Report on the Deliberation Results August 3, 2010 Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare [Brand name] Inavir Dry Powder Inhaler 20 mg [Non-proprietary name] Laninamivir Octanoate Hydrate (JAN*) [Applicant] Daiichi Sankyo Company, Limited [Date of application] January 29, 2010 [Results of deliberation] In the meeting held on July 29, 2010, the Second Committee on New Drugs concluded that the product may be approved and that this result should be reported to the Pharmaceutical Affairs Department of the Pharmaceutical Affairs and Food Sanitation Council. The product is not classified as a biological product or a specified biological product, and the re- examination period is 8 years. Neither the drug substance nor the drug product is classified as a poisonous drug or a powerful drug. *Japanese Accepted Name (modified INN) This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. Review Report July 7, 2010 Pharmaceuticals and Medical Devices Agency The results of a regulatory review conducted by the Pharmaceuticals and Medical Devices Agency on the following pharmaceutical product submitted for registration are as follows. [Brand name] Inavir Dry Powder Inhaler 20 mg [Non-proprietary name] Laninamivir Octanoate Hydrate [Applicant] Daiichi Sankyo Company, Limited [Date of application] January 29, 2010 [Dosage form/Strength] Dry powder for inhalation: One inhaler contains 20.76 mg of Laninamivir Octanoate Hydrate (equivalent to 20 mg of laninamivir octanoate) [Application classification] Prescription drug- (1) Drug with a new active ingredient [Chemical structure] Molecular formula: C21H36N4O8 · H2O Molecular weight: 490.55 Chemical name: (2R,3R,4S)-3-Acetamido-4-guanidino-2-[(1R,2R)-2-hydroxy-1-methoxy-3- (octanoyloxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylic acid monohydrate (2R,3R,4S)-3-Acetamido-4-guanidino-2-[(1S,2R)-3-hydroxy-1-methoxy-2- (octanoyloxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylic acid monohydrate [Items warranting special mention] None [Reviewing office] Office of New Drug IV This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. Review Results July 7, 2010 [Brand name] Inavir Dry Powder Inhaler 20 mg [Non-proprietary name] Laninamivir Octanoate Hydrate [Applicant] Daiichi Sankyo Company, Limited [Date of application] January 29, 2010 [Results of review] Based on the submitted data, it is concluded that the efficacy of the product in patients with influenza A or B virus infection has been demonstrated, and the safety is acceptable in view of the observed benefits. Further investigations via post-marketing surveillance are needed on the efficacy of the product against each type/subtype of influenza virus such as subtype A/H3N2, type B, and novel subtype A/H1N1 as well as the safety in high-risk patients, which have not been sufficiently studied in the clinical studies of the product. As a result of its regulatory review, the Pharmaceuticals and Medical Devices Agency has concluded that the product may be approved for the following indication and dosage and administration. A prior assessment consultation was conducted on this product. [Indication] Treatment of influenza A or B virus infection [Dosage and administration] Adults: Laninamivir octanoate 40 mg is administered by inhalation as a single dose. Children aged <10 years: Laninamivir octanoate 20 mg is administered by inhalation as a single dose. Children aged ≥10 years: Laninamivir octanoate 40 mg is administered by inhalation as a single dose. 3 Review Report (1) May 20, 2010 I. Product Submitted for Registration [Brand name] Inavir Dry Powder Inhaler 20 mg [Non-proprietary name] Laninamivir Octanoate Hydrate [Applicant] Daiichi Sankyo Company, Limited [Date of application] January 29, 2010 [Dosage form/Strength] Dry powder for inhalation: One inhaler contains 20.76 mg of Laninamivir Octanoate Hydrate (equivalent to 20 mg of laninamivir octanoate). [Proposed indications] Treatment of influenza A or B virus infection [Proposed dosage and administration] The usual dose for adults and children is 40 mg of laninamivir octanoate administered by inhalation in a single dose. II. Summary of the Submitted Data and Outline of Review by Pharmaceuticals and Medical Devices Agency The data submitted in this application and the outline of review by the Pharmaceuticals and Medical Devices Agency (PMDA) are as shown below. 1. Origin or history of discovery and usage conditions in foreign countries etc. Laninamivir Octanoate Hydrate (hereinafter also referred to as “laninamivir octanoate”), which was discovered by Daiichi Sankyo Company, Limited, is a novel antiviral drug against influenza that selectively inhibits neuraminidase (NA) of influenza A or B virus. Similarly to existing NA inhibitors (oseltamivir phosphate, zanamivir hydrate), laninamivir octanoate is expected to prevent the growth of the virus by inhibiting NA and to improve influenza symptoms, leading to a shorter duration of illness. Laninamivir octanoate is a prodrug of R-125489,1 a compound that has NA-inhibitory activity. Results of nonclinical studies suggested that R-125489 is generally active in inhibiting NA of drug-resistant human influenza viruses reported with existing NA inhibitors. Also, R-125489 exhibited potent activity against animal influenza virus strains of all known NA subtypes. These results suggest that laninamivir octanoate may be an important option for the treatment of influenza in a situation involving a serious mutation, more specifically, a spread of a drug-resistant virus strain or an outbreak of pandemic influenza virus infection. The world experiences pandemics once every 10 years to several decades. In 2009, a pandemic of the H1N1 influenza virus was confirmed in the American Continent. Since 2003, human infection with highly pathogenic H5N1 avian influenza virus has been reported from many countries. Oseltamivir- resistant strains of the virus have been isolated from samples and are drawing attention of the international community. In this rapidly changing situation, the use of antiviral drugs is the only way to tackle influenza in the early stage of a pandemic, the need for which is growing from both medical and social points of view. Thus, the addition of a new treatment option is important. Inavir Dry Powder Inhaler 20 mg (“Inavir”) is administered by inhalation. Inhalation is expected to deliver a sufficient amount of drug to the target organs such as the airway immediately where 1 R-125489, (2R,3R,4S)-3-Acetamido-2-[(1R,2R)–2,3-dihydroxy-1-methoxypropyl]-4-guanidino-3,4-dihydro-2H-pyran-6- carboxylic acid 4 viral growth occurs, thereby producing an efficient therapeutic effect. Since laninamivir octanoate is a prodrug designed to achieve increased retention at the infection site, the drug remains in the target organ for an extended period of time, resulting in the long-lasting therapeutic effect. Thus, whereas existing NA inhibitors need to be administered for 5 consecutive days, treatment with laninamivir octanoate is expected to complete with a single dose. This will increase drug compliance, and the drug is expected to decrease the shedding of the virus from the body while staying for an extended period of time in the target organ so that a spread of infection is contained. The applicant explained that, based on the above discussion, laninamivir octanoate was developed to be a novel influenza antiviral drug with unique characteristics not shared by the existing drugs. ************************************* ************************************ *****************************************************************************. As of May 2010, laninamivir octanoate has not been approved in foreign countries. 2. Data relating to quality 2.A Summary of the submitted data 2.A.(1) Drug substance 2.A.(1).1) Characterization ***************************************************************************** ************. (a) General properties The determined physicochemical properties of the drug substance include description, solubility, hygroscopicity, thermal analysis, melting point (decomposition point), pH, partition coefficient, crystallinity, and crystalline polymorphism. The drug substance is a white powder. It is freely soluble in dimethyl sulfoxide and in methanol, slightly soluble in ethanol (99.5), very slightly soluble in water, and practically insoluble in acetonitrile and in hexane. ****************************************************** ************ . Under the condition of **°C/**% RH, a **% increase in the mass was observed after ** hours, from which the drug substance was considered to be slightly hygroscopic. The pH of the saturated aqueous solution at 20°C was 5.8, and the partition coefficient (LogPow) in water/octanol system at 25°C was 0.0. (b) Structure determination The chemical structure of the drug substance is supported by elemental analysis, infrared spectrophotometry, nuclear magnetic resonance spectrum (1H-NMR, 13C-NMR), and