1. Nyaradzo Mgodi, MBChB, MMed
Satellite Session - Injectable PrEP Antibody Mediated Prevention: The AMP Studies
Nyaradzo Mgodi, MBChB, MMed
Co-Chair, The AMP Studies
University of Zimbabwe - University of California San Francisco Collaborative Research Program
20 July 2016

2. Conflict of Interest Disclosures
I have no potential conflict of interest to report

3. Passive Immunization
Long history of use of antibodies against viral infections
Passive Antibody Prevention of HIV/SHIV in NHP for over 20 years
NHP studies tell us that physiologically achievable levels of Ab could prevent HIV-1 infection
There are no human data regarding passive protection by HIV-1 monoclonal antibodies
Learn from proof of concept in humans:
Many unanswered questions
Convert the mAb levels to serum level of neutralization needed to protect
Provide a benchmark for vaccine development; i.e., what antibody level does a vaccine need to achieve
Effective biomedical interventions are needed to reduce the acquisition of HIV. The global HIV-1 epidemic continues and while many countries have made progress toward leveling HIV prevalence over the last few years, micro-epidemics of infection continue to occur in nearly all regions, even in countries possessing the full toolkit of proven prevention approaches.
Despite early optimism about immunological approaches to prevent and treat human immunodeficiency virus (HIV), after more than three decades there are no li-censed HIV preventative or therapeutic vaccines. This session outlines the path toward novel vaccine designs that employ active and passive immunization strategies to prevent HIV acquisition.
My talk will focus on passive immunisation
An alternative approach to prevention and/or treatment of infectious diseases is passive administration of antibodies, a strategy that has been employed for more than 100 years against diverse disease targets and that is still used for hepatitis A and B prophylaxis [9,10] and for PEP for rabies, measles, varicella zoster, and other infectious diseases [11]. Most notably, palivizumab has been used for respiratory syncytial virus (RSV) prophylaxis in pre-term and other high-risk infants for nearly two decades.
Antibodies have been isolated which can neutralize a broad range of HIV strains in vitro, raising
Hopes for antibody-mediated prevention (AMP) of HIV. The first antibody to enter advanced human clinical trials is VRC01, discovered in an elite viral controller [26 ]. It is a
Human monoclonal antibody targeting the HIV-1 CD4 binding site. VRC01 demonstrated protection in animal studies, and has acceptable human safety [27 ]. HVTN 703
Will investigate the effectiveness of VRC01 and the level of neutralizing activity required in reducing HIV acquisition.

4. CAN ANTIBODIES BE USED TO PREVENT HIV in humans?

5. Many Unanswered Questions
Can antibodies prevent HIV-infection in humans?
What level of mAb is needed to protect?
Where and how does the mAb work:
lumen, epithelial surface,
mucosal or lymphoid tissue
Are Fc-mediated effector functions (ADCC, ADCVI) needed for protection?

6. The Antibody Response to HIV
B-cell responses to HIV-1 develop within approx. 1 week of detectable viraemia
Initially, Ag-Ab complexes
Circulating anti-gp41 antibodies within days
Circulating anti-gp120 antibodies weeks later
These binding Abs do not have a detectable effect on viraemia
nAbs against the infecting strain appear months later – are not able to neutralise more divergent viruses
Autologous nAbs drive immune escape - contemporaneous viruses are less sensitive to autologous nAbs than earlier strains

7. VRC01 – Breadth and Potency
Panel of 190 Diverse Viral Isolates
Thanks to Barney Graham and
Wu et al. Rational design of
envelope identifies broadly
neutralizing human monoclonal
Antibodies to HIV. Science. 2010

8. VRC01: NHP Studies

9. VRC01 Protects Against Mucosal SHIV-Challenge in Non-Human Primates
20 mg/kg infusion of VRC01: Challenge with SHIV SF162P3
RECTAL CHALLENGE
VAGINAL CHALLENGE
4/4 protected
4/4 protected
0/4 protected
1/4 protected
Pegu et al. Science Transl Med (2014), Ko et al. Nature (2014), Rudicell et al. J Virol (2014)

10. VRC01: From NHP to Human Studies

11. VRC01 in Phase 1 Studies: Safe and Well-tolerated
3 Phase 1 trials: VRC601, VRC602, HVTN 104
Safe and well-tolerated in about 140 participants
No serious adverse events
Mild adverse events only, which included mild lab changes in liver & kidney tests that resolved on their own

12. AMP = Antibody Mediated Prevention
Can a passively infused monoclonal antibody prevent HIV-1 infection in high risk adults?
Two harmonized protocols:
The AMP Studies:
HVTN 704/HPTN 085
( 2700 MSM and TG in the Americas)
HVTN 703/HPTN 081
( 1500 Women in sub-Saharan Africa)

13. The AMP Studies HVTN 703/HPTN 081, HVTN 704/HPTN 085
AMP = Antibody Mediated Prevention
Defining a new path forward: This is the idea of using an antibody made in the lab and giving it to people directly, i.e. using an intravenous (IV) infusion, to prevent HIV infections.

14. Who is Doing the AMP Studies?
The study is being conducted by two groups, the HIV Vaccine Trials Network and the HIV Prevention Trials Network, in partnership with their combined clinical trial sites.

15. AMP Study Research Sites (As of July, 2016)

16. AMP in sub-Saharan Africa
7 Countries
HARARE
CHITUNGWIZA
LILONGWE
BLANTYRE
BLANTYRE
LILONGWE
GAUTENG
KZN
W CAPE
MAPUTO
KISUMU
15 Sites
MBEYA
GABORONE

17. Why Study VRC01? Promising antibody for HIV prevention
Broadly neutralizing & potent in lab studies
Good results in early Phase I studies
May supplement other prevention approaches
Move the HIV vaccine search forward
Teach us the amount of antibody a vaccine may need to elicit to prevent HIV
Help us find a safe, effective HIV vaccine more efficiently
PREVENTION
HIV VACCINE

18. The AMP Study: Objectives & Endpoints
Safety & Tolerability of VRC01 infusion
Reactogenicity, AEs, SAEs, discontinuation rates
Efficacy to prevent HIV infection
HIV infection by week 80 in those HIV-negative at enrollment
Develop a marker(s) of VRC01 that correlates with the level and antigenic specificity of efficacy
Serum VRC01 concentration
Serum mAb effector functions
Breakthrough HIV infection sequences
VRC01 neutralization sensitivity of, & effector functions against, HIV strains from infected trial participants
PRIMARY
SECONDARY
11/15/2018

19. The Main AMP Study Questions
Is the VRC01 antibody safe to give to people?
Are people able to “tolerate” the antibody without becoming too uncomfortable?
Does the antibody lower people’s chances of getting infected with HIV?
If the antibody does lower people’s chances of getting infected with HIV, how much of it is needed to provide protection from HIV?

20. Study Schema for The AMP Studies
HVTN 704/HPTN 085
HVTN 703/HPTN 081
REGIMEN
MSM & TG in the Americas
Women in
sub-Saharan Africa
TOTAL
VRC mg/kg
900
500
1300
10 infusions total -
given every 8 weeks
Study duration:
~22 months
VRC mg/kg
Control
Total
2700
1500
4200

21. MSM+TG AMP Schema: HVTN 704/HPTN 085
Infusion schedule (Weeks)
[A = VRC01 infusion; C = Control infusion]
Treatment N* W0 W8
W16
W24
W32
W40
W48
W56
W64
W72
W80♦
W92†
Group 1
VRC01
10 mg/kg
900 A
Group 2
30 mg/kg
Group 3
Control C
Total: (900 VRC01 30 mg/kg; 900 VRC01 10 mg/kg; 900 control)
♦ Week 80 is the last study visit for the primary endpoint analysis of prevention efficacy.
† Week 92 is the last study visit for the co-primary endpoint analysis of safety and tolerability.
*An interim safety assessment will be performed through the Week 24 visit for the first 450 enrolled participants. Infusions for those 450 participants will continue while the interim safety assessment is conducted. Following enrollment of the 450th participant, enrollment can continue, subject to the following condition: No more than 25% of the total study population may be enrolled before the interim safety report is complete, reviewed by the DSMB, and submitted to the US FDA. Enrollment will then continue only if the safety record for the run-in subgroup is deemed satisfactory.

22. SSA Women AMP Schema: HVTN 703/HPTN 081
Infusion schedule (Weeks)
[A = VRC01 infusion; C = Control infusion]
Treatment N* W0 W8
W16
W24
W32
W40
W48
W56
W64
W72
W80♦
W92†
Group 1
VRC01
10 mg/kg
500 A
Group 2
30 mg/kg
Group 3
Control C
Total: (500 VRC01 30 mg/kg; 500 VRC01 10 mg/kg; 500 control)
♦ Week 80 is the last study visit for the primary endpoint analysis of prevention efficacy.
† Week 92 is the last study visit for the co-primary endpoint analysis of safety and tolerability.
*An interim safety assessment will be performed through the Week 24 visit for the first 300 enrolled participants. Infusions for those 300 participants will continue while the interim safety assessment is conducted. Following enrollment of the 300th participant, enrollment can continue, subject to the following condition: No more than 25% of the total study population may be enrolled before the interim safety report is complete and reviewed by the DSMB. Enrollment will then continue only if the safety record for the run-in subgroup is deemed satisfactory. Data from VRC01 administration in HVTN 704/HPTN 085 may inform the safety assessment in HVTN 703/HPTN 081.
An interim safety assessment will be performed through the Week 24 visit for the first 450/300 enrolled participants. Infusions for those 450 participants will continue while the interim safety assessment is conducted. Following enrollment of the 450th participant, enrollment can continue, subject to the following condition: No more than 25% of the total study population may be enrolled before the interim safety report is complete, reviewed by the DSMB, and submitted to the US FDA. Enrollment will then continue only if the safety record for the run-in subgroup is deemed satisfactory

23. Rationale for 2 Cohorts
As these are test-of-concept trials we selected the two populations in which novel biomedical interventions are needed
MSM + TG
Heterosexual women in sub-Saharan Africa
We suspect that route of acquisition and genital tract immunology and anatomy may influence the distribution of VRC01 and potential efficacy

24. HVTN 704/HPTN 085: Select Eligibility Criteria
Men & transgender people who have sex with men, years of age
HIV uninfected
Risk behavior related criteria:
Male or TG who has had condomless anal intercourse with ≥ 1 male or TG partner(s) or any anal intercourse with ≥ 2 male or TG partners in the past 6 months
All volunteers in a mutually monogamous relationship with an HIV(-) partner for > 1 year are excluded.
Volunteers with clinically significant medical conditions are excluded
11/15/2018

25. HVTN 703/HPTN 081: Select Eligibility Criteria
Heterosexual Women, years of age
HIV uninfected
Risk behavior related criteria:
Female who has had vaginal or anal
intercourse with a male partner in the
past 6 months
All volunteers in a mutually monogamous relationship with an HIV(-) partner for > 1 year are excluded.
Volunteers with clinically significant medical conditions are excluded

26. STUDY DURATION: about 22 months
AMP Study Procedures
IV: receive an IV over a minute period every 8 weeks (10 times total)
Blood draw: get a blood draw at the clinic every 4 weeks (includes an HIV test)
STI testing: get STI testing (urine and rectal swabs) about every 6 months
Questionnaires: complete questionnaires about sexual behavior & general health every 4-8 weeks
STUDY DURATION: about 22 months

27. Study Progress, as of 18 July 2016
Americas
SSA
Protocol opened March 31, 2016 (N=2700)
First participant enrolled April 6, 2016
Sites activated – 19/24
Number currently enrolled (received VRC01/control): 249
Number randomized (not yet received VRC01/control: 15
Protocol opened May 9, 2016 (N=1500)
First participant enrolled: May 17, 2016
Sites activated – 5/15
Number currently enrolled (received VRC01/control): 29
Number randomized (not yet received VRC01/control: 9

28. What happens with success?
We define the level of plasma mAb needed to protect against infection
Translate that into:
Single dose administration of mAbs to achieve this level
Incentive to develop next generation mAb (more potent, longer half life)
Options for genetic immunization to provide medium to long- term protective antibody levels
Knowledge that neutralizing mAb can protect will guide vaccine field

29. What happens with success?
How could bnAbs be used for HIV prevention in the future?
Cover a period of risk for newborns (during & right after birth, during breastfeeding)
Cover the “tail” of a long-acting PrEP injection, when protection may not be as strong
Cover the ramp-up period of an HIV vaccine regimen that is given over several months
Combine with other mAbs in a prevention “cocktail”

30. Finding Info About the AMP Studies
HVTN 703/HPTN 081 (Africa):
HVTN 704/HPTN 085 (US):
Websites for Brazil & Peru in development
Stop by our booth in the Global Village for more information!

31. Acknowledgements
Some of this slide set was adapted from versions created by Dr. J Mascola, Dr. S Edupuganti, Dr S Karuna, Dr L Corey, Dr M Cohen.

32. AMP Protocol Team Chairs: Larry Corey & Mike Cohen
co-Chairs: Sri Edupuganti & Nyaradzo Mgodi
Protocol Team Leader & Core Medical Monitor: Shelly Karuna
DAIDS Medical Officers: Marga Gomez & David Burns
Statisticians: Allan DeCamp, Deborah Donnell, Peter Gilbert, Michal Juraska, Nidhi Kochar
Laboratory Representatives: John Hural, Sue Eshleman, On Ho, David Montefiori, Vanessa Cummings, Estelle Piwowar-Manning
VRC Representatives: Julie Ledgerwood, Barney Graham, John Mascola
Investigator Representatives: Ken Mayer, LaRon Nelson, Manuel Villaran, Sinead Delany-Moretlwe
Social & Behavioral Scientist: Michele Andrasik
DAIDS Protocol Pharmacist: Scharla Estep
Regional Medical Liaison: Simba Takuva
Clinical Safety Specialist: Maija Anderson
Protocol Development Manager: Carter Bentley
FHI360/HPTN LOC Director: Niru Sista
Senior Research Clinician: Phil Andrew
Clinical Research Manager: Liz Greene
Clinical Trials Manager: Carissa Karg
SDMC Representatives: Lynda Emel, Gina Escamilla, Evangelyn Nkwopara
Regulatory Affairs Representative: Meg Brandon
Communications Representatives: Jim Maynard & Eric Miller
Community Engagement Representatives: Gail Broder, Jonathan Lucas, Jontraye Davis
Clinic Coordinators: Deb Dunbar, Lilian Saavedra, Elaine Sebastian
CAB Representatives: Likhapha Faku, Mark Hubbard, Jim Wick
Community Educators/Recruiters: DaShawn Usher & Luciana Kamel
Technical Editor: Erik Schwab

33. QUESTIONS?