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Setting the Stage: Long-acting agents for PrEP
Martin Markowitz MD
Aaron Diamond AIDS Research Center
Rockefeller University
May 6, 2013
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Setting the Stage
• Results of PrEP studies
- Focus on adherence
• Long-acting agents suitable for PrEP
- GSK744LAP
- Ibalizumab
• Next generation long-acting agents
- Ibalizumab-based
- Cross reactive antibodies
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Advances in the HIV Prevention Toolbox: 2013
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Study Population Design Relative
Reduction in
HIV incidence
Protection as
related to PrEP
use
iPrEx 2499 MSM 1:1 TDF/FTC vs.
placebo
44% (p=0.005)
TFV
50% vs. 9%
FEM-PrEP 2120 women 1:1 TDF/FTC vs.
placebo
6% (p=0.8)
TFV <30%
Partners PrEP
4758 HIV
discordant
partners
1:1:1 TDF/FTC
vs. TDF vs.
placebo
75%; 67% (p<0.0001;
p<0.0001)
TFV
82% vs. 31%
TDF2 1219
heterosexuals 1:1 TDF/FTC vs.
placebo
63% (p=0.01)
TFV
80%
VOICE 5021 women
1:1:1:1:1
TDF/FTC v. TDF
vs. TFV gel vs.
placebo x2
TDF, TFV gel
stopped;
TDF/FTC 4%
(p>0.2)
TFV 29%
(TDF/FTC)
50% no drug
Bangkok TDF 2413 IDU 1:1 TDF vs.
placebo
Results
2013 N/A
IPERGAY 1900 MSM 1:1 TDF/FTC “on
demand” vs.
placebo
Results
2016 N/A
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Dosing of Truvada in IPERGAY
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Case-control drug detection in IPrEx
Anderson P.L. et al, Sci Translational Med 2012
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Exponential regression model of TFV-DP levels in IPrEx
Anderson P.L. et al, Sci Translational Med 2012
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Conclusions
• Daily oral Truvada is effective as PrEP
• Adherence limits its effectiveness
– Adherence is highly variable
– Highest amongst discordant couples
– Lowest amongst young women in FEM-PrEP and VOICE
• Alternatives are clearly indicated
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Why target MSM?
Beyrer C. et al. Lancet 2012
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Beyrer C. et al Lancet 2012
Why target MSM?
HPTN061
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GSK744 Is a Potent Inhibitor of Integrase-Mediated Strand Transfer and HIV-1 Replication
W. Spreen, et al, 19th IAC July 2012. Abstract TUPE040 S. Min, et al, 49th ICAAC, Sept 2009. Abstract H-1228
Y. Taoda, et al, 11th International Congress on Drug Therapy in HIV Infection, Nov 2012. Abstract P206
GSK1265744 (GSK744)
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W. Spreen, et al, 19th IAC July 2012. Abstract TUPE040
Pharmacokinetic Evaluation of Single Dose GSK744LAP in Human Volunteers
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Pharmacokinetic profile of 744LAP in rhesus macaques
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Repeated Low-Dose Intrarectal Challenges to Evaluate GSK744LAP as PrEP in 16 Indian Rhesus
Macaques
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• SHIV RNA in plasma
- Quantified by real-time RT-PCR
- Limit of detection = 40 copies/mL
- Systemic infection: 2 consecutive positive vRNA signals
- Time of infection: 2 weeks prior to the first detectable vRNA
Materials and Methods
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• Proviral DNA from PBMCs - Quantified by real-time PCR
• Virus-specific antibody responses
- Synthetic-peptide enzyme immunoassay
• GSK744 concentrations in plasma - Protein precipitation followed by
HPLC/MS/MS - Limit of quantitation = 10 ng/mL
Materials and Methods
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GSK744LAP Is an Effective PrEP Agent in Rhesus Macaques
0 2 4 6 8 10 12 14 160
20
40
60
80
100
Weeks Post First Challenge
Pe
rce
nt A
vir
em
ic in
Pla
sm
a
Placebo
GSK744LAP
p<0.0001
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• Proviral DNA
- Not detected in PBMCs from any GSK744LAP-treated macaques in post challenge follow-up phase
- Detected in PBMCs from all placebo animals in follow-up phase
Proviral DNA and Anti-SHIV Antibodies Are Not Detected in GSK744LAP-Treated Macaques
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• Virus-specific antibody responses - Not detected in any GSK744LAP-
treated macaques throughout study
- Detectable 1 to 3 weeks after first plasma RNA detection in all placebo animals
Proviral DNA and Anti-SHIV Antibodies Are Not Detected in GSK744LAP-Treated Macaques
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GSK744 Plasma Concentrations in Protected Macaques Are Comparable to Those Achieved in Humans
W. Spreen, unpublished data. Abstract submitted for presentation.
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Summary and Conclusions
• GSK744LAP prevented rectal transmission of SHIV162P3 in rhesus macaques repeatedly exposed to the virus
• Future GSK744LAP studies in macaques:
- Determine the plasma level of GSK744LAP at which protection against low-dose intrarectal challenge is lost
- Proof-of-concept PrEP studies in female macaques
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Threshold/Challenge Experiment in Male Rhesus Macaques
N= 12 active N=4 placebo
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(h IgG4, KD 100pM)
Ibalizumab: HIV-neutralizing mAb
directed to domain 2 of human CD4
• Originated as mouse mAb that
binds to domain 2 of human/rhesus
CD4 with a KD of 100 pM and
blocks HIV/SIV entry post
attachment
• Humanized with human IgG4 to
minimize effector function via FcR
• Advanced into the clinic for patients
in need of salvage therapy
• Shown to be safe in 247 patients
with no drug-related SAEs, some
for up to 4 years
• Shown to be active in patients,
lowering viral load by 1-log or more,
in phase 1a, 1b, 2a, and 2b clinical
trials by TaiMed Biologics and its
predecessors
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Mean change from Baseline viral
load at Wk 24
• 800mg q2wk: -1.6 log10 copies/mL
• 2000mg q4wk: -1.5 log10 copies/mL
Mean change from Baseline in CD4+
T-cells at Wk 24
• 800mg q2wk: +37 cells/μL
• 2000mg q4wk: +40 cells/μL
TaiMed Biologics
RO <30% RO >30%
N 21/113 72/113
WK24 Change
from BL -1.1 -1.9
% <50 copies/mL 14% 46%
% <400 copies/mL 29% 65%
Viral Load and CD4
receptor occupancy
correlation
Ibalizumab is active in humans: phase 2b in 113 HIV+ patients
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b12
2G12 2F
5
4E10
PGT 1
21
VRC-P
G04
PGT 1
45
PG16
PG9
VRC01
3BNC11
7
ibal
izum
ab
0.00001
0.0001
0.001
0.01
0.1
1
10
100
IC50 (
g/m
L)
35 56 97 86 81 88 70 78 92 21 76 89
median ± interquartile range of all viruses
Breadth:
Breadth and potency of ibalizumab
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Phase-1 ibalizumab safety and PK/PD clinical trial 120mg weekly x 4 doses
(n=6 ibalizumab, 2 placebo)
240mg weekly x 4 doses
(n=6 ibalizumab, 2 placebo)
480mg weekly x 4 doses
(n=6 ibalizumab, 2 placebo)
Ibalizumab SC
DSMB review 6 weeks after 4 subjects in Group 1
receive all 4 doses
DSMB review 6 weeks after 4 subjects in Group 2
receive all 4 doses
“At-risk” HIV-negative
subjects (n=24)
Age 18-40 years
Healthy
Effective contraception
No current STD
No HepA vaccination
PK & RO
HAV vaccine
Genital secretions
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No SAEs or Injection Site
Reactogenicities Observed
Number (%) of Subjects with
Ibalizumab Overall
N=26 Placebo
N=7
120 mg
N=6
240 mg
N=7
480 mg
N=6
Total
N=19
TEAEs 3 4 6 3 13 (68.4) 16 (61.5)
Serious TEAEs 0 0 0 0 0 (0.0) 0 (0.0)
Deaths 0 0 0 0 0 (0.0) 0 (0.0)
TEAEs Leading to Discontinuation 0 0 0 0 0 (0.0) 0 (0.0)
TEAEs Related to Study Drug 2 0 4 2 6 (31.6) 8 (30.8)
Severe TEAEs 0 0 1 0 1 (5.3) 1 (3.8)
No subjects in the study reported any injection site reactions
(erythema, induration, swelling, pain, or tenderness)
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Ibalizumab pharmacokinetics and
CD4 receptor occupancy
• ibalizumab remains in serum for >14 days following four weekly 480 mg doses
• ibalizumab coats CD4 (RO) for >14 days following four weekly 480 mg doses
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Mathematical Modeling Suggests
Monthly Dosing is Feasible
480 mg q Week x 2 Then 480 mg q 4 Weeks
Time (hr)
0 168 336 504 672 840 1008 1176 1344 1512 1680 1848 2016 2184
Con
cen
trati
on
(n
g/m
L)
0
10000
20000
30000
40000
50000
640 mg q 4 Weeks
Time (hr)
0 672 1344 2016 2688C
on
cen
trati
on
(n
g/m
L)
0
10000
20000
30000
40000
50000
0 1 2 3
Month
0 1 2
Month
4 3
600 mg q 4 Weeks 480 mg q Week x 2 Then 480 mg q 4 Weeks
Co
nc
en
tra
tio
n (
ng
/mL
)
Co
nc
en
tra
tio
n (
ng
/mL
)
mathematical modeling predicts a 480 mg or 600 mg monthly dose could provide
continuous drug exposure at sufficient and physiologically relevant concentrations over a
28-day dosing interval
TaiMed Biologics
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Glycan modification of ibalizumab
Vir
al c
ove
rag
e (
%)
mAb concentration (µg/ml)
V5 C’
CD4
Ibalizumab
gp120
V5 N’
11-mer sugar at L-AA52
Glyco-iMab
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Multi-prong attack on HIV entry to add
breadth and potency
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Gly
co-iM
ab
VRC01
PG9
PGT12
8
10E8
VRC01
-iMab
PG9-
iMab
PGT12
8-iM
ab*
iMab
^/10
E8
CM
10- 5
10- 4
10- 3
10- 2
10- 1
100
101
102
IC8
0 (
g/m
l)
Enhanced breadth and potency with
bispecific antibodies IC80 coverage (%, <10g/ml)
99 99 95 100
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Acknowledgements: GSK744LAP
The Aaron Diamond AIDS Research Center The Rockefeller University
Chasity Andrews David D. Ho
Cecilia Cheng-Mayer Agegnehu Gettie
Mar Boente-Carrera Hiroshi Mohri
Neal Padte Yaoxing Huang
Faye Yu
GlaxoSmithKline Zhi Hong
Bill Spreen Gary Bowers
Lee Moss Glenn Talbot Paul Savina Susan Ford
David Margolis
Tulane National Primate Research Center Kasi Russell-Lodrigue Rudolph P. Bohm, Jr
ViiV Healthcare Alex Rinehart
James Goodrich
NIAID R01AI100724
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The Aaron Diamond AIDS Research Center The Rockefeller University
David D. Ho Yaoxing Huang
Craig Pace Neal Padte
Chasity Andrews Ruijiang Song
Jian Yu Mar Boente-Carrera
Tai Med Biologics Steve Weinheimer
Stanley Lewis Helen Shu
Jonathan Ho James Chang
Clinical Investigators
Michael Keefer
Paul Goepfert
Shannon Schrader
Jerome DeVente
Jerome Ernst
Jacob Lalezari
CAVD Michael Seaman
Bill and Melinda Gates Foundation
Nina Russell Pervin Anklesaria Magda Moutaftsi
Acknowledgements: Ibalizumab Program
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Setting the Stage
• Clinical trial design for long acting PrEP agents
• Introduction to multinational clinical sites
- Thailand
- China
• Ethical considerations
• Community perspectives
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• Facilitated discussion of POC Phase 2b/3 study of long-acting PrEP - Objectives - Design - Procedures
• Phase 2a study based on design of Phase 2b/3
Setting the Stage