Transcript PPT - IAS-USA

Future Directions: Investigational
Approaches to Antiretroviral Therapy
Joseph J. Eron, Jr, MD
Professor of Medicine and Epidemiology
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Washington, DC: August 24, 2016
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Future Directions:
Investigational Approaches to
Antiretroviral Therapy
Joseph J. Eron, Jr, MD
Professor of Medicine and Epidemiology
UNC Chapel Hill
August 2016
Financial Relationships With Commercial Entities
 Dr Eron has received research grants awarded
to his institution from AbbVie, Bristol-Myers
Squibb, Merck & Co, Inc, and ViiV Healthcare.
He has served as a consultant to AbbVie,
Bristol-Myers Squibb, Gilead Sciences, Inc,
GlaxoSmithKline, Janssen Therapeutics, and
ViiV Healthcare. (Updated 08/16/16)
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Learning Objectives
After attending this presentation, participants will
be able to:
 Describe why new antiretroviral approaches
are needed
 List mechanisms of action of investigational
antiretroviral drugs
 Describe how these new drugs and formulations
might be incorporated into clinical practice
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Goals of Antiretroviral Therapy
• Maintain or restore the health of people living with HIV-1 (PLWHIV)
through suppression of HIV-1 replication
• Minimize or eliminate short and long-term adverse effects of the
therapy
• Have therapies that are accessible to all PLWHIV
• Prevent transmission of HIV-1 to others via any route of exposure
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Published July 20, 2015
at NEJM.org
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Why Do We Need
New Antiretroviral Agents?
• A 25 year old started on therapy today may need treatment for 6
decades! An infected infant – 8 decades
• Therapy must be incredibly safe, maximally tolerated and include a
range of choices
–
–
–
–
–
Renal, cardiovascular, liver and bone toxicity
Safety of ART in pregnancy
Therapy options for infants and children
Adherence, life chaos, treatment fatigue, tolerability
Aging and drug interactions (e.g. CYP 3A4 inhibition)
• TREATMENT GAP -Not all PLWHIV in care are treated
– Stigma, substance use, mental health, access to clinics, transportation, clinic capacity,
country stocks, availability of 3rd line therapy
• HIV-1 resistance will always be with us
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Continued Improvement in Currently Available ART Classes
• Doravirine (NNRTI)
– Fewer side effects (?) and no food or PPI requirements
– Phase III in naïve patients
• Raltegravir
– Once daily
• Bictegravir (GS-9883; integrase inhibitor)
– Single tablet, unboosted, TAF-based
– Phase III in naïve and switch
• Integrase-based two drug therapy
– Phase III in switch (DTG or CTG plus RPV)
– Phase III in naïve in development (DTG plus 3TC)
• MRK-8591 (eFdA – NRTI)
– Long acting oral and injectable (?)
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New NNRTI
Doravirine Versus Efavirenz in ART-Naïve Patients
• Phase 2b study (n=216)
HIV RNA <40 Copies/mL (Week 48)
– HIV RNA >1000 copies/mL
100
– CD4 >100 cells/mm3
80
• Randomized arms
• Non-success at week 48
– Doravirine arm (n=18)
– Efavirenz arm (n=14)
Patients (%)
– DOR 100 mg or EFV 600 mg + FTC/TDF
• Discontinuations due to AE
– Doravirine arm: 3%
– Efavirenz arm: 6%
Doravirine
Efavirenz
87% 87%
78% 79%
84%
74%
60
40
20
0
Overall
<100K
>100K
(NC=F)
(OF)
(OF)
Baseline HIV RNA (copies/mL)
Gatell J-M, et al. 23rd CROI. Boston, 2016. Abstract 470.
NC=F: non-completer=failure; OF: observed failure
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New NNRTI
DOR vs. EFV: Clinical Adverse Events
DOR +
TDF/FTC
(n = 108)
EFV + TDF/FTC
(n = 108)
≥ 1 AE
87.0
88.9
Serious AEs
6.5
8.3
Discontinued for AEs
2.8
5.6
Drug-related AEs*
31.5
56.5
 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
Clinical AEs,[1] %
Gatell JM, et al. CROI 2016. Abstract 470.
*Specific AEs occurring in ≥ 5% of pts included.
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Raltegravir once daily
In treatment naïve patients
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New Integrase Inhibitor
Bictegravir – 10 d Monotherapy
4 participants in each group
100 mg daily dose:
• Half life ~ 20 hours
• paIQ = 25
• Peak VL decline = 2.9 log10
• Single tablet combination with FTC and TAF
• Phase III studies in naïve patients vs. DTG plus TAF/FTC or DTG/ABC/3TC fully enrolled
• Switch study from DRV/r or ATV/r also fully enrolled
Gallant et al ASM Microbe 2016
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InSTI based 2-drug therapy
Dolutegravir plus 3TC 48 week data: PADDLE Study
PDVF = HIV RNA 99 (wk 36, 246 retest, 61 wk 48, then BDL)
ACTG single arm (N = 120) underway (HIV RNA up to 500,000)
Phase III comparative trial in development
Cahn et al WAC Durban 2016
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Maintaining therapy for Life in all PLWHIV
• Adherence
– Hard to reach populations, substance use, depression, children,
adolescents …….
• Life Chaos
– Travel, dislocation for work or safety, surgery, drug interactions, pill
fatigue, patient preference ……
Long acting antiretroviral Therapy!
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Cabotegravir LA and Rilpivirine LA
Nanosuspensions
•
•
•
Drug nanocrystal suspended in liquid = nanosuspension
Nanomilled to increase surface area and drug dissolution rate
Allows ~100% drug loading vs. matrix approaches for lower inj. volumes
GSK744 200mg/mL
Component
Function
GSK1265744 (d50 ~200 nm)
Active
Mannitol
Tonicity agent
Surfactant System
Wetting/Stabilizer
Water for Injection
Solvent
TMC278 300mg/mL
R H. Müller, et al. European Journal of Pharmaceutics
and Biopharmaceutics 78 (2011) 1-9
Spreen et al. IAS 2013; Kuala Lumpur. Abstract WEAB0103.
Component
Function
TMC278 (d50 ~200 nm)
Active
Glucose
Tonicity agent
Surfactant System
Wetting/Stabilizer
Water for Injection
Solvent
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Margolis et al WAC Durban 2016
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Grobler et al CROI 2016
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Antiretroviral Therapy: The Next Generation?
• Implantable (and removable) combination antiretrovirals
• Vectored delivery of combinations of antibody-based
therapy or protein based therapy
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RESISTANT HIV-1 WILL ALWAYS BE
WITH US
Four to eight decades of therapy!
Previous exposure to suboptimal treatment in the developed world
Limited monitoring of virologic response world-wide
Transmitted drug resistance
Settings with Viral load Monitoring and
Multiple Treatment Options and Past Sub-optimal ART
Viremic patients with multi-drug resistant HIV-1
Patients currently suppressed on therapy
That have multi-drug resistant HIV-1
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New Agents for Resistant HIV-1
• Integrase Inhibitors
– Bictegravir
• N(t)RTI
• Maturation Inhibitors
– BMS 955176 (Phase II)
• Attachment inhibitors
– TAF (approved)
– EFdA (4'-ethynyl-2-fluoro-2'deoxyadenosine)(Phase I-II)
• NNRTI
– Doravirine (Phase III)
– BMS 663068 -> 626529 (Phase III)
• Monoclonal antibodies
– Broadly virus neutralizing
– Targeting entry receptors
• Ibalizumab
• PRO140
New Targets: e.g. LEDGF, combination entry, additional
maturation sites, HIV-1 RNA processing
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Integrase Inhibitor Activity Against Resistant Variants in Vitro
Kirsten White, Tomas Cihlar and Michael D. Miller
ASM Microbe 2016
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Activity of NRTI vs. Resistant variants
Fold change
Grobler et al ASM Microbe 2016
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Maturation Inhibitors (MIs):
BMS-955176 Mode of Action
Gag
polyprotein
Lataillade et al. CROI 2015, Abstract 114LB
Mature virus
Maturation Inhibitors (MIs):
BMS-955176 Mode of Action
Maturation
Protease
Untreated
Gag
polyprotein
Lataillade et al. CROI 2015, Abstract 114LB
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Mature virus
Maturation Inhibitors (MIs):
BMS-955176 Mode of Action
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
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BMS-955176: Median Change in HIV-1 RNA over Time
1
Dosing period
Median change in HIV-1 RNA from baseline,
log10 copies/mL
0.8
Placebo
0.6
0.4
5 mg
0.2
0
10 mg
-0.2
-0.4
20 mg
-0.6
-0.8
40 mg
-1
-1.2
80 mg
-1.4
-1.6
Study days
-1.8
1
•
2
3
4
5
6
7
8
9
120 mg
10 11 12 13 14//17//19// 24 25
Median change in HIV-1 RNA from baseline to Day 11 reached ~-1.4 log10 c/mL
See Abstract 425, 464
Lataillade et al. CROI 2015, Abstract 114LB
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HIV Entry Inhibitors
CD4
Binding
Coreceptor
Binding
CCR5 Inhibitors
maraviroc
gp41
BMS 663068
Virus-Cell
Fusion
enfuvirtide
gp120
V3 loop
CD4
Cell
Membrane
CCR5/CXCR4
(R5/X4)
Adapted from Moore JP, PNAS 2003;100:10598-10602.
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AI438011: BMS-663068 Attachment Inhibitor
Monotherapy Substudy: Mean Change in HIV-1 RNA
from Baseline*
*Error bars represent standard error of the mean.
Abstract 472
Lalezari et al CROI 2014 abstract 86
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Attachment Inhibitor – Clinical Development
BMS-663068
• HIV-1 variants have a range of susceptibility
– In Phase IIB study 6% had a BMS-626529 IC50 >100 nM at screening
• Phase IIB study in participants with limited resistance
– Attachment Inhibitor (over a range of doses) plus RAL and TDF had similar activity over
48 weeks to ATV/r plus RAL plus TDF
• Phase III study: highly ARV-experienced pts with MDR HIV
– If at least one fully active ARV then
• BMS-663068 600 mg or placebo BID for 8 days with no change in background
ART followed by BMS-663068 600 mg BID for 48 weeks or longer with
optimized background
– If no fully active ARV then
• BMS-663068 600 mg BID for 48 weeks or longer with optimized background
therapy
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BROADLY NEUTRALIZING
ANTIBODIES
Can they be harnessed as therapy?
Combined Antibodies:
Fraction of HIV-1 strains
neutralized
Improved Potency and Breadth
2 mAbs > 98% coverage
1.0
0.8
VRC07
PG9
PGT128
10E8
2 mAb Combinations
3 mAb Combinations
4 mAb Combination
0.6
0.4
0.2
0.0
0.001
0.01
0.1
1
IC50 cut-off (mg/ml)
10
100
Kong, Montefiori Korber et al.
J. Virol (2015)
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Antiretroviral Therapy: The Future
?????
Long Acting Injectable?
The Integrase Era
Single Tablet Regimens
Triple Drug Therapy
ZDV/3TC
ZDV monotherapy
HIV-1 discovered
1983
1987
1995
1996
2006
2012-13
2017
2020
Future Directions: Investigational
Approaches to Antiretroviral Therapy
Joseph J. Eron, Jr, MD
Professor of Medicine and Epidemiology
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Washington, DC: August 24, 2016