UK CAB 2018 · Reduced cost9,10 • Reduced drug costs, and long-term care/societal costs • Improvements in access Improved quality of life11 • Improvements in patient satisfaction

UK CAB 2018

Dr Nadine Chamay, PhD

Medical Advisor

ViiV Healthcare, UK

UK/HIVP/0009/18

Date of preparation October 2018

Rationale for 2DR

Agenda

2DR, the rationale

o Gemini 1&2

o SWORD 1&2

Pregnancy: an update

ViiV pipeline

Your questions

TPV

ETR

1987 1988…1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

AZT

SQV

RTV

IDV

Core agents

Backbone therapies

NVP

NFV*EFV

APV*LPV

ENF

EVGDTG

ATV

FPV

DRV

MVC

RAL

ddC*

Year of EMA approval of ARVs used in the treatment of HIV

d4T

3TC ABCddl

TDFFTC

TAF

Evolution of the backbone 1987–1996 HAART: Rise of the core agents 1996–2007 Core agents driving advancements 2007+

10

No.

of b

ackb

one

agen

ts d

evel

oped

No.

of c

ore

agen

ts d

evel

oped

8

6

4

2

0

0

2

4

6

8

10

12

14

16

18

20

*No longer marketed in the European Union

Licence dates from individual SmPCs, available upon request

RPV

The evolution of new ARV agents

ABC, abacavir; APV, amprenavir; ARV, antiretroviral; ATV, atazanavir; AZT, azidothymidine;

d4T, stavudine; ddC, zalcitabine; ddl, didanosine; DRV, darunavir; DTG, dolutegravir; EMA,

European Medicines Agency; ENF, enfuvirtide; ETR, etravirine; EFV, efavirenz; EVG,

elvitegravir; FPV, fosamprenavir; FTC, emtricitabine; HAART, highly active antiretroviral

therapy; IDV, indinavir; LPV, lopinavir; MVC, maraviroc; NFV, nelfinavir; NVP, nevirapine;

RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; SQV, saquinavir; TAF, tenofovir alafenamide;

TDF, tenofovir disoproxil fumarate; TPV, tipranavir; 3TC lamivudine

*No longer available in the European Union

Why 2DR?

AE, adverse event; DDI, drug-drug interaction; HCP, healthcare professional; SoC, standard of care

Reduce potential impact of long-term

exposure to multiple ARVs

Less potential for AEs?

“As much as needed, as little as possible”

“Why take 3 (or 4), when 2 can do?”

Why 2DR?

Potential to reduce DDIs

Ageing patients

Co-morbidities

Potential preservation of future

treatment options

Clinical profile of newer agents allow

us to investigate 2DR

High expectations – HCPs and patients

Establishing new treatment paradigms

and evolving the SoC

Costs

ART, antiretroviral therapy; ARV, antiretroviral; EFV, efavirenz; FDA, Food and Drug Administration; FTC, emtricitabine; HAART, highly active antiretroviral therapy; INI, integrase

inhibitor; NRTI, nucleos(t)ide reverse transcriptase inhibitor; TDF, tenofovir disoproxil fumarate.

Adapted from: 1. Lacey et al. Available from: http://truvenhealth.com/Portals/0/Assets/Life-Sciences/White-Papers/pharma-innovation-hiv-aids-treatment.pdf. 2. Palmisano et al. Ann Ist

Super Sanità 2011;47:44–8. 3. Drugs.com. Available from https://www.drugs.com/history/atripla.html. 4. Drugs.com. Available from: https://www.drugs.com/history/isentress.html. 5.

Drugs.com. Available from: https://www.drugs.com/newdrugs/fda-approves-tivicay-dolutegravir-hiv-infection-3867.html. All URLs accessed May 2018.

Significant medical advances in HIV therapy have

changed the focus from saving lives to chronic

management1

1987The first ARV, an

NRTI, is approved,

for the treatment of

HIV2

1995–1996The introduction

of third agents

marked the

beginning of the era

of HAART2

2006The FDA approves the

single-tablet triple

regimen

(EFV/FTC/TDF)3

2007The FDA approves

the first INI,

raltegravir4

2013The first ARV with head-to-

head data in multiple patient

populations at approval

launches, dolutegravir5

2018A new advance in

HIV management

Antiretroviral therapy coverage and number

of AIDS-related deaths, globally, 2000–2015

Adapted from: Global AIDS Update 2016, UNAIDS 2016.

An

tire

tro

vir

al

the

rap

y c

ove

rag

e (

%)

Nu

mb

er

of

AID

S-r

ela

ted

de

ath

s (

mil

lio

ns

)

Life expectancy among PLHIV is

approaching normal

ART, antiretroviral therapy; ARV, antiretroviral; PLHIV, people living with HIV.

Adapted from: 1. Antiretroviral Therapy Cohort Collaboration. Lancet HIV 2017;4:e349–56. 2. Marcus et al. JAIDS 2016;73:39–46. 3. Nakagawa et al. AIDS 2012;26:335–43.

Life expectancy in patients on ART has increased to near normal1

However, even with early treatment and access to care, an 11.8-year

gap in life expectancy remains for HIV-infected compared with HIV-

uninfected individuals2

PLHIV will be on ARV therapy for decades; the mean estimated

duration of lifetime treatment in 2012 was 39.1 years3

Adapted from: 1. Hasse et al. Clin Infect Dis 2011;53:1130–9.

Among PLHIV, the prevalence of comorbidities and

comedication use increases with age1

Proportion of patients having ≥ 1 comorbidity or receiving

≥ 1 comedication increased with age1

As part of the Swiss HIV Cohort Study, Hasse et al. investigated how the number of

comorbidities and the number of non-AIDS comedications taken by HIV-positive patients

differed with age (8444 PLHIV in cohort)

Comedications Comorbidities

Age

groups

Age

groups

Pa

rtic

ipa

nts

(%

)

n =

5761

n =

2233

n =

450

n =

5761

n =

2233

n =

450

PLHIV, people living with HIV.

Patients are being exposed to drugs

for decades longer than previously

Boosted triple-therapy regimen

(QD)

Unboosted triple therapy

(QD)

Unboosted 2DR (QD)

No. of drug

doses/year1460 1095 730

No. of drug

doses per

39.1 years1

57,086 42,815 28,543

2DR, two-drug regimen; QD, once-daily.

Adapted from: 1. Nakagawa et al. AIDS 2012;26:335–43.

There are many potential benefits

to reducing ARV drug exposure

AE, adverse event; ARV, antiretroviral.

Adapted from: 1. Saint-Marc et al. AIDS 1999;13:2188–9. 2. Saint-Marc et al. AIDS 1999;13:1659–67. 3. Fris-Moller et al. N Engl J Med 2003;349:1993–2003. 4. D:A:D

Study Group. Lancet 2008;371:1417–26. 5. Cooper et al. Clin Infect Dis 2010;51:496–505. 6. Bedimo et al. AIDS 2012;26:825–31. 7. Lee et al. JAIDS 2013;62:525–33. 8.

Mollan et al. Presented at IDWeek 2013; Abstract 670. 9. Hill. Curr Opin HIV AIDS 2013;8:34–40. 10. Girouard et al. Clin Infect Dis 2016;62:784–91. 11. Eron et al.

Presented at IAS 2017; Slides MOAX0205LB.

Drug preservation

• Preservation of drug effect for

ARVs not included in regimen

Reduced cost9,10

• Reduced drug costs, and long-

term care/societal costs

• Improvements in accessImproved quality of life11

• Improvements in patient

satisfaction

Reduced toxicity and AEs1–8

• Short- and long-term tolerability/AEs

• Unknown toxicities, including organ

dysfunction

Potential benefits of

reducing ARV exposure

ARV, antiretroviral.

Three strategies are being explored

to reduce ARV exposure

1. Dose reduction

2. Reduce the frequencyof drug administration

3. Reduce the number of ARV drugs given

CD4 BINDING

CO-RECEPTOR

BINDING

FUSIONBUDDING

HIV

viron

gp120

CD4

Assembly

Translation

Viral RNAs

Transcription

Proviral DNA

Reverse transcription

of viral RNA genome

Integration

Chemokine

Co-receptor

(CCR5 or

CXCR4)

ssRNA

MATURATION

NEW HIV VIRON

Targeting the HIV life-cycle

CCR5, C-C chemokine receptor type 5; CD4, cluster of differentiation 4; CXCR4,

C-X-C chemokine receptor type 4; ssRNA, single-strand RNA.

Figure adapted from Reyskens et al. Biochim Biophys Acta

2014;1842:256–68.

1Fundación Huésped, Buenos Aires, Argentina; 2Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán,

Mexico City, Mexico; 3Hospital La Paz, Madrid, Spain; 4Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani,

Rome, Italy; 5Bliss Healthcare Services, Orlando, FL, USA; 6Royal Sussex County Hospital, Brighton, UK; 7National Taiwan University Hospital, Taipei, Taiwan, Province of China; 8Rheinische Friedrich-Wilhelms Universität,

Bonn, Germany; 9Hôpital Saint Antoine, Paris, France; 10ViiV Healthcare, Research Triangle Park, NC, USA;

11ViiV Healthcare, Brentford, UK; 12GlaxoSmithKline, Stockley Park, UK

Non-Inferior Efficacy of Dolutegravir (DTG) PlusLamivudine (3TC) vs DTG Plus Tenofovir/Emtricitabine (TDF/FTC) Fixed-Dose Combination in Antiretroviral Treatment–Naive Adults With HIV-1 Infection—Week 48 Results From the GEMINI Studies

P. Cahn,1 J. Sierra Madero,2 J. Arribas,3 A. Antinori,4 R. Ortiz,5 A. Clarke,6

C.-C. Hung,7 J. Rockstroh,8 P.-M. Girard,9 C. Man,10 J. Sievers,11 A. Currie,12

M. Underwood,10 A. Tenorio,10 K. Pappa,10 B. Wynne,10 M. Gartland,10

M. Aboud,11 K. Smith10

a−10% non-inferiority margin for individual studies.

Methods: GEMINI-1 and -2 Phase III Study

Design

Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

DTG + 3TC (N=716)

Day

1

Screening

(28 d)

Identically designed, randomized, double-blind, parallel-group,

multicentre, non-inferiority studies

DTG + TDF/FTC (N=717)

DTG + 3TC

Week

48

Primary endpoint

at Week 48:

participants with

HIV-1 RNA <50 c/mL

(ITT-E snapshot)a

Double-blind

phase

Open-label

phase

Continuation

phase

CountriesArgentina Australia Belgium

Canada France Germany

Italy Republic of Korea Mexico

Netherlands Peru Poland

Portugal Romania Russian Federation

South Africa Spain Switzerland

Taiwan United Kingdom United States

Week

144

Week

24

Week

96

• ART-naive adults

• VL 1000-500,000 c/mL

1:1

Eligibility criteria• ≤10 days of prior ART

• No evidence of pre-existing viral resistance

based on presence of any major resistance-

associated mutation

• No HBV infection or need for HCV therapy

Baseline stratification factors: plasma HIV-1 RNA (≤100,000 c/mL vs >100,000 c/mL) CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3).

Methods: Demographic and Baseline Characteristics for

the Pooled GEMINI-1 and -2 Population

Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands.

Slides TUAB0106LB.

Characteristic

DTG + 3TC

(N=716)

DTG + TDF/FTC

(N=717)

Age, median (range), y

≥50 y, n (%)

32.0 (18-72)

65 (9)

33.0 (18-70)

80 (11)

Female, n (%) 113 (16) 98 (14)

Race, n (%)

African American/African heritage

Asian

White

Other

Ethnicity, n (%)

Hispanic or Latino

Not Hispanic or Latino

99 (14)

71 (10)

480 (67)

66 (9)

215 (30)

501 (70)

76 (11)

72 (10)

497 (69)

72 (10)

232 (32)

485 (68)

HIV-1 RNA, median (range), log10 c/mL

≤100,000

>100,000a

4.43 (1.59-6.27)

576 (80)

140 (20)

4.46 (2.11-6.37)

564 (79)

153 (21)

CD4+ cell count, median (range), cells/mm3

>200

≤200

427.0 (19-1399)

653 (91)

63 (9)

438.0 (19-1497)

662 (92)

55 (8)

a2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL

Results: Pooled Snapshot Outcomes at Week

48: ITT-E and Per Protocol Populations


aBased on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1

RNA (≤100,000 c/mL vs >100,000 c/mL), CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3), and study (GEMINI-1 vs GEMINI-2). bPP, per protocol: population consisted of participants in the ITT-E population except for significant protocol violators, which could

potentially affect efficacy outcomes as determined by the medical monitor prior to database lock.

Virologic outcome Adjusted treatment difference (95% CI)a

DTG + TDF/FTC DTG + 3TC

-10 -8 -6 -4 -2 0 2 4 6 8 10

-4.4 1.1

-1.7

Percentage-point difference

DTG + 3TC is non-inferior to DTG +

TDF/FTC with respect to proportion

<50 c/mL at Week 48 (snapshot, ITT-E

population) in both studies

-1.3

-3.9 1.2

ITT-E

PP

91

36

93

25

93

25

94

14

0

20

40

60

80

100

Virologicsuccess

Virologicnonresponse

No virologicdata

HIV

-1 R

NA

<50

c/m

L, %

ITT-E DTG + 3TC (N=716) DTG + TDF/FTC (N=717)

PPb DTG + 3TC (N=694) DTG + TDF/FTC (N=693)

Results: Snapshot Analysis by Visit:

Pooled ITT-E Population


0

70

85 89

90

93

91 93

72

87 89

88

93

9091

-20

0

20

40

60

80

100

-4 0 4 8 12 16 20 24 28 32 36 40 44 48

HIV

-1 R

NA

<50 c

/mL, %

Study visit

CD4+ cell count (cells/mm3)

Adjusted mean change

from baseline at Week 48a

DTG + 3TC 224

DTG + TDF/FTC 218

DTG + 3TC (n=716)

DTG + TDF/FTC (n=717)

aCalculated from a repeated measures model adjusting for study, treatment, visit (repeated factor), baseline plasma HIV -1 RNA,

baseline CD4+ cell count, treatment and visit interaction, and baseline CD4+ cell count and visit interaction.

98 9898 9899 9897 100

0

20

40

60

80

100

Wit

ho

ut

TR

DF,

%

TRDF Analysis

566

576

>100,000≤100,000 >200 ≤200

Baseline HIV-1

RNA, c/mL

Baseline CD4+

cell count, cell/mm3

Results: Pooled Outcomes at Week 48 Stratified by Baseline

HIV-1 RNA and CD4+ Cell Count: Snapshot and TRDF

Analysis

Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands.

Slides TUAB0106LB.

91 9394 9392

79

9093

0

20

40

60

80

100

HIV

-1 R

NA

<5

0 c

/mL

, %

Snapshot Analysis

• 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL

• Treatment related discontinuation = failure (TRDF) population accounts for confirmed virologic withdrawal (CVW), withdrawal

due to lack of efficacy, withdrawal due to treatment-related AE, and participants who met protocol-defined stopping criteria

• DTG + 3TC CD4 <200 Snapshot non-response (n=13): 1 CVW, 3 with VL >50 in window (2 of 3 re-suppressed), 2 discontinued due to AE (TB,

Chagas disease), 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART (incarcerated)

• DTG + TDF/FTC < 200 Snapshot non-response (n=4):1 investigator discretion, 1 withdrew consent, 1 lost to follow-up, 1 VL >50 (re-suppressed)

DTG + 3TC DTG + TDF/FTC

>100,000≤100,000 >200 ≤200

Baseline HIV-1

RNA, c/mL

Baseline CD4+

cell count, cell/mm3

553

564

138

140

149

153

642

653

647

662

62

63

55

55

526

576

531

564

129

140

138

153

605

653

618

662

50

63

51

55

DTG + 3TC CD4 <200 Snapshot non-response (n=13):

o 1 CVW,

o 3 with VL >50 in window (2 of 3 re-suppressed),

o 2 discontinued due to AE (TB, Chagas disease),

o 2 protocol violations

o 2 lost to follow-up

o 1 withdrew consent

o 1 withdrew to start HCV treatment

o 1 change in ART (incarcerated)

DTG + TDF/FTC < 200 Snapshot non-response (n=4):o 1 investigator discretion

o 1 withdrew consent

o 1 lost to follow-up

o 1 VL >50 (re-suppressed)

Results: Confirmed Virologic Withdrawals

Through Week 48: ITT-E Population

GEMINI 1 GEMINI 2 Pooled

Variable, n (%)

DTG + 3TC

(N=356)

DTG +

TDF/FTC

(N=358)

DTG + 3TC

(N=360)

DTG +

TDF/FTC

(N=359)

DTG + 3TC

(N=716)

DTG +

TDF/FTC

(N=717)

CVW 4 (1) 2 (<1) 2 (<1) 2 (<1) 6 (<1) 4 (<1)

Treatment-emergent

resistance

0 0 0 0 0 0

• Low rates of virologic withdrawals were observed at Week 48


• No treatment-emergent INSTI mutations or NRTI mutations were

observed among participants who met CVW (confirmed virologic

withdrawal) criteria

Confirmed virologic withdrawal criteria is defined as a second and consecutive HIV-1 RNA value meeting virologic non-response or rebound. Virologic non-response is defined as either a decrease in

plasma HIV-1 RNA of less than 1 log10 c/mL by Week 12 with subsequent confirmation unless plasma HIV-1 RNA is <200 c/mL, or confirmed plasma HIV-1 RNA levels ≥200 c/mL on or after Week 24.

Virologic rebound is defined as confirmed rebound in plasma HIV-1 RNA levels to ≥200 c/mL after prior confirmed suppression to <200 c/mL.

.

Results: Adverse Events − Pooled ITT-E

Population


n (%)

DTG +

3TC

(N=716)

DTG +

TDF/FTC

(N=717)

Any AE 543 (76) 579 (81)

AE occurring in ≥5% of participants in either group

Headache

Diarrhea

Nasopharyngitis

Upper respiratory tract infection

Nausea

Insomnia

Pharyngitis

Back pain

71 (10)

68 (9)

55 (8)

56 (8)

27 (4)

27 (4)

36 (5)

35 (5)

75 (10)

77 (11)

78 (11)

44 (6)

53 (7)

45 (6)

32 (4)

31 (4)

Drug-related AE

Grade 2-4 AE occurring in ≥1% of participants

Headache

126 (18)

42 (6)

8 (1)

169 (24)

47 (7)

8 (1)

AE leading to withdrawal from the study

Neuropsychiatric AEs leading to withdrawal

15 (2)

6 (<1)

16 (2)

4 (<1)

Any serious AEa 50 (7) 55 (8)

a2 deaths (acute myocardial infarction, n=1; Burkitt’s lymphoma, n=1) in the GEMINI-2 study; both were in the DTG + 3TC group and were

considered unrelated to the study drug regimen.

Results: Change in Renal Biomarkers at

Week 48: Pooled ITT-E Population


6.3

10.4

-12.1

4.1

13.5

-15.5

-20

-15

-10

-5

0

5

10

15

Ad

jus

ted

me

an

ch

an

ge f

rom

ba

se

lin

ea

GFR from

cystatin C,

CKD-EPI

(mL/min/

1.73 m2)

GFR from

creatinine,

CKD-EPI

(mL/min/1.73 m2)

Creatinine

(µmol/L)

aEstimated mean change from baseline at Week 48 in each arm calculated from ANCOVA model adjusting for: study, treatment, baseline

plasma HIV-1 RNA, baseline CD4+ cell count, age, sex, race, presence of diabetes mellitus, presence of hypertension, and baseline

biomarker value. Multiple imputed dataset (missing at random). bEstimated from geometric mean ratio for baseline and Week 48.

Plasma/Serum markers

-13.1

-7.4 -7.7

2.9

11.4

31.2

-20

-10

0

10

20

30

40

Ch

an

ge f

rom

ba

se

lin

e, %

b

Urine markers

Protein/

Creatinine

(g/mol)

Retinol-binding

protein/

Creatinine

(µg/mmol)

Beta-2

microglobulin/

Creatinine

(mg/mmol)

DTG + 3TC (n=716) DTG + TDF/FTC (n=717)

*

*

*

*

*

*

*p<0.001a

Results: Change in Bone Markers at

Week 48: Pooled ITT-E Population


1.220.60 0.40 0.14

4.07

6.17

13.10

0.330

5

10

15

Serum bone specificalkaline phosphatase

Serumosteocalcin

Serum procollagen 1N-terminal propeptide

Serum type 1 collagenC-telopeptide

Ad

jus

ted

me

an

ch

an

ge

fro

m

ba

se

lin

e (

µg

/L)a

aEstimated mean change from baseline at Week 48 in each arm calculated from ANCOVA model adjusting for study, treatment, baseline

plasma HIV-1 RNA, baseline CD4+ cell count, age, sex, race, BMI, smoking status, current vitamin D use, and baseline biomarker value.

Multiple imputed dataset (missing at random).

DTG + 3TC (n=716)

DTG + TDF/FTC (n=717)

*

*

*

*

*p<0.001

Orkin C et al. HIV Glasgow 2018; Glasgow,

UK. Slides P021.

Subanalysis

• GEMINI-1 and-2 results demonstrate non-inferior virologic efficacy for the 2DR

DTG + 3TC vs the 3DR DTG + TDF/FTC at Week 48

• Both DTG + 3TC and DTG + TDF/FTC were associated with low rates of

confirmed virologic withdrawals through Week 48

– No treatment-emergent INSTI or NRTI mutations were observed among participants

who met CVW criteria

• Overall safety and tolerability profile at Week 48 was comparable between the

2 regimens

– Fewer drug-related AEs with DTG + 3TC

– Change in renal and bone biomarkers significantly favors DTG + 3TC

• These data support DTG + 3TC as an effective option for the treatment of HIV-1

infection

Conclusions


Phase III, randomised, multicentre, parallel-group, non-inferiority study

• Objective: to demonstrate non-inferior antiviral activity of switching to DTG + 3TC QD compared with

continuation of current ARV regimen over 48 weeks in HIV-1-infected ART-experienced subjects

• Primary endpoint: the proportion of participants who meet the Snapshot virologic failure criteria at

Week 48 using the ITT-E population

– non-inferiority margin = 4%; Week 48 primary endpoint

TANGO: Switch Study

TAF-based

regimens

Randomisation

1:1N=600

DTG + 3TC

Primary

endpoints

Secondary

endpoints

Baseline Week 24 Week 48 Week 96 Week 144

TAF-based regimens

North America + EU + international

TANGO. Available from: https://clinicaltrials.gov/ct2/show/NCT03446573 Accessed May 2018

https://clinicaltrials.gov/ct2/show/NCT03446573

Phase III, randomised, multicentre, parallel-group, non-inferiority study

• Objective: to demonstrate the non-inferior antiviral activity of switching to DTG/3TC QD compared

with continuation of current ART regimen over 48 weeks in HIV-1 infected patients (n= 600)

• Primary endpoint: the proportion of participants who meet the snapshot virological failure criteria at

Week 48, using the ITT-E population

– Non-inferiority margin = 4%; Week 48 primary endpoint

• Planned start: H1 2019

SALSA: Second Switch Study Design

ViiV Healthcare, data on file 2018

VL <50 c/mL

on INI, NNRTI,

or PI + 2 NRTIs

1:1

Baseline Week 52 Week 100

CAR

DTG/3TC

Primary endpoint at Week 48:

subjects with VL <50 c/mL (ITT-E snapshot)

DTG/3TC

• HIV-1 infected patients

• On stable CAR for >6

months before screening

• 1st or 2nd ART with no

change in prior regimen

due to VF

• Confirmed HIV-1 RNA

<50 c/mL during the 12

months before screening

• HBV negative

Screening Early switch Late switch

Proposed study: Information not yet published

Dolutegravir + Rilpivirine

1ViiV Healthcare, Brentford, UK; 2Barts Health NHS Trust, London, UK; 3Hospital Universitari de Bellvitge,

Barcelona, Spain; 4Hospital of the University of Munich, Munich, Germany; 5East Sydney Doctors, Darlinghurst,

Sydney, Australia; 6CHG - Hôpital Delafontaine, Saint Denis Cedex, France; 7Central West Clinical Research, St

Louis, MO, USA; 8GlaxoSmithKline, Uxbridge, UK; 9ViiV Healthcare, Research Triangle Park, NC, USA;

10ViiV Healthcare, Collegeville, PA, USA; 11Janssen Pharmaceutica NV, Beerse, Belgium

Durable Suppression 2 Years After

Switch to DTG + RPV 2-Drug Regimen:

SWORD-1 and SWORD-2 Studies

Aboud M,1 Orkin C,2 Podzamczer D,3 Bogner J,4 Baker D,5

Khuong-Josses M-A,6 Parks D,7 Angelis K,8 Kahl L,1 Blair E,9

Underwood M, 9 Wynne B,10 Vandermeulen K,11 Gartland M,9 Smith K9

Adapted from: Aboud et al. AIDS 2018; Amsterdam, the Netherlands. Slides THPEB047.

Study Design

• SWORD-1 and SWORD-2 are identically designed, randomized, multicentre,

open-label, parallel-group, non-inferiority phase III studies

– A full description of the study design, including eligibility criteria and endpoints, has

been previously reported1

Methods (1)

Adapted from: Aboud et al. AIDS 2018; Amsterdam, the Netherlands.

Slides THPEB047.Llibre et al. Lancet. 2018;391:839-849.

Study Populations

• Participants randomized to DTG + RPV on Day 1 who received at least 1

dose of DTG + RPV (early-switch group)

• Participants randomized to continue their current antiretroviral regimen (CAR)

on Day 1, completed early-switch phase at Week 52, and received at least 1

dose of DTG + RPV upon switching at Week 52 (late-switch group)

Methods (2)


Slides THPEB047.

• Through 100 weeks of treatment, DTG + RPV continued to be efficacious in the

early-switch group

• Virologic efficacy in the late-switch group at Week 100 was similar to that of the early-

switch group at Week 481

Results: virologic efficacy (1)


Slides THPEB047.

1. Llibre et al. Lancet. 2018;391:839-849.

aOther reasons for discontinuation while treated with DTG + RPV were lost to follow-up,

n=3; protocol deviation, n=5 (prohibited medication use, n=3; pregnancy, n=2);

withdrawal of consent, n=18 (participant relocated, n=5; travel burden, n=2; other, n=9);

and investigator discretion, n=2.

HIV-1 RNA <50 c/mL (FDA Snapshot) at Week 48 and Week 100

• Through Week 100, there

was a low number of

confirmed virologic

withdrawals (CVWs)

across study populations

(1%; 10/990)

• CVWs with resistance-

associated treatment-

emergent mutations were

low across both groups

and detected in 3

participants, all receiving

DTG + RPV (0.3%; 3/990)

– In all 3 participants, at least

1 NNRTI resistance–

associated mutation was

detected

Results: virologic efficacy (2)

Adapted from: Aboud et al. AIDS 2018;

Amsterdam, the Netherlands. Slides THPEB047.

aShading represents participants with treatment-emergent NNRTI resistance–associated mutations. bUnderlined value denotes viral load when participant met virologic withdrawal.cHIV-1 baseline resistance testing was performed on integrated HIV-1 proviral DNA using GenoSure

Archive® assay (Monogram Biosciences, South San Francisco, CA). On-study resistance testing

used standard plasma-based genotypic and phenotypic resistance testing.dParticipants in the late-switch group. eResistance testing not performed because of low viral load.

DTG + RPV: Low Rates of CVW Through Week 100

• Cumulative AEs reported in the early-switch group were consistent with the

respective antiretroviral drugs

Results: safety and tolerability

Adapted from: Aboud et al. AIDS 2018;

Amsterdam, the Netherlands. Slides

THPEB047.

aPreferred term coding based on MedDRA version 20.1 rather than 19.1 used in the Week 48 analysis, wherein “cold” and

“common cold” changed in preferred term from “nasopharyngitis” to “viral upper respiratory tract infection.” bThere were no grade

2-4 drug-related AEs of ≥2% frequency in any group. cA participant might have had >1 AE that led to discontinuation. dGrouped

term includes multiple adverse events. Psychiatric AEs that led to discontinuation in the early switch group were anxiety (n=4),

suicidal ideation (n=4), insomnia (n=2), depression (n=2), affective disorder, depressed mood, nightmare, and completed suicide

(n=1 each); those in the late-switch group were insomnia (n=3), depression (n=2), abulia, confusional state, loss of libido, major

depression, and suicidal ideation (n=1 each).

Adverse Events (Grades 1-4) at Week 48 and Week 100

• All bone turnover biomarkers

were decreased from baseline

at Week 100 except

procollagen 1 N-terminal

propeptide in the early-switch

group

• DTG + RPV was associated

with a neutral effect on

atherogenesis and

inflammation biomarkers, with

no pattern of change noted at

Week 100

• No further changes at Week

100 compared with Week 48,

as previously presented1

Results: biomarker analyses (1)


Slides THPEB047.

Llibre et al. Lancet. 2018;391:839-849.aLast pre-switch data (usually Week 48) used for late-switch baseline. *P<0.05 vs

baseline. **P<0.001 vs baseline.

Bone Turnover Biomarkers at Week 48 and Week 100

• Improvements in renal tubular function, as measured by changes from baseline in urine

retinol-binding protein/creatinine ratio and urine beta-2 microglobulin/creatinine ratio

(not shown), were maintained at Week 100 in the early-switch group



Slides THPEB047.

Change From Baseline in Retinol-Binding Protein/Creatinine Ratios at Week 48 and Week 100

• No discernable pattern of changes from baseline in mean serum concentration of lipids

(total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein

cholesterol, or triglycerides) was noted in the early- or late-switch groups



Slides THPEB047.aLast pre-switch data (usually Week 48) used for late-switch baseline.

Total Cholesterol/HDL Cholesterol Ratio at Week 48 and Week 100

• Durable efficacy: high level of virologic suppression maintained through 100

weeks in the early-switch group

• Reproducible outcomes: 93% efficacy in the late-switch group (48 weeks after

switching to DTG + RPV), consistent with 95% efficacy in the early-switch

group at Week 48

• No CVWs with INSTI mutations; CVWs with NNRTI mutations rare (0.3%;

3/990 through Week 100), with minimal impact on future treatment options

• Safety profile of late-switch group similar to early-switch group 48 weeks post-

switch

• Switching to DTG + RPV had a favourable effect on renal tubular function as

evidenced by changes from baseline in retinol-binding protein/creatinine ratio

and beta-2 microglobulin/creatinine ratio

• Data through Week 100 support efficacy and safety of switching to once-daily

DTG + RPV for patients with HIV-1 on stable, suppressive 3- or 4-drug ART

Conclusions


Slides THPEB047.

Dolutegravir and Neural Tube

Defects (NTDs)

The data to be presented is in response to an unsolicited request.

This includes information on unlicensed indications.

UK/DGR/0016/18

Date of Preparation May 2018

• NTDs are congenital abnormalities affecting the brain, spine, or

spinal cord and result from failure of complete closure of the neural

tube, which usually occurs by Day 28 of pregnancy.

• Most common NTDs are spina bifida (usually compatible with life)

and anencephaly (usually incompatible with life).

• Diagnosis is through imaging or blood tests during pregnancy, or

made at birth.

• Risk factors include: Genetic factors, Folate/B12 deficiency,

Obesity, Diabetes, Medications (e.g. anti-epileptics)

• Prevalence rates of NTDs can vary widely between regions

– UK: 0.13%

– Europe: 0.09%

– USA: 0.02 – 0.2%

– India: 0.45%

– Africa: 0.05 – 0.75%

What are NTDs?

Wilde J et al Annu Rev Genet 2014;48:583-611; Relton C et al J Med Genet 2004;41:256-260; Morris JK et al http:dx.doi.org/10:1136/archdischild-2015-309226; Khoshnood

B et al. BMJ 2015;351:h5949; MMWR August 25,1995;44(SS-4):1-13; Allagh et al PLoS One 2015;10(3):e0118961; Zaganjor I et al PLoS One 2016;11(4):e0151586

• A number of data sources describe the use of DTG in pregnancy*:

– ViiV sponsored clinical trials: 74 pregnancies - no NTDs reported.

– Post-marketing reports: Approximately 500 pregnancy outcomes - 3 NTDs

reported.

– Non-ViiV Data: Approximately 4,150 pregnancies with approximately 880

exposed at time of conception. From the Botswana cohort: 4 NTDs with

exposure at conception, 1 NTD with exposure during pregnancy (8 weeks

GA).

* Due to potential for double reporting of individual cases into different sources,

these numbers should not be combined

DTG use in pregnancy: Additional data

ViiV Data on File

Surveillance for Neural Tube Defects following Antiretroviral Exposure from Conception

Rebecca Zash, Lewis Holmes, Joseph Makhema, Modiegi Diseko, Denise L. Jacobson, Gloria Mayondi, Mompati Mmalane, Lynne Mofenson, Tendani Gaolathe, Chipo Petlo, Max Essex, Shahin

Lockman and Roger L Shapiro

Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15

• The Tsepamo Study started in August 2014– Birth Outcomes Surveillance

– Funding: NIH/NICHD (R01, R Shapiro PI)

• Primary aims::– (1) Evaluate adverse birth outcomes by HIV-status and

ART regimen

– (2) Determine if there is an increased risk of neural tube defects (NTDs) among infants exposed to efavirenz (EFV) from conception

Background


Study Setting: Botswana

1. Ability to capture outcomes

• Antenatal record available at

delivery for >99% of women

• >95% of women deliver in a

healthcare facility

• Early termination extremely rare

2. Large # of exposures

• High HIV prevalence (~25%)

• High uptake of ART in pregnancy

(>90%)

• Multiple ART regimens in use

concurrently

• 52% start prior to conception


GHANZI

MAUN

SELEBI-PHIKWE

SEROWE

MAHALAPYE

MOLEPOLOLE

FRANCISTOWN

Study Population: Methods

Tsepamo takes place at 8 of the largest maternity wards in Botswana• ~45% of the total births in the

country

Research assistants abstract data from the obstetric cards for all in-hospital deliveries.


• Compared to EFV, no increased risk of adverse birth outcomes (stillbirth, preterm birth, small for gestational age, or neonatal death) among 1729 women who started DTG during pregnancy1

– No increased risk of major congenital abnormalities identified in the small number (N=280) who started DTG during the first trimester

Recent results from DTG started during pregnancy

1. Zash et al Lancet Global Health 2018;6:e804-810


Results: Neural Tube Defect by Exposure

Deliveries up to 1 MAY 2018• DTG at conception:

• 4/426 (0.94%; 95%CI 0.37%, 2.4%)• Non-DTG ART at conception:

• 14/11,300 (0.12%; 95%CI 0.07%, 0.21%) • EFV at conception:

• 3/5787 (0.05%; 95%CI 0.02%, 0.15%) • DTG started during pregnancy:

• 0/2812 (0.00%; 95%CI 0.0%, 0.13%) • Non-DTG ART started during pregnancy:

• 3/5624 (0.05%, 95% CI 0.02%, 0.16%)• HIV-uninfected

• 61/66057 (0.09%, 95%CI 0.07%, 0.12%) Adapted from: Zash R et al. IAC 2018; Amsterdam, The Netherlands. TUSY15

Neural Tube Defects on DTG at conception

• The 4 defects identified were all pre-specified as NTDs, and included: – encephalocele (with photo)

– anencephaly (no photo)

– myelomeningocele (with photo)

– iniencephaly (with photo)

• None of the women were reported to be on folate supplementation PRIOR to pregnancy – Botswana does not fortify grains with folate

• Review of maternal data found no other risk factor for NTD present

NEJM Botto 1999


0

5

10

Sep

t

Dec

Mar

Jun

e

Sep

t

Dec

Mar

Jun

e

Sep

t

Dec

Mar

Jun

e

Sep

t

Dec

Mar

Jun

e

Other

2014 2015 2016 2017 2018

• From 1 May-15 July, there were 2 more NTDs; 1 in an infant exposed to DTG started during pregnancy (8 weeks GA) and 1 birth to an HIV-uninfected woman- NTDs in DTG started in pregnancy: 1/3104 (0.03%, 95% CI

0.01%, 0.18%)

Update since 1 May 2018

Updated prevalence of DTG exposure at conception is 4/596 (0.67%, 95% CI 0.26%, 1.7%)-- 95% CI still does not overlap with any other exposure group


Updated Analysis Plan

• Next formal analysis will occur after 31 March 2019– Will include women already exposed to DTG from conception

prior to recent guideline change

– Plans in place to expand from 8 to 18 sites, increasing from 45% to 72% of births in the country

• Final analysis in 2019 to include:– NTDs

– All major malformations

– Other adverse birth outcomes (stillbirth, preterm, SGA, NND)


Projections for March 2019

• With expanded surveillance to 18 sites, we estimate ~ 1226 births with exposure to DTG from conception by end of March 2019

With 0 more NTDs, the lower CI overlaps with the upper CI for other ART at conception (0.21%), EFV at conception (0.15%) and with HIV-uninfected (0.13%)

With 1 more NTD, the lower CI overlaps with the upper CI for other ART at conception (0.21%)


Conclusion

• We have identified a concerning preliminary early signal for DTG and neural tube defects that requires further data to confirm or refute– Based on only 4 cases (though 95% confidence intervals do

not overlap with other exposure groups)

– Absolute prevalence difference is small (~ 0.8%)

– The 4 different defects among infants exposed to DTG at conception is unusual


Overview of ViiV Pipeline

Name

Medical Advisor

ViiV Healthcare

UK/HIVP/0004/18 March 2018

Key Ongoing Trials with DTG (Adults)

1. http://clinicaltrials.gov/ct2/show/NCT02227238; 2. http://clinicaltrials.gov/ct2/show/NCT02178592 3. https://clinicaltrials.gov/ct2/show/NCT02429791; 4. http://clinicaltrials.gov/show/NCT02422797

5. https://clinicaltrials.gov/ct2/show/NCT02831673; 6. https://clinicaltrials.gov/ct2/show/NCT02831764

3TC, lamivudine; ATV/r, atazanavir; c/mL, copies/mL; DTG, dolutegravir; FTC, emtricitabine; LPV, lopinavir; NRTI, nucleoside reverse transcriptase inhibitor; QD, once-daily; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate

N=125

N=612

N>500

each

N=700

each

Phase IIIb, randomised, open-label study to assess

the safety and efficacy of DTG or EFV in adults

starting treatment for rifampicin-sensitive TB

Phase IIIb, open-label, non-inferiority,

randomised, second-line study of:

• DTG 50 mg QD + 2 NRTIs

• LPV/r (800/200 mg QD or 400/100 mg BID) +

2 NRTIs

Phase III, randomised, open-label study to assess the safety

and efficacy of switching to DTG + RPV versus continuing

current antiretroviral regimen

Phase III, randomised, multicentre, non-inferiority studies to

evaluate the efficacy, safety, and tolerability of DTG + 3TC QD

versus DTG + TDF/FTC FDC over 148 weeks5,6

INSPIRING2

Treatment-naïve,

TB co-infected

DAWNING1

Treatment-experienced,

failing on first-line

therapy

SWORD-13 and

SWORD-24

Virologically

suppressed adults

GEMINI 15 and 26

Treatment-naïve adults

Trials Starting in 2018-19 with DTG (Adults)

N=600

N=766

Phase III, randomised, non-inferiority study to assess the safety and efficacy of switching to DTG + 3TC versus continuing witha triple therapy regimen

Phase III, randomised, non-inferiority study to assess the safety and efficacy of switching to DTG + 3TC versus continuing with a triple TAF-containing regimen

Study 2080902

Treatment-experienced, stable patients

TANGO1

Treatment-experienced,stable patients

1. ViiV Healthcare. TANGO Protocol 2. ViiV Healthcare. Study 208090 Protocol

2017 20192018 2020

SWORD

SWORD DEXA W48

Anticipated Data Readouts

W144

GEMINI

W144W96W48

W24 W96W48 W144

Tango W48 W96

DAWNING

INSPIRING W24 W48

W24

First available congress presentation =

Interim Analysis=

Key Ongoing Trials with DTG (Paediatrics)

1. http://clinicaltrials.gov/show/NCT01302847; 2. Hazra R, et al. IAS 2012. Abstract TUAB0203 3. Viani RM, et al. Pediatr Infect Dis J 2015;34:1207–13; 4. https://clinicaltrials.gov/ct2/show/NCT02259127

PK, pharmacokinetics

N=700

N=160

Phase II/III, open label, multicentre, randomised (1:1), non-inferiority clinical trial in paediatric subjects (≥6–18 years) of first- or second-line: • DTG QD + 2 NRTIs vs • SOC (NNRTI or PI + 2 or 3 NRTIs)

Phase I/II, multicentre, open-label, non-comparative intensive PK andsafety study in paediatric subjects aged ≥4 weeks–<18 years(in age descending cohorts) receiving DTG as tablets or paediatric formulation

ODYSSEY4

ARV-naïve or experienced (first- or second-line)

paediatric

P10931–3

Treatment-experienced, INI-naïve paediatric

ViiV Healthcare: HIV Pipeline

ViiV Healthcare, Available from: https://www.viivhealthcare.com/our-medicines/medicines-in-development.aspx Accessed February 2018LA, long-acting; IM, intramuscular

Product Class Phase

DTG + RPV INSTI + NNRTI III

DTG + 3TC INSTI + NRTI III

LA CAB + LA RPV* (for IM injection)

INSTI + NNRTIIII

(for treatment of HIV infection)

LA CAB (for IM injection)

INSTIIII

(for prevention of HIV infection)

Fostemsavir Attachment inhibitor III

Combinectin(GSK3732394)

Entry Inhibitor Pre-clinical

GSK3640254 Maturation Inhibitor I

https://www.viivhealthcare.com/our-medicines/medicines-in-development.aspx

Cabotegravir nanosuspension

• Drug crystal suspended in aqueous vehicle

• Nanomilled to increase surface area and drug dissolution rate

– Wet bead milling with terminal sterilisation by gamma irradiation

• Higher drug loading versus matrix approaches for lower injection volume

16th HIV-HEPPK Müller RH et al. Eur J Pharm Biopharm 2011:78;1–959

CAB LA 200 mg/mL

Component Function

Cabotegravir free acid(d50 ~200 nm)

Active drug

Mannitol Tonicity agent

Surfactant system Wetting agent/stabiliser

Water for injection Solvent

16th European AIDS Conference; October 25-27, 2017; Milan, Italy

gp160

gp120 trimer gp41 trimer

CD4 binding site

CD4 receptor

CCR5/CXCR4

TemsavirTemsavir binds near

the CD4 binding site

Temsavir prevents gp120 conformational change, inhibiting HIV-1 attachment

Attachment inhibited

Temsavir Proposed Mode of Action

Conceptualization and Design by Max Lataillade (ViiV Healthcare) and John Wong (Nucleus Global), funded by ViiV Healthcare

16th European AIDS Conference; October 25-27, 2017; Milan, Italy

Viruses accumulate in

extracellular space

and are subsequently

removed by the host

immune system

Viruses accumulate in

extracellular space…

Conceptualization and Design by Max Lataillade (ViiV Healthcare) and John Wong (Nucleus Global), funded by ViiV Healthcare

ViiV Healthcare: Pipeline

• *Investigational treatments; †Subject to validation by appropriate regulatory authorities

• CAB, cabotegravir; RPV, rilpivirine

Long-acting two-drug regimensCAB + RPV*

PreventionCabotegravir*

Search for remission

and cureCollaborations

Advanced therapeutics Tivicay®

Legacy ARV drug portfolio Epzicom/Kivexa®

and Celsentri/Selzentry®

Dolutegravir regimensTriumeq®

Two-drug regimensDTG/RPV

DTG/3TC

Attachment inhibitor*† for heavily

treatment-experienced patients

Maturation inhibitor*† with possible

combinations with DTG and/or CAB

Next-generation*† agents

DTG and Weight Gain – Summary

See slide notes for references

• Weight gain has been associated with ARV use,1–6 and is mentioned in the SmPCs of many

commonly used ARVs7–18

• Increased weight is not mentioned in the Tivicay (DTG) SmPC19

• Despite ART-related weight gain, HIV-positive patients generally have similar or lower weight

than HIV-negative persons of a similar age5,6,20

• Data are not available to determine whether observed weight gain is reflective of a return to

health or is clinically significant

• Data on weight gain with DTG are limited, largely consisting of case reports21 and

retrospective, observational studies22–24

• Two comparative studies reported weight/BMI gain with DTG-based regimens23,24

‒ One large study found significant BMI increases after 12 months of treatment with DTG, EVG,

RAL, DRV and RPV, with little difference between them23

‒ Another study found significantly greater weight gains with INI- or PI-based regimens versus EFV,

with most notable increases after 18 months of DTG/ABC/3TC24

• In a post-hoc weight analysis of the NEAT-022 study in virologically suppressed patients with high

CV risk, switch from Pl/r to DTG was associated with a small but statistically significant weight &

BMI gain over 48 weeks; risk of weight gain was higher amongst individuals switching from

darunavir/r vs other protease inhibitors.25

• Weight changes will continue to be monitored and evaluated in current and future DTG RCTs

Weight/BMI Gain in ART-naïve

Patients: Summary

ACTG, AIDS Clinical Trial Group; INI, integrase inhibitor

Adapted from: 1. Lakey W, et al. AIDS Res Hum Retroviruses 2013;29:435–40; 2. Erlandson KM, et al. AIDS 2013;27:2069–79. 3. Bhagwat P, et al. CROI 2017. Poster 695; 4. McComsey GA, et al. Clin Infect Dis 2016;62:853–62. . Bakal D, et al. J

Antimicrob Chemother 2018;73:2177–85; 6. Nguyen A, et al. HIV Med 2008;9:142–150

Group Duration

Weight Change

(kg)

BMI change

(kg/m2)

Significant change

from baseline

Duke clinic1 (HIV+ n=92)

Overall

12 months

+4.4 +1.5

All significantly

increased

Women +8.6 –

Men +3.6 –

PI/r +9.0 –

Non-PI/r +2.7 –

ACTG 5224s Substudy A52022

(N=269)Overall 96 weeks +4.8 – Significantly increased

ATV/r

versus EFV96 weeks Difference +3.35

Difference

+0.88

Significantly greater

gains with ATV vs EFV

ACTG 52573 (N=1,809)Overall 96 weeks +3.8 +1.3

Greater risk of severe weight gain with RAL vs ATV/r (p=0.0427) or DRV/r (p=0.0555)

ACTG 5260s Substudy A52574

(N=328)

Overall 96 weeks – +3.8–4.7%

No significant difference between ATV/r, DRV/r or RAL

Brazil5 (N=1,794)

Overall

Median 4.1

years

– +2.4 Significantly increased

INI – +1.6INI use associated with

development of obesityPI/r – +0.4

NNRTI – +0.4

Swiss Cohort6 (N=5,427) ATV and LPV associated with risk of >5 kg weight gain (DRV and INIs not tested)

Published

Literature

ART-naive

Weight/BMI Gain in ART-experienced

Patients: Summary

Published

Literature ART-

experienced

Adapted from: 1. Currier J, et al. AIDS Patient Care STDS 2011;25:333–40; 2. Menard A, et al. AIDS.2017;31:1499–1500

3. Taramasso L, et al. Open Forum Infect Dis 2017;4:ofx2394. Norwood J, et al. J Acquir Immune Defic Syndr 2017;76:527–31

Group Duration

Weight change

(kg)

BMI change

(kg/m2)

Significant change

from baseline

GRACE1

DRV/r + OBT (N=429)

Women 48

weeks

+3.2 +1.2 Significant in women

not menMen +1.8 +0.5

Marseille2

DTG (N=462)

OverallMean

276 days

+3 +1Significant in women

not menWomen +4 +2

Men +2 +1

SCOLTA3

(N=1118)

DRV

12

months

– +0.48

All significantly

increased

DTG – +0.37

EVG – +0.42

RAL – +0.36

RPV – +0.30

Vanderbilt4

(N=495)

EFV

18

months

+0.9 –

Significant increase

with INI versus EFV

INI +2.9 –

PI/r +0.7 –

DTG/ABC/3TC +5.3

RAL or EVG +2.8

GRACE, Gender, Race And Clinical Experience; /r, ritonavir boosterSCOLTA, surveillance cohort long-term toxicity antiretrovirals

Questions?

Documents

UK CAB 2018 · Reduced cost9,10 • Reduced drug costs, and long-term care/societal costs • Improvements in access Improved quality of life11 • Improvements in patient satisfaction