Clinical:Peramivir

FDA had approved the use of the first new drug intravenous Peramivir for the treatment of 2009 H1N1 hospitalized patients under the Emergency Use Act which terminated on June 23, 2010. Peramivir is the new neuraminidase inhibitor from BioCryst under FDA Review and in Phase III trials. The low bioavailability of oral formulation resulted in development of intramuscular and intravenous formulation. Shionogi has licensed the marketing rights for Japan. Phase III trials were completed during the 2008-2009 flu season. NIH has granted BioCryst $180 million to speed up the development of Peramivir. CDC tested the drug in H1N1 clinical isolates and drug was effective. FDA has granted fast track review. CDC has ordered existing stocks of the drug for its stockpile of Pandemic Influenza A/2009 H1N1 treatment. As most of the Phase II-III trials with the oral and im formulation failed to show clear advantage of Peramivir over placebo, it use should be limited for patients nor responding to Tamiflu or Relenza during Pandemic outbreak. The EUA approval was valid only during the Pandemic emergency period and ended on June 23, 2010. Shionoggi has announced approval of the drug in Japan and it has been launched on 27 January 2010. In the US, 1000 critically ill patients were successfully treated with iv Peramivir and 2009 sales were $ 22.5 million. Peramivir reverts back to its earlier position of an investigational drug. The safety data generated under EUA use can be used in the NDA/MAA, the use of life saving efficacy data (a strong point for Peramivir) can be discussed with the CDC/FDA /EMA. The EUA termination allows existing patients started on the drug before 23 June to complete their treatment course even after 23rd June.

This article deals with the unlabeled and unapproved uses of an investigational drug which was used during the Influenza 2009 H1N1 Pandemic EUA act. The drug has not been reviewed or approved by the FDA or EMA.

Other Names

BCX-1812 RWJ-270201

Brand Name in Japan (Shionogi): Rapiacta

Brand names in Europe (Merck KGa); (Hikma) not yet announced.

Under Creative Commons Attribution 3.0 License

Image source:

Promising Antiviral Drugs for Swine flu A/H1N1 Revealed by Virtual Screening Using Ensemble-based Docking By Hung T. Nguyen, Thanh Truong and Ly Le http://knol.google.com/k/top-hits-for-a-h1n1-identified-by-virtual-screening-using-ensemble-based-docking#

Uses

Clinicians considering Peramivir under EUA must read and understand the content of the FDA-issued Emergency Use Authorization of Peramivir IV: Fact Sheet For Health Care Providers prior to initiating a request and must agree to comply with terms and conditions of authorized use of Peramivir per the FDA-issued EUA in order to successfully complete and transmit the request for this product.

Additionally, clinical studies of Peramivir IV in hospitalized patients are currently being conducted. Clinicians who wish to consider whether their patients would be appropriate for inclusion in these clinical studies, please refer to clinicaltrials.gov for more information on these trials.

Image:Http://emergency.cdc.gov/h1n1antivirals/assets/images/btn request 1 blue.png.

The FDA-issued EUA for Tamiflu® authorizes use of Tamiflu® for the treatment of patients hospitalized due to complicated influenza and in patients symptomatic for more than 2 days, including pediatric patients less than 1 year old. The authorized use of Tamiflu® is subject to the terms and conditions of the EUA. For more information on the Tamiflu® EUA, please see: www.cdc.gov/h1n1flu/eua/tamiflu.htm

Regulatory status

The approval was valid only during the 2009 H1N1 emergency and ended when the emergency is lifted or by a notification from the FDA as on 23 June, 2010.

Termination of Declarations of Emergency Justifying Emergency Use Authorization (EUA) of Certain Antiviral Drugs—Zanamivir, Oseltamivir Phosphate, and Peramivir

Peramivir Emergency Use Authorization Disposition Letter and Question and Answer Attachment

http://edocket.access.gpo.gov/2010/2010-14881.htm

FDA had approved intravenous (i.v.) peramivir after a emergency use authorization (EUA) review. Government agencies and healthcare providers have the option of providing peramivir through an EUA in the event of a severe influenza outbreak with significant hospitalizations. Specifically, peramivir iv 600 mg OID for 5 to 10 days, is authorized only for hospitalized adult and pediatric patients for whom therapy with an IV drug is clinically appropriate,based on one or more of the following reasons:

1. The patient is not responding to either oral or inhaled antiviral therapy, or

2. When drug delivery by a route other than an intravenous route -- e.g., enteral (absorbed by the intestines) or inhaled -- is not expected to be dependable or feasible;

3. For adults only, when the clinician judges IV therapy is appropriate due to other circumstances.

The approval is valid only during the 2009 H1N1 emergency and will end when the emergency is lifted or by a notification from the FDA.

The drug has been approved in Japan and regulatory filing in Europe were completed in 2009.

History

Peramivir was first licensed from the University of Alabama by BioCryst in 1994. In 1998 Johnson and Johnson licensed the global marketing and development rights to the drug. In early 2001 its development was discontinued due to low bioavailability of the oral formulation, failure in clinical trials and all the rights were returned to BioCryst. BioCryst Phase III study with the oral formulation showed poor results due to low bioavilability in mid 2002. BioCryst picked up the project and with the help of NIAID/CDC concentrated on development of the injectable intramuscular formulation only. In 2006, Bio Cryst received a grant of $180 million from NIH to test and develop the product for pandemic and seasonal flu and use in flu strains resistant to Tamiflu. FDA approved the use of the first new drug intravenous Peramivir for the treatment of 2009 H1N1 hospitalized patients under the Emergency Use Act in 2009 during the H1N1 Pandemic outbreak.

It was licensed to Shionogi for the market in japan and was approved and launched there.

The European Marketing rights were awarded to Merck KGa and Hikma and the dossier was filed with the European Medicines Agency EMA and awaiting approval in Europe.

Research

In vitro tests

The clinical activity of peramivir has previously been demonstrated in various clinical studies. The sensitivity of the swine flu virus to peramivir has recently been reported by the CDC . Ten of the thirteen isolates of the 2009 H1N1 virus were tested for sensitivity to peramivir and all ten isolates were susceptible to peramivir.

Phase I trials

The results of single dose Phase I study in Japan were presented at the 48th Annual ICAAC/IDSA 46th Annual Meeting in late 2008. Patients (n 300, age 20-64 years) were randomized into 3 groups to receive peramivir 600 mg im (n 97), 300 mg (n 99) or placebo(n 100). Influenza symptoms were assessed by patients and their daily body tempratures. The investigators determined virus titer using nasal and pharyngeal swabs. The active drug was effective in both the doses and a significant change in virus titres was observed with the 600 mg dose. The adverse events were similar to the placebo group.

Phase II trials

Peramivir i.m. Phase 2 Study Results for Seasonal Influenza

Preliminary results from its Phase 2 study of peramivir for the treatment of seasonal influenza did not show any difference in time to alleviate symptoms with the placebo group. The drug was safe and well tolerated. A single 600 mg im injection reduced the symptoms by median 91 hours vs 106 for the placebo group. The study was a randomized, DB. placebo controlled trial in 4 countries during 2008-2009 flu season and had 405 subjects.

A second Phase II double blind placebo controlled study failed to show any differences with placebo. Acute influenza patients with a positive rapid antigen test were randomized to placebo or 150 mg or 300 mg im dose of peramivir. The primary end point alleviation of symptoms and adverse events was similar in all groups.

Phase III Studies

Shionogi conducted two Phase III trials during the 2008-2009 influenza season. In the first of these studies, a total of 1,099 patients with uncomplicated seasonal influenza were enrolled in A three-armed, multi-center, randomized, double-blind, multi-national Phase 3 study of peramivir at 300 or 600 mg doses im. to treatment with Tamiflu (75 mg BID X5 days). The results were similar in all 3 groups.

Another double-blind, multi-center Phase 3 study of peramivir IV with dosing over multiple days. The study enrolled 42 influenza patients at high-risk of serious complications due to one or more qualifying conditions: diagnosis with poorly controlled diabetes mellitus, a chronic respiratory disease requiring pharmacotherapy, or current treatment with any immunosuppressive drug. Peramivir was administered at 300 mg or 600 mg per day, and the duration was adjusted (up to five days) on a case-by-case basis, depending on the patient's temperature and clinical condition. In this study, the median time to alleviation of symptoms in all 37 evaluable patients treated with either 300 mg or 600 mg peramivir daily was 68.6 hours. There was no statistical difference with the Tamiflu treated group.

FDA reviewed data from 4 efficacy trials with iv dose peramivir. Only 1891 trial subjects have received Peramivir at any dose (iv or im) and only 478 persons received a single dose of 600 mg. Only 33 subjects were treated with 600 mg dose iv for 5 or more days. No infant or child has been treated with iv Peramivir in clinical trials. A limited number of children and adults have received Peramivir iv under Emergency IND procedures. Despite limited data, FDA determined that peramivir may be effective as rescue therapy and there is lack of any alternative treatment and decided to approve it under EUA. The CDC is responsible for managing its distribution and 1200 courses of 600 mg for 5 days or 600 coursed for 10 days are available for hospitals.

References

Published at www.nejm.org November 2, 2009 (10.1056/NEJMp0910479) The Emergency Use Authorization of Peramivir for Treatment of 2009 H1N1 Influenza Debra Birnkrant, M.D., and Edward Cox, M.D., M.P.H.

Emergency Use Authorization of medical products: guidance — Emergency Use Authorization of medical products. Silver Spring, MD: Food and Drug Administration, 2009. (Accessed November 2, 2009, at http://www.fda.gov/RegulatoryInformation/Guidances/ucm125127.htm.) Emergency Use Authorization of peramivir: fact sheet for health care providers. Silver Spring, MD: Food and Drug Administration, 2009. (Accessed November 2, 2009, at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM187811.pdf.)

Emergency Use Authorization of peramivir: fact sheet for patients and parents/caregivers. Silver Spring, MD: Food and Drug Administration, 2009. (Accessed November 2, 2009, at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM187799.pdf.)

Maggon, Krishan; Guild (KPG), Knol Publishing. Peramivir Review:Peramivir, FDA Approval, Emergency Approval, Influenza , 2009 H1N1, Swine Flu [Internet]. Version 57. Knol. 2010 Apr 5. Available from: http://knol.google.com/k/krishan-maggon/peramivir-review/3fy5eowy8suq3/74.

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Maggon, Krishan; Guild (KPG), Knol Publishing. Influenza Antivirals Market 2009:Global Influenza ( 2009 H1N1 ) or Swine Flu Tamiflu and Relenza Market [Internet]. Version 85. Knol. 2010 Mar 11. Available from: http://knol.google.com/k/krishan-maggon/influenza-antivirals-market-2009/3fy5eowy8suq3/83.

Termination of Declarations of Emergency Justifying Emergency Use Authorization (EUA) of Certain Antiviral Drugs—Zanamivir, Oseltamivir Phosphate, and Peramivir

Peramivir Emergency Use Authorization Disposition Letter and Question and Answer Attachment

Republished and modified (by self permission) from

Peramivir Review http://knol.google.com/k/-/peramivir-review/3fy5eowy8suq3/74#

Acknowledgements

Thanks are due to Mr. Jean-Antoine de Mandato (PDP, Geneva) for providing office facilities and administrative support.[[Category:|Category:]]