Antiviral Therapy

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Antiviral Therapy

• Rutgers Graduate Virology
• April 29, 2008
• Catherine Laughlin, Ph.D.
• claughlin_at_niaid.nih.gov

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Why Are There so Few Antivirals?

• Viruses are Obligate Intracellular Parasites
• Viral Target -gt Potency Specificity-gt
  Resistance
• Host Target -gt Less Potent but Broad-Spectrum?
  Toxicity?

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Central Concepts

• Obligate Intracellular Parasite vs Safe and
  Effective
• Antiviral Activity often Guarantees Resistance
  Can We Deal?
• Selective Index, Therapeutic Window
• EC 50, look for nM activity
• CC 50 tox
• SI, TI, window
• Drug Discovery by Screening or Rational Design
• High thru-put
• Cell-based
• Structure-based, enzyme based, in silico docking
• Is lead druggable?
• Iterative process

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Central Concepts, cont.

• Importance of PK, PD properties (absorption,
  distribution, metabolism, elimination)
• Dosing Strategies Prodrugs, Prophylactic,
  Pre-emptive, Intermittent, Topical, Therapeutic
  Vaccines
• Resistance, esp. in ic popns,
• (Quasi) broad spectrum Fantasy?
• Combination and Targeted Delivery for toxicity
  and resistance control
• Surrogate markers
• Approval Process
• FDA Animal Rule

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Drug Development Resources for Anti-Infectives
Candidate
Drug
Fundamental Science
IND Enabling Studies
Identification
Characterization
Clinical

• Compound
• Acquisition
• Screening (HTS)
• In vitro and in vivo
• Assays/Screens
• Lead Optimization
• Chemistry

• Safety
• PK/PD (Dose
• Selection)
• Metabolism/
• Toxicology Studies
• GMP

• Clinical Trials
• Formulations

• Target
• Identification/
• Validation
• Assay
• Development

• Microbiology
• Animal Efficacy/
• Preliminary Drug
• Exposure

Management and Coordination Go/No-Go Decisions

of Candidates
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VIRAL TARGETS

• ADSORPTION
• PENETRATION
• UNCOATING
• GENOME REPLICATION
• VIRAL RNA AND PROTEIN SYNTHESIS AND PROCESSING
• PACKAGING
• MATURATION AND EGRESS

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In Vitro Antiviral Activity vs. Variola Major
Monkeypox (EC50 in mM))

• Neutral Red CPE Protection Assay
• Data from John Huggins, USAMRIID

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Anti-Ebola Virus Activity
Name IC50 (µM) TC50 (µM) TI CaAdo 4 30 8 Ca-c3Ado
30 5640 188 Me-Ca-c3Ado 64 gt1016 gt16 Npc
A 4 60 15 c3-Npc A 2 gt1700 gt850 HDCpAdo 17 gt1700
gt100 HDCp-c3Ado 9 gt1700 gt200
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PHARMACOKINETICS

• ABSORPTION ORAL DELIVERY PREFERABLE
• DISTRIBUTION
• RIBAVIRIN
• METABOLISM
• REDUCE ACTIVITY
• CAUSE TOXICITY
• SERUM/TROUGH
• ELIMINATION

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Oseltamivir Exposure in Children (2 mg/kg)
Oo et al. Paediatr Drugs 3229 2001
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CMX001 for Smallpox
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14C-labeled CMX001 Distribution 4 hrs After
Oral Dosing
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Lipid Conjugation Reduces Potential for Acute
Kidney Toxicity
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Metabolism of CMX001 by Liver S9 Fractions
CONFIDENTIAL
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Brain Specific siRNA Delivery by RVG-9R
N6
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Intravenous siRNA Treatment Protects Against JEV
Encephalitis
Mice were infected with JEN and treated IV with
JEV- or control Luci siRNA bound to RVG-9R or
RV-MAT-9R and examined for survival.
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Palese P. Nature Med 10S82, 2004
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Oseltamivir Prophylaxis

• Seasonal prophylaxis in adults
• 75 mg once daily for 6 weeks
• 84 reduction in influenza illness in ambulatory
  adults (Hayden et al. NEJM 3411336, 1999)
• 92 reduction in nursing home residents (Peters
  et al. JAGS 491025, 2001)
• Post-exposure prophylaxis in households
• Once daily dosing for 7-10 days
• 89 reduction in adults/teens (Welliver et al.
  JAMA 285748, 2000)
• 64 reduction in children 1-12 yrs old (Hayden et
  al. JID 189440, 2004)

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RESISTANCE

• SELECTION
• MUTATION RATES OF GENOME
• REPLICATION
• GOOD NEWS/BAD NEWS
• MOST EVIDENT IN IMMUNOCOMPROMISED/CHRONIC
• CONTROL WITH COMBOS

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Detection Of Antiviral Resistant Influenza
During Treatment
Roberts N. Phil Trans R Soc Lond 3561895,
2001 Kiso et al. Lancet 364 759, 2004
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COMBINATION THERAPY

• SYNERGISTIC OR ADDICTIVE ACTIVITY
• TOXICITY
• DELAY/PREVENT RESISTANCE
• HAART
• USUALLY 2 NRTI and 1 NNRTI or PI
• SWITCH AT LEAST 2 AT SAME TIME
• IMPACT ON IMMUNE FUNCTION, OIs

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COMBINATIONSWHAT?

• TWO OR MORE ANTIVIRALS
• ANTIVIRAL IMMUNOMODULATOR
• ANTIVIRAL OTHER (TOXICITY)
• ANTIVIRAL OTHER (POLYPHARMACY)

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A Combination of ST-246 and CMX-001 is Effective
against IL-4 Ectromelia Infections

• Failed Treatments
• Single and/or boosted Dryvax vaccinations
• Single antiviral alone or in combination with
  boosted Dryvax vaccination
• VIG

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Oseltamivir-Rimantadine for A/Qa/HK/G1/97 (H9N2)
in Mice
Percent Survival (day 14)
Oseltamivir dose (mg/kg/d)
Leneva et al. Antiviral Research 48101, 2000
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CHALLENGES TO PURSUIT OF STRATEGIES FOR RARE
AND/OR BioT

• ECONOMIC INCENTIVE
• DUAL USE
• GOVT ASSISTANCE
• GOOD CITIZEN
• LOGISTIC
• HIGH LEVEL CONTAINMENT
• SURROGATE SYSTEMS

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Animal Rule 21 CFR 601.91(a)(1-4)

• There is a reasonably well-understood
  pathophysiological mechanism of the toxicity of
  the substance and its prevention
• The effect is demonstrated in more than one
  animal species with response expected to be
  predictive for humans or a single animal model
  that is sufficiently well-characterized
• The animal study endpoint is clearly related to
  the desired benefit in humans, generally survival
  enhancement or prevention of major morbidity
• The kinetics and pharmacodynamics of the product
  or other relevant data or information, in animals
  and humans, allows selection of an effective dose
  in humans.

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Monotherapies

• Herpes simplex, chickenpox, shingles
• Acyclovir, Valacyclovir, Famcyclovir (guanosine
  analog)
• Target viral TK (also pol)
• 2 are prodrugs
• DNA chain terminators (lack 3 hydroxyl)
• Different potency (10x)
• Cytomegalovirus
• Ganciclovir, Cidofovir, Foscarnet
• UL97, DNA pol

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Monotherapies, cont. Influenza

• Amantadine, Rimantadine
• M2 Ion channel
• Uncoating primary, also maturation
• Resistance
• Only vs type A
• Zanamavir, Oseltamivir
• Neuraminidase Inhibitors
• Sialic acid analogs
• Inhibit maturation
• Vs both A and B
• Delivery
• Pandemic Plan
• Rx vs Px

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Normal Budding and Release of Influenzavirus from
an Infected Cell (Panel A) and Release Restricted
by a Neuraminidase Inhibitor (Panel B)
Monto, A. S. N Engl J Med 2005352323-325
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Detection Of Antiviral Resistant Influenza
During Treatment
Roberts N. Phil Trans R Soc Lond 3561895,
2001 Kiso et al. Lancet 364 759, 2004
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Influenza Treatment in Children Primary
Endpoint
Time to resolution of all illness
Plt0.001 compared to placebo recipients, using
weighed Mantel-Henszel test,stratified for region
and otitis media
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Influenza Treatment in Children Tertiary
Endpoint
Number of subjects with Otitis Media (without OM
at baseline)
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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) T-705
  viramidine
• Protease inhibitors
• Aprotinin

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Hepatitis

• B
• Interferon, Pegylated Ifn
• Lamivudine (R)
• Adefovir dipivoxil
• Entecavir
• C
• Ribavirin (pegylated) interferon
• Still lt50 response
• Genotype differences

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Detection Of Antiviral Resistant Influenza
During Treatment
et al. Lancet 364 759, Roberts N. Phil Trans R
Soc Lond 3561895, 2001 Kiso 2004
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ECZEMA VACCINATUM
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