ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZA IOM Briefing April 4, 2005

ANTIVIRALS and IMMUNOTHERAPIES in PANDEMIC INFLUENZA

IOM Briefing

April 4, 2005

Frederick G. Hayden, M.D.

Division of Infectious Diseases and International Health

University of Virginia School of Medicine

Antiviral Agents for Influenza

Class/agent Brand name Route

M2 inhibitors Amantadine Rimantadine

Symmetrel Flumadine

PO PO

NA inhibitors Zanamivir (GG167) Oseltamivir (GS4104) Permavir (RWJ-270201)*

Relenza Tamiflu

Inhaled

PO PO

*Investigational in USA

Amantadine Prophylaxis During Pandemic Influenza

Protective efficacy

Pandemic Influenza A illness

Seroconversion

1968 H3N2

1977 H1N1

59-100%

31-71%

28-52%

19-39%

Hayden. J Infect Dis 176:S56, 1997

Chemoprophylaxis of Epidemic Influenza

Strategy AM/RM ZNV OSEL

Seasonal Non-immunized adults 85-91% 84% 84% Immunized NH elderly 58-75% ? 92% Post-contact / post-exposure Households 3-100% 82% 67-89% Nursing homes Variable Yes Yes

?= No placebo-controlled study or not reported

Efficacy (vs placebo or no drug)

Oseltamivir PEP in Households: Reduction in Influenza Illness, 2000-01

Contact Age

No. Observa-tion

Osel PEP

Efficacy

(95% CI)

13+ 373 8% 2% 74%

1-5 yrs 20 36% 22% 39% (-211%, 88%)

6-12 yrs 109 22% 9% 61%(-19%, 87%)

Note: All index cases influenza-positive and treated with oseltamivir (ITTI)

Hayden et al. JID 189:440, 2004

Antiviral Treatment of Influenza

Outcome AM/RM ZNV OSEL

Symptom relief Yes Yes Yes

Prevention of complications ? Yes Yes

Decrease antibiotic use ? 28% 24-40%

Decrease hospitalizations ? ? ~50%

Treatment of viral complications

? ? ?

Reduction in transmission ? (30%) ? ?

?= No placebo-controlled study or not reported

Oseltamivir Treatment: Effect on Hospitalizations

Hospitalizations % Reduction

Placebo Oseltamivir

Healthy adults 5/662 (0.8%) 3/982 (0.3%) 60%

High-risk + elderly

13/401 (3.2%) 6/368 (1.6%) 50%

Total 18/1063 (1.7%) 9/1350 (0.7%) 59% (P=0.019)

Kaiser et al. Arch Intern Med 163:1667, 2003

Oseltamivir and Complications: Retrospective Cohort Study, USA

Outcome Exposed Unexposed Adj. Hazard Ratio (95% CI)

Age 1-12

Pneumonia

Hosp.

(n=586)

4 (0.7%)

1 (0.2%)

(n=17,886)

453 (2.5%)

120 (0.7%)

0.34 (0.13, 0.90)

0.29 (0.04, 2.07)

Age 13-59

Pneumonia

Hosp.

(n=10,649)

138 (1.3%)

99 (0.9%)

(n=41,007)

885 (2.1%)

510 (1.2%)

0.81 (0.68, 0.97)

0.75 (0.60, 0.93)

Age 60+

Pneumonia

Hosp.

(n=463)

8 (1.7%)

10 (2.2%)

(n=3,298)

290 (8.8%)

163 (4.9%)

0.41 (0.20, 0.82)

0.55 (0.29, 1.05)

Nordstrom et al. 44th ICAAC, abst no. V-1260, 2004

Anti-Influenza Agents: Adverse Drug Reaction Profiles

Agent ADR Severity Freq Dose-related

Amantadine CNS

GI

Mild- severe

Mild

10-30%

Common

Yes

Yes

Rimantadine CNS

GI

Mild- moderate

Mild

<10%

Common

Yes

Yes

Zanamivir Broncho-spasm

Mild- severe Very un-common

No

Oseltamivir GI Mild Common Yes

Influenza Antivirals: Pregnancy Risks

Drug Embryo-toxicity*

Terato-genicity*

Pregnancy category

Breast milk excretion

Amantadine Yes Yes+ C Yes

Rimantadine Yes Yes C Yes

Oseltamivir No No C Yes+

Zanamivir No No C Yes+

Ribavirin Yes Yes X ?

* Animal models+ Case reports in humans

Drug Resistance in Influenza A Viruses

M2 Inhibitor Oseltamivir

Magnitude of resistance High High

Primary resistance 1-2.5% No

Frequency during therapy High Low

Rapid development Yes Variable

Person-person transmission Yes Not-to-date

Pathogenicity Yes Reduced*

Competition with wild-type Yes* Reduced*

*Animal models

Detection Of Antiviral Resistant Influenza During Treatment

Frequency of resistance

Oseltamivir M2 inhibitor

Out-patient adults

Out-patient children

0.4%

5.5%

~30%

~30%

Inpatient children 18% 80%

Immunocompromised

? >33%

Roberts N. Phil Trans R Soc Lond 356:1895, 2001

Kiso et al. Lancet 364: 759, 2004

Oseltamivir Resistance In N1 Neuraminidase

• Single nucleotide substitution (His274Tyr) → ↓oseltamivir susceptibility (≥ 400–fold) • Frequency drug therapy

– Children: 16% (7/43)– Adults: 4% (2/50)

• Reduced replication in cell culture (> 2.0 log10)– ↓infectivity in mouse (1,000-fold) and ferret

(100-fold)– Variable↓pathogenicity in ferret

•Transmissible in ferret model

Ives et al. Antiviral Res 5:307, 2002

Herlocher et al. JID 190:1627, 2004

Inhibitors of Influenza A and B Virus Neuraminidases

• Potent and specific inhibitors of influenza NAs in nM range

• Varied potencies for NAs of different types (A and B) and subtypes

• Zanamivir (RelenzaTM) and oseltamivir (TamifluTM) are commercially available

• Peramivir (BCX-1812, RWJ - 270201) and A-315675 are investigational.

NA Inhibitor Resistance Profiles

NA mutation

NA type/ subtype

Susceptibility in the NAI assay (fold )

Oseltamr Zanamivir Peramivir A-315675

E119V A/N2 R (>50) S (1) S S

R292K A/N2 R (>1000) S (4-25) R (30) S (8)

H274Y A/N1 R (900) S (1) R (40) S (3)

R152K B R (>30-750) R (10-100) R (>500) R (150)

Gubareva LV. Virus Res 103:199, 2004; Wetherall et al. AAC 41:742, 2003

Antiviral and Immunotherapy Research Topics in Pandemic Influenza

• Current agents–Decreased/increased dose and duration–Other risk populations; infants, pregnant

women, immunocompromised, hospitalized–Delayed treatment benefit (>48 hr)

• Parenteral route of administration• Resistance prevention and management• Combinations of antivirals• New antiviral targets

Oseltamivir Treatment in Adults: Antiviral Effects

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 2 4 6 8

Day

Placebo

Oseltamivir 75 BID

Oseltamivir 150 BID

Median viral titer, log10 TCID50/ml

Treanor et al. JAMA 283:1016, 2000

Oseltamivir Treatment in Children:Antiviral Effects

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 2 4 6 8 10

PlaceboOseltamivir

p<0.05

Viral titer log10 TCID/mL

DaysWhitley et al. PIDJ 20:127, 2001

Palese P. Nature Med 10:S82, 2004

IV Zanamivir in Experimental Influenza A

• Double-blind, randomized, placebo-controlled • Healthy adults with serum HAI titers < 1:8• IV zanamivir 600 mg q12 hr or saline starting 4 hr

before intranasal inoculation with 105 TCID50

A/Texas/36/91(H1N1)– Nasal wash ZNV median 10-12 ng/ml

• Outcomes (saline [n=8] vs ZNV [n=7]):– Infection- 100% vs 14%, P<0.005 – Virus shedding- 100% vs 0%, P<0.005– URI- 100% vs 0%, P<0.005

Calfee et al. Antimicrob Agents Chemother 43:1616, 1999

0

50

100

150

200

250

0 2 4 6 8 10 12 14 16 18 20 22 24

0.5 mg/kg 1 mg/kg 1.5 mg/kg 2 mg/kg 5 mg/kg 10 mg/kg

Peramivir Single-Dose PharmacokineticsPeramivir Single-Dose Pharmacokinetics

Mean plasma concentrations in healthy males: oral solution

ng

/ml

Time

Peramivir Phase 3 Treatment: Quantity of Viral Shedding

Treatment Group

Days·log TCID50/ml

P Value

Placebo 5.61

Peramivir 800/400

-1.38 P=0.0003

Peramivir 800 -1.92 P<0.0001

Investigational Anti-Influenza Agents

• Neuraminidase (NA) inhibitors- Peramivir (oral/IV), A-315675 (oral)

• Long-acting NA inhibitors (LANI)–R-118958 (topical), Flunet (topical)

• Conjugated sialidase–Fludase™ (topical)

• HA inhibitors- cyanovirin-N• Polymerase inhibitors

–siRNA; ribavirin (aerosol/IV/PO)• Protease inhibitors

–Aprotinin

Yamashita et al. 43rd ICAAC, abst. no. F-1830, 2003

Summary

A quantitative assay for human interferon is described. Analysis of lung specimens from 11 fatal cases of influenzal pneumonia revealed a complete absence of interferon. The implications of this finding are discussed.

Absence of Interferon in Lungsfrom Fatal Cases of Influenza

National Institute for Medical Research, Mill Hill, LondonInterferon and Influenza, S Baron and A Isaacs, January 1962

Potential Immunomodulatory Therapies

• Replacement of deficient responses • Stimulation of protective innate immune responses

– TLR-4 agonists*• Modulation of immunopathologic host responses

– Pro-inflammatory cytokines/chemokines/NO• Anti-TNF*, corticosteroids• Statins, fluoroquinolones, macrolides

– Reactive oxygen species• N-acetylcysteine, allopurinol*, superoxide dismutase*

• Potentiation of viral replication combined antiviral and anti-mediator therapies

*Beneficial in murine models of influenza

Effect of Prior Statin Therapy on Sepsis

• Prospective, observational cohort study• 361 hospitalized pts with proven/suspected

acute bacterial infection– Statin therapy > 1 mo in 23%

– Pneumonia 49%, UTI 39%, cellulitis 12%

• Outcomes (no statin vs statin):– Severe sepsis- 19.0% vs 2.4% (RR 0.13, 0.03-0.52)

– ICU admit- 12.2% vs 3.7% (RR 0.30, 0.1-0.95)

– Mortality day 28- 8.6% vs 3.7% (RR 0.43, 0.13-1.38)

Almog et al. Circulation 110:880, 2004

Time, h

* p0.01† p0.001‡ p0.05

PlaceboOseltamivir

Hayden et al.JAMA 1999

Oseltamivir reduces cytokine levels

-36-24

-120

1224

3648

6072

8496

108120

132144

156

0

3

6

9

12

‡

0.0

0.2

0.4

0.6 *

0

3

6

9

12 *

†

IL-6

TNF

IFN

Drug administration

Med

ian

co

nce

ntr

atio

n p

g/m

L

Drug administration

Research Priorities: Short-term (1-2 Years)

• Obtain data on virologic course and host immune responses in human H5 infections

• License orally inhaled zanamivir for prophylaxis • Study oseltamivir PK + tolerance in infants <1 yr• Determine PK and tolerability of IV/IM peramivir• Assess long-term (8 –12 weeks) tolerability of

oseltamivir and inhaled zanamivir prophylaxis– Trial in risk populations in SE Asia

• Study H5N1 resistance emergence in animal models and strategies for prevention

Research Priorities: Mid-term (2-5 Years)

• Test oseltamivir monotherapy vs combination with M2 or ribavirin in high-risk population

• Develop contemporary virus challenge pools for studies of experimental human influenza– Test candidate immunomodulators and antivirals

• Test therapeutic efficacy of IVIM peramivir in hospitalized influenza patients

• Test prophylactic efficacy and tolerability of topical LANI

• Trial combination of antiviral and immunomodulator therapy

Research Priorities: Longer-term (5-10 Years)

• siRNA as systemic or topical antiviral• New antiviral agents (eg, polymerase)• Innate immune effector molecules

– Surfactants– Mannose-binding lectins– Defensins

• Innate immune activation– TLR-3, 4, 7, 8. 9 agonists– NOD receptors

• Modulation of inflammatory cascades