further evolution of hiv therapy a gsk-viiv perspective...-well-established and favorable rpv safety...

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


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


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


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


Maturation Inhibitors (MIs):BMS-955176 Mode of Action


Gag

polyprotein

Gag

polyprotein

Protease

Untreated

Maturation


Mature virus


Gag

polyprotein

Immature virus


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


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


• 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

[email protected]

further evolution of hiv therapy a gsk-viiv perspective...-well-established and favorable rpv safety...

Documents