Gilead Sciences, a biopharmaceutical company, announced that the U.S. Food and Drug Administration (FDA) has granted priority review status to the New Drug Application (NDA) for the fixed dose co-formulation of the company's anti-HIV medications Viread (tenofovir disoproxil fumarate) and Emtriva (emtricitabine).
Gilead submitted its application to the FDA on March 12, 2004 and had anticipated a decision by January 12, 2005 based on a 10-month traditional review. Under priority review, the NDA will be reviewed within six months and the action date by which the FDA will make a decision, under the Prescription Drug User Fee Act (PDUFA), is September 12, 2004.
Priority designation is granted to drugs that if approved, address unmet medical needs, offering a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious or life-threatening disease, according to FDA policies and procedures.
"We are pleased that the FDA has granted priority review of the NDA for our co-formulation of Viread and Emtriva," said John C. Martin, PhD, president and CEO of Gilead Sciences. "The FDA's commitment to expedited review of new therapies and fixed-dose combinations for HIV/AIDS will help us continue to deliver important new medicines to help fight this disease. We believe this potential product represents an important advancement, and if approved, we will work to rapidly make the fixed-dose combination available to physicians and their patients."
The proposed co-formulated tablet will contain 300 mg of tenofovir disoproxil fumarate (Viread) and 200 mg of emtricitabine (Emtriva) and will be administered in combination with at least one other anti-HIV product. Viread was cleared for marketing by the FDA in 2001 and is available as a single 300 mg tablet taken once daily. Emtriva was cleared for marketing by the FDA and is available as a single 200 mg capsule that is also taken once daily. Both medications work by blocking reverse transcriptase, an enzyme crucial for HIV replication. Following approval of the fixed dose co-formulation, each drug would continue to be sold individually.
Viread is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. Assessment of adverse reactions, as described in the U.S. package insert, is based on one study of treatment-experienced patients and one study of treatment-naïve patients. In Study 907, a total of 550 treatment-experienced patients received treatment with Viread 300 mg (n=368) or placebo (n=182) for 24 weeks followed by extended treatment with the drug. In Study 903, a total of 600 patients received treatment with Viread (n=299) or stavudine (n=301) in combination with lamivudine and efavirenz for 48 weeks. The most common adverse events in these patients were dizziness and mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting and flatulence.
In clinical practice, a number of adverse events, including renal impairment, nausea, rash and asthenia (weakness) have been reported. Renal impairment occurred most often in patients with underlying systemic or renal disease or in patients taking concomitant nephrotoxic agents, though some cases have appeared in patients without identified risk factors. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. In patients co-infected with HIV and the hepatitis B virus, exacerbations of hepatitis B have been reported in patients after discontinuation of Viread. Decreases in bone mineral density (BMD) at the lumbar spine and hip have been seen with the use of Viread. The clinical significance of changes in BMD and biochemical markers is unknown and follow-up is continuing to assess long-term impact.
Emtriva is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. Assessment of adverse events, as described in the U.S. package insert, is based on pooled data from two Phase III studies in which 571 treatment-naïve and 440 treatment-experienced patients received Emtriva (n=580) or a comparator drug (n=431) for 48 weeks. The most common adverse events that occurred in patients receiving Emtriva were headache, diarrhea, nausea and rash, which were generally of mild to moderate severity. Approximately one percent of patients discontinued participation in the clinical studies due to these events. All adverse events were reported with similar frequency in Emtriva and control treatment groups with the exception of skin discoloration, which was reported with higher frequency in the Emtriva treated group. Skin discoloration, manifested by hyperpigmentation (excess pigmentation) on the palms and/or soles, was generally mild and asymptomatic.
The mechanism and clinical significance are unknown. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. In patients co-infected with HIV and chronic hepatitis B, exacerbations of hepatitis B have been reported in patients after discontinuation of Emtriva.