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Zanamivir in the Managementof Influenza A and B
Introduction to Relenza
Relenza has unsurpassed efficacy in the treatment and prophylaxis of influenza infection1-6
Relenza reduces potentially life threatening complications of influenza3
Relenza has an established safety profile7
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 stockpile8
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.
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.
1. Cass et al. 1999; Peng et al. 2000; 2. Moscona A. NEJM 2005; 353: 1363-1373.
Relenza Delivered Direct to theRespiratory Tract and Acts Rapidly
Drug levels in the lung following inhalation (ng/mL; induced sputum)1
Immediate ~6,900 (> 1,000-fold IC50)
6 hours 1,366 (> 670-fold IC50)
12 hours 304 (> 300-fold IC50)
24 hours 47 (> 50-fold IC50)
Relenza begins to work within 10 seconds2
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 (IC50) 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 nasopharynx1
– 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.
Relenza Has Unsurpassed Efficacy in the Treatment of Influenza
Shortens the duration of influenza symptoms1
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 bronchitis2
1. Relenza SPC. GlaxoSmithKline 2006; 2 Monto et al J Antimicrob Chemother 1999; 44:23-29.
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.
Relenza Has Unsurpassed Efficacy in the Prophylaxis of Influenza Infection
Study design Study Setting Nr. subjectsProtective efficacy vs
placebo
Post-exposure prophylaxis
Hayden et al NEJM 2000;
343;1282-1289
Household contacts
337 families 79%
Post-exposure prophylaxis
Monto et alJID 2002;
186:1582-1588
Household contacts
487 families 81%
Seasonal prophylaxis
Monto et alJAMA 1999; 282:31-35
Healthy adults (University)
1,107 67%
Seasonal prophylaxis
LaForce et alClin Ther 2007; 29(8):1579-1590
High risk 3,363 83%
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 diagnosedwith symptomatic, laboratory-confirmed influenza
0 25 50
Number Of Families
Relenza n = 10/245 (4.1%)
Placebo n = 46/242 (19%)
P<.001
Monto Study
81% protective efficacy rate vs placebo
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 brain2
Clinical isolate of oseltamivir-resistant H5N1 (H274Y) from treated child in Vietnam
– Susceptible to treatment with Relenzain the ferret3
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 Relenza4
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 – 19th January 2007. Available from: http://WWW.pharmatimes.com/clinicalnews/articles/10228-tamiflu-resistance.aspx?src=cn, ACCESSED 12th November 2007.
Relenza Treatment Reduces Viral Shedding
Study in military personnel receiving standard Relenza treatment course
– 8.48 log10 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.
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].
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.
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.
Summary of Adverse Events With 1.5% Incidence During Treatment in Adults and Adolescents
Relenza10 mg BID (%) Placebo (%)
Adverse event (n = 1,132) (n = 1,520)
Headaches 2 3
Diarrhea 3 4
Nausea 3 3
Vomiting 1 2
Nasal signs and symptoms 2 3
Bronchitis 2 3
Cough 2 3
Sinusitis 3 2
Ear, nose and throat infections 2 2
Dizziness 2 <1
Relenza prescribing information. GlaxoSmithKline; 2006.
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.
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.
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..
Relenza is Delivered Direct to the Site of Action via Inhalation
Rotadisk Inhalation PowderCover
Mouthpiece Piercing Needle
DISKHALER is Easy to Use
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.
Viral Resistance
Neuraminidase (NA) Inhibitors Bind to NA Receptor
Reproduced from Moscona A. N Engl J Med 2005;353:1363-1373, with permission.
Mechanism of Resistance to Oseltamivir
Reproduced from Moscona A. N Engl J Med 2005;353:1363-1373, with permission
Neu5Ac2en/DANA(Natural Substrate)
O
ORO
H
AcNH
NH2
O
O
OH
H
AcNH
OH OH
OH
OH
O
O
OH
H
AcNH
OH OH
OH
NH
NH
NH2
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
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 subtypes1,2,3
There are no reports of resistance during zanamivir treatment in immunocompetent patients
– One resistant influenza B isolate was identified in an immunocompromised child4 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.
Oseltamivir Resistant Subtypes of Virus with Potential for Transmission Remain Sensitive to Zanamivir
Mutant SubtypeSelected
by
Resistance Oseltamivir (Fold-shift)
Resistance Zanamivir
(Fold-shift)
Potential for Transmission
292K A/N2 Oseltamivir R (>8,000) R (4 - 25) Unlikely
152K B Zanamivir R (13 -100) R (9 -150) Unlikely
274Y* A/N1 Oseltamivir R (400 - 900) S Possible
119V A/N2 Oseltamivir R (130 - 277) S Possible
198N B Oseltamivir R (9) R (9) Possible
294SA/N2* Oseltamivir R (300) S Possible
A/N1* # Oseltamivir R (12-15) S (3 - 4.8) Possible
402S B Oseltamivir R (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.
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
Zanamivir E119G N9, N2 (human), BE119A or D N2 (avian)
R292K - N2 (avian)
Oseltamivir R292K N2 (human)H274Y N1 (human)E119D N9
Many HA mutations selected around 1st and 2nd sialic acid binding site lead to reduced binding affinity
H274Y H5N1 Isolate From the Clinic was Susceptible to Relenza in the Ferret Model
Vir
us ti
tre
(lo
g 10
PF
U p
er
ml)
Le et al. Nature 2005;437:1108.
O
Zn
6
5
4
3
2
≤1
Drug sensitivity of H5N1 viral clones isolated from a human patient
1 3 5 7 9
O
Zn
6
5
4
3
2
1 3 5 7 9
Open symbols: mock treated
Closed circles: oseltamivir treated
Closed triangles: zanamivir treated
Oseltamivir-sensitive virus
Oseltamivir-resistant virus
Days post infection
In Vitro Activity Against Different NAs
Human subtypes (Mean IC50 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 IC50 values)
– H5N1, zanamivir 1-10 nM, oseltamivir 6.1-7.9 nM2,3
– H9N2, zanamivir 6-12 nM, oseltamivir 9.6-15.7 nM2,3
– H6N1, zanamivir 5-23.6 nM, oseltamivir 27.8-44.4 nM4
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.
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.
2nd Dose
Combined Fluorescent & Chemiluminescent NA assays0.1
1
10
100
1000
10000
0 2 4 6 8 10 12 16 18 20 22 24
Time after dosing (h)
Rel
enza
co
nce
ntr
atio
ns
(ng
/ml)
Sputum samples
Mean IC50 (H1N1)n=139
Mean IC50 (H3N2)n=767
Mean IC50 (B)n=148
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.
Ctrough Prophylaxis
Combined Fluorescent & Chemiluminescent NA Assays
2nd Dose
0.1
1
10
100
1000
10000
0 6 12 24
Time after dosing (h)
Rel
enza
co
nce
ntr
atio
ns
(ng
/ml)
Sputum samples
Mean IC50 (H1N1)n=139
Mean IC50 (H3N2)n=767
Mean IC50 (B)n=148
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 passage1-5
Mutations in two genes may be required to produce resistance to Relenza6
– 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 oseltamivir7,8
.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
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.
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
00 5,000 10,000 15,000 20,000 25,000
Est
imat
ed h
osp
ital
isat
ion
sp
er 1
00,0
00 p
op
ula
tio
n
Stockpiled antivirals per 100,000 population
All groupsChildren and studyAt-risk groupsWorking population
An Antiviral Stockpile of 20-25% Could Provide 67% Reduction in Hospitalisations
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.pdf
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.
Antiviral Stockpiles for 50% of the Population is Recommended
WHO recommends that national governments stockpile antiviral drugs in advance of an influenza pandemic1
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
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.
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 confirmedor suspected avian or pandemic influenzavirus infection and high risk exposuregroups
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