1. Are animal models a good surrogate of efficacy?
/ Division of HIV/AIDS Prevention
Are animal models a good surrogate of efficacy?
J. Gerardo Garcia-Lerma, Ph.D.
Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA

2. Conflict of Interest
Named in patents on “Inhibition of HIV Infection Through Chemoprophylaxis”

3. Importance of animal models for HIV prevention research
Possibility to model PrEP under highly controlled conditions (dose of drug and timing of dosing, size of virus inoculum, route of virus exposure)
Assess relationship between efficacy and pharmacologic parameters (PK-PD relationship)
Help product prioritization and advancement of most promising products into human clinical trials

4. Key considerations for assessing PrEP strategies in animal models
Pharmacological aspects
Transmission component
Model clinically-relevant drug doses
Adjust doses based on differences in size/metabolism with humans (allometric scaling)
Incorporate drug measurements at the mucosal sites of infection
Use physiologic virus doses that better mimic HIV infectious doses in humans
Select appropriate animal species (humanized mice, rhesus/pigtail macaques) and transmission model (single vs. repeated virus exposures)
Combine relevant drug pharmacology and physiologic HIV transmission

5. Key features of the repeat low dose macaque model
Exposures to low and more physiologic virus doses
Virus exposures repeated to mimic high-risk human exposures to HIV
Better simulate HIV exposures in humans than do previous models with single high-dose virus challenge
Stronger statistics but small animal numbers
Rectal and vaginal models in rhesus and pigtail macaques
Pigtails are preferred species to evaluate efficacy against vaginal infection

6. Pre-clinical testing in the repeat low dose macaque model
Dose selection
Protective efficacy (rectal/vaginal)
Drug correlate of protection
Oral FTC/TDF Injectable cabotegravir long-acting Oral tenofovir alafenamide Oral maraviroc

7. Clinically-relevant doses of FTC and TDF in macaques

8. Efficacy of oral FTC/TDF combination in the repeat low-dose macaque model
Garcia-Lerma et al., PLoS Med 2008
Radzio et al., PLoS One 2012

9. High efficacy of oral FTC/TDF in the presence of potential modifiers
Exposure to FTC and TFV-resistant viruses containing M184V or K65R (Cong et al., J Virol 2011; Cong et al., J Infect Dis 2013)
Thinning of the vaginal epithelium associated with DMPA treatment (Radzio et al., AIDS 2014; Radzio et al., J AIDS 2014)
Increased susceptibility to infection due to co-infection with Chlamydia trachomatis and Trichomonas vaginalis (Radzio et al., J Infect Dis 2016)

10. Biological efficacy of FTC and TDF in macaques and correlation with humans

11. iPrEX: 16 fmols/106 cells (95% CI; 3-28)
TFV-DP EC90 for protective efficacy
23 fmols/106 cells (95% CI; 14-61)
(5 fmols/106 cells ~ 40% reduction in risk of SHIV acquisition)
Anderson et al., J Antimicrob Chemother 2014
Anderson et al., Sci Trans Med 2012

12. Injectable cabotegravir long-acting

13. Cabotegravir long-acting: dose selection studies
HUMANS
MACAQUES
Half-life; days
Half-life; ~11 days
I am going to now move on into 2 next-generation PrEP agents that are now in clinical testing. The first is cabotegravir, an HIV integrase inhibitor analog of dolutegravir that has been formulated as a long-acting nanosuspension. As you know, one of the most attractive characteristic of this formulation is the long plasma half-life life that makes it suitable for administration every 2 months. Indeed, pre-clinical evaluation of CAB LA in macaque first required dose-selection studies to identify clinically-relevant doses. This is the work that was done at the ADARC where they identified a 50 mg/kg dose as sufficient to maintain drug concentrations above the target 4x PA-IC90. Now, because of the shorter half-life of CAB in macaques and humans, this dose needs to be administered every month and not every 2-3 months as in humans.
Andrews et al., Science 2014
Spreen et al., J AIDS 2014

14. The same research group designed a series of very elegant studies where they investigated both the protective efficacy of CAB LA and the concentrations of plasma CAB that are associated with protection. In these studies the macaques received a dose of CAB and were exposed weekly to SHIV as the concentrations of drug declined over the weeks. This panel shows how virus breakthroughs started to come up as the concentrations of CAB fell below the significant delayed infection.
Andrews et al., Science 2014

15. CAB LA protects macaques against high and low dose intravaginal SHIV challenges
High dose SHIV transmission model
Low dose SHIV transmission model
Andrews et al., Sci Trans Med 2015
Radzio et al., Sci Trans Med 2015

16. Oral tenofovir alafenamide

17. Tenofovir alafenamide: dose selection
Massud et al., J Infect Dis 2016
Cottrell et al., J Antimicrob Chemother 2017

18. Efficacy of oral FTC/TAF and TAF against rectal SHIV infection
FTC/TAF combination
TAF alone (1 weekly dose)
Massud et al., J Infect Dis 2016
Garcia-Lerma et al., J Virol 2011

19. Oral maraviroc

20. Lack of prophylactic efficacy of oral maraviroc despite high drug concentrations in rectal tissues
High and durable MVC concentrations in rectal tissues not sufficient to prevent infection in macaques
[MVC] below the threshold required to block a dense population of CCR5+ cells in the rectal mucosa
Biochemical differences between human and macaque CCR5
Other mechanisms associated with MVC treatment including potential modulation of immune responses and susceptibility to infection
Massud et al., J Virol 2013

21. Summary
Macaque modeling that incorporates clinically-relevant drug doses predicted efficacy of PrEP with FTC/TDF
Identified similar TFV-DP protective levels than in humans
Reassuring data with FTC/TDF reinforces the need to build on this modeling approach
Proof of concept studies with CAB LA and TAF; defined CAB protective levels in macaques
Data on efficacy in humans (Discover, HPTN 083/084) will further inform on predictive value of the model
Approach may help prioritization and advancement of promising products; large product pipeline (implants, inserts, others) and increased cost of phase 3 trials

22. Acknowledgements Division of HIV/AIDS Prevention, CDC Jessica Radzio
Ivana Massud
Mian-er Cong
Wutyi Aung
James Mitchell
Shanon Ellis
Frank Deyounks
Kristen Kelley
Leecresia Jenkins
David Garber
Debra Hanson
Chou-Pong Pau
Amy Martin
Angela Holder
Susan Kuklenyik (NCEH)
John Barr (NCEH)
Ron Otten
Tom Folks
Walid Heneine
UCSF
David Glidden
University of Colorado
Peter Anderson
Lane Bushman
Gilead Sciences
Darius Babusis
Adrian Ray
Michael Miller
James Rooney
ViiV Healthcare
Yun Lan Yueh
William Spreen