Nuevos fármacos’ anretrovirales · Nuevos fármacos’ anretrovirales ... Tenofovir disoproxil fumarate ... !5 University!Miguel!Hernandez,!Alicante,!Spain;!6 ICH

Nuevos fármacos an/retrovirales

Pere Domingo Malal/es Infeccioses

Hospitals Universitaris Arnau de Vilanova & Santa María IRB Lleida

Universitat de Lleida [email protected]

La escasez persiste....

•  Combinec/n: BMS-‐986197 •  EFdA (MK-‐8591): análogo nucleósido •  BMS-‐955176: inhibidor maduración •  BMS-‐663068: inhibidor de la adhesión (AI438011)

•  Tenofovir alafenamida (TAF): estudio 311-‐1089 •  Doravirina: study 007 •  Cabotegravir LA + RPV LA: LATTE-‐2

La escasez persiste....

•  Combinec/n: BMS-‐986197 •  EFdA (MK-‐8591): análogo nucleósido •  BMS-‐955176: inhibidor maduración •  BMS-‐663068: inhibidor de la adhesión (AI438011)

•  Tenofovir alafenamida (TAF): estudio 311-‐1089 •  Doravirina: study 007 •  Cabotegravir LA + RPV LA: LATTE-‐2

MK-‐8591

•  4,-‐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

Friedman et al. #437LB; Grobler et al. #98

AI438011: inclusion criteria

DeJesus E et al. #472

AI438011: study design


AI438011: baseline characteris/cs


AI438011: Subject disposi/on-‐96 w


AI438011: virologic efficacy


AI438011: Efficacy 96 w: observed analysis


AI438011: mean change CD4 cell count


AI438011: efficacy by baseline viral load


AI438011: safety summary and G3-‐4 AEs


AI438011: conclusions

CROI 2016, Boston

Switching to F/TAF (Tenofovir Alafenamide) from F/TDF (Tenofovir DF) based Regimen

Study 311-1089: 48-Week Data

Joel Gallant1, Eric Daar2, Francois Raffi3, Cynthia Brinson4, Peter Ruane5, Edwin DeJesus6, Mingjin Yan 7, Andrew Plummer7,

Andrew Cheng7, Martin S Rhee7

1Southwest CARE Center, Santa Fe, NM; 2Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA; 3CHU Hotel Dieu-CHU De Nantes, Nantes, France; 4Central Texas Clinical Research, Austin, TX; 5Ruane Medical and Liver Health Institute, Los Angeles, CA; 6Orlando Immunology Center, Orlando, FL;

7Gilead Sciences, Foster City, CA

Abstract 29

Background

§  Emtricitabine/TDF (F/TDF) –  N(t)RTI backbone of most regimens recommended by major guidelines1,2

§  Tenofovir disoproxil fumarate (TDF) –  Associated with renal and bone toxicities

§  Tenofovir alafenamide (TAF) –  91% lower plasma tenofovir exposures than TDF3

§  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 TDF3,4

–  Can be used in patients with eGFR as low as 30 mL/min5

–  A recommended initial regimen by US DHHS1 and several European country guidelines

1. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf; 2. http://www.eacsociety.org/files/2015_eacsguidelines_8.0-english_rev-20151221.pdf; 3. Sax PE, et al. Lancet 2015;385:2606-15; 4. Mills A, et al. Lancet Infect Dis 2016;16:43-52 [Epub 2015 Nov 2]; 5. GENVOYA US PI and EU SmPC 16

Switch from F/TDF to F/TAF

§  Randomized, double-blind, double-dummy, active-controlled study

*F/TAF Dose: •  200/10 mg with boosted PIs •  200/25 mg with unboosted third agents

17

Secondary Endpoint

n=333

n=330

Primary Endpoint HIV-1 RNA <50 c/mL

BL Wk 96 Wk 48

F/TAF (200/10 or 200/25 mg)* QD

F/TDF Placebo QD

Continue Third Agent

F/TDF (200/300 mg) QD

F/TAF* Placebo QD

Continue Third Agent

Virologically Suppressed (< 50 c/mL) §  F/TDF + Third Agent §  eGFR ≥50 mL/min

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/mm3 663 624

<200 cells/mm3, n (%) 5 (2) 4 (1)

Median eGFR*, mL/min 99 100

Use of third agent, n (%)

Boosted PI 155 (47) 150 (45)

Unboosted third agents 178 (53) 180 (55)

18

*eGFR calculated with Cockcroft-Gault equation

Patient Disposition through Week 48

19

F/TAF Randomized and Treated

n=333

94% Continuing n=312

F/TDF Randomized and Treated

n=330

94% Continuing n=309

21 (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

Efficacy at Week 48 (Snapshot)

F/TDF F/TAF

0

HIV

-1 R

NA

<50

c/m

L, %

‒10% +10%

5.1 -2.5

1.3

20

Non-success

Treatment Difference (95% CI) Virologic Outcome

Virologic Success in Select Subgroups

269 285

262 276

45 48

45 54

Male Female

248 263

246 262

65 69

60 67

Non-black Black

F/TAF (n=333) F/TDF (n=330)

170 183

<50 yr ≥50 yr

171 186

144 150

136 144

HIV

-1 R

NA

<50

c/m

L, %

307 330

314 333

Sex Race Age Overall

21

Virologic Success by Third Agent H

IV-1

RN

A <5

0 c/

mL,

%

142 155

140 151

F/TAF (n=333) F/TDF (n=330)

172 178

167 179

22

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

Adverse Events

24

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)

Adverse Events Leading to Discontinuation

25

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

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

Changes in eGFR

*eGFR calculated with Cockcroft-Gault equation

0 1 2 2 4 3 6 4 8

0

1 0

2 0F /T A F (n = 3 3 3 )

F /T D F (n = 3 3 0 )

W e e k s

Me

dia

n (

Q1

, Q

3)

ch

an

ge

eG

FR

* (m

L/m

in)

-10

8.4 mL/min

2.8 mL/min

p <0.001

RBP, retinol-binding protein; β2M, β2-microglobulin.

Change in Renal Biomarkers at Week 48

All differences between treatments statistically significant (p <0.001)

28

F/TAF

F/TDF

Albumin Protein β2M RBP

Urine Protein to Creatinine Ratio

Med

ian

% c

hang

e

B L 24 48

0

2

4

B L 24 48

0

2

4

Change in Bone Mineral Density through Week 48

29

≥ 3% BMD increase at Week 48

F/TAF 30% p<0.001

17% p=0.003

F/TDF 14% 9%

321 310 300

320 310 306

321 309 300

317 305 303

F/TAF, n

F/TDF, n

Mea

n %

cha

nge

(95%

CI)

Spine

1.5

-0.2

1.1

-0.2

Weeks Weeks

p <0.001

Hip

p <0.001

0

1

2

3

4

Fasting Lipid Results

Total Cholesterol

LDL HDL Triglycerides TC: HDL Ratio

Med

ian

valu

e (m

g/dL

)

p <0.001 p <0.001

p=0.12

p=0.004

p=0.069

200

187 183 182

128

112 115 110

52 49

50 50

124

118 112 112

3.7

3.6 3.6 3.6

F/TAF F/TDF

Patients initiating lipid-lowering agents 4% 4%

F/TAF F/TDF

Week 48

Baseline

30

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

Copyright © 2016 Merck & Co. Inc. All Rights Reserved.

Doravirine 100 mg QD vs Efavirenz +TDF/FTC in ART-‐Naive HIV+ Pa/ents:

Week 48 Results Jose M. Gatell1, Francois Raffi2, Andreas PleEenberg3, Don Smith4,

Joaquin PorNlla5, ChrisNan Hoffmann6, Keikawus Arasteh7, Melanie Thompson8, Xia Xu9, Hedy Teppler9 for the 1439-‐007 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

CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007

33



Background o  Commonly used non-‐nucleoside reverse transcriptase inhibitors (NNRTIs) are associated

with subopNmal efficacy and/or safety profiles •  Efavirenz – frequent CNS adverse events1; no longer recommended as first-‐line therapy

for HIV infecNon in mulNple guidelines1-‐3 •  Rilpivirine – treatment-‐naïve indicaNon only for RNA ≤100,000 copies/mL in US1 and

EU2

o  Doravirine (DOR, aka MK-‐1439) is a novel NNRTI •  High in vitro potency vs broad panel of isolates including common NNRTI-‐resistant

variants4

•  Primary metabolism by CYP3A4; not an inducer or inhibitor5

•  Once daily dosing (without regard to food) •  No interacNons expected with proton pump inhibitors

o  In Part 1 of this Phase 2 study (MK-‐1439 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 246 and week 487 •  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


34



Protocol 007 Study Schema Part 1 Dose Ranging Phase

(N=210) Part 1

Extension Phase DOR 25 mg

DOR 50 mg

DOR 100 mg (n=42) DOR 100 mg

DOR 200 mg

EFV 600 mg (n=43) Con/nue EFV

Part 2: Addi/onal Pa/ents, DOR Selected Dose vs EFV

(N=132) DOR 100 mg (n=66)

EFV 600 mg (n=66)

Week 48 Week 96

Week 48 Week 96

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.

35



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

36



Sta/s/cal Analysis (cont.) 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

37



Pa/ent Status, Week 48

DOR 100 mg EFV 600 mg

PaNents randomized, n 108 109 PaNents treated, n 108 108 PaNents disconNnued, % 12.0 14.7 Adverse event 2.8 5.5 Lack of efficacy 0.0 0.9 Lost to follow-‐up 2.8 3.7 Non-‐compliance with study drug† 4.6 0.0 Physician decision 0.0 0.9 Withdrawal by subject 1.9 3.7 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.

38



Baseline Pa/ent Characteris/cs

DOR 100 mg EFV 600 mg

Treated paNents N=108 N=108 % Male 91.7 93.5 Age (years), median (range) 35 (19 – 67) 34 (20 – 57) % White 79.6 79.6 % with AIDS 3.7 6.5 HIV RNA (log10 c/mL), median (range) 4.6 (2.6 – 6.5) 4.6 (3.0 – 6.7) % with HIV RNA >100,000 c/mL, at screening 35.2 37.0 CD4 Count (cells/µL), median (range) 402 (92 – 1110) 430 (118 – 1121) % with CD4 count ≤ 200 cells/µL 6.5 9.3 % with Clade B viral subtype 69.4 79.6 All paNents also received TDF/FTC.

39



Summary of Week 48 Outcomes (NC=F Approach)* DOR 100 mg (N=108)

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)

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.

40



HIV RNA <40 copies/mL (NC=F Approach)

3,7

15,7

27,8

42,1

63,0

72,9 77,8 77,8

6,5 12,0

26,9

47,2

57,5

73,1

81,5 78,7

0

10

20

30

40

50

60

70

80

90

100

0 4 8 12 16 20 24 28 32 36 40 44 48

% of P

a/en

ts (9

5% CI)

Treatment Week

DOR 100 mg +TDF/FTC

EFV 600 mg +TDF/FTC

Week 48 n/N (%)

DOR 84/108 (77.8)

EFV 85/108 (78.7)

Difference (95% CI): -‐1.1 (-‐12.2, 10.0)

41



HIV RNA <200 copies/mL (NC=F Approach)

21,3

33,3

65,7

79,4

83,3 89,7 89,8

85,2

27,8

39,8

65,7

75,0 83,0

87,0 86,1 84,3

0

10

20

30

40

50

60

70

80

90

100

0 4 8 12 16 20 24 28 32 36 40 44 48

% of p

a/en

ts (9

5% CI)

Treatment Week

DOR 100 mg +TDF/FTC

EFV 600 mg +TDF/FTC

Week 48: n/N (%)

DOR 92/108 (85.2)

EFV 91/108 (84.3)

Difference (95% CI): 0.9 ( -‐8.9, 10.8)

42



Mean Change in CD4 T-‐Cell Count (OF Approach)

53

77

111 129 121

152 159

192

60

96 102

133 124 146

186 195

0

50

100

150

200

0 4 8 12 16 20 24 28 32 36 40 44 48

Cells/µL (95%

CI)

Treatment Week

DOR 100 mg + TDF/FTC

EFV 600 mg +TDF/FTC

43



86,6 89,6 74,3

91,4 87,1 91,9 83,8 91,9

0

20

40

60

80

100

% <40 c/mL % <200 c/mL % <40 c/mL % <200 c/mL

DOR 100 mg +TDF/FTC EFV 600 mg +TDF/FTC

25 60/67 57/62 11 26/35 31/37

32/35 34/37

≤100,000 c/mL >100,000 c/mL

Virologic Response by Screening RNA Week 48 (OF Approach*)

n/N: 58/67 54/62

*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.

44



Clinical Adverse Events (%)

DOR 100 mg (N=108)

EFV 600 mg (N=108)

Difference [DOR – EFV] (95% CI)

One or more adverse events (AE) 87.0 88.9 -‐1.9 (-‐10.9, 7.1) Serious AE† 6.5 8.3 -‐1.9 (-‐9.5, 5.6) Death 0 0 DisconNnued due to AE 2.8 5.6 -‐2.8 (-‐9.2, 3.0) Drug-‐related‡ AE 31.5 56.5 -‐25.0 (-‐37.3, -‐11.8)

Diarrhea 0.9 6.5 -‐-‐-‐ Nausea 7.4 5.6 -‐-‐-‐ Dizziness 6.5 25.9 -‐-‐-‐ Headache 2.8 5.6 -‐-‐-‐ Abnormal dreams 5.6 14.8 -‐-‐-‐ Insomnia 6.5 2.8 -‐-‐-‐ Nightmares 5.6 8.3 -‐-‐-‐ Sleep disorder 4.6 6.5 -‐-‐-‐

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).

45 Copyright © 2016 Merck & Co. Inc. All Rights Reserved.

CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007 Common† Laboratory Abnormali/es (%)

Laboratory Test

Grade (criteria)

DOR 100 mg (N=108)

EFV 600 mg (N=108)

Difference [DOR – EFV] (95% CI)

Absolute neutrophil count 1 (1.0-‐1.3 103/µL) 7.5 5.6 1.9 (-‐5.1, 9.3)

LDL-‐cholesterol, fasNng 1 (130 – 159 mg/dL) 2.9 15.5 -‐12.6 (-‐21.2, -‐5.1)

2 (160-‐189 mg/dL) 2.0 3.9 -‐1.9 (-‐7.9, 3.5)

Total cholesterol, fasNng 1 (200 – 239 mg/dL) 5.8 20.2 -‐14.4 (-‐23.9, -‐5.6)

2 (240 – 300 mg/dL) 0 6.7 -‐6.7 (-‐13.3, -‐3.0)

Glucose, fasNng 1 (110 – 125 mg/dL) 9.6 11.0 -‐1.4 (-‐10.8, 7.7)

Bilirubin, total 1 (1.1 – 1.5 x ULN) 5.6 0.9 4.7 (-‐0.1, 10.9)

Aspartate aminotransferase 1 (1.25 ‒ 2.5 x ULN) 9.3 12.0 -‐2.7 (-‐11.4, 5.9)

2 (2.6 – 5.0 x ULN) 0.9 3.7 -‐2.8 (-‐8.3, 1.8)

Alanine aminotransferase 1 (1.25 – 2.5 x ULN) 7.5 12.0 -‐4.6 (-‐13.0, 3.6)

Alkaline phosphatase 1 (1.25 – 2.5 x ULN) 1.9 6.5 -‐4.6 (-‐11.2, 0.9)

Lipase 1 (1.1 – 1.5 x ULN) 11.2 9.3 2.0 (-‐6.5, 10.5) 2 (1.6 – 3.0 x ULN) 4.7 7.4 -‐2.7 (-‐9.9, 4.1) 3 (3.1 – 5.0 x ULN) 3.7 4.6 -‐0.9 (-‐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.

46 Copyright © 2016 Merck & Co. Inc. All Rights Reserved.


All Laboratory Abnormali/es Grade ≥ 2 (%) Laboratory Test

Grade (criteria)

DOR 100 mg (N=108)

EFV 600 mg (N=108)

Absolute neutrophil count 2 (0.75-‐0.999 x 103/µL) 1.9 1.9

4 (<0.50 x 103/µL) 0 0.9

Platelet count 2 (50 – 99.9 x 103/µL) 0.9 0.9

LDL-‐cholesterol, fasNng 2 (160 – 189 mg/dL) 2.0 3.9 3 (≥190 mg/dL) 0 1.9 Total cholesterol, fasNng 2 (240 – 300 mg/dL) 0 6.7 3 (>300 mg/dL) 0 1.9 Triglycerides, fasNng 2 (500 – 750 mg/dL) 0 1.9

Glucose, fasNng 2 (126 – 250 mg/dL) 3.2 1.1

Aspartate aminotransferase 2 (2.6 – 5.0 x ULN) 0.9 3.7 3 (5.1 – 10.0 x ULN) 0.9 0 4 (>10.0 x ULN) 0 0.9

Alanine aminotransferase 2 (2.6 – 5.0 x ULN) 0.9 0 3 (5.1 – 10.0 x ULN) 0.9 1.9

Lipase 2 (1.6–3.0 x ULN) 4.7 7.4 3 (3.1 – 5.0 x ULN) 3.7 4.6 4 (>5.0 x ULN) 0.9 1.9

All paNents also received TDF/FTC.

47



Conclusions 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.

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA

1ViiV Healthcare, Research Triangle Park, NC; 2Hospital La Paz, Madrid, Spain; 3ICH Hamburg, Germany; 4University of North Carolina, Chapel Hill, NC; 5Hôpital Bichat Claude Bernard, Paris, France; 6GlaxoSmithKiline, Mississauga, Ontario, Canada; 7Janssen Research and Development, Beerse, Belgium

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. Spreen1


•  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-1

Background

Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.

Margolis et al. Lancet Infect Dis. 2015;15:1145-1155. BL, baseline; CAB, cabotegravir; CI, confidence interval; EFV, efavirenz; LA, long-acting; NNRTI, non-nucleoside reverse transcriptase inhibitor; RPV, rilpivirine; t1/2, half-life.

0

20

40

60

80

100

CAB 10 mg (n=60) CAB 30 mg (n=60)CAB 60 mg (n=61) EFV 600 mg (n=62)

12 16 8 4 BL 2 242628 32 36 40 48 60 72 84 96

Prop

ortio

n, %

(95%

CI)


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

LATTE-2 Objectives



Inclusion criteria •  >18 years old •  Naive to antiretroviral therapy •  CD4+ >200 cells/mm3

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

LATTE-2 Study Design


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. aSubjects who withdrew after at least 1 IM dose entered the long-term follow-up period. bSubjects can elect to enter LA Extension Phase beyond Week 96.

Induction period

CAB 30 mg + ABC/3TC for 20 weeks

(N=309)

Add RPV

4 weeks


LATTE-2 Study Design


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. aSubjects who withdrew after at least 1 IM dose entered the long-term follow-up period. bSubjects can elect to enter LA Extension Phase beyond Week 96.

Induction period

Week 32 Primary analysis Dosing regimen

selection

Day 1 Randomization

2:2:1

Week 48 Analysis

Dosing regimen confirmation

CAB 400 mg IM + RPV 600 mg IM Q4W (n=115)

CAB 600 mg IM + RPV 900 mg IM Q8W (n=115)

Week 96b

CAB loading dose at Day 1

CAB loading doses at Day 1 and Week 4

CAB 30 mg + ABC/3TC for

20 weeks

CAB 30 mg + ABC/3TC PO QD (n=56)

Maintenance perioda


Baseline Characteristics: ITT-ME Population


CDC, Centers for Disease Control and Prevention; ITT-ME, intent-to-treat maintenance exposed.

Q8W IM (n=115)

Q4W IM (n=115)

Oral CAB (n=56)

Total (N=286)

Median age, years 35.0 36.0 35.0 35.0 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, log10 c/mL 4.419 4.455 4.289 4.393

≥100,000, n (%) 16 (14) 28 (24) 7 (12) 51 (18) Median CD4+, cells/mm3 449.0 499.0 517.5 489.0


LATTE-2 Week 32 Results: HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)


Study visit BL W-16 W-12 W-8 W-4 D1 W4 W8 W12 W16 W20 W24 W28 W32

Snapshot success: D1 Q4W 99%

Q8W 95%

Oral CAB 98%

100

80

60

40

20

0

Prop

ortio

n of

pat

ient

s w

ith

viro

logi

cal s

uppr

essi

on, %


LATTE-2 Week 32 Primary Endpoint: HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)


*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).

Both Q8W and Q4W comparable to oral CAB at Week 32

Virologic outcomes Treatment differences (95% CI)

Oral

-4.8 12.2

Q8W

-5.8 11.5

Q4W

* * IM


Snapshot Outcomes: HIV-1 RNA <50 c/mL at Week 32 (ITT-ME)


aWeek 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. bQ4W: hepatitis C, rash, depression, and psychosis; oral CAB: hepatitis C. cQ8W: ISR; Q4W: pregnancy and prohibited medication; oral CAB: lost to follow-up, relocation.

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/mLa 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 deathb 0 4 (3%) 1 (2%) Discontinued for other reasonsc 1 (<1%) 2 (2%) 2 (4%)


• No INI, NNRTI, or NRTI mutations were detected through Induction or Maintenance

Protocol-Defined Virologic Failure (PDVF): Genotype


PDVF: <1.0 log10 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 log10 c/mL increase from nadir HIV-1 RNA value ≥200 c/mL.

Maintenance period Q8W IM (n=115)

Q4W IM (n=115)

Oral CAB (n=56)

Subjects with PDVFa 1b (1%) 0 1 (2%) INI-r mutations 0 0 0

NRTI-r mutations 0 0 0 NNRTI-r mutations 0 0 0


Adverse Events and Labs— Maintenance Period


aQ8W: influenza-like illness, chills and pain, and lipase; Q4W: influenza-like illness, rash, depression, and psychosis. bNone drug related; one death (epilepsy) evaluated as not likely related to study drug. cQ8W: 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.

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 AEsa, excluding ISRs

3 (3) 4 (3) 0 7 (3)

Serious AEsb 7 (6) 6 (5) 3 (5) 13 (6) AEs leading to withdrawalc 2 (2) 6 (5) 1 (2) 8 (3) Grade 3 and 4 labsd 17 (15) 20 (17) 8 (14) 37 (16)


• 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)

Adverse Events and Labs— Maintenance Period


aRepresents percent of subjects with a Week 32 visit (n=220).

Q8W IM (n=115)

Q4W IM (n=115)

IM subtotal (N=230)

Number of injections 1623 2663 4286 Number of ISRs (events/injection) 1054 (0.65) 1228 (0.46) 2282 (0.53) Grades

Grade 1 839 (80%) 1021 (83%) 1860 (82%) Grade 2 202 (19%) 197 (16%) 399 (17%) Grade 3 12 (1%) 10 (<1%) 22 (<1%) Grade 4 0 0 0

Duration, days ≤7 943 (89%) 1121 (91%) 2064 (90%) Median 3.0 3.0 3.0


Patient-Reported Outcomes at Week 32: Maintenance Treatment Compared With Oral Induction Treatmenta


Note: based on observed case dataset of subjects who completed Week 32 questionnaires. aHIV Treatment Satisfaction Questionnaire change version (HIVTSQc).

How satisfied are you with your current treatment?

How satisfied would you be to continue with your present form of treatment?

3% 3% 2%

1% 1% 1%


•  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

Conclusions


Documents

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