DRUGS IN PIPELINE
Pr JC YOMBI
UCL-AIDS REFERENCE CENTRE
BREACH Sept 27, 2015
N(t)RTI
The Development of TAF
TAF Delivers the High Potency of TDF While Minimizing OffTarget Kidney and Bone Side Effects
GI TRACT
PLASMA
RENAL
TUBULAR
CELL
LYMPHOCYTE
TDF
TFV
(tenofovir
disoproxil
fumarate)
300 mg
TFV
TAF
(tenofovir
alafenamide)
HIV
91% lower
plasma TFV
25 mg
RENAL
TUBULAR
CELL
1. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. 3. Babusis D, et al. Mol Pharm 2013;10(2):459-66. 4. Ruane P, et al. J
Acquir Immune Defic Syndr 2013; 63:449-5. 5. Sax P, et al. JAIDS 2014. 2014 Sep 1;67(1):52-8. 6. Sax P, et al. Lancet 2015. Jun 27;385(9987):2606-15
FTC/TAF
TAF combinations
• EVG/COBI/FTC/TAF (Genvoya®):
• FTC/TAF and RPV/FTC/TAF:
• TAF treatment HBV infection : Phase III
• DRV/COBI/FTC/TAF: Johnson&Johnson
EMA: European Medicines Agency approval
DARU/COBI/FTC/TAF
• AMBRE: Double BLIND 1:1
• Daru/cobi/TAF/FTC VS Daru/cobi/TDF/FTC
NAÏF, CV≥1000 copies CD4>50 GFR≥50ml/min
• EMERALD: Open label 2:1
-Daru/cobi/TAF/FTC VS PI/r – TDF/FTC
Indetectable, CV<50copies, GFR≥50ml/min sous
PI/r – TDF/FTC
TAF Program Expected Approvals –
and EU
Europe
E/C/F/TAF
F/TAF
5th Nov 2015
23th Nov 2015
Q2-2016
R/F/TAF
Q2/3-2016
D/C/F/TAF (Johnson & Johnson)
2017–2018
TAF single agent (for HBV)
2017
15
NNRTI
DORAVIRINE
P007: DOR + TDF/FTC vs EFV + TDF/FTC in
ART-Naive Pts Infected With HIV
• Double-blind, randomized, 2-part study
Pts were stratified by HIV-1 RNA
≤ or > 100,000 copies/mL
Wk 96§
ART-naive, HIV-positive pts
with HIV-1 RNA ≥ 1000
copies/mL and CD4+ cell
count ≥ 100 cells/mm3
(N = 216*)
Doravirine† + TDF/FTC
(n = 108)
Efavirenz‡ + TDF/FTC*
(n = 108)
*Combined pts from 2 study parts: Part 1 was a dose-finding study (n = 84) and Part 2 enrolled additional
pts with the current dosing schema (n = 132).
†Doravirine dosed at 100 mg QD.
‡Efavirenz dosed at 600 mg QD.
§Wk 24 results reported.
Gatell JM, et al. IAS 2015. Abstract TUAB0104.
P007: Key Results
DOR +
TDF/FTC
(N = 108)
EFV +
TDF/FTC
(N = 108)
One or more AE
75.9
84.3
57.5
Serious AE
0.9
4.6
72.2
73.1
0.9
5.6
Baseline HIV-1 RNA
≤ 100,000 c/mL (n/N)†
83.3
(55/66)
85.7
(54/63)
Discontinued due to
AE
Drug-related AE
27.8
55.6
Baseline HIV-1 RNA
> 100,000 c/mL (n/N)†
60.5
(23/38)
65.8
(25/38)
Pts with ≥ 1 CNS
event
26.9
46.3
DOR +
TDF/FTC
(n = 108)
EFV +
TDF/FTC
(n = 108)
Wk 8
27.8
26.9
Wk 16
63.6
Wk 24
Pts With HIV-1 RNA
< 40 c/mL, %*
Event, %
*NC = F approach.
†Observed failure approach.
•
Most virologic failure was due to low-level viremia
–
–
•
Virologic failure, HIV-1 RNA ≥ 40 copies/mL: DOR, 15.7%; EFV, 10.2%
Virologic failure, HIV-1 RNA ≥ 200 copies/mL: DOR, 3.7%; EFV, 0.9%
Resistance testing was performed in 1 pt in each arm who failed treatment; no NRTI or
NNRTI mutations detected
Gatell JM, et al. IAS 2015. Abstract TUAB0104.
DORAVIRINE
• MERCK 021: Placebo Dble blind Ratio 1:1
• Dorarivine: MK1439 100mg + Lamivudine 300mg
+ TDF 300mg OU Atripla Naïfs CV≥1000
GFR≥50ml/min
• MERCK 024: Open Label 2:1
Doravirine OU PI/r - 2 NRTI CV<40copies since 6
months and 2X GFR≥50ml/min
First or second treatment PI/r- NRTI (2)
INHIBITORS OF MATURATION
HIV-1 Life Cycle
Maturation
Fusion
Release
Assembly/
cleavage
gp120
Chemokine
co-receptor
Attachment
Accessory viral
proteins
Reverse
transcription
Budding
CD4
Translation
Viral DNA
Human genomic DNA
Integration
(strand transfer)
Transcription
Gag
Gag Pol
Lataillade et al. CROI 2015, Abstract 114LB.
Maturation Inhibitors (MIs):
BMS-955176 Mode of Action
Mature virus
Maturation
Protease
Untreated
Immature virus
Treated with
BMS-955176
BMS-955176
Gag
polyprotein
•
Protease
Maturation
inhibitor
BMS-955176 inhibits the last protease cleavage event between
capsid (CA) protein p24 and spacer peptide 1 (SP1) in Gag,
resulting in the release of immature, non-infectious virions
Adamson et al. Expert Opin Ther Targets 2009; 13:895–908;
Sundquist et al. Cold Spring Harb Perspect Med 2012; 2:7.
Lataillade et al. CROI 2015, Abstract 114LB.
BMS-955176: Profile of a Second‐Generation MI
•
BMS-955176 is a second-generation MI that binds reversibly and with greater affinity to HIV-1
Gag than a first-generation MI (bevirimat; BVM)1,2
– Potent in vitro activity towards HIV-1, even in the presence of naturally occurring Gag
polymorphisms associated with reduced BVM susceptibility2
– In vitro activity against PI-, NRTI-, NNRTI-, and INSTI-resistant isolates2
– In a 10-day BMS-955176 monotherapy proof-of-concept study:
• Maximum median declines in HIV-1 RNA of >1 log10 c/mL (at doses 20–120 mg QD) were achieved that
plateaued at ~1.64 log10 c/mL at doses between 40 mg and 120 mg QD3
• Similar antiviral activity toward both wild-type HIV-1 and HIV-1 with Gag polymorphisms not responsive to
BVM3
• BMS-955176 was generally well tolerated3
– Two drug combination studies in vitro demonstrated that BMS-955176 + ATV had an additive
effect. Due to the proximity of their sites of inhibition in the virus life cycle and the potential for
synergy, we assessed the antiviral activity and safety of BMS-955176 with ATV±RTV
1. Lin et al. CROI 2015; Abstract 42; 2. Nowicka-Sans et al. IAS 2015; Poster TUPEA078; 3. Lataillade et al. CROI 2015; Abstract 114LB.
ATV, atazanavir; INSTI, integrase strand transfer inhibitors; PI, protease inhibitor; RTV, ritonavir
AI468002: Part B Study Design*
TDF/FTC
300/200 mg
+ ATV 300 mg
+ RTV 100 mg†
BMS-955176
40 mg
+ ATV 300 mg
+ RTV 100 mg
BMS-955176
40 mg
+ ATV 400 mg
Days 1–28
Dosing period
Day 30
Furloughed
Days 35‡
Outpatient visits
Day 42
Discharge
BMS-955176
80 mg
+ ATV 400 mg
Inpatient days: Day -1 to Day 30
Objectives:
Key inclusion criteria:
•
Change in plasma HIV-1 RNA levels from baseline to
Day 28
•
•
•
Safety and tolerability of BMS-955176 during
combination therapy
•
•
HIV-1 subtype B-infected subjects
Treatment-naïve (<1 week of antiretroviral treatment) or experienced (PI and MI naïve) subjects
Plasma HIV-1 RNA ≥5,000 c/mL
CD4+ T-cell count ≥200 cells/µL
* For all dose groups: BMS-955176 (n=8) and standard of care (n=4). † Standard-of-care control arm. TDF/FTC given as a fixed-dose combination.
‡ or per investigator’s discretion. All doses were QD.
ATV, atazanavir; FTC, emtricitabine; MI, maturation inhibitor; PI, protease inhibitor; RTV, ritonavir; TDF, tenofovir disoproxil fumarate.
Conclusions
• BMS-955176 is a potent, once-daily, second-generation MI
• BMS-955176 80 mg + ATV and BMS-955176 40 mg + ATV + RTV demonstrated
similar antiviral activity (~2.2 log10 c/mL median decline) compared to the
standard of care control over the 28-day treatment period
• BMS-955176 was generally well tolerated
•
There were no SAEs or AEs leading to discontinuation
•
BMS-955176 + unboosted ATV was associated with lower median changes from baseline
in bilirubin levels compared to the arms with boosted ATV
• A Phase IIb study investigating BMS-955176 + ATV in a booster-sparing and
nucleot(s)ide-sparing regimen in treatment-experienced patients initiated July
2015
ATTACHMENT INHIBITOR
AI438011: Efficacy of Fostemsavir + RAL + TDF in
Treatment-Experienced Pts
• Randomized, active-controlled, phase IIb study, blinded to dose
– Fostemsavir (BMS-663068): HIV-1 attachment inhibitor prodrug,
metabolized to temsavir attachment inhibitor; proposed MOA is by
binding gp120 to prevent viral attachment and host CD4+ cell entry;
active against R5, X4, and dual tropic HIV-1
Wk 24: 1̊ endpoint
Wk 48
Fostemsavir 400 mg BID + RAL + TDF
(n = 50)
HIV-infected pts with exposure
to ≥ 1 ARV for ≥ 1 wk,
HIV-1 RNA ≥ 1000 c/mL,
CD4+ ≥ 50 cells/mm3, virus
susceptible to RAL, TDF, ATV,
and temsavir IC50 < 100 nM
(N = 251)
Fostemsavir 800 mg BID + RAL + TDF
(n = 49)
Fostemsavir 600 mg QD + RAL + TDF
(n = 51)
Fostemsavir 1200 mg QD + RAL + TDF
(n = 50)
ATV/RTV 300/100 mg QD + RAL + TDF
(n = 51)
Feinberg J, et al. IDWeek 2015. Abstract 1075.
Wk 96
HIV-1 RNA < 50 c/mL, % (95% CI)
AI438011 : Virologic Suppression
With Fostemsavir + RAL + TDF at
Wk 48
Wk 48 HIV-1 RNA
< 50 c/mL (%)
100
80
60
400 mg BID
91
800 mg BID
73
600 mg QD
69
1200 mg QD
79
ATV/RTV
88
40
20
0
0
4
8
12
16
20
24
32
40
48
Wk
• No significant differences in virologic efficacy through Wk 48
regardless of race, sex, age, baseline HIV-1 RNA, or baseline CD4+
cell count in subgroup analyses
Feinberg J, et al. IDWeek 2015. Abstract 1075. Reproduced with permission.
INTEGRASE INHIBITORS
• CABOTEGRAVIR orale or Long Acting
• GS-9883
LATTE: NRTI-Sparing Maintenance
With Cabotegravir + Rilpivirine
Induction Phase
Maintenance Phase (NRTI Sparing)
VL < 50 c/mL by Snapshot
Algorithm (%)
100
80
60
Induction Regimen
40
Maintenance Regimen
CAB 10 mg + 2 NRTIs* CAB + RPV (n = 60)
CAB 30 mg + 2 NRTIs* CAB + RPV (n = 60)†
CAB 60 mg + 2 NRTIs* CAB + RPV (n = 61)
EFV 600 mg + 2 NRTIs* (n = 62)
20
0
BL 4

84%
75%
68%
63%
12
24 28
36
48
Wks
72
6 pts in CAB arms with PDVF at Wk 96; 4 additional pts since Wk 48
*TDF/FTC or ABC/3TC.
†Cabotegravir 30 mg selected for future development.
Margolis D, et al. CROI 2015. Abstract 554LB.
96
CABOTEGRAVIR LA +RILPIVIRINE LA
OTHERS FORMULATIONS
PROJECTION
QUESTIONS AND REMARKS ??