Post on 10-Apr-2018
Nuevos fármacos an/retrovirales
Pere Domingo Malal/es Infeccioses
Hospitals Universitaris Arnau de Vilanova & Santa María IRB Lleida
Universitat de Lleida pdomingo@gss.scs.es
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
DeJesus E et al. #472
AI438011: baseline characteris/cs
DeJesus E et al. #472
AI438011: Subject disposi/on-‐96 w
DeJesus E et al. #472
AI438011: virologic efficacy
DeJesus E et al. #472
AI438011: Efficacy 96 w: observed analysis
DeJesus E et al. #472
AI438011: mean change CD4 cell count
DeJesus E et al. #472
AI438011: efficacy by baseline viral load
DeJesus E et al. #472
AI438011: safety summary and G3-‐4 AEs
DeJesus E et al. #472
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
34
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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.
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
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
CROI 2016 Abstract #470 Boston, MA MK-‐1439 P007
Copyright © 2016 Merck & Co. Inc. All Rights Reserved.
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
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
• 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)
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
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
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
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
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
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
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
LATTE-2 Study Design
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
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
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
Baseline Characteristics: ITT-ME Population
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
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
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
LATTE-2 Week 32 Results: HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
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, %
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)
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
*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
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
Snapshot Outcomes: HIV-1 RNA <50 c/mL at Week 32 (ITT-ME)
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
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%)
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
• No INI, NNRTI, or NRTI mutations were detected through Induction or Maintenance
Protocol-Defined Virologic Failure (PDVF): Genotype
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
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
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
Adverse Events and Labs— Maintenance Period
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
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)
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
• 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
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
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
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
Patient-Reported Outcomes at Week 32: Maintenance Treatment Compared With Oral Induction Treatmenta
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.
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%
23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA
• 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
Margolis et al. CROI 2016; Boston, MA. Abstract 31LB.