CROI 2016: Top Ten for Clinicians

Hynes Convention Center. Boston, MA; US. Feb 22-25, 2016 CROI 2016: Top Ten for Clinicians Josep M Llibre Hospital Universitari Germans Trias i Pujol Fundació Lluita contra la SIDA Badalona, Barcelona jmllibre@flsida.org

1. LATTE-2: Dual NRTI/PI-sparing maintenance ART with IM LA CAB + RPV. 2. TAF non-inf to TDF in switch. 3. Doravirine vs EFV naives (+ FTC/TDF): similar efficacy. 4. A single LA CAB dose protects macaques from IV SIV challenge. 5. Dapivirine vaginal rings as PrEP: Significant but limited efficacy. 6. LED/SOF 6 weeks in Acute HCV in HIV+: uncertainty. 7. HIV epidemic through PWID in US could happen again! 8. VRC01 bnab fails to impact viral kinetic rebound. 9. A new 3-in-1 LA adnectin could block any HIV-1 entry. 10. MK-8591: New LA oral and parenteral NRTI translocation inh.

LATTE-2 Study Design Primary endpoint: Safety and dose-selection. Induction period CAB 30 mg + + ABC/3TC ABC/3TC for 20 for weeks 20 weeks (N=309) Add RPV Maintenance period a Inclusion criteria CAB 400 mg >18 IM years + RPV old 600 mg IM Naive Q4W to (n=115) antiretroviral therapy CD4+ >200 cells/mm 3 CAB loading dose at Day 1 CAB 600 mg IM + RPV 900 mg IM Exclusion criteria Positive for hepatitis B Q8W (n=115) ALT 5 ULN Creatinine clearance <50 ml/min CAB loading doses at Day 1 and Week 4 Qualification for maintenance CAB 30 mg + ABC/3TC PO QD (n=56) HIV-1 RNA <50 c/ml between Week -4 and Day 1 4 weeks Day 1 Randomization 2:2:1 286/309 (93%) Week 32 Primary analysis Dosing regimen selection Week 48 Analysis Dosing regimen confirmation Week 96 b ABC/3TC, abacavir/lamivudine; ALT, alanine aminotransferase; IM, intramuscular; PO, orally; Q4W, every 4 weeks; Q8W, every 8 weeks; QD, once daily; ULN, upper limit of normal. a Subjects who withdrew after at least 1 IM dose entered the long-term follow-up period. b Subjects can elect to enter LA Extension Phase beyond Week 96. Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

LATTE-2 Week 32 Primary Endpoint: HIV-1 RNA <50 c/ml by Snapshot (ITT-ME) Virologic outcomes Treatment differences (95% CI) * * Oral IM Q8W -4.8 12.2 Q4W -5.8 11.5 Both Q8W and Q4W comparable to oral CAB at Week 32 No resistance selection (2VF: 1 Q8W, 1 Oral CAB). ISR common (G1/2) but only 1% of subjects D/C. *Met pre-specified threshold for concluding IM regimen is comparable to oral regimen (Bayesian posterior probability >90% that true IM response rate is no worse than -10% compared with the oral regimen). Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

Gallant J. CROI 2016, Boston. #29. Descovy Switch from F/TDF to F/TAF (GS 311-1089) Randomized, double-blind, double-dummy, active-controlled study n=333 F/TAF (200/10 or 200/25 mg)* QD F/TDF Placebo QD Virologically Suppressed (< 50 c/ml) F/TDF + Third Agent egfr 50 ml/min 46% Boosted PI 54% Unboosted regimens n=330 Continue Third Agent F/TDF (200/300 mg) QD F/TAF* Placebo QD Continue Third Agent BL Wk 48 Wk 96 Primary Endpoint Secondary * F/TAF Dose: 200/10 mg with boosted PIs 200/25 mg with unboosted third agents HIV-1 RNA <50 c/ml Endpoint 5

HIV-1 RNA <50 c/ml, % Gallant J. CROI 2016, Boston. #29. Efficacy at Week 48 (Snapshot) Virologic Outcome Treatment Difference (95% CI) F/TDF F/TAF 1.3-2.5 5.1 10% 0 +10% AEs D/C: 2% vs 1 % 6

HIV-1 RNA <50 c/ml, % Gallant J. CROI 2016, Boston. #29. Virologic Success by Third Agent F/TAF (n=333) F/TDF (n=330) 142 155 140 151 172 178 167 179 Resistance selection: 1 M184V (F/TAF.) 7

Median % change M e d ia n (Q 1, Q 3 ) c h a n g e e G F R * (m L /m in ) Gallant J. CROI 2016, Boston. #29. 2 0 Change in Renal Biomarkers at Week 48 1 0 F /T A F (n = 3 3 3 ) F /T D F (n = 3 3 0 ) 8.4 ml/min 2.8 ml/min 0-1 0 Protein Urine Protein to Creatinine Ratio Albumin 0 1 2 2 4 3 6 4 8 W e e k s p<0.001 (dif: 5.6 ml/min) RBP β2m F/TAF F/TDF All differences between treatments statistically significant (p <0.001) RBP, retinol-binding protein; β2m, β2-microglobulin.

Mean % change (95% CI) Gallant J. CROI 2016, Boston. #29. Change in Bone Mineral Density through Week 48 Spine Hip 4 4 2 1.5 p <0.001 2 1.1 p <0.001 0-0.2 0-0.2 F/TAF, n F/TDF, n B L 2 4 4 8 Weeks 321 310 300 320 310 306 B L 2 4 4 8 Weeks 321 309 300 317 305 303 3% BMD increase at Week 48 F/TAF 30% 17% p<0.001 F/TDF 14% 9% p=0.003 9

% of Patients (95% CI) 100 DOR vs EFV (+ FTC/TDF). Phase 2 HIV RNA <40 copies/ml (NC=F Approach) CROI 2016 Abstract #470 Boston, MA MK-1439 P007 Gatell JM 90 80 70 73,1 72,9 81,5 78,7 77,8 77,8 60 63,0 57,5 Week 48 n/n (%) 50 47,2 DOR 84/108 (77.8) 40 30 27,8 26,9 42,1 EFV 85/108 (78.7) Difference (95% CI): -1.1 (-12.2, 10.0) 20 10 0 15,7 12,0 6,5 3,7 DOR 100 mg +TDF/FTC EFV 600 mg +TDF/FTC 0 4 8 12 16 20 24 28 32 36 40 44 48 Treatment Week Good activity against K103N, Y181C, K103N/Y181C, E138K, & K101E, but not Y188L, V106A, M230L Copyright 2016 Merck & Co. Inc. All Rights Reserved. 10

Virologic Response by Screening RNA Week 48 (OF Approach*) CROI 2016 Abstract #470 Boston, MA MK-1439 P007 Gatell JM 100,000 c/ml >100,000 c/ml 100 80 60 40 86,6 87,1 89,6 91,9 74,3 83,8 91,4 91,9 20 0 n/n: 58/67 54/62 25 60/67 57/62 11 26/35 31/37 32/35 34/37 % <40 c/ml % <200 c/ml % <40 c/ml % <200 c/ml DOR 100 mg +TDF/FTC EFV 600 mg +TDF/FTC *Excludes patients who (1)discontinued due to AE, (2) discontinued due to non-treatment related reasons and had last RNA <40 c/ml, or (3) were on-study but missing data in week 48 window. Copyright 2016 Merck & Co. Inc. All Rights Reserved. 11

Summary of Week 48 Outcomes (NC=F Approach)* DOR 100 mg (N=108) CROI 2016 Abstract #470 Boston, MA MK-1439 P007 Gatell JM EFV 600 mg (N=108) n (%) n (%) Success (HIV RNA <40 copies/ml) at week 48 84 (77.8) 85 (78.7) Non-success at week 48 24 (22.2) 23 (21.3) HIV RNA 40 copies/ml 18 (16.7) 14 (13.0) 40 and <200 copies/ml 8 (7.4) 6 (5.6) 200 copies/ml 3 (2.8) 2 (1.9) discontinued study due to lack of efficacy, or discontinued for other reasons with last HIV RNA 40 copies/ml 7 (6.5) 6 (5.6) No virologic data at week 48 window 6 (5.6) 9 (8.3) discontinued study due to AE or death 3 (2.8) 6 (5.6) discontinued study for other reasons with last HIV RNA <40 copies/ml 3 (2.8) 2 (1.9) on study but missing data in week 48 window 0 (0.0) 1 (0.9) All patients also received TDF/FTC. * Overall success/non-success rates are identical for NC=F and the FDA snapshot approach. Majority of patients in this category (5 of 7 in DOR group; 4 of 6 in EFV group) had last HIV RNA 200 c/ml. No treatment-emergent resistance mutations were detected in the 4 patients (3 DOR, 1 EFV) who had HIV RNA >500 c/ml at the time of virologic failure. DOR Significantly lower rates of: AEs, Neuropsych AEs, Total/LDL Chol G1/2. Copyright 2016 Merck & Co. Inc. All Rights Reserved. 12

Aviremic (%) Two Doses of 50 mg/kg CAB LA Protect 7 of 8 Treated Macaques against SIV IV Challenge CAB LA 100 7/8 80 CAB LA 60 40 0/5 p=0.0047 Untreated 20 CAB LA Untreated 0 0 2 4 6 8 10 12 14 16 18 20 22 24 IV Challenge Time (weeks) Infectious dose comparable to a human blood transfusion. No differences in plasma levels in the infected macaque. Andrews C. CROI 2016,Boston, MA. #105.

Aviremic (%) Determine if a Single 50 mg/kg CAB LA Dose Provides Sustained CAB Plasma Levels for Protection against IV Challenge CAB LA 1/16 infected (93.3% protection) 100 80 8/8 60 40 0/5 p=0.0008 A Second Dose of CAB LA at Week 4 Is Not Required for Protection against IV Challenge. Results support the evaluation of CAB LA as PrEP in people who inject drugs. 20 CAB LA Untreated 0 0 2 4 6 8 10 12 14 16 18 20 IV Challenge Time (weeks) Andrews C. CROI 2016,Boston, MA. #105.

Implantable LA ARV Formulations Solid drug core Thin-film polymer membrane Tenofovir alafenamide polycaprolactone biodegradable implant Dissolved drug (saturated) Biological fluid in Dissolved drug out Schlesinger EB. CROI 2016, Boston, MA.#879

MTN-020/ASPIRE / The Ring Study Multi-center, randomized, double-blind, placebocontrolled phase III trials of a vaginal matrix ring containing the NNRTI dapivirine. Primary objectives: to determine the effectiveness and safety of dapivirine (25 mg), when inserted once every 4 weeks, in preventing HIV-1 infection among healthy sexually active HIV-1 uninfected women. Median age 26 years, 50% reported not using condoms. Median follow-up: 1.6 (2) years. Pregnancy incidence: 4 (3) %/year. Baeten J. CROI 2016, Boston, MA, #109LB. Nel A. #110 LB.

Objective Adherence Assessment Two objective measures, testing dapivirine, were used to assess adherence: Plasma. Measured in quarterly-collected plasma samples: levels >95 pg/ml, indicating at least 8 hours of continuous use, defined adherence. Ring. After the first year of the study, residual drug in returned, used rings was also measured: levels <23.5 mg (= 1.5 mg released, indicating at least some use during the month) defined adherence. Median adherence: 82% (83%). 75% if only residual ring levels. Both studies have 1-2 sites with bad conduct/adherence. Baeten J. CROI 2016, Boston, MA, #109LB. Nel A. #110 LB.

ASPIRE / The Ring Study. HIV-1 Protection Primary HIV-1 effectiveness intention-to-treat analysis (15 sites) Dapivirine Placebo # HIV-1 infections 71 (77) 97 (56) HIV-1 incidence, per 100 person-years 3.3 4.1 4.5 6-1 HIV-1 protection effectiveness 95% CI, p-value 27% (1, 46) p=0.046 31% (1, 51) P=0.040 No significant protection in women <21 years (HIV incidence: 8.2%/year pbo). Baeten J. CROI 2016, Boston, MA, #109LB. Nel A. #110 LB.

The Ring Study. Efficacy by adherence. Note: Adherence based on ring residual level only Nel A. CROI 2016, Boston, MA. #110 LB.

LED/SOF Acute HCV in HIV+. Study Design? Week 0 6 18 N=26 LDV/SOF FDC Patients with chronic HIV and acute HCV infection HCV GT 1a (69%) or 4 (31%) ART consistent with LDV/SOF co-administration with HIV <200 copies/ml or not receiving ART with no plans to start Acute HCV infection with detectable HCV RNA (Roche COBAS AmpliPrep/COBAS TaqMan version 2.0, LLOQ=15 IU/mL) for <24 weeks, defined by HCV RNA-positive and negative anti-hcv antibody/hcv RNA test within last 6 months or Elevated ALT/AST >2.5 x ULN in past 6 months with normal LFTs in past year, and other causes excluded 5 sites in Germany and UK SVR12 Rochstroh JK. CROI 2016, Boston, MA. #154LB. 23

Patients, % Results: SVR4 and SVR12 100 80 85 3 relapsers (2 GT1A, 1 GT4; all IL28B CT) No new NS5A or NS5B RAVs observed at relapse. 77 60 40 4 Virologic failures* 4 Virologic failures* 2 Lost to follow-up 20 0 22/26 SVR4 20/26 SVR12 *3 patients relapsed, 1 was reinfected (GT 1a at baseline, 4d in post-treatment). Error bars represent 95% confidence intervals. Rochstroh JK. CROI 2016, Boston, MA. #154LB. 24

HCV RNA (log 10 IU/mL) Results: BL HCV RNA and Outcome (SVR) SVR12 SVR4 Relapse Reinfection 8 7 6 5 4 3 2 1 0 Rochstroh JK. CROI 2016, Boston, MA. #154LB. 25

Austin city pop: 4.200. Lowest life expectancy. 9% unemployed, 19% poverty, 21% no high school Early 2015: 11 new HIV infections in Scott county (<1/year past decade) 90% coinfected HCV. Network of PWID, oxymorphone (92%) and heroin (23%) N=181 non-hispanic whites (4.6% of adult population) JT Brooks. CROI 2016, Boston, MA. #132. Available at: http://www.croiwebcasts.org/console/player/29695?mediatype=slidevideo&

Time Magazine, 15 June 2015. JT Brooks. CROI 2016, Boston, MA. #132. Available at: http://www.croiwebcasts.org/console/player/29695?mediatype=slidevideo&

JT Brooks. CROI 2016, Boston, MA. #132. Available at: http://www.croiwebcasts.org/console/player/29695?mediatype=slidevideo&

IVDU very difficult to monitor HCV epidemic heralds PWID-mediated HIV epidemic. Incidence disproportionally higher in non-urban areas. JT Brooks. CROI 2016, Boston, MA. #132. Available at: http://www.croiwebcasts.org/console/player/29695?mediatype=slidevideo&

JT Brooks. CROI 2016, Boston, MA. #132. Available at: http://www.croiwebcasts.org/console/player/29695?mediatype=slidevideo&

Anti-PD-L1, Vacc-4x/GM-CSF + Romidepsin, TL7 Agonists, Briostatin,. Mascola JR. CROI 2016, Boston MA. #15.

ACTG A5340. VRC01 bnab. Study Design STEP 1: VRC01 administration and Analytical Treatment Interruption Screening Pre-Entry Entry Viral Rebound 1 ary endpoint Study Weeks ATI Weeks HIV <50 for 6 months CD4 > 400 ART 0-1 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 Variable duration until HIV VL 1000 copies/ml OR CD4 < 350 HIV viral load/pk Safety (CBC, CD4, CMP) Rectal Biopsy/Leukopheresis VRC01 40 mg/kg ATI 1 week after VRC01 initiation Participants: Chronically infected, on ART with VL<50 copies/ml for > 6 months CD4 count > 400 cells/ml, nadir CD4 > 200 cells/ml INSTI (71%) or PI-based regimen Power: 13 evaluable participants 90% power to detect 40% increase in suppression at week 8 Bar KJ. CROI 2016, Boston, MA. #32LB.

Results: Viral rebound HIV-1 RNA (copies/ml) 100000 10000 1000 100 enrollee 1 2 3 4 5 6 7 8 9 10 12 13 14 0 2 4 6 8 10 12 Weeks post-ati Majority of participants rebounded by week 5 2 participants with delayed rebound at 8, 11 weeks Time to rebound not associated with VRC01 level, age, nadir or entry CD4 ct, time on ART Bar KJ. CROI 2016, Boston, MA. #32LB. A5340

Time to HIV-1 RNA 200 c/ml 38% vs. 13% suppression at 4 weeks, p=0.04 8% vs. 3% suppression at 8 weeks, p=0.44 compared to historical controls on non-nnrti regimens undergoing ATI in ACTG studies A5340 Bar KJ. CROI 2016, Boston, MA. #32LB. Li AIDS 2016

VRC01 (mcg/ ml) VRC01 (ug/ml) Results: VRC01 levels at rebound 3000 1000 VRC01 <3 Doses Washout VRC01 at Rebound 100 50 ug/ml 10-2 0 2 4 6 8 10 12 Weeks post- ATI Weeks 12/13 participants rebounded with plasma VRC01 >50 ug/ml. VRC01 No evidence of viral selection Evidence of resistance development. Bar KJ. CROI 2016, Boston, MA. #32LB. VRC01 at Rebound ATI A5340

Mascola JR. CROI 2016, Boston MA. #15.

What is an Adnectin? monobodies Adnectins are engineered versions of the 10 th Type III domain of human fibronectin Contain Ig-domain like natural protein binding characteristics A LA (projected human t1/2 40 h) adnectin combining 3 different non-overlapping a-hiv-1 inhibitors would have synergistic advantages Restricted to processes outside the cell (HIV-1 entry) Ability to obtain high potency at low receptor occupancy 3 in 1: αcd4 Adnectin (prevents conformational changes in gp120) + α-gp41 Inhibitors: αn17adnectin (N17 region of HIV) + peptide (more specific that ENF). Krystal M. CROI 2016, Boston, MA. #97.

HIV-1 Combinectin: BMS-986197 BMS-986197 contains 2 a-hiv-1 Adnectins and a peptide fusion inh BMS-626529 Ibalizumab CD4 CD4 Binding Coreceptor Binding CCR5 antagonists Maraviroc Virus-Cell Fusion Enfuvirtide Cell Membrane CCR5/CXCR4 NH 2 HSA a-cd4 a-gp41 a-gp41 COOH Krystal M. CROI 2016, Boston, MA. #97.

Heightened Resistance Barrier Recombinant viruses were constructed to contain resistance substitutions against one or multiple inhibitors Inhibitor acd4 R an17 R pep R an17 R /pep R acd4 R /an17 R / pep R acd4 Adn 6.8* 0.1 1.2 0.8 3.2 an17 Adn 0.4 >660 1.8 >799.8 >660 peptide 0.4 1.4 7.0 83.1 39.9 BMS- 986197 1.1 1.9 2.1 89.1 98.0 *Fold-Change vs WT virus No significant change in susceptibility with viruses resistant to one of the inhibitors. Only viruses resistant to 2 (an17 + pep) or all 3 inhibitors exhibit high FCs. Suggests resistance barrier to the Combinectin should be higher than mixture of individual components. Krystal M. CROI 2016, Boston, MA. #97.

Avg. Change in HIV-1 RNA (log10 c/ml) 1,00 0,50 0,00-0,50-1,00-1,50-2,00-2,50-3,00-3,50-4,00 Efficacy of BMS-986197 at Day 36 Vehicle Low dose 1 died Med dose 1/8 Undetectable HAART* 3/6 Undetectable: 2 died Highest dose 6/8 Undetectable 0 9 18 27 36 Days After Treatment Initiation * RAL + TDF/FTC Dose dependent decrease in viral load Efficacy at highest dose of 197 similar to HAART Study is continuing for an additional 27 days Receptor occupancy and PK consistent over 36 days Krystal M. CROI 2016, Boston, MA. #97.

MK-8591, a translocation inh., has an outstanding resistance profile Most potent ARV reported to date (sub-nm in PBMC cell-based assays) Estimated oral t1/2 50 h, plasma (weekly administration) 150-160 h, PBMCs, phosphorilated metabolite Compound IC 50 (nm) (fold-shift vs WT) WT K65R* M184V** M184I** MK-8591 0.2 0.1 (0.5) 1.6 (8) 0.9 (5) TAF 3.3 7.0 (2.1) 1.6 (0.5) 2.2 (0.7) 3TC 122 1100 (10) >42000 (382) 8900 (81) FTC 20 200 (8) >42000 (1750) 1400 (58) K65R, the most prevalent mutant associated with TFV, is hypersensitive to MK-8591 MK-8591 exhibits lower fold-changes in potency with M184V/I mutations than 3TC/FTC. Grobler J. CROI 2016, Boston, MA. #98.

10 mg oral single dose -1.78 log Grobler J. CROI 2016, Boston, MA. #98.

MK-8591 parenteral formulations release for >180 days Note: < 50% drug released after 180 days >180 day extended release after a single injection in rat Data suggest the potential to provide coverage for up to 1 year Grobler J. CROI 2016, Boston, MA. #98.