Setting the Stage: Long-acting agents for PrEP · Setting the Stage: Long-acting agents for PrEP Martin Markowitz MD Aaron Diamond AIDS Research Center Rockefeller University May

Setting the Stage: Long-acting agents for PrEP

Martin Markowitz MD

Aaron Diamond AIDS Research Center

Rockefeller University

May 6, 2013

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

Advances in the HIV Prevention Toolbox: 2013

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

Dosing of Truvada in IPERGAY

Case-control drug detection in IPrEx

Anderson P.L. et al, Sci Translational Med 2012

Exponential regression model of TFV-DP levels in IPrEx

Anderson P.L. et al, Sci Translational Med 2012

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

Why target MSM?

Beyrer C. et al. Lancet 2012

Beyrer C. et al Lancet 2012

Why target MSM?

HPTN061

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)

W. Spreen, et al, 19th IAC July 2012. Abstract TUPE040

Pharmacokinetic Evaluation of Single Dose GSK744LAP in Human Volunteers

Pharmacokinetic profile of 744LAP in rhesus macaques

Repeated Low-Dose Intrarectal Challenges to Evaluate GSK744LAP as PrEP in 16 Indian Rhesus

Macaques

• 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

• 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

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

• 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

• 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

GSK744 Plasma Concentrations in Protected Macaques Are Comparable to Those Achieved in Humans

W. Spreen, unpublished data. Abstract submitted for presentation.

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

Threshold/Challenge Experiment in Male Rhesus Macaques

N= 12 active N=4 placebo

(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

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

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

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

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)

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

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

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

Multi-prong attack on HIV entry to add

breadth and potency

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

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

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

Setting the Stage

• Clinical trial design for long acting PrEP agents

• Introduction to multinational clinical sites

- Thailand

- China

• Ethical considerations

• Community perspectives

• 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