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Introduction to Human Challenge Models (HCMs) for Respiratory Viruses and the Application of Quantitative Pharmacology to Enhance Drug Development

Craig Rayner PharmD MBA

22nd August 2016

Disclosures and Acknowledgements

The information is derived from publically available sources and key

material for further reading is provided. Any representation/interpretation

does not necessarily reflect perspectives of others.

Data presented represents the efforts of many colleagues, over many

years across many organizations

- Roche / Genentech

- d3 Medicine LLC

- ICPD, University at Buffalo, Monash University

- Alios Biopharma, hVIVO, University of Tennessee

- 360 Biolabs

Primary investigators and clinical trials staff

Clinical trials participants

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Related Work

• Publications

1. Wollacott AM et al. Safety and Upper Respiratory Pharmacokinetics of the Hemagglutinin Stalk-

Binding Antibody VIS410 Support Treatment and Prophylaxis Based on Population Modeling of

Seasonal Influenza A Outbreaks. EBioMedicine. 2016 Feb 26;5:147-55

2. Kamal M, Rayner C et al. A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase

Inhibition on Influenza Virus Progression. Antimicrob Agents Chemother (2016).

3. Rayner C et al. Pharmacokinetic-pharmacodynamic determinants of oseltamivir efficacy using data

from phase 2 inoculation studies. Antimicrob Agents Chemother (2013).

4. Dobrovolny H, Rayner C et al. Assessing mathematical models of influenza infections using features

of the immune response. PLoS One (2013).

5. Reddy MB, · Yang KH, · Rao G, · Rayner CR, · Nie J, · Pamulapati C, · Marathe BM, · Forrest A, ·

Govorkova EA. Oseltamivir Population Pharmacokinetics in the Ferret: Model Application for

Pharmacokinetic/Pharmacodynamic Study Design. PLoS ONE 10/2015; 10(10)

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Related Work• Abstracts

1. Lutz J, Patel K et al. A mechanistic model describing

the effect of respiratory syncytial virus (RSV) kinetics

on clinical symptom score by presatovir (GS-5806).

ACOP7 (2016 accepted).

2. Fidler M, Patel K et al. A Symptom Driven Multiscale

Model of Influenza. ISIRV (2016 accepted).

3. Patel K et al. Population PK/PD Modeling of Human

Respiratory Syncytial Virus Infection and the Antiviral

Effect of AL-8176. IDWeek (2015).

4. Patel K et al. Population

Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling

of MHAA4549A, an Anti-influenza Monoclonal

Antibody, In Subjects Challenged With Influenza A

Virus. ICAAC (2015).

5. Patel K et al. Population modelling of influenza viral

kinetics, immune response, symptom dynamics and

the effect of oseltamivir. PAGANZ (2015).

6. Rayner C, Kirkpatrick et al. A Novel Interdisciplinary

Pharmacometric Approach: A Systems Approach to

Support Pharmacology to the Payer. ACOP (2015).

7. Patel K at al. Modelling the kinetics of human

respiratory syncytial virus (RSV) and clinical disease

symptoms. ACOP (2014).

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8. Wu D, Chaiyakunapruk N, Pratoomsoot C, Lee K, Chong HY,

Nelson NE, Smith PF, Kirkpatrick CM, Kamal M, Nieforth K,

Dall G, · Toovey S, ·Kong DC, · Kamauu A, Rayner CR. Cost-

Utility Analysis of Optimal Dosing of Oseltamivir Under Pandemic

Influenza Using a Novel Approach: Linking Health Economics

and Transmission Dynamic Models Value in Health 11/2014;

17(7):A807.

9. Wu D, Chaiyakunapruk N, Pratoomsoot C, Lee K, Chong HY,

Nelson NE, Smith PF, Kirkpatrick CM, Kamal M, Nieforth K,

Dall G, · Toovey S, ·Kong DC, · Kamauu A, Rayner CR.

Oseltamivir use in an Influenza Outbreak: Linking Pharmacology

to Pharmacoeconomics. IDWeek 2014 Meeting of the Infectious

Diseases Society of America; 10/2014

10. Smith PF, Kirkpatrick CM, Rayner CR Wu D, Chaiyakunapruk N,

Pratoomsoot C, Lee K, Chong HY, Nelson NE, Nieforth K, Dall

G, · Toovey S, ·Kong DC, Kamauu A, Kamal M. Estimating

Health Outcomes of Antiviral Use in Influenza Outbreaks by

Linking PK/PD and Epidemiology via a Transmission Dynamic

Model: A Novel Approach. IDWeek 2014 Meeting of the

Infectious Diseases Society of America; 10/2014

11. Rayner CR, Bulik CC, Kamal MA, Reynolds DK, Toovey S,

Hammel JP, Smith PF, Bhavnani SM, Ambrose PG, Forrest A.

Pharmacokinetic-Pharmacodynamic (PK-PD) Determinants of

Oseltamivir Efficacy Using Data from Two Phase 2 Inoculation

Studies. XIV International Symposium on Respiratory Viral

Infections (ISRVI), Istanbul, Turkey, 23–26 March 2012

12. Yang KH, Reddy M, Pamulapati C, Rayner CR,

Forrest A. Development of a Pharmacokinetic

Model for Oseltamivir in Ferrets Using Iterative

Two-Stage Analysis. American College of Clinical

Pharmacy Virtual Poster Symposium, May 22–

24, 2012

13. E. Hershberger et al. Pharmacokinetics of the

Hemagglutinin (HA) Stalk-Binding Antibody,

VIS410, in a Human Challenge Model of Infection

with a p2009 H1N1 Virus. ISIRV 2016

14. GG Rao et al. Population Modelling of Influenza A

Kinetics, Innate Immune Response & Symptom

Dynamics. 54th Interscience Conference on

Antimicrobial Agents and Chemotherapy (ICAAC).

Washington, DC Sept 2014.

15. M Fidler et al. Modeling the Spread of Pandemic

Influenza in the United States: Impact of Antiviral

Interventions, Pharmacology, and Resistance.

American Conference on Pharmacometrics;

October 2014, Las Vegas, NV.

16. E Lakota et al. Development and optimization of

an adaptive study design for respiratory virus

human challenge models. ACCP, 2014.

Background

• Human challenge models (HCM) are employed as part of many

development programs for ARI such as influenza, rhinovirus and respiratory

syncytial virus (RSV)

• Infections are deliberately induced under carefully controlled and monitored

conditions, involving virus inocula of known virulence and provenance

• Key variables, such as baseline infection load, timing of Rx, and

immunological status can be tightly controlled to isolate drug effect

• PK, PD (Virologic, clinical, biomarker) and safety can be diligently evaluated

• Quantitative pharmacology can optimize HCM study design and analysis to

enhance drug development for respiratory viruses.

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HCMs as Applied to Respiratory Viruses

• Highly controlled nature of experimental

pharmacology HCMs enables “rich and clean”

interrogation of drug effect

• Intensive safety surveillance

• Specialist units creates opportunity for novel

designs (eg. adaptive design to capture ER

surface, expansive dose ranges, frequent

invasive sampling) to mitigate expense and

accelerate

• Not dependent on seasonal disease, means

study durations can be short

• Rich data enables quantitative pharmacological

approaches (MBM) to support development

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Pro’s Con’s

• Regulatory challenges in obtaining an

acceptable inocula

• Ethical considerations (infecting volunteers,

transmission risk)

• Transferability to the field is debated as

important variability ignored including virus

(strains, virulence, replication, IC50, tropism,

baseline VL), time to Rx, host immune status

etc), abrogated/different clinical course of

disease

• Artefact of study including inoculation

techniques, impost of frequent invasive

sampling (dilution, loss of virus)

• Specialist clinical trial units, strain availability

and need to pre-screen to obtain sero-negative

subjects can create availability bottlenecks and

high costs

Considerations for Quantitative Pharmacology Application to HCM of Respiratory Viruses

- Case 1: HCM for Oseltamivir for influenza

- Case 2: HCM for ALS-008176 for RSV

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CASE 1 - HCM FOR OSELTAMIVIR FOR INFLUENZA

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Methods – Pooled Available Ph2 Studies

• Healthy volunteers in Studies PV15616 and NP15717 were experimentally infected with

influenza (TCID50 of virus 106)and treatment was initiated with oseltamivir or placebo after 24h

• Symptoms (feeling feverish, headache, muscle ache, sore throat, cough, overall discomfort,

nasal symptoms) individually ranked b.i.d. for symptom severity (0, 1, 2, or 3) for 9 days

• Nasal lavage b.i.d. for viral culture Days 1–3 and o.d. on Days 4–8

Study

Number of

subjects

(infected) Virus

IC50

(nM) Dosing regimens PK Sampling

PV15616 80 (69)Influenza

A/Texas0.18

20, 100 or 200mg b.i.d.

or

200mg q.d.

or placebo for 5 days

Sparse PK samples

pre-dose and on Days

3, 4 and 7

NP15717 60 (46)Influenza

B/Yamagata16.76

75 or 150mg b.i.d.

or placebo b.i.d. for

5 days

Intensive PK on Days

1 and 5

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Methods - PK

• A robust population PK model based on nine clinical studies was developed to provide individual

OC exposures

• Individual predicted steady-state exposures for OC were determined: AUC0–24h, Cmin, Cmax

CLoc = clearance of OC; CLop = clearance of OP; F = fractional bioavailability

of OP; Fm = fractional bioavailability of oseltamivir that is metabolised;

Ka = the first order rate of absorption ; Q = inter-compartmental clearance

term; Voc = volume of OC; Vop = central volume of OP; Vp = peripheral volume

of OP

(Fm)

Oral

Depot

Ka

(F)

Central (OP)

Vop

Q/Vop

Q/Vp

Peripheral

(OP) Vp

CLop/Vop

Central (OC)

Voc

CLoc/Voc

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Independent Variables

Exposure, PK-PD

or potency measureDemographic / other

AUC0–24h Age

AUC0–24h:IC50 ratio Race

Cmax Sex

Cmax:IC50 ratio Height

Cmin Weight

Cmin:IC50 ratio Body mass index

Total daily dose Creatinine clearance

Treatment regimen Antipyretic anilides

IC50

Note: co-linearity reduced focus to AUC related metrics

consistent with PKPD index from preclinical models

Methods:

12JAMA. 1999;282(13):1240-1246. doi:10.1001/jama.282.13.1240

The viral titer area under the curve value was lower in the combined oseltamivir group (n=56) compared with placebo (n=13); P=.02.

“Typical” time-course of viral load (PV15616)

Time-course is a blend of “fact”

and experimental “fiction”

- Inoculation

- Serial nasal washings

- Measurement

Detection of PK/PD effect influenced by VT time-course and form of dependent variable (eg. Peak VT<rate of decline< AUC<< TSVR =Tshed )

13JAMA. 1999;282(13):1240-1246. doi:10.1001/jama.282.13.1240

“Typical” symptom and cytokine time-course (PV15616)

The total symptom score area under the curve value was lower in the combined oseltamivir groups (n=56) compared with placebo

(n=13); P=.05; Cytokine levels for days 1, 3, 5, and 9 were determined using commercially available enzyme-linked immunosorbent

assay kits. Asterisk indicates P≤.01; dagger, P≤.001; and double dagger, P<.05.

Patel et al. ICAAC 2015

MHAA4549A

Oseltamivir

HCM viruses can provide biophase PK, VK, cytokines and symptoms to inform MBMs

Understand the inputs!

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Sampling procedures

- Procedure (disruptive, dilutive)

- Replicate (same/different site)

- Pooled/Combined(wash + swab)

- Standardisation (within study,

across studies)

VT / biomarker measurement

- Sampling error

- Method (culture/ PCR)

- Performance (BLQ)

It is essential to have a detailed understanding of the sampling and measurement methodologies

CROs and PROs

- Validated instruments

- Relevance to HCM

- Fever

- Composite vs

individual symptom

scores

- Frequency / learning

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Methods:

Time-to-event Continuous

• Time to alleviation of composite symptom

score

• Time at which any of the seven individual

symptoms scores were >1 to the time at

which all applicable individual symptom

scores were ≤1

• Time to cessation of viral shedding

• Time from the first positive viral culture to the

time of the first negative viral culture

• Composite symptom score AUC

– Symptom scores added together and AUC of

composite score calculated from the time at

which any of the seven individual symptoms

scores were >1 to the time at which all

applicable individual symptom scores were ≤1

• Viral titre AUC

– The AUC of the viral titre values spanning the

time from the first positive viral culture to the

time of the first negative viral culture

• Peak viral titre– The maximum viral titre value achieved for

each subject during study Days 1–9

A diverse set of univariate and multivariable PK-PD analyses were performed

against the following dependent variables:

Results

• Higher OC Exposures are

Associated with a Faster

Cessation of Viral Shedding - Peak VT and AUCVT ND

• Higher OC Exposures are

Associated with a Lower

Severity of Illness

• A Faster Time to Alleviation of

Composite Symptoms is Seen

with Higher OC Exposures

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Findings consistent with observations of exposure-response nested within Phase III trials1,2

1Evaluation of Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships for Influenza

Symptom and Quality of Life (QOL) Endpoints Among Oseltamivir- Treated Patients

(ICAAC 2014); 2Pharmacokinetic-Pharmacodynamic (PK-PD) Evaluation of the Impact

of Oseltamivir on Influenza Viral Endpoints (ICAAC 2014)

CASE 2 - ALS008176 INOCULATION STUDY FOR RSV

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- PCR guided Rx start- Adaptive design (safety, PK, PD) to establish ER/DR

-008176 is an oral nucleoside prodrug converted intracellularly to its active

triphosphate ALS-008112.

Methods

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Results ALS-8176 Dose-Response in a Human RSV Challenge Model

500 mg LD/500 mg q12h

500 mg LD/ 150 mg q12h

375 mg q12hLonger VT time-course than influenza HCM

ALS-8176 had significant improvements on VT AUC, Time to undetectable PCR, Peak VT and AUC symptom score

N Engl J Med 373;21 (2015)

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K Patel, et al. ID Week 2015

Even Abbreviated Designs Enable MBM Approaches

Rich PK/PD data provided in RSV HCM enables quantitative pharmacology approaches to address complex nucleoside pharmacology

Considerations for Quantitative Pharmacology for Respiratory Virus HCMs

• Critical to understand sampling and assay methods as they can impact

integrity of observations and assumptions

• Consider the time-course of PD markers (eg. VK) to guide the most

appropriate form of a PD variable

• Don’t forget about other endpoints, as HCM virus can cause symptoms

• Consider potential for MBM to connect PK, VK, immune-system

components, and symptoms to enable better extrapolation to clinic

(especially for complex examples such as nucleoside analogues)

• Numerous opportunities to optimise HCMs through quantitative

pharmacology methods (adaptive design, optimal design based on ER)

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