ViiV – R&D Strategy Where are we heading?

Jan van Lunzen, MD PhD

Head of Translational Medical Research

ViiV Healthcare, London, UK

With the introduction of the INSTIs, the efficacy of first-line treatment has risen to >90%

1. Gallant et al. Lancet 2017;390:2063–2072; 2. Sax et al. Lancet 2017;390:2073–82; 3. Sax et al. Lancet 2015;385:2606–15; 4. Clotet et al. Lancet 2014;383:2222–31;

5. DeJesus et al. Lancet 2012;379:2429–38; 6. Raffi et al. Lancet 2013;381:735–43; 7. Eron Jr et al. Lancet Infect Dis 2011;11:907–15; 8. Walmsley et al. N Engl J Med 2013;369:1807–18;

9. Sax et al. Lancet 2012;379:2439–48; 10. Lennox et al. Lancet 2009;374:796–806.

0 20 40 60 80 100

RAL+TDF/FTC (SPRING-2)

RAL+TDF/FTC (STARTMRK)

DTG+ABC/3TC (SPRING-2)

RAL+ABC/3TC (SPRING-2)

EVG/c/TDF/FTC (GS 102)

DTG+ABC/3TC (SINGLE)

RAL+TDF/FTC (QDMRK)

DTG+TDF/FTC (SPRING-2)

BIC/FTC/TAF (Study 1490)

EVG/c/TDF/FTC (GS 103)

DTG+TDF/FTC (FLAMINGO)

DTG+ABC/3TC (FLAMINGO)

EVG/c/TDF/FTC (GS 104-111)

EVG/c/TAF/FTC (GS 104-111)

BIC/FTC/TAF (Study 1489)

DTG + FTC/TAF (Study 1490)

DTG/ABC/3TC (Study 1489)1

86%, n=280

89%, n=386

90%, n=353

88%, n=348

88%, n=414

89%, n=242

86%, n=169

90%, n=867

92%, n=866

90%, n=79

90%, n=163

85%, n=247

87%, n=164

93%, n=315

92%, n=314

93%, n=325

89%, n=320

82%, n=248

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CONFIDENTIAL – FOR INTERNAL USE AND PLANNING PURPOSES ONLY

Do I have to take ART forever?

What is the impact of

chronic ART intake?

I must manage a lifetime of dealing

with HIV stigma

Can I ever be certain

of my viral load not

rebounding and

transmitting my HIV

Will my immune system be fully

restored?

ART is improved, but there are always unforeseen side

effects

Will there ever be a cure for HIV? Are

there any companies working on it?

Despite Effective ART, Serious Unmet Needs Remain

Can I take drug holidays? What are the

consequences?

Is my life expectancy reduced and am I at

higher risk of comorbidities?

We invest in R&D to benefit PLHIV

4

Our focus areas have the potential to change the way we treat HIV with the goal to reduce long-term toxicities and target unmet medical needs

Small molecule ARVs

Biologic (monoclonal

antibody) ARVs

Alternative methods of

delivery (e.g. long-

acting injectables)

Simplified regimens with improved long-term outcomes

Maturation inhibitor as

possible addition to arsenal of treatment

options

Attachment inhibitor for

heavily treatment-

experienced patients

Ensure what we do helps PLHIV

Involve PLHIV in process

PLHIV benefit from our R&D efforts

HIV Evolution – Past and Future

HAART

Long Acting ART with Reservoir Reduction

First ART (AZT) Approved

Functional Cure Therapies

Sterilizing Cure 2045+

1981

Long Acting ART

1996

2025-

2035

2030-

2045 Long term ART free periods (AKA remission)

Long acting ART with improved profiles that

reduce reservoir size

Complete eradication of HIV-infected cells

2019-

2030 Q3M long-acting injectables

Viral control via combination ART

HIV Reported Epidemic begins with first diagnosed case

1987

Optimization of Oral ART (2DR) Highly efficacious, safe, and well-tolerated ART

in daily single tablet regimens

2006-

2019

Discovery Strategy:

•New mechanism drugs to combine with dolutegravir

•Wholly owned 2 drug regimens

•Nuc- and booster-sparing regimens

•“Insurance policy” for a 3 drug regimen

•New drugs for resistant viruses

Dolutegravir-based regimens

ViiV Healthcare owned

•Imagine a biologic regimen that could last a year “feels like remission”

•Cabotegravir will establish long-acting depot concept

•Combinectin is a first step to a convenient biologic regimen

•bNAb’s show promise of long half-life

Long-acting regimens

A path to a once-yearly therapy

•ViiV has a “toe in the water” with Qura

•Unclear as to what approaches will lead to a cure

•“Shock and Kill”; checkpoint inhibitors; reservoir micro-environment; therapeutic vaccines; bNAbs; gene therapy;

•Qura gives opportunity to participate; observe and invest when time is right

HIV Cure One course of therapy for long-

term remission

Short-term

Medium

Long-term

This extends our planning to 2030 and beyond

CONFIDENTIAL

Innovative and competitive pipeline

Prevention Cabotegravir LA*

Search for

Remission

and Cure

Legacy ARV Drug Portfolio abacavir/lamivudine, maraviroc & others

Dolutegravir-based

Regimens Tivicay

Triumeq

*Investigational Treatments ǂ Discovery and Early Development Programs

Current standard of care

= HAART/legacy drugs

New treatment

paradigm = 2DR

Pipeline Strategy

Long-acting (LA)

Treatment Regimens cabotegravir + rilpivirine*

Two Drug Regimens Juluca: dolutegravir/rilpivirine

dolutegravir/lamivudine FDC*

New MOA Attachment inhibitor (fostemsavir)*

Combinectin (GSK3732394)*ǂ

Maturation inhibitor portfolio*ǂ

Allosteric integrase inhibitor *ǂ

Capsid inhibitor*ǂ

CONFIDENTIAL

Development Pipeline

Preclinical Phase 1 Phase 2 Phase 3

DTG / 3TC (STR) INSTI/NRTI

CAB LA + RPV LA* (Treatment) INSTI/NNRTI

CAB LA (Prevention) INSTI

Fostemsavir attachment inhibitor

GSK3640254 maturation inhibitor

GSK3732394 Combinectin

Discovery Programs

*In collaboration with Janssen

3TC, lamivudine; CAB, cabotegravir; DTG, dolutegravir; INSTI, integrase strand transfer

inhibitor; LA, long-acting; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-

nucleoside reverse transcriptase inhibitor; RPV, rilpivirine; STR, single tablet regimen

CONFIDENTIAL

• Cabotegravir (CAB) is a novel integrase inhibitor formulated as a

long-acting injectable

• CAB’s innovative mode of

delivery may enable monthly or

less frequent dosing schedules

to help overcome the barriers of

medication adherence in HIV

treatment and prevention

• First ARV development program

with simultaneous progression of

global registration programs for

both treatment and prevention

indications

Pioneering Long-Acting Injectables for HIV-1 Treatment and Prevention

CONFIDENTIAL

Fostemsavir: a life-saving investigational medicine

for patients with few or no treatment options left

1. Nowicka-Sans B, et al. Antimicrob Agents Chemother. 2012;56:3498–350 2. https://news.bms.com/press-release/bristol-myers-squibb-receives-

us-fda-breakthrough-therapy-designation-investigational-3. Li Z, et al. Antimicrob Agents Chemother. 2013;57:4172–4180. 4. Aberg J et al. HIV Drug

Therapy Glasgow 2018, 28 –31 October 2018. Oral abstract O344A.(URLs accessed November 2018).

First-in-class – unique mechanism

that blocks initial CD4 binding1

FDA breakthrough therapy

designation2 US regulatory filing

planned for 2019

No cross-resistance to other

antiretrovirals1,3

Demonstrated efficacy for heavily

treatment-experienced patients –

BRIGHTE study showed 54 % of

patients4 achieved virologic

suppression at 48 weeks and had

continued increase in CD4+ t-cell

counts

CONFIDENTIAL

Maturation Inhibitors (GSK3640254)

Maturation inhibitors block

protein processing late in the

viral replication cycle

ViiV is progressing oral and

long-acting MI programs

Oral program to include

single entity and combination

product with DTG Long acting MI could serve as a

partner for CAB LA

Targeting frequency of every

two months or less

CONFIDENTIAL

Vision for Biologics

1. Krystal et al. HIV Glasgow 2016; Glasgow, UK. Poster P022. 2. Caskey M, et al. NEJM 2016;375:2019–2021. 3. Hua CK, et al. Front Immunol 2017;8:1655.

Combinectin bNAbs

• Three modes of action in a single

injectable1

• Broad-spectrum biologic agent

• Capable of once-monthly self-

administered, subcutaneous dosing

• All-in-one regimen, or as a partner

for CAB, or another LA agent

• Long acting2

• Naturally long half-life (2-3 weeks)

and modifiable

• Role in remission and cure3

• Potential for targeting HIV reservoir

• Partner for CAB or another LA

agent

Membrane-proximal external region (MPER)

10E8VLS

Glycan-V3 Supersite PGT121, 10-1074 (LS)

V1V2 Glycan PGDM1400

CD4 Supersite N6LS, VRC07-523LS

VRC01(LS), 3BNC117 (LS)

gp120-gp41Interface

„Today we treat the virus,

….tomorrow we will treat the host!“

Perspective

CONFIDENTIAL – FOR INTERNAL USE AND PLANNING PURPOSES ONLY

HIV, immune activation, and inflammation

CONFIDENTIAL – FOR INTERNAL USE AND PLANNING PURPOSES ONLY

HIV INFECTION

Novel therapeutic strategies?

INFLAMMATION & CHRONIC IMMUNE ACTIVATION

EARLY

ANTIRETROVIRAL TREATMENT

THERAPEUTIC OPTIONS

TARGETING HOST

FACTORS/RESPONSES?

RESTORE IMMUNE FUNCTION

PREVENT AIDS

IMPROVE QUALITY OF LIFE

PROLONG LIFE

EFFICIENT IMMUNE FUNCTION?

LOW HIV RESERVOIRS?

REMISSION / CURE?

Bridging from ART to Cure

ART CURE

Improved ART Therapy

Cure Regimens

Can future innovations in ART

deliver incremental gains before

cure regimens become a reality?

Can incremental innovation

on curative therapies

represent value to patients as

stand alone therapies?

Bridging from ART to Cure

Long Acting ARV

Therapy

Improve

Immune

Response

Latency

Reversal

Non-

Communicable

Diseases

(NCD)

Reservoir

Reduction

We aim to reduce the HIV reservoir and/or improve host immunity to achieve ART-free duration >2 years

Upside: May lessen NCD risk

HIV Cure Product Vision

Requirements to Deliver for Patients:

Extra benefit beyond classic ART

Reservoir reduction capacity and/or enhancement of anti-HIV immune responses

Acceptable safety/tolerability profile

Viral suppression comparable to SOC

Long-acting (durability >2 years) without drug on board

No viral transmission in the absence of ART

Cost? Access?

Initial treatment course with cure regimen

in combination with long acting ART

Follow-up treatments every 2-5 yrs

Tolerability no worse than flu like

symptoms at each treatment

HIV Functional Cure

Building the HIV Cure Regimen: Extending the Long Acting Portfolio

bnAb(s)+

SMACm

bnAb(s)+

SMACm+

TherVax Example

Regimens

Intervention

Interval Q3M Q1yr Q2-5yr

Safety SOC Flu-like

symptoms

Market

Timeline

Flu-like

symptoms

Q1M/

Q2M

Filed 2027+ 2030+ 2035+

CAB+

bnAb(s) CARLA

SMACm: A More Effective Latency Reversal

Strategy

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• SMACm directly reactivate

latent SIV and HIV in vivo

• Limited immunologic

impacts

• Contrast to indirect,

inconsistent, inflammatory

TLR7 agonist approach

• Potential selective killing

of HIV-infected cells

• Novel lead molecules

discovered at Qura

SMACm

SMACm are a refined LRA strategy with potential to

reduce the reservoir

N6LS/VRC07: bnAb with Potent Antiviral Activity

and Potential Reservoir Reduction Properties

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Bind HIV envelope and

prevent virus entry into

target cells

N6LS demonstrates superior antiviral potency/

clade coverage compared to other bnAbs

Neutralization (Direct acting antiviral)

Enhanced Host Immune Response (Clearance of infected cells)

bnAb+virus can form complexes that

are presented to the host immune

system and may induce:

~ Antibody responses

~ T cell responses

bnAbs can facilitate clearance of infected cells

Fc region binds to Fc Receptors on innate cells

Antigen binding

Prime/Boost

B cell or

N6 Neutralization of Clinical Isolates

Radboud Collaboration to Identify HIV Patient Specific NCD Pathways and Biomarkers

LifeLines DEEP UMCG

N = 1500

Radboud UMC N = 500+200

Currently Available

• Environmental data

• Psychiatric data

• (Longitudinal) clinical data

• Immunophenotyping

• Functional immunology

(PBMCs cytokine

production)

• Platelet function

• Soluble markers

(inflammation, microbial

translocation, coagulation)

• Metabolomics

In Progress

• Genetics

• Microbiome

• Platelet RNA/mtDNA

• Carotid thickness and

pulse wave velocity

• Fibroscan

Future Capabilities

• HIV reservoir

• Transcriptomics

• Proteomics (O-LINK)

200HIV -> 2000HIV