We are a biotech company focused on developing and commercializing innovative therapies in pulmonology and hepatology. Pulmonology is the field of medicine concerned with the diagnosis and treatment of lung conditions. Hepatology is the field of medicine concerned with the diagnosis and treatment of disorders of the liver. We were incorporated in California in 1998 and reincorporated in Delaware in 2000 upon becoming a public company. During the past several years, we have reorganized our business by curtailing new investment in non-core areas and focusing our development and commercial efforts in pulmonology and hepatology. In October 2006, we entered into an Exclusive License and Collaboration Agreement (the “Collaboration Agreement”) with Hoffmann-LaRoche Inc. and F. Hoffmann-LaRoche Ltd. (collectively, “Roche”) to develop and commercialize products from our chronic hepatitis C virus (“HCV”) protease inhibitor program, including our lead candidate compound RG7227, previously referred to as ITMN-191. Effective March 2007, as a result of disappointing clinical trial results and based upon the recommendation of the study’s independent data monitoring committee (“DMC”), we discontinued further development of Actimmune for idiopathic pulmonary fibrosis (“IPF”). Subsequent to the discontinuation of Actimmune for IPF, we now have the following key development programs in place: pirfenidone for IPF and the HCV protease inhibitor program. We announced results of the Phase III CAPACITY trials of pirfenidone in February 2009 and submitted our New Drug Application (“NDA”) to the U.S. Food and Drug Administration (“FDA”), for pirfenidone for the reduction of decline in lung function in IPF in the United States in November 2009. Our NDA was accepted by the FDA and granted Priority Review on January 4, 2010. The FDA has set an action date of May 4, 2010 for the NDA, which may not be met by the FDA or which may be extended by the FDA under certain circumstances. On March 9, 2010, the Pulmonary-Allergy Drugs Advisory Committee (“PADAC”) of the FDA recommended approval of Esbriet® (pirfenidone) to reduce decline in lung function in patients with IPF. PADAC’s recommendations are not binding, but will be considered as the FDA completes its review of our NDA for Esbriet®.
Approved Product
Our sole approved product is Actimmune, approved for the treatment of patients with severe, malignant osteopetrosis and chronic granulomatous disease (“CGD”). For the years ended December 31, 2009, 2008 and 2007, Actimmune accounted for all of our product revenue and a majority of that revenue was derived from physicians’ prescriptions for the off-label use of Actimmune in the treatment of IPF.
Product Development
Drug development in the United States is a process that includes several steps required by the FDA. The process begins with the submission of an Investigational New Drug Application (“IND”) with the FDA, which if accepted by the FDA, allows for the opportunity for clinical study of the potential new medicine. Clinical development typically involves three phases of clinical trials prior to approval: Phase I, II and III. Within the pharmaceutical industry, clinical development takes approximately seven years of a drug’s total development time. The FDA may require, or companies may pursue, additional clinical trials, known as Phase IV clinical trials, after a product is approved. The results of Phase IV clinical trials can confirm the effectiveness of a drug and can provide important safety information to supplement the FDA’s voluntary adverse drug reaction reporting system. The most significant costs associated with clinical development are Phase III clinical trials, as they tend to be the longest and largest studies conducted during the drug development process. It is possible for a drug that appears promising in a Phase II clinical trial to fail in a more rigorous Phase III clinical trial.
In responding to an NDA, a Biologic License Application, (“BLA”), or an NDA or BLA supplement, the FDA may grant marketing approval (i.e., a license), request additional information or refuse to approve the application if it determines that the application does not provide an adequate basis for approval.
We have an advanced-stage development pipeline in the pulmonology area and a research and development-stage pipeline in the hepatology area.
Pulmonology
In pulmonology, we are developing a single therapy for the treatment of IPF. IPF is a fatal disease characterized by progressive scarring, or fibrosis, of the lungs, which leads to the deterioration and destruction of lung function. There is no FDA-approved therapy for IPF. Although conclusive data does not exist, it is estimated that approximately 100,000 people suffer from IPF in the United States, with a median survival rate of two to five years and approximately 30,000 new cases developing each year. The incidence and prevalence of the disease is thought to be similar in Europe.
We are currently developing one clinically advanced compound for the treatment of IPF, pirfenidone. Pirfenidone is an orally available small molecule. It may have activity in multiple fibrotic indications, and in vitro experiments show that it inhibits collagen synthesis, down-regulates profibrotic and proinflammatory cytokines and decreases fibroblast proliferation. In 2004, the FDA granted pirfenidone orphan drug status in the United States, and the European Medicines Agency (“EMEA”) granted pirfenidone orphan drug designation in the European Union, for the treatment of IPF. To develop and commercialize pirfenidone for all fibrotic diseases, we have acquired from Marnac, Inc. (“Marnac”) and KDL GmbH (“KDL”) substantially all of their remaining worldwide rights to the compound. Shionogi and Co. Ltd., or Shionogi, holds the rights to pirfenidone in Japan, Korea and Taiwan. Both we and Shionogi have undertaken clinical trials seeking to demonstrate that pirfenidone may positively affect lung function and disease progression in patients with IPF.
In December 2006, Shionogi reported positive results from its pivotal Phase III trial conducted in Japan evaluating pirfenidone for the treatment of patients with IPF. The trial was designed to evaluate a high-dose treatment regimen versus a placebo for 52 weeks. A low-dose treatment arm was also included. The Shionogi Phase III trial, in which 261 patients were enrolled and which used a measure of lung function called vital capacity (“VC”) as the primary endpoint, showed that pirfenidone significantly slowed the worsening of the disease. Both the high-dose group and the low-dose group showed statistically significant positive results as compared to a placebo for the primary endpoint. Additionally, Shionogi reported a statistically significant improvement in progression-free survival (“PFS”), a key secondary endpoint, for the high-dose group compared to a placebo. In March 2007, Shionogi submitted an application to the Japanese Health Authorities for approval to market pirfenidone and in October 2008, received regulatory approval to market pirfenidone for the treatment of patients with IPF in Japan where the compound is sold as Pirespa®.
Our CAPACITY trials for pirfenidone, which were initiated in April 2006, included two separate, concurrent Phase III trials conducted at 110 centers in North America and Europe. In May 2007, we completed enrollment of 779 patients with mild to moderate forms of IPF in the trials following our decision to refine and expand the CAPACITY program to include an increase in the number of patients enrolled and a lengthening of the treatment duration. We made these refinements based on the data from the Shionogi Phase III trial and the knowledge gained from the unblinded placebo arm of our INSPIRE trial for Actimmune. We began our CAPACITY trials following Shionogi’s successful Phase II clinical trial in which pirfenidone was generally well tolerated, with the most frequent side effects reported being photosensitivity rash and gastrointestinal symptoms. The primary endpoint of our CAPACITY trials was lung function, as measured by change in forced vital capacity (“FVC”), which is believed to be an important measure of disease progression in IPF. Our CAPACITY program was designed similarly to the Shionogi Phase III trial in that the maximum doses, on a mg/kg basis, were approximately the same and the primary endpoints (FVC versus VC) were expected to be clinically very similar. The CAPACITY trials were longer (72 weeks versus 52 weeks) than the Shionogi Phase III trial, which we anticipated would allow for better statistical power to demonstrate the efficacy of pirfenidone. On February 3, 2009, we announced results from the two Phase 3 CAPACITY studies. The primary endpoint of change in percent predicted FVC at Week 72 was met with statistical significance in CAPACITY 2 (p=0.001), along with the secondary endpoints of categorical change in FVC and PFS. The primary endpoint was not met in CAPACITY 1 (p=0.501), but supportive evidence of a pirfenidone treatment effect was observed on a number of measures. Pirfenidone was safe and generally well tolerated in both CAPACITY studies.
We submitted our NDA for pirfenidone for the reduction of decline in lung function in IPF in the United States in November 2009. Our NDA was accepted by the FDA and granted Priority Review on January 4, 2010. Priority Review designation may be granted by the FDA to an NDA for drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. The designation has the potential to expedite the NDA approval process by reducing the target review period for the application from approximately ten to six months. The FDA, based on the Prescription Drug User Fee Act, has set an action date of May 4, 2010 for the NDA, which may not be met by the FDA or which may be extended by the FDA under certain circumstances. Although the FDA has indicated that a direct measure of mortality is the ideal endpoint for IPF clinical trials, the FDA has also advised us that it will evaluate the outcome of our trials based on the totality of the data, including the effect of pirfenidone on the primary and secondary endpoint for both CAPACITY trials, as well as the safety data to help determine the risk-benefit profile of pirfenidone in IPF patients. While the results of Shionogi studies have been shared with us by Shionogi and have been published, the data base from that study is not available to the FDA for review in connection with its evaluation of our NDA. Therefore, while we expect that the data from the Shionogi Phase III study will be viewed by the FDA as supportive of the safety experience of pirfenidone we observed in the CAPACITY trials, the FDA has indicated that it will not consider the efficacy data from the Shionogi Phase III study in evaluating the efficacy of pirfenidone for purposes of our NDA. On March 9, 2010, PADAC of the FDA recommended approval of Esbriet® (pirfenidone) to reduce decline in lung function in patients with IPF. PADAC’s recommendations are not binding, but will be considered as the FDA completes its review of our NDA for Esbriet®.
On March 2, 2010, we submitted a Marketing Authorization Application (“MAA”) to the European Medicines Agency (“EMA”) seeking approval to market pirfenidone for the treatment of patients with IPF in the European Union. We currently expect the validation process by the EMA to be completed by late March 2010, which would indicate that our application is complete and that the review process by the EMA has begun. If approved by the EMA, we plan to commercialize pirfenidone independently in Europe and are prepared to expand our commercial infrastructure to support European marketing efforts.
We initiated a second Phase III clinical trial of Actimmune for the treatment of patients with mild to moderate IPF (otherwise known as the “INSPIRE” trial) in December 2003. Effective March 2007, we discontinued the Phase III INSPIRE trial based upon the recommendation of the study’s independent DMC. In a planned interim analysis that included a total of 115 deaths, the DMC found the overall survival result crossed a predefined stopping boundary for lack of benefit of Actimmune relative to placebo. Among the 826 randomized patients, there was not a statistically significant difference between treatment groups in overall mortality (14.5% in the Actimmune group as compared to 12.7% in the placebo group). The adverse events associated with Actimmune therapy appeared generally consistent with prior clinical experience and most commonly involved constitutional symptoms.
Hepatology
In hepatology, we are developing product candidates to provide expanded treatment options for patients suffering from HCV infection. According to the Centers for Disease Control and Prevention (“CDC”) an estimated 3.9 million Americans have been infected with HCV, of whom 2.7 million are chronically infected. It is estimated that there are 170 million people worldwide afflicted with this disease. The primary mode of transmission of HCV is through contaminated blood. Despite the currently available therapies, interferon alphas and ribavirin, there is considerable need for the development of novel therapeutic approaches since approximately 50% of patients are not cured with these currently available therapies. Patients who are not cured can develop cirrhosis, liver failure and hepatocellular carcinoma.
Our lead compound in hepatology is RG7227, formerly ITMN-191, an orally available HCV protease inhibitor currently in Phase 2b clinical testing in collaboration with Roche, based on a collaboration agreement we entered into with Roche in 2006. As a result of this collaboration agreement, Roche is responsible for 67% of the global development costs. It is anticipated that the companies will co-commercialize the product in the United States and share profits on a 50-50 basis and we will receive royalties on sales outside the United States.
Preclinical toxicology and pharmacokinetic studies in multiple species suggest that RG7227 has attractive therapeutic characteristics for the treatment of HCV, including significant liver exposure, slow dissociation from the NS3/4A protease and high in vitro potency and specificity. Our preclinical pharmacokinetic results also support the exploration of twice-daily oral dosing.
In May 2007, we reported that RG7227 had completed dosing in a Phase Ia single ascending-dose (“SAD”) trial in 64 healthy volunteers. No serious adverse events were reported in the SAD trial. All adverse events were classified as mild (CTCAE Grade 1), and no volunteers were discontinued due to an adverse event. The most common adverse events were gastrointestinal-related, were all classified as mild (CTCAE Grade 1), occurred predominantly in the highest dose cohort, appeared to be attenuated in the presence of food and rapidly resolved without intervention. No clinically significant laboratory abnormalities or ECG changes were reported. Plasma exposure was observed in all dosage cohorts. The doses given in this SAD trial ranged from less than 10% to many-fold higher than those planned to be given in the Phase 1b multiple ascending dose (“MAD”) trial which began in September 2007. Subjects who were administered RG7227 with a meal demonstrated significantly higher plasma levels of RG7227 compared to subjects given the same dose of RG7227 without a meal.