providing immediate access to Esbriet, and that all other provinces will quickly follow suit.
“This announcement is the best news the Canadian IPF patient community has heard since this journey began two years ago, and we applaud the government of Ontario on its leadership decision to provide access to funding for patients who can benefit from Esbriet,” said Robert Davidson, president and founder of the Canadian Pulmonary Fibrosis Foundation (CPFF). “Unfortunately, we’ve seen too many people lose the battle to this devastating disease while fighting for access to the only treatment that could have extended and improved their lives. We won’t give up our efforts until all Canadians with IPF are given the same chance to breathe.”
Newly Published Data Supports Need For Access To Treatment
Earlier in May, data presented at the 2014 International Conference of the American Thoracic Society (ATS) and concurrently published in the New England Journal of Medicine (NEJM) gave the IPF patient community renewed hope that publicly funded-access may soon be reality. The Phase 3 ASCEND Study: A Randomized, Double-Blind, Placebo-Controlled Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (IPF) confirmed the proven efficacy and safety of Esbriet through a number of key primary endpoints.
According to the published data, the study demonstrated that Esbriet significantly reduced the decline in lung function by 47.9 per cent, as measured by a decline in forced vital capacity of 10 per cent or more. Additionally, the study showed that 27.5 per cent of patients experienced a reduced decline in the 6-minute walk distance (6MWD) test, and almost half (43 per cent) saw an improvement in progression-free survival with IPF. Most importantly, a pooled analysis of data from ASCEND and two previous phase 3 trials (CAPACITY) with Esbriet showed that the risk of all-cause mortality in IPF patients was reduced by 48 per cent compared with placebo. For more on Esbriet, see below.
“As a physician, I am gratified that all IPF patients in Ontario who meet the criteria will have the opportunity to benefit from Esbriet and have access to this much-needed treatment,” says Dr. Shane Shapera, a respirologist and IPF specialist at Toronto General Hospital, University Health Network. “The ASCEND data presented at ATS further reinforces the extensive body of clinical evidence and international expert consensus supporting the use of Esbriet for adults with mild to moderate IPF, and should be reconsidered by the Common Drug Review to decide if it will be listed on all provincial formularies.”
Permanent Funding Resolution In All Canadian Provinces Still Needed
While the public funding of Esbriet in Ontario is good news and will serve the needs of some IPF patients in the short-term, the CPFF contends that a permanent solution is needed for all patients in Canada’s other nine provinces and three northern territories who could benefit from this treatment before their time runs out. Based on the strength of recently published data, compelling patient evidence submissions and expert clinical opinion, the CPFF urges the CDR to provide a positive recommendation for listing Esbriet on provincial formularies so that all Canadians with IPF can have long-term access to this proven medication. This recommendation is expected by spring of 2015.
“We are beyond thrilled to hear that the Ontario government has taken the lead to finally make steps towards granting IPF patients access to the treatment they deserve, ” says Larkell Bradley, North York, Toronto resident and IPF patient. “It is our hope, that since we have fought so hard to come this far, that a full listing will soon be imminent.”
In order for Ontarians to receive funding for Esbriet, eligible patients must first receive a prescription from their respirologist, and be enrolled in the Inspiration Program, a patient support program offered by InterMune Canada. Esbriet will then be funded through the Exceptional Access Program (EAP), based on clinical criteria which are expected to be available in the coming weeks.
InterMune’s Esbriet (pirfenidone) is an orally active, small molecule drug that inhibits the synthesis of TGF-beta, a chemical mediator that controls many cell functions including proliferation and differentiation, and plays a key role in fibrosis. It also inhibits synthesis of TNF-alpha, a cytokine that is known to have an active role in inflammation. Pirfenidone has demonstrated activity in multiple fibrotic conditions, including those of the lung, kidney and liver.
InterMune licensed certain rights to pirfenidone from Marnac, Inc. and its co-licensor, KDL GmbH, in 2002. In 2007 the company purchased from Marnac and KDL the rights to sell the compound under the patents in the United States, Europe and other territories, except in Japan, Taiwan and South Korea, where rights to the molecule were licensed to Shionogi & Co. Ltd. of Japan.
Pirfenidone is approved for marketing in 30 European countries (28 in EU 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. Pirfenidone is not approved for marketing in the United States but InterMune has announced intent to resubmit the pirfenidone New Drug Application (NDA) to the U.S. FDA early in the third quarter of 2014 to support regulatory registration in the United States.
Clinical Trial Results
InterMune says pirfenidone has been studied in multiple Phase 2 and Phase 3 clinical trials in patients with IPF, including the two Phase 3 CAPACITY trials conducted by InterMune, the ASCEND Phase 3 trial, as well as a Phase 3 trial designed and conducted by Shionogi.
According to InterMune, the CAPACITY 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. The studies were designed to evaluate the safety and efficacy of pirfenidone in IPF patients with mild to moderate impairment in lung function. The primary endpoint in each study was the absolute mean change from baseline to week 72 in percent predicted forced vital capacity (FVC). This endpoint was met with statistical significance in CAPACITY 2 (p=0.001). The secondary endpoints of progression-free survival (PFS) and categorical change in FVC were also met with statistical significance (p< 0.05). The primary endpoint was not met in CAPACITY 1 (p=0.501).
In the CAPACITY studies, pirfenidone showed a favorable safety profile and was generally well tolerated in both CAPACITY studies, the most frequent side effects reported being photosensitivity rash, gastrointestinal symptoms such as nausea and dyspepsia, and dizziness. Patients completing the CAPACITY trials were allowed to enroll in RECAP, an ongoing open-label roll-over study from CAPACITY to evaluate the long-term safety of pirfenidone in patients with IPF. In RECAP, all patients receive pirfenidone.
InterMune reported top-line results from the Phase 3 ASCEND trial in February 2014. ASCEND, a randomized, double-blind, placebo-controlled trial that enrolled 555 patients, was conducted to support marketing approval of pirfenidone in the United States.
The company says ASCEND data confirmed observations from other clinical studies that pirfenidone significantly reduced IPF disease progression as measured by change in percent predicted forced vital capacity (FVC) from Baseline to Week 52. Additionally, in ASCEND, pirfenidone showed a favorable safety profile and was generally well tolerated.
For additional information about InterMune and its R&D pipeline, visit:
The Canadian Pulmonary Fibrosis Foundation (CPFF) is a registered not-for-profit charitable organization established to provide support, hope and resources for those people affected by pulmonary fibrosis. Robert Davidson, president of the CPFF, who had IPF and received a double lung transplant in January 2010, founded the organization in 2009 to help support and educate others, and to answer non-medical questions frequently asked by those suffering with the disease. For more information, visit:
Canadian Pulmonary Fibrosis Foundation
Toronto General Hospital University Health Network