1. Zanamivir in the Management of Influenza A and B

2. Introduction to Relenza Relenza has unsurpassed efficacy in the treatment and prophylaxis of influenza infection 1-6 Relenza reduces potentially life threatening complications of influenza 3 Relenza has an established safety profile 7 Viral resistance to Relenza is extremely rare Stockpiles of antivirals should contain significant amounts of Relenza –The UK Royal Society of Medicine recommend Relenza should represent 50% of the stockpile 8 1. Monto et al. J Antimicrob Chemother 1999; 44 (Topic B): 23-29; 2. Makela et al. J Infect 2000; 40: 42-48; 3. The Mist Study Group. Lancet 1998; 352: 1877-1881; 4. Hayden et al. NEJM 2000; 343 (18): 1282-1289; 5. Monto et al. J Infect Dis 2002: 186; 1582-1588; 6. Monto et al. JAMA 1999; 282: 31-35. 7. Relenza, SPC, GSK, September 2006; 8. Pandemic influenza: science to policy. Royal Society and the Academy of Medical Sciences. Policy document 36/06. November 2006.

3. Relenza Indications (In Most European Countries) Relenza is indicated for the treatment of influenza A and B virus in adults and children ≥ 5 years of age Relenza is indicated for post-exposure prophylaxis of influenza A and B in adults and children ≥ 5 years of age following contact with a clinically diagnosed case in a household In exceptional circumstances, Relenza may be considered for seasonal prophylaxis during a community outbreak (e.g., mismatch between vaccine and circulating strain, and a pandemic) Relenza SPC. GlaxoSmithKline; 2006.

4. 1. Cass et al. 1999; Peng et al. 2000; 2. Moscona A. NEJM 2005; 353: 1363-1373. Relenza Delivered Direct to the Respiratory Tract and Acts Rapidly Drug levels in the lung following inhalation (ng/mL; induced sputum) 1 Immediate ~6,900 (> 1,000-fold IC 50 ) 6 hours 1,366 (> 670-fold IC 50 ) 12 hours 304 (> 300-fold IC 50 ) 24 hours 47 (> 50-fold IC 50 ) Relenza b egins to work within 10 seconds 2

5. Relenza Acts Rapidly to Suppress Viral Replication and Shedding Drug levels that are more than 1,000-fold above the concentration needed to inhibit the virus (IC 50 ) are achieved immediately following inhalation of a 10 mg dose High local concentrations maximises NA inhibition and rate of onset of inhibition –Could limit emergence of resistance Maximises suppression of virus replication – significantly reduces virus excretion in the throat and nasopharynx 1 –Could limit spread of virus from respiratory tract Zanamivir associated with significantly more rapid reduction in viral shedding vs placebo within 24 hours of initiating treatment 1. Puhakka et al Scand J Infect Dis 2003; 35:52-58.

6. Relenza Has Unsurpassed Efficacy in the Treatment of Influenza Shortens the duration of influenza symptoms 1 Effective in treatment of influenza A and B Effective in adults and children (≥ 5 years) Significantly reduces (28% less) use of antibiotics for influenza complications such as sinusitis and bronchitis 2 1. Relenza SPC. GlaxoSmithKline 2006; 2 Monto et al J Antimicrob Chemother 1999; 44:23-29.

7. Relenza Reduces Duration of Illness and Complications in High-Risk Patients Pooled analysis of 750 patients at high risk of influenza complications* Median time to alleviation of symptoms (compared to placebo)1.5 days earlier (p=0.003) Incidence of complications requiring antibiotics reduced by 28% compared with placebo (p=0.028) in patients with confirmed influenza High-risk patients defined as elderly (≥65 years of age) patients with or without underlying medical conditions, patients with chronic respiratory disease (asthma or COPD), or significant cardiovascular disease (excluding those with hypertension only). GlaxoSmithKline, Data on file.

8. Relenza Has Unsurpassed Efficacy in the Prophylaxis of Influenza Infection Study designStudySettingNr. subjects Protective efficacy vs placebo Post-exposure prophylaxis Hayden et al NEJM 2000; 343;1282-1289 Household contacts 337 families79% Post-exposure prophylaxis Monto et al JID 2002; 186:1582-1588 Household contacts 487 families81% Seasonal prophylaxis Monto et al JAMA 1999; 282:31-35 Healthy adults (University) 1,10767% Seasonal prophylaxis LaForce et al Clin Ther 2007; 29(8):1579-1590 High risk3,36383%

9. Relenza Has Excellent Efficacy in Post-Exposure Prophylaxis Monto AS et al. J Infect Dis 2002;186:1582-1588. N = 487 households with suspected case of influenza Incidence of households with ≥1 family member diagnosed with symptomatic, laboratory-confirmed influenza Relenza n = 10/245 (4.1%) Placebon = 46/242 (19%) P<.001 Monto Study 81% protective efficacy rate vs placebo

10. Relenza Has Activity Against H5N1 and Oseltamivir-Resistant H5N1 Intranasal zanamivir protects mice against lethal challenge with influenza A/HK/156/97 (H5N1) 1 –Reduced viral replication in lungs –Reduced mortality and morbidity –Prevented viral spread to the brain 2 Clinical isolate of oseltamivir-resistant H5N1 (H274Y) from treated child in Vietnam –Susceptible to treatment with Relenza in the ferret 3 A further oseltamivir-resistant strain (294S) has been isolated from two patients who died from H5N1 in Egypt in December 2006 –The oseltamivir-resistant strain in Egypt was shown susceptible to Relenza 4 1. Gubareva et al. JID 1998; 178:1592-1596; 2. Leneva et al. AAC 2001; 45:1216-1224; 3. Le et al. Nature 2005; 437:1108; 4. WHO warns of Tamiflu resistance – 19 th January 2007. Available from: http://WWW.pharmatimes.com/clinicalnews/articles/10228-tamiflu-resistance.aspx?src=cn, ACCESSED 12 th November 2007.

11. Relenza Treatment Reduces Viral Shedding Study in military personnel receiving standard Relenza treatment course –8.48 log 10 mean reduction in viral shedding in throat swabs (copies/ml x h) area under the curve over the first 48 hours, compared with placebo (p=0.003) –56% patients (vs 29% for placebo) have unquantifiable virus in throat swabs at 48h (p≤0.001) –Similar reduction in virus in nasopharynx This may impact transmissability of infection Puhakka et al. Scand J Infect Dis 2003; 35:52-58.

12. Study Comparing Efficacy of Relenza and Oseltamivir Study Suggests Zanamivir Has Superior Efficacy Compared with Oseltamivir Against Influenza B For influenza A, marginally significant differences between duration of fever after first dose of zanamivir (31.8 ± 8.4 h) and oseltamivir (35.5 ± 23.9 h) (p < 0.05) For influenza B, duration of fever with zanamivir (35.8 ± 22.4 h) significantly shorter vs oseltamivir (52.7 ± 31.3 h) (p < 0.001). Therapy (zanamivir or oseltamivir) was the major determinant affecting duration of fever for influenza B Kawai et al. J Infect 2007 Oct 12; [Epub ahead of print].

13. Relenza Has Established Safety Profile Adverse events profile similar to placebo in clinical trials: treatment and prophylaxis in adults/adolescents/paediatric, including elderly and high risk CNS, gastrointestinal and other systemic effects are comparable to placebo Minimal potential to cross blood-brain barrier May be taken with or without food Long-term prophylaxis (4 months) safety study planned Relenza SPC. GlaxoSmithKline; 2006.

14. Relenza Has a Simple Standard Dose and Minimal Potential to Cause Drug Interactions Renally excreted as unchanged drug No need to adjust dosing in children, elderly or those with chronic disease (incl. renal) Does not affect cytochrome P450 isoenzymes No clinically significant drug interactions expected, based on data from in vitro studies Does not interfere with inactivated influenza vaccination Relenza SPC GlaxoSmithKline; 2006.

15. Summary of Adverse Events With  1.5% Incidence During Treatment in Adults and Adolescents Relenza 10 mg BID (%) Placebo (%) Adverse event(n = 1,132)(n = 1,520) Headaches23 Diarrhea34 Nausea33 Vomiting12 Nasal signs and symptoms23 Bronchitis23 Cough23 Sinusitis32 Ear, nose and throat infections22 Dizziness2<1 Relenza prescribing information. GlaxoSmithKline; 2006.

16. Safety Considerations Safety and efficacy not demonstrated in high-risk patients with severe/unstable underlying medical conditions including severe asthma and other chronic respiratory disease There have been very rare reports of bronchospasm and/or decline in respiratory function in patients taking Relenza –Refer to warnings/precautions in SPC Due to the limited experience, patients with severe asthma require a careful consideration of the risk in relation to the expected benefit, and Relenza should not be administered unless close medical monitoring and appropriate clinical facilities are available in case of bronchoconstriction. In patients with persistent asthma or severe COPD, management of the underlying disease should be optimised during therapy with Relenza There is no evidence of causal association with neuropsychiatric side effects in any age groups with Relenza Used in more than 14,000 patients in clinical trials Relenza SPC. GlaxoSmithKline; 2006.

17. Relenza Treatment Dosing Administered to respiratory tract by oral inhalation using DISKHALER  Treatment should begin as soon as possible, within 48 hours of symptom onset for adults, and within 36 hours for children Recommended dose for treatment of influenza in adults and children  5 years of age is two inhalations (2 x 5 mg) twice daily for 5 days Relenza SPC. GlaxoSmithKline; 2006.

18. Relenza Prophylaxis Dosing Post-exposure prophylaxis –Recommended dose for prevention of influenza, following close contact with an individual is two inhalations (2 x 5 mg) once daily for 10 days –Therapy should begin as soon as possible and within 36 hours of exposure to an individual Seasonal prophylaxis –Recommended dose for prevention of influenza during a community outbreak is two inhalations (2 x 5 mg) once daily for up to 28 days Plans in place for long-term (4-month) prophylaxis study Relenza SPC. GlaxoSmithKline; 2006..

19. Relenza is Delivered Direct to the Site of Action via Inhalation Rotadisk Inhalation Powder Cover MouthpiecePiercing Needle

20. DISKHALER is Easy to Use

21. Diskhaler commonly used to deliver asthma medications Diskhaler studied in 171 asthmatic children aged 4-11 years Device satisfaction questionnaire completed by their parents/caregivers Ease of Use of Diskhaler Very Easy / Easy 89% Neutral 7% Difficult 3% Very Difficult 1% Data on file: GSK.

22. Viral Resistance

23. Neuraminidase (NA) Inhibitors Bind to NA Receptor Reproduced from Moscona A. N Engl J Med 2005;353:1363-1373, with permission.

24. Mechanism of Resistance to Oseltamivir Reproduced from Moscona A. N Engl J Med 2005;353:1363-1373, with permission

25. Neu5Ac2en/DANA (Natural Substrate) Zanamivir/Relenza Oseltamivir/Tamiflu Oseltamivir does not fit well into the sialic acid binding site of the viral neuraminidase, whereas zanamivir binds tightly with the viral neuraminidase This may explain the observed differences in development of resistance Conformational change of active site required to allow binding No conformational change required to allow binding The Structure of Zanamivir May Confer A Lower Propensity for Resistance Than Oseltamivir

26. Resistance to Oseltamivir Observed More Commonly than with Zanamivir Resistance to oseltamivir seen in 1% adults, 4-18% paediatrics –Different resistance mutations observed for different influenza subtypes 1,2,3 There are no reports of resistance during zanamivir treatment in immunocompetent patients –One resistant influenza B isolate was identified in an immunocompromised child 4 treated with zanamivir for 15 days Resistance to either neuraminidase inhibitor is difficult to generate in vitro – requires several passages. Oseltamivir-resistant mutants may remain sensitive to zanamivir 1. Kiso M et al. Lancet 2004; 364: 759-65; 2. Ward P et al. J Antimicrob Chemoter 2005; 55(Suppl. 1): 13-21; 3. The Writing Committee of the World Health Organisation (WHO) N Engl J Med, 2005; 353: 1374-85; 4. Gubareva L et al. J Infect Dis 1998; 178:1257-62.

27. Oseltamivir Resistant Subtypes of Virus with Potential for Transmission Remain Sensitive to Zanamivir MutantSubtype Selected by Resistance Oseltamivir (Fold-shift) Resistance Zanamivir (Fold-shift) Potential for Transmission 292KA/N2OseltamivirR (>8,000)R (4 - 25)Unlikely 152KBZanamivirR (13 -100)R (9 -150)Unlikely 274Y * A/N1OseltamivirR (400 - 900)SPossible 119VA/N2OseltamivirR (130 - 277)SPossible 198NBOseltamivirR (9) Possible 294S A/N2*OseltamivirR (300)SPossible A/N1* # OseltamivirR (12-15)S (3 - 4.8)Possible 402SBOseltamivirR (high)R(7)Not Known * Reported in human case(s) of avian flu treated with oseltamivir in Vietnam, # and from patients in Turkey 1. Wetherall et al. J Clin Microbiol 2003; 41:742-50; 2. Guvareva et al. J Infect Dis 2001;183: 523-531; 3. Guvareva et al. Virus Res 2004;103: 199-203.; 4. Kiso et al. Lancet 2004; 364: 759-765; 5. Mishin et al. Antimicrob Agents Chemother 2005; 49: 4515- 4520; 6. Ison et al. J Infect Dis 2006 15;193: 765-772; 7. De Jong et al. NEJM 2005; 353:2667-2672; 8. Le et al. Nature 2005;437:1108. 9. Hatakeyama et al. JAMA 2007.

28. Summary of In Vitro Resistance Studies Resistance to both inhibitors difficult to generate in vitro –requires several passages Both NA and HA mutations selected and both can confer resistance in vitro NA mutations selected plus NA subtype ZanamivirE119GN9, N2 (human), B E119A or DN2 (avian) R292K-N2 (avian) OseltamivirR292KN2 (human) H274YN1 (human) E119DN9 Many HA mutations selected around 1st and 2nd sialic acid binding site lead to reduced binding affinity

29. H274Y H5N1 Isolate From the Clinic was Susceptible to Relenza in the Ferret Model Virus titre (log 10 PFU per ml) Le et al. Nature 2005;437:1108. O Zn 6 5 4 3 2 ≤1≤1 Drug sensitivity of H5N1 viral clones isolated from a human patient 13579 O Zn 6 5 4 3 2 13579 Open symbols: mock treated Closed circles: oseltamivir treated Closed triangles: zanamivir treated Oseltamivir-sensitive virus Oseltamivir-resistant virus Days post infection

30. In Vitro Activity Against Different NAs Human subtypes (Mean IC 50 values >1,000 isolates) 1 –A/H1N1, zanamivir 0.76 nM, oseltamivir 1.2 nM –AH3N2, zanamivir 1.82 nM, oseltamivir 0.5 nM –B, zanamivir 2.28 nM, oseltamivir 8.8 nM Avian subtypes (range of published IC 50 values) –H5N1, zanamivir 1-10 nM, oseltamivir 6.1-7.9 nM 2,3 –H9N2, zanamivir 6-12 nM, oseltamivir 9.6-15.7 nM 2,3 –H6N1, zanamivir 5-23.6 nM, oseltamivir 27.8-44.4 nM 4 1. McKimm-Breshkin et al. Antimicrob Agents Chemother. 2003; 47: 2264-2272; 2. Leneva et al. Antiviral Res 2000; 48:101-115; 3. Govorkova et al. Antimicrob Agents Chemother 2001; 45: 2723-2732; 4. Leneva et al. Antimicrob Agents Chemother 2001; 45: 1216-1224.

31. Relenza Therapeutic Respiratory Concentrations (Estimated Steady State for q12h Dosing) Peng et al. Antimicrobial Agents Chemother 2000; 44: 1974-1976; McKimm-Breschkin et al. Antimicrobial Agents Chemother 2003; 47: 2264-2272. 2 nd Dose Combined Fluorescent & Chemiluminescent NA assays

32. Relenza Therapeutic Respiratory Concentrations at Steady State for QD Prophylaxis Dosing Peng et al. Antimicrobial Agents Chemother 2000; 44: 1974-1976; McKimm-Breschkin et al. Antimicrobial Agents Chemother 2003; 47: 2264-2272. C trough Prophylaxis Combined Fluorescent & Chemiluminescent NA Assays 2 nd Dose

33. Risk of Resistance to Relenza is Low In vitro studies have shown that mutations in both haemagglutinin and neuraminidase genes are selected during resistance development over prolonged passage 1-5 Mutations in two genes may be required to produce resistance to Relenza 6 –The risk of this occurring within 5 days of treatment is low Just one mutation (NA) appears to be required to produce a very high level resistance to oseltamivir 7,8. 1. Barnett et al. Virology 1999; 265: 286-295; 2. Blick et al. Virology 1995; 214: 475-484; 3. Blick et al. Virology 1998; 246: 95-103; 4. Gubareva et al. J Virol 1997; 71: 3385-3390; 5. McKimm-Breschkin et al. Virol 1996; 225: 240-242; 6. Gubareva et al. J Infect Dis 1998; 178: 1257-1262; 7. Le et al. Nature 2005; 437: 11088; 8. De Jong et al. NEJM 2005; 353 (25): 2667

34. The Favourable Resistance Profile of Zanamivir is Important in Choice of Antivirals for Stockpiling “...although both (Relenza [zanamivir] and Tamiflu [oseltamivir]) have similar efficacy, zanamivir has … a favourable resistance profile. The resistance factor would be an important consideration in a pandemic situation” Tsang et al. Lancet 2005; 366; 533-534. “If this frequent emergence of resistant mutants is found to be a general occurrence in children, it is a serious concern, especially since children are an important source of the spread of infection in the community.” Moscona A. NEJM 2005; 353: 1363-1373. “Resistant strains have been generated in vitro and such strains have also been found in a small proportion of patients during or after treatment with oseltamivir. Oseltamivir-resistant strains have also been detected in individuals not exposed to oseltamivir” “The development of viral resistance is possible and might have a substantial impact on the clinical usefulness of oseltamivir” EMEA Report 2007.

35. Adapted from Gani et al. Emerg Infect Dis 2005;11: 1355-1362. Based on 1957 pandemic Estimated hospitalisations per 100,000 population when different antiviral treatment strategies are applied 200 180 160 140 120 100 80 60 40 20 0 05,00010,00015,00020,00025,000 Estimated hospitalisations per 100,000 population Stockpiled antivirals per 100,000 population All groups Children and study At-risk groups Working population An Antiviral Stockpile of 20-25% Could Provide 67% Reduction in Hospitalisations

36. French Government Has Ordered Antivirals to Cover 54% of the Population With 28% of the Stockpile Being Relenza "These 33 million antiviral treatments will far exceed requirements for covering 25% of the population, the figure recommended by WHO " "This will enable resistance risks to be prevented and a more flexible and adaptable approach to be taken to the strategies implemented in accordance with the characteristics of the virus and the pandemic" Presentation of the French Government’s Updated Plan to Combat the Avian Influenza Pandemic Published on 6 January 2006. Available from: http://www.info-france-usa.org/news/statmnts/2006/avianflu.pdfhttp://www.info-france-usa.org/news/statmnts/2006/avianflu.pdf

37. U.S. Department of Health & Human Services (HHS) Recommends 20% of Stockpile Should be Relenza HHS has focused its recent antiviral stockpiling efforts on purchasing Tamiflu and Relenza even though recent reports have surfaced that some strains of the H5N1 virus are becoming resistant to Tamiflu In response, HHS has changed its stockpiling strategy to decrease the target share of Tamiflu held in reserve from 90% to 80% and increase the share of Relenza from 10% to 20% The Congress of the United States Congressional Budget Office. A Potential Influenza Pandemic: An Update on Possible Macroeconomic Effects and Policy Issues. May 22, 2006; revised July 27, 2006.

38. Antiviral Stockpiles for 50% of the Population is Recommended WHO recommends that national governments stockpile antiviral drugs in advance of an influenza pandemic 1 Stockpiles equivalent to 50% of the population, allowing post-exposure prophylaxis in households could reduce clinical attack rates by 40- 50% 2 1. WHO. WHO Rapid Advice Guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus. Geneva: World Health Organization, 2006; 2. Ferguson NM et al. Nature 2006, 442:448-452. The emergency stockpile of flu drugs will be doubled in Britain so that half of the population is covered in the event of a pandemic” Alan Johnson, the Health Secretary, November 22, 2007

39. WHO Recommendations (2007) Antiviral treatment in patients with confirmed or strongly suspected H5N1 infection –Applies to adults (including pregnant women) and children –Regimen for H5N1 is as recommended for seasonal influenza Antiviral chemoprophylaxis in management of avian (H5N1) influenza –In high risk exposure groups oseltamivir or zanamivir should be administered (strong recommendation) –In moderate risk exposure groups oseltamivir / zanamivir might be administered (weak recommendation) –Continuing for 7-10 days after the last known exposure Schünemann et al. WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus. Lancet Infect Dis 2007; 7: 21-31.

40. WHO Recommends National Stockpiles of Antivirals for Treatment and Prophylaxis Purpose: Response to outbreaks within the country or the treatment and prophylaxis of citizens during a pandemic Timing: Pandemic phase III and later Application: Stockpile under the control of a specific nation and positioned within its borders. Treatment of individuals with confirmed or suspected avian or pandemic influenza virus infection and high risk exposure groups

41. Antiviral Stockpiles for 50% of the Population is Recommended 1. Glezen WP. Epidemiol Rev 1996; 18: 64-76. Overall clinical attack rates during pandemics have reached 30-35% 1 Coverage required depends upon the virulence of the virus once a pandemic starts Stocks required for treatment and for prophylaxis –Post exposure prophylaxis –Prophylaxis for essential services workers