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NBSB Pandemic Influenza Working Group Detailed Report Following its meeting with FDA, and after reviewing the recent FDA draft guidance, specifically the guidance on clinical trial design in severe hospitalized patients, GSK sees no feasible path to registration; therefore IV-zanamivir remains on hold. GSK will consider a clinical development proposal from a third party for influenza antiviral drug development if it includes a clinical development plan that is reasonable, feasible, scientifically robust, and likely to lead to registration and approval. If the clinical development plan does not meet these criteria, GSK would not support a trial, execute the trial, or provide the drug. However, GSK would not prohibit a third party from sourcing the product from another licensed manufacturer. Peramivir: Pandemic Influenza Response, Advanced Clinical Development— William Sheridan, M.B. B.S., BioCryst Pharmaceuticals Peramivir, an investigational drug, is a potent, specific influenza viral neuraminidase inhibitor (NAI) discovered at BioCryst using structure-based design, based on a highresolution crystal structure of viral NA. Dr. Sheridan said BioCryst was encouraged to develop parenteral peramivir by the CDC, and brought the program forward in the U.S. under contract from BARDA in 2007. BioCryst is pursuing two indications for peramivir in the United States: acute, uncomplicated influenza and influenza requiring hospitalization. Parenteral peramivir is now completing phase-3 clinical trials conducted by BioCryst’s partner Shionogi & Co. Ltd. in Japan and is ready to enter phase-3 trials in the United States for influenza indications. Peramivir has been studied in vitro with a large variety of clinical isolates representing many different strains of influenza. These studies have characterized the unique laboratory susceptibility patterns to this novel NAI. Recently, Dr. Larisa Gubareva at the CDC has expanded her earlier research on susceptibility patterns of the 2009 pandemic influenza <strong>H1N1</strong> strain. These expanded studies of 204 unique clinical isolates have demonstrated that this new virus is very sensitive to peramivir, with a median IC 50 of 0.09nM in the NAI chemiluminesence assay; the IC 50 for peramivir is significantly lower than that for either zanamivir or oseltamivir (p < 0.001). Peramivir improves survival in preclinical influenza models, including mouse and ferret models of highly pathogenic avian influenza H5N1. One day of peramivir treatment is active, and multiple days of treatment rescues most or all mice with H5N1. Similar results have been observed in ongoing murine experiments with seasonal influenza A (<strong>H1N1</strong>)/H274Y. Extensive human pharmacology research has been completed for peramivir intramuscular injection and IV infusion, and our understanding of peramivir clinical pharmacology is now very thorough, including in special situations such as renal impairment and the elderly. Peramivir achieves very high plasma levels after parenteral administration, is not metabolized, and is cleared by renal filtration. It has a long half-life, especially compared with other NAIs. Because the drug is not metabolized, is widely distributed, and is excreted unchanged in urine, dosing regimens can be adapted easily for patients with renal impairment and for pediatric populations. Clinical data has been generated for peramivir in several phase-2 and phase-3 studies, and the drug has been administered safely to more than 1,300 subjects in clinical studies. The 74
NBSB Pandemic Influenza Working Group Detailed Report phase-3 studies in Japan have recently completed enrollment, but data from these studies is not yet available. The completed phase-2 study in Japan in 2008-2009 was a rigorously designed and executed randomized, double-blind, placebo-controlled trial comparing one short IV infusion of peramivir (two different doses were tested, 300mg and 600mg) with placebo in acute uncomplicated influenza. The primary endpoint was time to alleviation of symptoms (TTAS). The efficacy outcome was unequivocally positive, with all efficacy endpoints showing significant improvement over placebo. The time to alleviation of symptoms was 81.8 hours for placebo, and was shortened by about 22 hours with peramivir (p=0.0046). Time to resolution of fever was also significantly improved in the peramivir groups compared to placebo. Change in viral load, determined by nasal-pharyngeal swabs at baseline and at several protocol-specified post-treatment timepoints, is another important outcome, as it is a direct measure of antiviral activity. These evaluations showed that viral clearance was significantly accelerated in the 600mg peramivir group compared to placebo. The safety experience for peramivir was very satisfactory in this study. Reported AEs were mild, and no serious AEs were reported in the 198 subjects administered peramivir in the study. The reported AEs were of similar frequency and severity grade in the placebo and treatment groups. These efficacy and safety results formed the basis of the peramivir phase 3 program in Japan. BioCryst’s phase-2 study of peramivir in patients with influenza requiring hospitalization was difficult to perform, and is the only study ever completed in this patient population. It required multiple sites and countries and enrollment extended over 2 Northern Hemisphere and 1 Southern Hemisphere season. An important issue for influenza clinical research is lack of awareness of influenza in the hospital setting. This problem seems partly due to lack of reliable diagnostic tests in emergency rooms – it is estimated that only 5% of patients hospitalized with influenza actually receive that diagnosis. Better access to confirmatory diagnostic tests would greatly improve the ability to recruit patients for such studies. A placebo-controlled study was not practical for ethical reasons, so oral oseltamivir was used as a control, even though it is not approved for this indication. Two different doses of IV peramivir were evaluated, 200mg daily for 5 days and 400mg daily for 5 days. The primary endpoint was time to clinical stability, which was adapted from studies of community-acquired pneumonia. A main goal of this study was to evaluate peramivir in a patient population with more serious disease or underlying risk factors for complications. The patient population enrolled consisted mostly of individuals admitted with chronic illness that worsened with influenza, and not patients with influenza-pneumonia. The study patients had good clinical outcomes, and BioCryst was pleased with the rapidity of clearance of the virus. Viral cultures were obtained from nasopharyngeal swabs at regular intervals. Overall, viral load was reduced rapidly with treatment. Detailed analyses of the viral culture data indicated that the baseline viral load was higher in subjects with less that 48 hrs of symptoms at enrollment, and in influenza B subjects. In the influenza B subjects, a 75
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