Zanamivir in the Management of Influenza A and B

1
Zanamivir in the Managementof Influenza A and B
2
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.
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
Relenza Delivered Direct to theRespiratory Tract
and Acts Rapidly

• Drug levels in the lung following inhalation
  (ng/mL induced sputum)1
• Immediate 6,900 (gt 1,000-fold IC50)
• 6 hours 1,366 (gt 670-fold IC50)
• 12 hours 304 (gt 300-fold IC50)
• 24 hours 47 (gt 50-fold IC50)
• Relenza begins to work within 10 seconds2

1. Cass et al. 1999 Peng et al. 2000 2. Moscona
A. NEJM 2005 353 1363-1373.
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
  (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
3552-58.
6
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 4423-29.
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 (p0.003)
• Incidence of complications requiring antibiotics
  reduced by 28 compared with placebo (p0.028) 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 design Study Setting Nr. subjects Protective efficacy vs placebo
Post-exposure prophylaxis Hayden et al NEJM 2000 3431282-1289 Household contacts 337 families 79
Post-exposure prophylaxis Monto et alJID 2002 1861582-1588 Household contacts 487 families 81
Seasonal prophylaxis Monto et alJAMA 1999 28231-35 Healthy adults (University) 1,107 67
Seasonal prophylaxis LaForce et alClin Ther 2007 29(8)1579-1590 High risk 3,363 83
9
Relenza Has Excellent Efficacy in Post-Exposure
Prophylaxis
Monto Study
N 487 households with suspected case of
influenza Incidence of households with 1 family
member diagnosedwith symptomatic,
laboratory-confirmed influenza
Relenza n 10/245 (4.1)
Plt.001
Placebo n 46/242 (19)
81 protective efficacy rate vs placebo
Monto AS et al. J Infect Dis 20021861582-1588.
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 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 1781592-1596 2.
Leneva et al. AAC 2001 451216-1224 3. Le et
al. Nature 2005 4371108 4. WHO warns of
Tamiflu resistance 19th January 2007. Available
from http//WWW.pharmatimes.com/clinicalnews/arti
cles/10228-tamiflu-resistance.aspx?srccn,
ACCESSED 12th November 2007.
11
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
  (p0.003)
• 56 patients (vs 29 for placebo) have
  unquantifiable virus in throat swabs at 48h
  (p0.001)
• Similar reduction in virus in nasopharynx
• This may impact transmissability of infection

Puhakka et al. Scand J Infect Dis 2003 3552-58.
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 lt 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 lt 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)
• 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 lt1

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
20
DISKHALER is Easy to Use
21
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.
22
Viral Resistance
23
Neuraminidase (NA) Inhibitors Bind to NA Receptor
Reproduced from Moscona A. N Engl J Med
20053531363-1373, with permission.
24
Mechanism of Resistance to Oseltamivir
Reproduced from Moscona A. N Engl J Med
20053531363-1373, with permission
25
The Structure of Zanamivir May Confer A Lower
Propensity for Resistance Than Oseltamivir
Neu5Ac2en/DANA (Natural Substrate)
Oseltamivir/Tamiflu
Zanamivir/Relenza
Conformational change of active site required to
allow binding
No conformational change required to allow binding
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
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 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 1781257-62.
27
Oseltamivir Resistant Subtypes of Virus with
Potential for Transmission Remain Sensitive to
Zanamivir
Mutant Subtype Selected by Resistance Oseltamivir (Fold-shift) Resistance Zanamivir (Fold-shift) Potential for Transmission
292K A/N2 Oseltamivir R (gt8,000) 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
294S A/N2 Oseltamivir R (300) S Possible
294S 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
41742-50 2. Guvareva et al. J Infect Dis
2001183 523-531 3. Guvareva et al. Virus Res
2004103 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 15193 765-772 7. De Jong et
al. NEJM 2005 3532667-2672 8. Le et al. Nature
20054371108. 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
• Zanamivir E119G N9, N2 (human), B E119A or
  D N2 (avian) R292K - N2 (avian) Oseltamivir R2
  92K N2 (human) H274Y N1 (human) E119D N9
• 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
Drug sensitivity of H5N1 viral clones isolated
from a human patient
Open symbols mock treated Closed circles
oseltamivir treated Closed triangles zanamivir
treated
6
Oseltamivir-sensitive virus
5
O
4
3
Zn
2
Virus titre (log10 PFU per ml)
1
1
3
5
7
9
6
Oseltamivir-resistant virus
5
O
4
3
Zn
2
1
3
5
7
9
Days post infection
Le et al. Nature 20054371108.
30
In Vitro Activity Against Different NAs

• Human subtypes (Mean IC50 values gt1,000
  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 48101-115 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)
2nd Dose
Combined Fluorescent Chemiluminescent NA assays
Peng et al. Antimicrobial Agents Chemother 2000
44 1974-1976 McKimm-Breschkin et al.
Antimicrobial Agents Chemother 2003 47
2264-2272.
32
Relenza Therapeutic Respiratory Concentrations at
Steady State for QD Prophylaxis Dosing
Ctrough Prophylaxis
Combined Fluorescent Chemiluminescent NA Assays
Peng et al. Antimicrobial Agents Chemother 2000
44 1974-1976 McKimm-Breschkin et al.
Antimicrobial Agents Chemother 2003 47
2264-2272.
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 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
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
An Antiviral Stockpile of 20-25 Could Provide
67 Reduction in Hospitalisations
200 180 160 140 120 100 80 60 40 20 0
Estimated hospitalisationsper 100,000 population
All groups Children and study At-risk
groups Working population
0
5,000
10,000
15,000
20,000
25,000
Stockpiled antivirals per 100,000 population
Adapted from Gani et al. Emerg Infect Dis
200511 1355-1362.Based on 1957 pandemic
Estimated hospitalisations per 100,000
population when different antiviral treatment
strategies are applied
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 Governments 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
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 pandemic1
• Stockpiles equivalent to 50 of the population,
  allowing post-exposure prophylaxis in households
  could reduce clinical attack rates by 40-502

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
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, 442448-452.
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
  confirmedor suspected avian or pandemic
  influenzavirus infection and high risk
  exposuregroups

41
Antiviral Stockpiles for 50 of the Population is
Recommended

• Overall clinical attack rates during pandemics
  have reached 30-351
• 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

1. Glezen WP. Epidemiol Rev 1996 18 64-76.