Nuevos fármacos an/retrovirales

Transcription

1 Nuevos fármacos an/retrovirales Pere Domingo Malal/es Infeccioses Hospitals Universitaris Arnau de Vilanova & Santa María IRB Lleida Universitat de Lleida

2 La escasez persiste... Combinec/n: BMS EFdA (MK- 8591): análogo nucleósido BMS : inhibidor maduración BMS : inhibidor de la adhesión (AI438011) Tenofovir alafenamida (TAF): estudio Doravirina: study 007 Cabotegravir LA + RPV LA: LATTE- 2

3 La escasez persiste... Combinec/n: BMS EFdA (MK- 8591): análogo nucleósido BMS : inhibidor maduración BMS : inhibidor de la adhesión (AI438011) Tenofovir alafenamida (TAF): estudio Doravirina: study 007 Cabotegravir LA + RPV LA: LATTE- 2

4 Friedman et al. #437LB; Grobler et al. #98 MK ,- ethyniyl- 2- fluoro- 2 - deoxyadenosine (EFdA) Nucleoside reverse transcriptase transloca/on inhibitor (NRTTI) Prolonged persistence of triphosphate form in PBMC Poten/al of weekly dosing Long- ac/ng formula/ons under development

5 AI438011: inclusion criteria DeJesus E et al. #472

6 AI438011: study design DeJesus E et al. #472

7 AI438011: baseline characteris/cs DeJesus E et al. #472

8 AI438011: Subject disposi/on- 96 w DeJesus E et al. #472

9 AI438011: virologic efficacy DeJesus E et al. #472

10 AI438011: Efficacy 96 w: observed analysis DeJesus E et al. #472

11 AI438011: mean change CD4 cell count DeJesus E et al. #472

12 AI438011: efficacy by baseline viral load DeJesus E et al. #472

13 AI438011: safety summary and G3-4 AEs DeJesus E et al. #472

14 AI438011: conclusions

15 Switching to F/TAF (Tenofovir Alafenamide) from F/TDF (Tenofovir DF) based Regimen Study : 48-Week Data Joel Gallant 1, Eric Daar 2, Francois Raffi 3, Cynthia Brinson 4, Peter Ruane 5, Edwin DeJesus 6, Mingjin Yan 7, Andrew Plummer 7, Andrew Cheng 7, Martin S Rhee 7 1 Southwest CARE Center, Santa Fe, NM; 2 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA; 3 CHU Hotel Dieu-CHU De Nantes, Nantes, France; 4 Central Texas Clinical Research, Austin, TX; 5 Ruane Medical and Liver Health Institute, Los Angeles, CA; 6 Orlando Immunology Center, Orlando, FL; 7 Gilead Sciences, Foster City, CA Abstract 29 CROI 2016, Boston

16 Background Emtricitabine/TDF (F/TDF) N(t)RTI backbone of most regimens recommended by major guidelines 1,2 Tenofovir disoproxil fumarate (TDF) Associated with renal and bone toxicities Tenofovir alafenamide (TAF) 91% lower plasma tenofovir exposures than TDF 3 Elvitegravir/cobicistat/F/TAF (E/C/F/TAF) In treatment naïve and virologically suppressed patients, TAF showed improved renal and bone safety profiles compared with TDF 3,4 Can be used in patients with egfr as low as 30 ml/min 5 A recommended initial regimen by US DHHS 1 and several European country guidelines Sax PE, et al. Lancet 2015;385: ; 4. Mills A, et al. Lancet Infect Dis 2016;16:43-52 [Epub 2015 Nov 2]; 5. GENVOYA US PI and EU SmPC 16

17 Switch from F/TDF to F/TAF 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 Continue Third Agent F/TDF (200/300 mg) QD n=330 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 17

18 Baseline Characteristics F/TAF n=333 F/TDF n=330 Median age (range), years 48 (22, 78) 49 (22, 79) Female, n (%) 48 (14) 54 (16) Race, n (%) White 244 (73) 253 (77) Black or African descent 69 (21) 67 (20) Other 20 (6) 10 (3) Hispanic/Latino ethnicity, n (%) 48 (14) 78 (24) Median CD4 count, cells/mm <200 cells/mm 3, n (%) 5 (2) 4 (1) Median egfr *, ml/min Use of third agent, n (%) Boosted PI 155 (47) 150 (45) Unboosted third agents 178 (53) 180 (55) * egfr calculated with Cockcroft-Gault equation 18

19 Patient Disposition through Week 48 F/TAF Randomized and Treated n=333 F/TDF Randomized and Treated n= (6%) Reason for D/C, n 21 (6%) 10 Withdrew consent 10 7 Adverse event 3 1 Lost to follow-up 1 1 Noncompliance 2 1 Investigator discretion 1 1 Pregnancy 0 0 Protocol violation 4 94% Continuing n=312 94% Continuing n=309 19

20 Efficacy at Week 48 (Snapshot) Virologic Outcome Treatment Difference (95% CI) F/TDF F/TAF HIV-1 RNA <50 c/ml, % Non-success 10% 0 +10% 20

21 Virologic Success in Select Subgroups F/TAF (n=333) F/TDF (n=330) Overall Age Sex Race HIV-1 RNA <50 c/ml, % <50 yr 50 yr Male Female Non-black Black 21

22 Virologic Success by Third Agent F/TAF (n=333) F/TDF (n=330) HIV-1 RNA <50 c/ml, %

23 Emergent Resistance n (%) F/TAF n=333 F/TDF n=330 Analyzed for resistance * 2 (<1) 1 (<1) Development of resistance 1 (<1) 0 NRTI: M184V 1 0 NNRTI 0 0 PI 0 0 INSTI 0 0 * Confirmed HIV-1 RNA 50 c/ml at any visit or unconfirmed >400 c/ml at endpoint or discontinuation 23

24 Adverse Events All grades >5% in either group, n (%) F/TAF n=333 F/TDF n=330 Upper respiratory tract infection 30 (9) 45 (14) Diarrhea 30 (9) 33 (10) Headache 27 (8) 15 (5) Nasopharyngitis 25 (8) 20 (6) Cough 21 (6) 16 (5) Bronchitis 21 (6) 17 (5) Back pain 21 (6) 15 (5) Arthralgia 19 (6) 9 (3) Fatigue 18 (5) 13 (4) Sinusitis 12 (4) 22 (7) 24

25 Adverse Events Leading to Discontinuation n (%) F/TAF n=333 F/TDF n=330 Overall 7 (2) 3 (1) Insomnia / Mood altered 1 0 Dysphagia 1 0 Atrial fibrillation 1 0 Diarrhea 1 0 Peripheral edema 1 0 Overdose 1 0 Lymphoma 1 0 Increased serum creatinine 0 1 Rectal tenesmus 0 1 Feeling abnormal / Headache 0 1 No reported cases of proximal renal tubulopathy or Fanconi syndrome in either group 25

26 Grade 3 to 4 Lab Abnormalities 1% in either group, n (%) F/TAF n=333 F/TDF n=330 Overall 71 (21) 62 (19) LDL 20 (6) 8 (3) Total bilirubin 17 (5) 18 (5) Creatine kinase 13 (4) 10 (3) Total cholesterol 9 (3) 3 (1) Glycosuria 8 (2) 5 (2) Hematuria 5 (2) 3 (1) AST 4 (1) 5 (2) Amylase 4 (1) 8 (2) Hyperglycemia 4 (1) 2 (1) GGT 3 (1) 9 (3) 26

27 Changes in egfr 2 0 F /T A F (n = ) F /T D F (n = ) M e d ia n (Q 1, Q 3 ) c h a n g e e G F R * (m L /m in ) ml/min 2.8 ml/min p < W e e k s * egfr calculated with Cockcroft-Gault equation

28 Change in Renal Biomarkers at Week 48 Urine Protein to Creatinine Ratio Protein Albumin RBP β2m Median % change F/TAF F/TDF All differences between treatments statistically significant (p <0.001) RBP, retinol-binding protein; β2m, β2-microglobulin. 28

29 Change in Bone Mineral Density through Week 48 Spine Hip Mean % change (95% CI) F/TAF, n B L Weeks p < B L Weeks p <0.001 F/TDF, n % BMD increase at Week 48 F/TAF 30% 17% p<0.001 F/TDF 14% 9% p=

30 Fasting Lipid Results F/TAF F/TDF Median value (mg/dl) p < Week 48 Baseline p < p= p= p= Total Cholesterol 0 LDL HDL Triglycerides TC: HDL Ratio F/TAF F/TDF Patients initiating lipid-lowering agents 4% 4% 30

31 Week 48 Conclusions F/TAF was noninferior to F/TDF in maintaining virologic suppression in combination with a variety of third agents Significant improvements in multiple measures of renal and bone safety after switching from F/TDF to F/TAF Improvements in egfr, proteinuria, including tubular proteinuria Improvements in BMD Efficacy and safety results are consistent with E/C/F/TAF studies These data support that F/TAF is an important NRTI backbone for antiretroviral treatment with safety benefits over F/TDF 31

32 CROI 2016 Abstract #470 Boston, MA MK P007 Doravirine 100 mg QD vs Efavirenz +TDF/FTC in ART- Naive HIV+ Pa/ents: Week 48 Results Jose M. Gatell 1, Francois Raffi 2, Andreas PleEenberg 3, Don Smith 4, Joaquin PorNlla 5, ChrisNan Hoffmann 6, Keikawus Arasteh 7, Melanie Thompson 8, Xia Xu 9, Hedy Teppler 9 for the Study Team 1 Hospital Clinic/IDIBAPS, University of Barcelona, Barcelona, Spain; 2 COREVIH Pays de Loire, France; 3 ifi- InsNtute for InfecNons, Hamburg, Germany; 4 Albion Centre, Sydney, Australia; 5 University Miguel Hernandez, Alicante, Spain; 6 ICH Study Center, Hamburg, Germany; 7 EPIMED/Vivantes Auguste- Viktoria- Klinikum, Berlin, Germany; 8 AIDS Research ConsorNum of Atlanta, Atlanta, GA; 9 Merck & Co., Inc., Kenilworth, NJ Copyright 2016 Merck & Co. Inc. All Rights Reserved.

33 Background CROI 2016 Abstract #470 Boston, MA MK P007 o o Commonly used non- nucleoside reverse transcriptase inhibitors (NNRTIs) are associated with subopnmal efficacy and/or safety profiles Efavirenz frequent CNS adverse events 1 ; no longer recommended as first- line therapy for HIV infecnon in mulnple guidelines 1-3 Rilpivirine treatment- naïve indicanon only for RNA 100,000 copies/ml in US 1 and EU 2 Doravirine (DOR, aka MK- 1439) is a novel NNRTI High in vitro potency vs broad panel of isolates including common NNRTI- resistant variants 4 Primary metabolism by CYP3A4; not an inducer or inhibitor 5 Once daily dosing (without regard to food) No interacnons expected with proton pump inhibitors o In Part 1 of this Phase 2 study (MK Protocol 007) AnNretroviral acnvity of DOR 25, 50, 100 and 200 mg QD, with tenofovir/emtricitabine (TDF/FTC), was similar to efavirenz with TDF/FTC at week 24 6 and week 48 7 Safety profile of DOR was favorable at all doses DOR 100 mg was selected for Part 2, and for evaluanon in the Phase 3 program Copyright 2016 Merck & Co. Inc. All Rights Reserved. 33

34 Protocol 007 Study Schema CROI 2016 Abstract #470 Boston, MA MK P007 RCT, DB, dose- finding, 2 part study PaNents: HIV- 1+ ART- naïve RNA 1,000 c/ml CD4 100 cells/µl StraNfied by screening RNA ( / > 100K c/ml) Part 2 began aqer dose selec/on based on Part 1 week 24 results. Part 1 Dose Ranging Phase (N=210) DOR 25 mg DOR 50 mg DOR 100 mg (n=42) DOR 200 mg EFV 600 mg (n=43) DOR 100 mg (n=66) EFV 600 mg (n=66) Part 1 Extension Phase DOR 100 mg Con/nue EFV Week 48 Week 96 Part 2: Addi/onal Pa/ents, DOR Selected Dose vs EFV (N=132) Week 48 Week 96 Copyright 2016 Merck & Co. Inc. All Rights Reserved. 34

35 CROI 2016 Abstract #470 Boston, MA MK P007 Sta/s/cal Analysis o Popula/ons analyzed PaNents randomized to DOR 100 mg or EFV 600 mg, both given with TDF/FTC DOR 100 mg: Part 1 (n=42) + Part 2 (n=66); total = 108 panents EFV 600 mg: Part 1 (n=43) + Part 2 (n=66); total = 109 panents Full Analysis Set (efficacy): all randomized panents who had at least one post- randomizanon observanon auer receiving at least one dose of blinded study treatment All- PaNents- as- Treated (safety): all randomized panents who received at least one dose of study treatment Copyright 2016 Merck & Co. Inc. All Rights Reserved. 35

36 Sta/s/cal Analysis (cont.) CROI 2016 Abstract #470 Boston, MA MK P007 o Efficacy endpoints Virologic response: ProporNon of panents with HIV RNA < 40 c/ml (primary), with HIV RNA < 200 c/ml (secondary) Non- completer = Failure (NC=F) approach for missing data Immunologic response: Change from baseline in CD4 count Observed Failure (OF) approach for missing data Virologic response by screening HIV RNA ( vs > 100,000 c/ml) OF approach for missing data: missing values imputed as failure for (1) disconnnuanon due to lack of efficacy, and (2) disconnnuanon for non- treatment related reasons, if final vrna is >40 c/ml o Safety endpoints Clinical adverse events: collected through 14 days post- treatment Laboratory parameters: predefined limits of change, DAIDS toxicity criteria Copyright 2016 Merck & Co. Inc. All Rights Reserved. 36

37 CROI 2016 Abstract #470 Boston, MA MK P007 Pa/ent Status, Week 48 DOR 100 mg EFV 600 mg PaNents randomized, n PaNents treated, n PaNents disconnnued, % Adverse event Lack of efficacy Lost to follow- up Non- compliance with study drug Physician decision Withdrawal by subject All panents also received TDF/FTC. Percentages are based on the number of panents randomized. Physician decision to disconnnue panent based on failure to comply with dosing requirements of the study; does not include disconnnuanon due to an adverse event. Copyright 2016 Merck & Co. Inc. All Rights Reserved. 37

38 CROI 2016 Abstract #470 Boston, MA MK P007 Baseline Pa/ent Characteris/cs DOR 100 mg EFV 600 mg Treated panents N=108 N=108 % Male Age (years), median (range) 35 (19 67) 34 (20 57) % White % with AIDS HIV RNA (log 10 c/ml), median (range) 4.6 ( ) 4.6 ( ) % with HIV RNA >100,000 c/ml, at screening CD4 Count (cells/µl), median (range) 402 ( ) 430 ( ) % with CD4 count 200 cells/µl % with Clade B viral subtype All panents also received TDF/FTC. Copyright 2016 Merck & Co. Inc. All Rights Reserved. 38

39 Summary of Week 48 Outcomes (NC=F Approach)* DOR 100 mg (N=108) CROI 2016 Abstract #470 Boston, MA MK P007 EFV 600 mg (N=108) n (%) n (%) Success (HIV RNA <40 copies/ml) at week (77.8) 85 (78.7) Non- success at week (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) disconnnued study due to lack of efficacy, or disconnnued 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) disconnnued study due to AE or death 3 (2.8) 6 (5.6) disconnnued 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 panents also received TDF/FTC. * Overall success/non- success rates are idenncal for NC=F and the FDA snapshot approach. Majority of panents 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 mutanons were detected in the 4 panents (3 DOR, 1 EFV) who had HIV RNA >500 c/ml at the Nme of virologic failure. Copyright 2016 Merck & Co. Inc. All Rights Reserved. 39

40 HIV RNA <40 copies/ml (NC=F Approach) CROI 2016 Abstract #470 Boston, MA MK P % of Pa/ents (95% CI) ,8 26,9 47,2 63,0 42,1 57,5 73,1 72,9 81,5 78,7 77,8 77,8 Week 48 n/n (%) DOR 84/108 (77.8) EFV 85/108 (78.7) Difference (95% CI): (- 12.2, 10.0) ,7 DOR 100 mg +TDF/FTC 12,0 6,5 EFV 600 mg +TDF/FTC 3, Treatment Week Copyright 2016 Merck & Co. Inc. All Rights Reserved. 40

41 HIV RNA <200 copies/ml (NC=F Approach) CROI 2016 Abstract #470 Boston, MA MK P ,3 89,7 89,8 85,2 % of pa/ents (95% CI) ,8 39,8 65,7 33,3 79,4 65,7 75,0 83,0 87,0 86,1 84,3 Week 48: n/n (%) DOR 92/108 (85.2) EFV 91/108 (84.3) Difference (95% CI): 0.9 ( - 8.9, 10.8) 20 21,3 DOR 100 mg +TDF/FTC 10 EFV 600 mg +TDF/FTC Treatment Week Copyright 2016 Merck & Co. Inc. All Rights Reserved. 41

42 CROI 2016 Abstract #470 Boston, MA MK P007 Mean Change in CD4 T- Cell Count (OF Approach) Cells/µL (95% CI) DOR 100 mg + TDF/FTC EFV 600 mg +TDF/FTC Treatment Week Copyright 2016 Merck & Co. Inc. All Rights Reserved. 42

43 Virologic Response by Screening RNA Week 48 (OF Approach*) CROI 2016 Abstract #470 Boston, MA MK P ,000 c/ml >100,000 c/ml ,6 87,1 89,6 91,9 74,3 83,8 91,4 91, n/n: 58/67 54/ /67 57/ /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 panents who (1)disconNnued due to AE, (2) disconnnued 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. 43

44 Clinical Adverse Events (%) DOR 100 mg (N=108) EFV 600 mg (N=108) CROI 2016 Abstract #470 Boston, MA MK P007 Difference [DOR EFV] (95% CI) One or more adverse events (AE) (- 10.9, 7.1) Serious AE (- 9.5, 5.6) Death 0 0 DisconNnued due to AE (- 9.2, 3.0) Drug- related AE (- 37.3, ) Diarrhea Nausea Dizziness Headache Abnormal dreams Insomnia Nightmares Sleep disorder All panents also received TDF/FTC. Two serious AEs in the EFV group were considered drug- related: depression (1) and dizziness (1). Determined by invesngator to be related to study therapy; specific AEs with >5% incidence are listed. Specific AEs causing disconnnuanon (n): DOR hallucinanon (1), B- cell lymphoma (1), Hodgkin s disease (1); EFV dysaesthesia (1), hallucinanons (2), drug erupnon (1), dizziness (1), disturbance in aeennon (1). Copyright 2016 Merck & Co. Inc. All Rights Reserved. 44

45 Common Laboratory Abnormali/es (%) CROI 2016 Abstract #470 Boston, MA MK P007 Laboratory Test Grade (criteria) DOR 100 mg (N=108) EFV 600 mg (N=108) Difference [DOR EFV] (95% CI) Absolute neutrophil count 1 ( /µl) (- 5.1, 9.3) LDL- cholesterol, fasnng 1 ( mg/dl) (- 21.2, - 5.1) 2 ( mg/dl) (- 7.9, 3.5) Total cholesterol, fasnng 1 ( mg/dl) (- 23.9, - 5.6) 2 ( mg/dl) (- 13.3, - 3.0) Glucose, fasnng 1 ( mg/dl) (- 10.8, 7.7) Bilirubin, total 1 ( x ULN) (- 0.1, 10.9) Aspartate aminotransferase 1 ( x ULN) (- 11.4, 5.9) 2 ( x ULN) (- 8.3, 1.8) Alanine aminotransferase 1 ( x ULN) (- 13.0, 3.6) Alkaline phosphatase 1 ( x ULN) (- 11.2, 0.9) Lipase 1 ( x ULN) (- 6.5, 10.5) 2 ( x ULN) (- 9.9, 4.1) 3 ( x ULN) (- 7.2, 5.2) occurred in at least 4 panents in one or more treatment groups, with indicated grade (based on DAIDS toxicity criteria) and was also an increase from baseline. All panents also received TDF/FTC. Copyright 2016 Merck & Co. Inc. All Rights Reserved. 45

46 All Laboratory Abnormali/es Grade 2 (%) CROI 2016 Abstract #470 Boston, MA MK P007 DOR 100 mg EFV 600 mg Laboratory Test Grade (criteria) (N=108) (N=108) Absolute neutrophil count 2 ( x 10 3 /µl) (<0.50 x 10 3 /µl) Platelet count 2 ( x 10 3 /µl) LDL- cholesterol, fasnng 2 ( mg/dl) ( 190 mg/dl) Total cholesterol, fasnng 2 ( mg/dl) (>300 mg/dl) Triglycerides, fasnng 2 ( mg/dl) Glucose, fasnng 2 ( mg/dl) Aspartate aminotransferase 2 ( x ULN) ( x ULN) (>10.0 x ULN) Alanine aminotransferase 2 ( x ULN) ( x ULN) Lipase 2 ( x ULN) All panents also received TDF/FTC. 3 ( x ULN) (>5.0 x ULN) Copyright 2016 Merck & Co. Inc. All Rights Reserved. 46

47 Conclusions CROI 2016 Abstract #470 Boston, MA MK P007 In ART- naïve subjects with HIV- 1 infec/on, Doravirine 100 mg QD in combina/on with TDF/FTC: Demonstrates annretroviral acnvity and immunological effect similar to efavirenz with TDF/FTC at week 48 Is safe and generally well tolerated through week 48 Drug- related AEs were significantly less common in the DOR group (31.5%) vs the EFV group (56.5%) Phase 3 trials of Doravirine 100 mg QD are currently ongoing. Copyright 2016 Merck & Co. Inc. All Rights Reserved. 47

48 Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE 2 Week 32 Results David A. Margolis, 1 Juan Gonzalez-Garcia, 2 Hans-Jürgen Stellbrink, 3 Joe Eron, 4 Yazdan Yazdanpanah, 5 Sandy K. Griffith, 1 David Dorey, 6 Kimberly Y. Smith, 1 Peter E. Williams, 7 William R. Spreen 1 1 ViiV Healthcare, Research Triangle Park, NC; 2 Hospital La Paz, Madrid, Spain; 3 ICH Hamburg, Germany; 4 University of North Carolina, Chapel Hill, NC; 5 Hôpital Bichat Claude Bernard, Paris, France; 6 GlaxoSmithKiline, Mississauga, Ontario, Canada; 7 Janssen Research and Development, Beerse, Belgium 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

49 Background CAB is an HIV-1 integrase inhibitor Oral 30 mg tablet (t½, ~40 hours) LA nanosuspension 200 mg/ml (t½, ~20-40 days) RPV is an HIV-1 NNRTI Oral 25 mg tablet (t½, ~50 hours) LA nanosuspension 300 mg/ml (t½, ~30-90 days) Oral 2-drug CAB + RPV proof of efficacy through Week 96 in LATTE Proportion, % (95% CI) BL CAB 10 mg (n=60) CAB 60 mg (n=61) CAB 30 mg (n=60) EFV 600 mg (n=62) Margolis et al. Lancet Infect Dis. 2015;15: BL, baseline; CAB, cabotegravir; CI, confidence interval; EFV, efavirenz; LA, long-acting; NNRTI, non-nucleoside reverse transcriptase inhibitor; RPV, rilpivirine; t 1/2, half-life. Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

50 LATTE-2 Objectives Establish proof of principle for the first ever LA HIV treatment regimen Primary Objective Evaluate the safety and efficacy of CAB LA + RPV LA as maintenance therapy, and Select a dosing schedule of CAB LA + RPV LA for progression into phase III studies Key Secondary Objectives Characterize LA pharmacokinetics Evaluate the tolerability and acceptability of injectable dosing Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

51 LATTE-2 Study Design Induction period CAB 30 mg + ABC/3TC for 20 weeks (N=309) Inclusion criteria >18 years old Naive to antiretroviral therapy CD4+ >200 cells/mm 3 Exclusion criteria Positive for hepatitis B ALT 5 ULN Creatinine clearance <50 ml/min Qualification for maintenance HIV-1 RNA <50 c/ml between Week -4 and Day 1 Add RPV 4 weeks 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

52 LATTE-2 Study Design Induction period Maintenance period a CAB 30 mg + ABC/ 3TC for 20 weeks CAB loading dose at Day 1 CAB 400 mg IM + RPV 600 mg IM Q4W (n=115) CAB 600 mg IM + RPV 900 mg IM Q8W (n=115) CAB loading doses at Day 1 and Week 4 CAB 30 mg + ABC/3TC PO QD (n=56) Day 1 Randomization 2:2:1 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

53 Baseline Characteristics: ITT-ME Population Q8W IM (n=115) Q4W IM (n=115) Oral CAB (n=56) Total (N=286) Median age, years Female, n (%) 8 (7) 6 (5) 10 (18) 24 (8) African American/African heritage, n (%) 17 (15) 12 (10) 15 (27) 44 (15) CDC class C, n (%) 1 (<1) 2 (2) 0 3 (1) Median HIV-1 RNA, log 10 c/ml ,000, n (%) 16 (14) 28 (24) 7 (12) 51 (18) Median CD4+, cells/mm CDC, Centers for Disease Control and Prevention; ITT-ME, intent-to-treat maintenance exposed. Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

54 LATTE-2 Week 32 Results: HIV-1 RNA <50 c/ml by Snapshot (ITT-ME) 100 Proportion of patients with virological suppression, % Snapshot success: D1 Q4W 99% Q8W 95% Oral CAB 98% BL W-16 W-12 W-8 W-4 D1 W4 W8 W12 W16 W20 W24 W28 W32 Study visit Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

55 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 Q4W Both Q8W and Q4W comparable to oral CAB at Week 32 *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

56 Snapshot Outcomes: HIV-1 RNA <50 c/ml at Week 32 (ITT-ME) Week 32 outcome Q8W IM (n=115) Q4W IM (n=115) Oral CAB (n=56) Virologic success 109 (95%) 108 (94%) 51 (91%) Virologic non-response 5 (4%) 1 (<1%) 2 (4%) Data in window not <50 c/ml a 3 (3%) 1 (<1%) 1 (2%) Discontinued for lack of efficacy 1 (<1%) 0 1 (2%) Discontinued for other reason while not <50 c/ml 1 (<1%) 0 0 No virologic data in window 1 (<1%) 6 (5%) 3 (5%) Discontinued due to adverse event or death b 0 4 (3%) 1 (2%) Discontinued for other reasons c 1 (<1%) 2 (2%) 2 (4%) a Week 32 HIV-1 RNA Q8W: 53 c/ml, 70 c/ml, 91 c/ml; Q4W: 70 c/ml; oral CAB: 243 c/ml. All 5 are still in the study. b Q4W: hepatitis C, rash, depression, and psychosis; oral CAB: hepatitis C. c Q8W: ISR; Q4W: pregnancy and prohibited medication; oral CAB: lost to follow-up, relocation. Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

57 Protocol-Defined Virologic Failure (PDVF): Genotype No INI, NNRTI, or NRTI mutations were detected through Induction or Maintenance Maintenance period Q8W IM (n=115) Q4W IM (n=115) Oral CAB (n=56) Subjects with PDVF a 1 b (1%) 0 1 (2%) INI-r mutations NRTI-r mutations NNRTI-r mutations PDVF: <1.0 log 10 c/ml decrease in plasma HIV-1 RNA by Week 4, OR confirmed HIV-1 RNA 200 c/ml after prior suppression to <200 c/ml, OR >0.5 log 10 c/ml increase from nadir HIV-1 RNA value 200 c/ml. Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

58 Adverse Events and Labs Maintenance Period ITT-ME population, n (%) Q8W IM (n=115) Q4W IM (n=115) Oral CAB (n=56) IM subtotal (N=230) Drug-related AEs, excluding ISRs ( 3%) Pyrexia 3 (3) 5 (4) 0 8 (3) Fatigue 2 (2) 4 (3) 1 (2) 6 (3) Influenza-like illness 3 (3) 2 (2) 0 5 (2) Grade 3 and 4 AEs, excluding ISRs 10 (9) 12 (10) 1 (2) 22 (10) Drug-related Grade 3/4 AEs a, excluding ISRs 3 (3) 4 (3) 0 7 (3) Serious AEs b 7 (6) 6 (5) 3 (5) 13 (6) AEs leading to withdrawal c 2 (2) 6 (5) 1 (2) 8 (3) Grade 3 and 4 labs d 17 (15) 20 (17) 8 (14) 37 (16) a Q8W: influenza-like illness, chills and pain, and lipase; Q4W: influenza-like illness, rash, depression, and psychosis. b None drug related; one death (epilepsy) evaluated as not likely related to study drug. c Q8W: ISR 2; Q4W: Churg Strauss vasculitis, hepatitis C, depression, epilepsy, psychosis, and rash; oral CAB: hepatitis C. dmaintenance emergent. AE, adverse event; ISR, injection-site reaction. Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

59 Adverse Events and Labs Maintenance Period Q8W IM (n=115) Q4W IM (n=115) IM subtotal (N=230) Number of injections Number of ISRs (events/injection) 1054 (0.65) 1228 (0.46) 2282 (0.53) Grades Grade (80%) 1021 (83%) 1860 (82%) Grade (19%) 197 (16%) 399 (17%) Grade 3 12 (1%) 10 (<1%) 22 (<1%) Grade Duration, days (89%) 1121 (91%) 2064 (90%) Median Most common ISR events overall were pain (67%), swelling (7%), and nodules (6%) Number of subjects reporting ISRs decreased over time, from 86% (Day 1) to 33% (Week 32) a 2/230 subjects (1%) withdrew as a result of injection reactions (Q8W) a Represents percent of subjects with a Week 32 visit (n=220). Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

60 Patient-Reported Outcomes at Week 32: Maintenance Treatment Compared With Oral Induction Treatment a How satisfied are you with your current treatment? 1% 3% 3% 2% How satisfied would you be to continue with your present form of treatment? 1% 1% Note: based on observed case dataset of subjects who completed Week 32 questionnaires. a HIV Treatment Satisfaction Questionnaire change version (HIVTSQc). Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

61 Conclusions LATTE-2 results successfully demonstrate the potential to maintain HIV-1 viral load <50 c/ml with LA IM CAB + RPV, dosed once Q4W or Q8W Two subjects met PDVF criteria Q8W (n=1), oral CAB (n=1); both without evidence of resistance at failure Injection tolerability Majority of ISRs were Grade 1 to 2 pain, with a median duration of 3 days Few subjects had an ISR that led to discontinuation, with high overall reported satisfaction Regimen selection criteria Neither Q4W IM or Q8W IM dosing was ruled out on the basis of pre-specified criteria Upcoming Week 48 analysis will contribute to final dose selection for phase III studies Margolis et al. CROI 2016; Boston, MA. Abstract 31LB. 23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

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