H1N1 COUNTERMEASURES STRATEGY AND ... - PHE Home

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NBSB Pandemic Influenza Working Group Detailed Report Polyclonal: Generated more rapidly o IVIG vs. plasma Less development expense Higher sustained manufacturing expense Heterogeneity/less potent o Advantage for resistance? o Most IgG not specific Large dose/volume May be easier to approve o Intrinsic targets unlikely Monoclonal: Slower to develop o More technically difficult Higher development expense Lower sustained manufacturing expense Homogeneity/more potent o More consistent o Select neutralizing monoclonal antibody only Small dose/volume More difficult to approve o Treated as novel compounds The timeline for developing monoclonal antibodies can reach 3–4 years. Dr. Beigel noted recent studies suggesting antibody isolation may be decreased from 6–12 months to 28 days, though this study was specifically looking at vaccines and not convalescent subjects. He said the time for monoclonal antibody engineering could be reduced from the current 6–12 months. Investigators are working to reduce the time to develop master cell lines from 12 months to 6 months. The time for manufacturing and release would stay the same. So while the timeline can be improved, it is still unlikely that monoclonal antibodies could be developed rapidly enough (with current technologies and approval processes) for emerging infectious diseases. The NIH is developing a protocol for H1N1 to collect plasma from convalescent subjects and vaccines. The protocol is still in draft form and needs IRB and FDA approval. Discussions are underway with a manufacturer for IVIG. Depending on the course of the H1N1 epidemic, the protocol may use source plasma or IVIG. Dr. Beigel concluded that passive antibody is an option for emerging infectious diseases, but it is labor-intensive. Plasma collection and IVIG development is not as rapid as assumed, but it’s still faster than de novo drug development. In the best-case-scenario, plasma could be available in 3 months, and IVIG in 7–12 months. Monoclonal 78
NBSB Pandemic Influenza Working Group Detailed Report antibodies are promising for emerging infectious diseases but would require some leaps in timeframes. TAMIINFLUENZA ® (oseltamivir) Strategy for Unmet H1N1 Treatment Needs— Regina Dutkowski, Ph.D., Hoffmann-La Roche Dr. Dutkowski said that before the 2007-2008 influenza season, resistance to oseltamivir was low, as evidenced by community surveillance. Naturally occurring resistance developed in 2007-2008 because of a mutation; resistance was not associated with use of oseltamivir in patients. Also, the resistant strain did not appear clinically worse than disease in patients with wild-type. The findings spurred Hoffmann-La Roche to study the incidence and clinical impact. Novel H1N1 is sensitive to zanamivir and oseltamivir. The company’s Influenza Resistance Information Study (IRIS) is seeking to improve early detection of resistance to all antivirals, and to better understand the clinical implications of resistance compared with susceptible viruses. It is an international, prospective study overseen by an international expert panel. Secondary objectives include examining the characteristics of circulating strains, determining regional changes in strains, evaluating signs and symptoms of patients with different subtypes, monitoring for resistance mutations at initial clinical presentation and after antiviral treatment, and comparing effects of antiviral treatment on clinical outcomes in patients with resistant or susceptible strains. The company hopes to enroll 1,200 patients over three seasons, and 400 have completed the study to date. The company plans to submit an end-of-season report at the end of 2009. Hoffmann-La Roche is also studying alternative routes of administration of oseltamivir for critically ill patients (IV and nasogastric [NG] tube). The study will evaluate a single ascending dose in an open-label, randomized format. Three different IV doses are being compared to a 75-mg oral dose. IV oseltamivir has been well tolerated, with GI symptoms and headache being the most frequent AEs. The company looked at the results of a study of NG oseltamivir in three patients with severe influenza (two had H5N1, one had H3N2). All three patients got double the usual does. The authors concluded that oseltamivir was adequately absorbed in these patients. Dr. Dutkowski explained the decision to focus on NG administration for hospitalized patients: To mimic the oral pharmacokinetic profile, IV requires a 2-hour infusion and a more controlled setting for administration. Oseltamivir has high (80%) oral bioavailability. Oseltamivir has a well established oral safety profile. NG administration is usable in most sick hospitalized patients, including those on ventilators. NG administration is an opportunity to provide a more immediate alternative dosing regimen. There are no barriers to availability and long-term storage with an oral formulation. 79
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