The University of North Carolina at Chapel Hill Chapel Hill North Carolina Future Directions Investigational Approaches to Antiretroviral Therapy Washington DC August 24 2016 Future Directions ID: 936021
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Slide1
Joseph J. Eron, Jr, MDProfessor of Medicine and EpidemiologyThe University of North Carolina at Chapel HillChapel Hill, North Carolina
Future Directions: Investigational Approaches to Antiretroviral Therapy
Washington, DC:
August
24,
2016
Slide2Future Directions: Investigational Approaches to Antiretroviral Therapy
Joseph J. Eron, Jr, MD
Professor
of Medicine and Epidemiology
UNC Chapel Hill
August 2016
Slide3Financial Relationships With Commercial EntitiesDr 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)
Slide4Learning ObjectivesAfter 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
Slide5Goals of Antiretroviral TherapyMaintain or restore the health of people living with HIV-1 (PLWHIV) through suppression of HIV-1 replicationMinimize or eliminate short and long-term adverse effects of the therapyHave therapies that are accessible to all PLWHIVPrevent transmission of HIV-1 to others via any route of exposure
Slide6Published July 20, 2015
at NEJM.org
Slide7Why Do We Need New Antiretroviral Agents?A 25 year old started on therapy today may need treatment for 6 decades! An infected infant – 8 decadesTherapy must be incredibly safe, maximally tolerated and include a range of choicesRenal, cardiovascular, liver and bone toxicity
Safety of ART in pregnancyTherapy options for infants and childrenAdherence, life chaos, treatment fatigue, tolerabilityAging 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 3
rd line therapyHIV-1 resistance will always be with us
Slide8Continued Improvement in Currently Available ART ClassesDoravirine (NNRTI)Fewer side effects (?) and no food or PPI requirementsPhase III in naïve patients RaltegravirOnce daily Bictegravir (GS-9883; integrase inhibitor)
Single tablet, unboosted, TAF-basedPhase III in naïve and switchIntegrase-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 (?)
Slide9New NNRTIDoravirine Versus Efavirenz in ART-Naïve PatientsPhase 2b study (n=216)HIV RNA >1000 copies/mLCD4
>100 cells/mm3Randomized armsDOR 100 mg or EFV 600 mg + FTC/TDF
Non-success at week 48
Doravirine arm (n=18)
Efavirenz arm (n=14)Discontinuations due to AEDoravirine arm: 3%Efavirenz arm: 6%
Overall
(NC=F)
HIV RNA <40 Copies/mL (Week 48)
Patients (%)
78%
Doravirine
Efavirenz
79%
87%
74%
<
100K
(OF)
Gatell J-M, et al. 23
rd
CROI. Boston, 2016. Abstract 470.
>100K
(OF)
Baseline HIV RNA (copies/mL)
87%
84%
NC=F: non-completer=failure; OF: observed failure
Slide10New NNRTIDOR vs. EFV: Clinical Adverse Events
Gatell JM, et al. CROI 2016. Abstract 470.
Clinical AEs,
[1]
%
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
*Specific AEs occurring in ≥ 5% of pts included.
Slide11Raltegravir once dailyIn treatment naïve patients
Slide12New Integrase InhibitorBictegravir – 10 d Monotherapy4 participants in each groupGallant et al ASM Microbe 2016
100 mg daily dose:
Half life ~ 20 hours
pa
IQ = 25Peak VL decline = 2.9 log10
Single tablet combination with FTC and TAFPhase III studies in naïve patients vs. DTG plus TAF/FTC or DTG/ABC/3TC fully enrolledSwitch study from DRV/r or ATV/r also fully enrolled
Slide13InSTI based 2-drug therapyDolutegravir plus 3TC 48 week data: PADDLE Study
Cahn et al WAC Durban 2016
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
Slide14Maintaining therapy for Life in all PLWHIVAdherenceHard to reach populations, substance use, depression, children, adolescents …….Life ChaosTravel, dislocation for work or safety, surgery, drug interactions, pill fatigue, patient preference ……Long acting antiretroviral Therapy!
Slide15Cabotegravir LA and Rilpivirine LA NanosuspensionsDrug nanocrystal suspended in liquid = nanosuspensionNanomilled to increase surface area and drug dissolution rate Allows ~100% drug loading vs. matrix approaches for lower inj. volumes
R H. Müller, et al. European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 1-9
Component
Function
GSK1265744 (d50 ~200 nm)
Active
Mannitol
Tonicity agent
Surfactant System
Wetting/Stabilizer
Water for Injection
Solvent
GSK744 200mg/mL
TMC278 300mg/mL
Component
Function
TMC278 (d50 ~200 nm)
Active
Glucose
Tonicity agent
Surfactant System
Wetting/Stabilizer
Water for Injection
Solvent
Spreen et al. IAS 2013; Kuala Lumpur. Abstract WEAB0103.
Slide16Margolis et al WAC Durban 2016
Slide17Slide18Grobler et al CROI 2016
Slide19Antiretroviral Therapy: The Next Generation? Implantable (and removable) combination antiretroviralsVectored delivery of combinations of antibody-based therapy or protein based therapy
Slide20Resistant HIV-1 will always be with usFour to eight decades of therapy!Previous exposure to suboptimal treatment in the developed world
Limited monitoring of virologic response world-wideTransmitted drug resistance
Slide21Viremic patients with multi-drug resistant HIV-1
Patients currently suppressed on therapy That have multi-drug resistant HIV-1
Settings with Viral load Monitoring and
Multiple Treatment Options and Past Sub-optimal ART
Slide22New Agents for Resistant HIV-1Integrase InhibitorsBictegravirN(t)RTITAF (approved)EFdA (4'-ethynyl-2-fluoro-2'-deoxyadenosine)(Phase I-II)NNRTIDoravirine (Phase III)
Maturation InhibitorsBMS 955176 (Phase II)Attachment inhibitorsBMS 663068 -> 626529 (Phase III)
Monoclonal antibodies
Broadly virus neutralizing
Targeting entry receptorsIbalizumabPRO140
New Targets: e.g. LEDGF, combination entry, additional maturation sites, HIV-1 RNA processing
Slide23Integrase Inhibitor Activity Against Resistant Variants in VitroKirsten White, Tomas Cihlar and Michael D. Miller
ASM Microbe 2016
Slide24Activity of NRTI vs. Resistant variantsFold changeGrobler et al ASM Microbe 2016
Slide25Maturation Inhibitors (MIs):BMS-955176 Mode of Action
Gag
polyprotein
Lataillade
et al. CROI
2015, Abstract 114LB
Slide26Gag
polyproteinProtease
Untreated
Maturation
Maturation Inhibitors (MIs):
BMS-955176 Mode of Action
Mature virus
Lataillade
et al. CROI
2015, Abstract 114LB
Slide27Gag
polyproteinImmature virus
Maturation Inhibitors (MIs):
BMS-955176 Mode of Action
Untreated
BMS-955176
MaturationInhibitor
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. Protease
Maturation
Mature virus
Protease
Treated with BMS-955176
Lataillade
et al. CROI
2015, Abstract 114LB
Slide28BMS-955176: Median Change in HIV-1 RNA over Time
Median change in HIV-1 RNA from baseline to Day 11 reached ~-1.4 log10 c/mL
Median change in HIV-1 RNA from baseline
, log
10
copies/mL
Study days
Dosing period
Lataillade
et al. CROI
2015, Abstract 114LB
See Abstract 425, 464
Slide29HIV Entry Inhibitors
Virus-Cell
Fusion
Adapted from Moore JP,
PNAS
2003;100:10598-10602.
gp41
gp120
V3 loop
CD4
Binding
CD4
Cell
Membrane
Coreceptor
Binding
CCR5/CXCR4
(R5/X4)
CCR5 Inhibitors
maraviroc
enfuvirtide
BMS 663068
Slide30AI438011: BMS-663068 Attachment Inhibitor Monotherapy Substudy: Mean Change in HIV-1 RNA from Baseline*
*Error bars represent standard error of the mean.
Lalezari et al CROI 2014 abstract 86
Abstract 472
Slide31Attachment Inhibitor – Clinical DevelopmentBMS-663068 HIV-1 variants have a range of susceptibilityIn Phase IIB study 6% had a BMS-626529 IC50 >100 nM at screening
Phase IIB study in participants with limited resistanceAttachment 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 backgroundIf no fully active ARV thenBMS-663068 600 mg BID for 48 weeks or longer with optimized background therapy
Slide32Broadly Neutralizing antibodiesCan they be harnessed as therapy?
Slide33Combined Antibodies:
Improved Potency and Breadth
Kong, Montefiori Korber et al. J. Virol (2015)
2 mAbs > 98% coverage
Slide34HIV-1 discovered
ZDV monotherapy
ZDV/3TC
Triple Drug Therapy
Single Tablet Regimens
The Integrase Era
Long
Acting
Injectable?
?????
1983
1987
1995
1996
2006
2012-13
2017
2020
Antiretroviral Therapy: The Future
Slide35Joseph J. Eron, Jr, MDProfessor of Medicine and EpidemiologyThe University of North Carolina at Chapel HillChapel Hill, North Carolina
Future Directions: Investigational Approaches to Antiretroviral Therapy
Washington, DC:
August
24,
2016