Summary: Clinical trials that are finished have given positive results. FDA has proceeded with a pre-Emergency Use Authorization (EUA) review of peramivir, and if an order is placed for the Strategic National Stockpile, BioCryst has the manufacturing supplies it needs to finish the product and make large quantities available.
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[snips]
Peramivir is a potent, specific influenza viral neuraminidase inhibitor (NAI) discovered at BioCryst that will be used for 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 (enrollment is completed but data is not yet available) and is ready to enter phase-3 trials in the United States for influenza indications.
These expanded studies of 204 unique clinical isolates have demonstrated that this new virus is very sensitive to peramivir, with a median IC50 of 0.09nM in the NAI chemiluminesence assay; the IC50 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 (H1N1)/H274Y.
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 primary endpoint (in the Japan studies) was time to alleviation of symptoms (TTAS) and was unequivocally positive. 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. Evaluations in the change in viral load 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.
BioCryst's phase-2 study of peramivir in patients with influenza requiring hospitalization
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.
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.
Looking at AEs, peramivir IV once daily for 5 days was generally safe and well-tolerated in adults hospitalized with acute influenza.
Dr. Sheridan described one case of compassionate use of peramivir under emergency IND regulations in Seattle.
Data for the presentation was kindly provided by the investigator, Dr. Anna Wald, Seattle WA. This patient had had a bone marrow transplant and presented to the ED with respiratory and GI symptoms 2 days after the transplant. The patient was diagnosed with influenza A (subsequently confirmed to be due to the pandemic strain) developed bilateral viral pneumonia, and rapidly deteriorated despite treatment with oseltamivir, adamantane and ribavirin. Virus was detected by PCR in blood and stool as well as bronchoalveolar lavage specimens. Intubation, 100% inspired oxygen and positive end-expiratory pressure were required. Following a 10-day course of peramivir combined with oseltamivir, the patient's condition improved, allowing discharge from the intensive care unit and cessation of antivirals. Dr. Sheridan said that although the case provides anecdotal evidence, it illustrates the potential for successful use of peramivir for severe illness.
Peramivir can be made available as a countermeasure for the current H1N1 pandemic. FDA has proceeded with a pre-Emergency Use Authorization (EUA) review of peramivir, and if an order is placed for the Strategic National Stockpile, BioCryst has the manufacturing supplies it needs to finish the product and make large quantities available. The manufacturing process is well developed.
From H1N1 COUNTERMEASURES STRATEGY AND DECISION-MAKING FORUM; 100 page .pdf http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf
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[snips]
Peramivir is a potent, specific influenza viral neuraminidase inhibitor (NAI) discovered at BioCryst that will be used for 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 (enrollment is completed but data is not yet available) and is ready to enter phase-3 trials in the United States for influenza indications.
These expanded studies of 204 unique clinical isolates have demonstrated that this new virus is very sensitive to peramivir, with a median IC50 of 0.09nM in the NAI chemiluminesence assay; the IC50 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 (H1N1)/H274Y.
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 primary endpoint (in the Japan studies) was time to alleviation of symptoms (TTAS) and was unequivocally positive. 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. Evaluations in the change in viral load 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.
BioCryst's phase-2 study of peramivir in patients with influenza requiring hospitalization
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.
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.
Looking at AEs, peramivir IV once daily for 5 days was generally safe and well-tolerated in adults hospitalized with acute influenza.
Dr. Sheridan described one case of compassionate use of peramivir under emergency IND regulations in Seattle.
Data for the presentation was kindly provided by the investigator, Dr. Anna Wald, Seattle WA. This patient had had a bone marrow transplant and presented to the ED with respiratory and GI symptoms 2 days after the transplant. The patient was diagnosed with influenza A (subsequently confirmed to be due to the pandemic strain) developed bilateral viral pneumonia, and rapidly deteriorated despite treatment with oseltamivir, adamantane and ribavirin. Virus was detected by PCR in blood and stool as well as bronchoalveolar lavage specimens. Intubation, 100% inspired oxygen and positive end-expiratory pressure were required. Following a 10-day course of peramivir combined with oseltamivir, the patient's condition improved, allowing discharge from the intensive care unit and cessation of antivirals. Dr. Sheridan said that although the case provides anecdotal evidence, it illustrates the potential for successful use of peramivir for severe illness.
Peramivir can be made available as a countermeasure for the current H1N1 pandemic. FDA has proceeded with a pre-Emergency Use Authorization (EUA) review of peramivir, and if an order is placed for the Strategic National Stockpile, BioCryst has the manufacturing supplies it needs to finish the product and make large quantities available. The manufacturing process is well developed.
From H1N1 COUNTERMEASURES STRATEGY AND DECISION-MAKING FORUM; 100 page .pdf http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf
