further evolution of hiv therapy a gsk-viiv perspective...-well-established and favorable rpv safety...
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Dr Piotr Budnik Medical Lead HIV GSK
MB BCh FCP(SA)
Further evolution of HIV therapy
A GSK-Viiv perspective
Our Approach
Expand
Meaningful
Partnerships
Drive
Innovation in
HIV R&D
Establish ViiV INI Portfolio as
the Heart of Care
We collaborate to innovate
Confidential and proprietary
Community partnerships Academic
Access partnerships Corporate
Addressing Access Challenges for All Populations
Our industry-leading access initiatives help address the barriers to
treating those in need
Royalty-free Voluntary
Licenses:
increase access to low-cost
generic medicines in all
low-income, all least
developed and sub-
Saharan African countries.
Flexible Pricing & Local
Partnerships:
support middle income
countries by reducing
costs & sharing expertise
to increase local capacity.
Collaboration with MPP
Provides access to 93.4% of
adults and to 99% children
Our commitment to the community
Patient-centric company
Patients at the forefront of all decisions
Leave no patient behind
Support priority
interventions
with meaningful
partnerships
Focus on
most
impacted
countries
Focus on
Key
Affected
Populations
Confidential and proprietary
Women and
infants
Young people
15-24
MSM &
transgender
IDUs
• Since 2010, the PACF has committed nearly £30million to 170 Grantees tackling
vertical transmission from mother to child in over 30 countries
• 70 receiving Technical Assistance
• PACF Programmes fully aligned to 4 prongs of WHO PMTCT Strategy
Grants vary in size from £3,000 pa to £200,000 pa
An example of the impact of our commitment: Positive Action for Children Fund
CIS2 partners
Asia5 Partners
Africa 160 Partners
Americas1 partner
Confidential and proprietary
Access to therapy
• Includes entire marketed portfolio
• Extends to all least-developed countries, low-income countries , lower middle income countries and sub-Saharan Africa
• 16 voluntary licences for ARVs
VOLUNTARY LICENCE POLICY: In middle-income countries:
• Flexible pricing policy factoring in GNI and the impact of the epidemic in each country
• Consideration on a case-by-case basis, taking into account local need and context
ACCESS PRICING POLICY:
Medicines Patent Pool voluntary licences
Voluntary licence agreement with the MMP to increase access to HIV medicines for children and adults
1. Royalty-free licence for dolutegravir and ABC containing paediatric formulations.
2. Royalty-free license for dolutegravir containing adult formulations covering all least developed; low income and sub-Saharan countries
3. Royalty-bearing license for dolutegravir containing adult formulations for lower middle-income countries (LMIC)
Include total of 121 countries where 92% of adults and 99% children living with HIV are
Confidential and proprietary
Integrase Inhibitor Pipeline bolsteredby BMS highly complementary assets
Long acting two drug regimenscabotegravir + RPV*
Preventioncabotegravir *
Search for remission and cureCollaborations
Advanced therapeuticsTivicay®
Legacy ARV drug portfolio Epzicom/Kivexa®
& Celsentri/Selzentry®
Dolutegravir regimensTriumeq ®
Two drug regimensDTG/RPV *DTG/3TC*
Attachment Inhibitor* for heavily treatment experienced patients
Maturation Inhibitor* w/ possible combinations with DTG and/or CAB
Next generation* agents with game changing potential
* investigational treatments
9
Attachment
Fusion
CD4
Chemokine
co-receptorReverse
transcription
Viral DNAHuman genomic DNA
Integration
(strand transfer) Transcription
Translation
Accessory
viral proteins
Gag Pol
Gag
Assembly/
cleavage
Release
Maturation
gp120
Budding
HIV-1 Lifecycle
Lataillade et al. CROI 2015
HIV-1 Life Cycle:Inhibitors of HIV-1 Replication
ATTACHMENT
FUSION
CD4
CHEMOKINE CO-RECEPTOR REVERSE
TRANSCRIPTION
VIRAL DNAHUMAN GENOMIC DNA
INTEGRATION (STRAND TRANSFER) TRANSCRIPTION
TRANSLATION
ACCESSORY VIRAL PROTEINS
GAG POL
GAG
ASSEMBLY/CLEAVAGE
RELEASE
MATURATION
GP120BUDDING
Attachment
inhibitor
Fusion inhibitor
RT inhibitor
Integrase inhibitor
Protease inhibitor
Protease inhibitor
Protease inhibitor
CCR5 antagonist
Maturation
Inhibitors
Lataillade et al. SOTS Symposium , BMS 3/2015
XX
X
XX
HIV Development Program:Attachment Inhibitor and Maturation Inhibitor
BMS-663068 (HIV-1 Attachment Inhibitor)
BMS-955176 (HIV-1 Maturation Inhibitor)
Phase 3
AI438-047: BMS-663068 in heavily treatment-experienced HIV-1 infected adults with multidrug resistance
On-going: FPFV 2/23/2015
Phase 2b
AI468-038: BMS-955176 dose ranging study in treatment-naïve HIV-1 infected adults.
FPFV 5/12/2015
AI468-048: BMS-955176 in combination with dolutegravir + atazanavir (with or without ritonavir) in treatment-experienced HIV-1 infected adults
FPFV 7/2015
Virus-cellfusion
gp41
gp120
CD4binding
CD4
Cellmembrane
Co-receptorbinding
CCR5/CXCR4(R5/X4) CCR5 antagonists
FusioninhibitorsAttachment
inhibitor
Attachment Inhibitor: BMS-663068 Blocking Entry by Inhibiting Viral Attachment to CD4
Nettles RE, et al. CROI, Feb 27–Mar 2, 2011; Boston, MA. Oral presentation 49
13
gp120
gp41
Conformationalchanges
CD4 bindingBlocked
No drug BMS-626529
Conformationalchanges inhibited
gp120
gp41
BMS-626529 binding
CD4 binding site
CD4 receptor
Cell surface
CD4 binding
Langley DL et al.
CCR5 co-receptor
BMS-626529 Attachment Inhibitor: Proposed Mechanism of Action
Attachment
Fusion
CD4
Chemokine
co-receptorReverse
transcription
Viral DNAHuman genomic DNA
Integration
(strand transfer) Transcription
Translation
Accessory viral
proteins
Gag Pol
Gag
Assembly/
cleavage
Release
Maturation
gp120
Budding
HIV-1 Lifecycle
Lataillade et al. CROI 2015, Abstract 114LB
HIV-1 Lifecycle
Assembly/
cleavage
Release
Maturatio
n
Budding
Maturation
inhibitor
Lataillade et al. CROI 2015, Abstract 114LB
Maturation Inhibitors (MIs):BMS-955176 Mode of Action
Lataillade et al. CROI 2015, Abstract 114LB
Gag
polyprotein
Gag
polyprotein
Protease
Untreated
Maturation
Maturation Inhibitors (MIs):BMS-955176 Mode of Action
Mature virus
Lataillade et al. CROI 2015, Abstract 114LB
Gag
polyprotein
Immature virus
Maturation Inhibitors (MIs):BMS-955176 Mode of Action
Adamson et al. Expert Opin Ther Targets 2009; 13:895–908. Lataillade et al. CROI 2015, Abstract 114LB
Untreated
BMS-955176
Maturation
Inhibitor
Protease
Maturation
Mature virus
Protease
Treated with
BMS-955176
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
20
Cabotegravir Long-Acting (LA)Injectable Nanosuspension
CABCABRPV RPV
• CAB is an investigational HIV INSTI and analogue of dolutegravir
• Low solubility crystalline drug suspended in aqueous vehicle
• Wet bead nanomilled; terminal sterilization by gamma irradiation
• Storage: 3-year shelf life at room temp; excursions permitted 2-30˚C
Cabotegravir Long-Acting Nanosuspension
R H. Müller, et al. European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 1-9
Component Function
Cabotegravir free acid
(d50 ~200 nm)
Active drug
Mannitol Tonicity agent
Surfactant System Wetting/Stabilizer
Water for Injection Solvent
CAB LA 200mg/mL
21
• HIV Treatment– CAB LA + RPV LA every 4 or 8 week IM injection as a
two-drug maintenance regimen for HIV-infected patients
– CAB + RPV attributes support LA approach
- Different MOA, resistance profiles, metabolic pathways
- Lack of drug interaction between CAB and RPV1
- Initial LA trials support q4-8 week synchronous dosing schedule
- Oral formulations to facilitate treatment initiation, oral-bridging and
discontinuation strategies
- Well-established and favorable RPV safety profile
• HIV PrEP– CAB LA monotherapy, dosed IM once every 2-3 months, to reduce
risk of sexually acquired HIV-1 (combined with safer sex practices)
Potential Indications
1 Ford S, AAC 2013:57, 5472-7
Progress Report:
HIV Treatment
ISRs for CAB LA or RPV LA Over Time
Bars represent incidence of onset ISR events relative to the most recent IM injection visit.
Subjects at visit
Q8W IM 115 115 114 113 113 113 113 112 112 112 112 112 111
Q4W IM 115 115 115 114 112 111 109 109 108 107 106 105 104
Day 1 W 4 W 8 W 12 W 16 W 20 W 24 W 28 W 32 W 36 W 40 W 44 W 48
Weeks
Overall ISR AE Incidence
• 99% of ISRs were mild (82%) or moderate (17%), and 90% resolved within 7 days
• Most common ISR events overall were pain (67%), nodules (7%), and swelling (6%)
• 2/230 subjects (<1%) withdrew as a result of injection reactions (Q8W)
Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.
Patient-Reported Outcomes at Week 48: Maintenance Treatmenta
Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.
Note: based on observed case data set of subjects who completed Week 48 questionnaires.aHIV Treatment Satisfaction Questionnaire status version (HIVTSQs).
How satisfied are you with
your current treatment?
83% 79% 67%
14%20%
29%
0%
20%
40%
60%
80%
100%
Q8W (n=109) Q4W (n=103) Oral CAB (n=49)
1% 4%1%
1%1%
How satisfied would you be to continue
with your present form of treatment?
88% 85% 55%
11%13%
33%
0%
20%
40%
60%
80%
100%
Q8W (n=109) Q4W (n=103) Oral CAB (n=49)
1%
8%1%
1%
2%
2%
very satisfied very dissatisfied6 5 4 3 2 1 0
• LATTE-2 results successfully demonstrate ability to maintain HIV-1
viral load <50 c/mL with LA IM CAB + RPV, dosed every 4 or 8 weeks
• Three subjects met PDVF criteria during maintenance– Q8W (n=2), oral CAB (n=1); one Q8W subject with emergent RPV and CAB resistance
• 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
– High overall reported satisfaction
• Dose selection– Q4W dosing resulted in lower rates of virologic non-response with similar safety to Q8W
– Q4W dosing was selected for pivotal phase III studies
– Q8W dosing remains under evaluation within LATTE-2
Conclusions
Margolis et al. AIDS 2016; Durban, South Africa. Abstract THAB0206LB.
• Phase 3 preparation underway; 3Q 2016 start
• Primary intent: develop CAB LA + RPV LA as maintenance
regimen in virologically-suppressed patients
– Q4W dose strategy selected for Phase 3
– Q8W dosing to be evaluated in future studies
• CAB oral tablets to be available for short-term use as oral
lead-in agent or for injection-free (“oral bridging”) periods
CAB LA + RPV LA Treatment Phase 3 Program
Progress Report:
HIV Prevention/PrEP
• Substantial progress made to characterize safety, PK and
efficacy potential of CAB LA + RPV LA as two-drug regimen
for HIV treatment
– LATTE-2 study is first demonstration of once every 4-8 Week
LA-ART and enables Phase 3 program
• CAB LA for HIV PrEP poised to start Phase 3
– ÉCLAIR and HPTN 077 data informing PPK model and final plans
– HPTN 083 (MSM/TGW) to use Q8W dose strategy
– HPTN 084 (women) dose strategy to be confirmed 2H 2016 with
ongoing HPTN 077 data
CONCLUSIONS - Cabotegravir LA Program
Adverse Events should be reported to
GlaxoSmithKline via telephone to
+27 11 745 6000 or via e-mail to
aereporting.sna@gsk.com
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