Setting the Stage: Long-acting agents for PrEP

Transcription

1 Setting the Stage: Long-acting agents for PrEP Martin Markowitz MD Aaron Diamond AIDS Research Center Rockefeller University May 6, 2013

2 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

3 Advances in the HIV Prevention Toolbox: 2013

4 Study Population Design iprex FEM-PrEP Partners PrEP TDF2 VOICE Bangkok TDF IPERGAY 2499 MSM 2120 women 4758 HIV discordant partners 1219 heterosexuals 5021 women 2413 IDU 1900 MSM 1:1 TDF/FTC vs. placebo 1:1 TDF/FTC vs. placebo 1:1:1 TDF/FTC vs. TDF vs. placebo 1:1 TDF/FTC vs. placebo 1:1:1:1:1 TDF/FTC v. TDF vs. TFV gel vs. placebo x2 1:1 TDF vs. placebo 1:1 TDF/FTC on demand vs. placebo Relative Reduction in HIV incidence 44% (p=0.005) 6% (p=0.8) 75%; 67% (p<0.0001; p<0.0001) 63% (p=0.01) TDF, TFV gel stopped; TDF/FTC 4% (p>0.2) Results 2013 Results 2016 Protection as related to PrEP use TFV 50% vs. 9% TFV <30% TFV 82% vs. 31% TFV 80% TFV 29% (TDF/FTC) 50% no drug N/A N/A

5 Dosing of Truvada in IPERGAY

6 Case-control drug detection in IPrEx Anderson P.L. et al, Sci Translational Med 2012

7 Exponential regression model of TFV-DP levels in IPrEx Anderson P.L. et al, Sci Translational Med 2012

8 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

9 Why target MSM? Beyrer C. et al. Lancet 2012

10 Why target MSM? HPTN061 Beyrer C. et al Lancet 2012

11 GSK744 Is a Potent Inhibitor of Integrase- Mediated Strand Transfer and HIV-1 Replication GSK (GSK744) W. Spreen, et al, 19 th IAC July Abstract TUPE040 S. Min, et al, 49 th ICAAC, Sept Abstract H-1228 Y. Taoda, et al, 11 th International Congress on Drug Therapy in HIV Infection, Nov Abstract P206

12 Pharmacokinetic Evaluation of Single Dose GSK744LAP in Human Volunteers W. Spreen, et al, 19 th IAC July Abstract TUPE040

13 Pharmacokinetic profile of 744LAP in rhesus macaques

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

15 Materials and Methods 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

16 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

17 Percent Aviremic in Plasma GSK744LAP Is an Effective PrEP Agent in Rhesus Macaques Placebo GSK744LAP p< Weeks Post First Challenge

18 Proviral DNA and Anti-SHIV Antibodies Are Not Detected in GSK744LAP-Treated Macaques 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

19 Proviral DNA and Anti-SHIV Antibodies Are Not Detected in GSK744LAP-Treated Macaques Virus-specific antibody responses - Not detected in any GSK744LAPtreated macaques throughout study - Detectable 1 to 3 weeks after first plasma RNA detection in all placebo animals

20 GSK744 Plasma Concentrations in Protected Macaques Are Comparable to Those Achieved in Humans W. Spreen, unpublished data. Abstract submitted for presentation.

21 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

22 Threshold/Challenge Experiment in Male Rhesus Macaques N= 12 active N=4 placebo

23 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 K D of 100 pm and blocks HIV/SIV entry post attachment (h IgG4, K D 100pM) 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

24 Ibalizumab is active in humans: phase 2b in 113 HIV+ patients Mean change from Baseline viral load at Wk mg q2wk: -1.6 log 10 copies/ml 2000mg q4wk: -1.5 log 10 copies/ml Mean change from Baseline in CD4 + T-cells at Wk mg q2wk: +37 cells/μl 2000mg q4wk: +40 cells/μl Viral Load and CD4 receptor occupancy correlation RO <30% RO >30% N 21/113 72/113 WK24 Change from BL % <50 copies/ml 14% 46% % <400 copies/ml 29% 65% TaiMed Biologics

25 IC50 ( g/ml) Breadth and potency of ibalizumab Breadth: b12 2G12 2F5 4E10 PGT 121 VRC-PG04 PGT 145 PG16 PG9 VRC01 3BNC117 ibalizumab median ± interquartile range of all viruses

26 Phase-1 ibalizumab safety and PK/PD clinical trial 120mg weekly x 4 doses (n=6 ibalizumab, 2 placebo) At-risk HIV-negative subjects (n=24) DSMB review 6 weeks after 4 subjects in Group 1 receive all 4 doses 240mg weekly x 4 doses (n=6 ibalizumab, 2 placebo) Age years Healthy Effective contraception No current STD No HepA vaccination DSMB review 6 weeks after 4 subjects in Group 2 receive all 4 doses Ibalizumab SC PK & RO HAV vaccine Genital secretions 480mg weekly x 4 doses (n=6 ibalizumab, 2 placebo)

27 No SAEs or Injection Site Reactogenicities Observed Number (%) of Subjects with Ibalizumab Overall Placebo 120 mg 240 mg 480 mg Total N=26 N=7 N=6 N=7 N=6 N=19 TEAEs (68.4) 16 (61.5) Serious TEAEs (0.0) 0 (0.0) Deaths (0.0) 0 (0.0) TEAEs Leading to Discontinuation (0.0) 0 (0.0) TEAEs Related to Study Drug (31.6) 8 (30.8) Severe TEAEs (5.3) 1 (3.8) No subjects in the study reported any injection site reactions (erythema, induration, swelling, pain, or tenderness)

28 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

29 Concentration (ng/ml) Concentration (ng/ml) Mathematical Modeling Suggests Monthly Dosing is Feasible 480 mg 480 q mg Week q x 2 Then 480 mg 480 q 4 mg Weeksq 4 Weeks 600 mg 640 mg q q 4 Weeks Concentration (ng/ml) Concentration (ng/ml) Time (hr) Month Time (hr) Month 3 4 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

30 Viral coverage (%) Glycan modification of ibalizumab V5 N gp120 V5 C 11-mer sugar at L-AA52 Ibalizumab CD4 Glyco-iMab mab concentration (µg/ml)

31 Multi-prong attack on HIV entry to add breadth and potency

32 IC80 ( g/ml) Enhanced breadth and potency with bispecific antibodies IC 80 coverage (%, <10 g/ml) Glyco-iMab VRC01 PG9 PGT128 10E8 VRC01-iMab PG9-iMab PGT128-iMab* imab^/10e8 CM

33 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 Tulane National Primate Research Center Kasi Russell-Lodrigue Rudolph P. Bohm, Jr GlaxoSmithKline Zhi Hong Bill Spreen Gary Bowers Lee Moss Glenn Talbot Paul Savina Susan Ford David Margolis ViiV Healthcare Alex Rinehart James Goodrich NIAID R01AI100724

34 Acknowledgements: Ibalizumab Program 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 Clinical Investigators Michael Keefer Paul Goepfert Shannon Schrader Jerome DeVente Jerome Ernst Jacob Lalezari Tai Med Biologics Steve Weinheimer Stanley Lewis Helen Shu Jonathan Ho James Chang CAVD Michael Seaman Bill and Melinda Gates Foundation Nina Russell Pervin Anklesaria Magda Moutaftsi

35 Setting the Stage Clinical trial design for long acting PrEP agents Introduction to multinational clinical sites - Thailand - China Ethical considerations Community perspectives

36 Setting the Stage 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