RESEARCH

Kirsten White

Gilead Sciences, Inc., Foster City, CA

B/F/TAF in Treatment-Naïve HIV-1 and

HIV-1 RNA Suppressed Switch Patients

‡

Background

▪ Bictegravir (BIC; B) is a novel, unboosted integrase strand transfer inhibitor (INSTI)

▪ Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single tablet regimen (STR) recently approved by the US FDA for treatment of HIV-1 infection in treatment-naïve and virologically suppressed adults without resistance to its components

▪ Two Phase 3 studies of treatment-naïve participants (1489 and 1490)

▪ Two Phase 3 studies of virologically suppressed participants (1844 and 1878)

▪ No development of resistance to B/F/TAF

‡

Outline

▪ BIC In Vitro Resistance Profile

▪ Efficacy Outcomes at Week 48

▪ Pre-Existing Resistance Substitutions and B/F/TAF Treatment Outcomes

▪ Future Clinical Trials of B/F/TAF

‡

Bictegravir has a Favorable Cross-Resistance Profile

HIV-1 PhenoSense IN Assay with Integrase Site-Directed Mutations

Single Primary Mutations

IN GenotypeFold Change vs WT

BIC DTG EVG RAL

T66I 0.3 0.4 15 1.1

T66A 0.4 0.4 11 1.2

T66K 1.4 2.1 50 9.8

E92Q 1.2 1.4 29 4.9

E92G 1.3 1.7 16 2.1

T97A 0.6 0.6 3.8 1.6

F121Y 0.4 0.6 16 5.3

Single Primary Mutations

IN GenotypeFold Change vs WT

BIC DTG EVG RAL

Y143R 1.3 1.2 3.4 16.0

Y143H 0.9 1.1 1.6 2.5

Y143C 0.9 0.9 2.2 4.3

S147G 1.0 1.0 5.8 1.3

Q148R 0.7 0.6 109 28

Q148H 0.7 0.8 8.7 4.3

Q148K 0.9 0.6 119 41

N155H 1.3 1.4 44 13

R263K 1.7 1.7 4.5 1.2

Margot et al.; Submitted

< 2.5 BIC ≥ 10 BIC2.5 to < 10 BIC

EC50 Fold Change (FC) vs Reference Wild Type

< 4.0 DTG 4.0 to < 13 DTG ≥ 13 DTG

< 2.5 EVG< 1.5 RAL

≥ 2.5 EVG≥ 1.5 RAL

‡

• BIC has an improved resistance profile compared to DTG (p=0.037)

White K, et al., European Workshop HIV & Hep 2016. Rome, Italy. Poster O-01. Tsiang M, et al., AAC 2016;60:7086-7097.

Bictegravir has a Favorable Cross-Resistance Profile

< 2.5 BIC ≥ 10 BIC2.5 to < 10 BIC

EC50 Fold Change (FC) vs Reference Wild Type

< 4.0 DTG 4.0 to < 13 DTG ≥ 13 DTG

< 2.5 EVG< 1.5 RAL

≥ 2.5 EVG≥ 1.5 RAL

G140A/C/S + Q148H/R/K +/- other

IN Genotype

Fold Change

vs WT

DTG BIC

G140S,Q148H 3.44 2.12

G140S,Q148H 3.52 2.03

G140S,Q148H 3.59 2.42

G140S,Q148H 3.60 1.99

G140S,Q148H 4.00 2.17

E138K,G140S,Q148H 4.73 2.46

G140S,Q148H 5.56 2.49

G140A/C/S + Q148H/R/K +/- other

IN Genotype

Fold Change

vs WT

DTG BIC

E138K,G140S,Q148H 5.34 2.52

G140S,Q148H 5.46 2.92

G140S,Q148R 6.15 3.01

E138K,G140C,Q148R 8.58 5.32

L74L/M,G140A,Q148R 8.81 5.38

L74M,G140C,Q148R 9.06 8.36

L74L/M,G140A,Q148R 8.81 5.38

L74M,G140C,Q148R 9.06 8.36

E138A, G140S,Q148H 10 7.23

G140S,Q148H 11 3.81

G140A/C/S + Q148H/R/K +/- other

IN Genotype

Fold Change

vs WT

DTG BIC

E138K,G140S,Q148H 13 2.62

G140S,Q148H 13 4.37

T97A,G140S,Q148H 14 7.62

T97A,G140S,Q148H 15 4.39

G140S,Q148R 17 7.05

E138K,G140A,Q148K 63 19

HIV-1 PhenoSense IN Assay with Clinical Isolates

‡

B/F/TAF Phase 3 Efficacy through Week 48

* For ART-naïve studies: Treatment outcomes [between treatment groups] were similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count.6

† For virologically suppressed studies: Treatment outcomes between treatment groups were similar across subgroups by age, sex, race, and region.5,6

‡ One boosted PI regimen participant on DRV+RTV+ABC/3TC developed ABC mutation L74V

** One E/C/F/TAF participant developed FTC mutation M184M/I/V

1. Gallant J, et al. Lancet 2017;390:2063-72.2. Sax P, et al. Lancet 2017;390:2073-82.3. Molina JM, et al. CROI 2018. Boston, MA. Oral 22

4. Daar E, et al. ID Week 2017. San Diego, CA. Oral LB-4

5. Kityo C, et al. CROI 2018. Boston, MA. Poster 500.

6. Gilead Sciences. Biktarvy US Prescribing Information. February 2018.

In five Phase 3 trials of 1,440 patients through Week 48

B/F/TAF had non-inferior efficacy with zero emergent resistance

Study Population Comparator Efficacy Resistance

14891 Naïve DTG/ABC/3TC Non-inferior* 0

14902 Naïve DTG+FTC/TAF Non-inferior* 0

18443 Suppressed DTG/ABC/3TC Non-inferior† 0

18784 Suppressed Boosted PI + 2 NRTIs Non-inferior† 0‡

19615 Women,

Suppressed

E/C/F/(TAF or TDF)

ATV+RTV + FTC/TDFNon-inferior† 0**

‡

Rapid Suppression of HIV-1 RNA to < 50 copies/mL (Missing = Excluded Approach); 1489 & 1490

B/F/TAF vs. DTG/ABC/3TC or vs. DTG + F/TAF: rapid viral suppression

and non-inferior efficacy at Week 48

Week 4

76%

76%

80%

Week 8

91%

92%

90%

Week 12

96%

96%

95%

Week 48

99% B/F/TAF

98% DTG/ABC/3TC

99% DTG+F/TAF

0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

W e e k

Pro

po

rti

on

wit

h

HIV

-1 R

NA

<5

0 c

op

ies

/mL

(%

)

B /F /T A F

D T G /A B C /3 T C

D T G + F /T A F

4 8 12 24 36 48

‡

Baseline Resistance Testing

White K, et al . CROI 2018. Boston, MA. Poster 532, Andreatta et al, CROI 2018 Boston, MA. Poster 506

No IN Genotype

Screening

PR, RT GenotypeGenoSure MG

Monogram

Tx Naïve

1489

1490

Switch

1844

1878

Historical Genotype if availablePR, RT, IN

Retrospective Baseline Testing

PR, RT, INDeep SequencingSeqIT, Germany

≥15% frequency reported

PR, RT, IN DNA GenotypeGenoSure Archive*

Monogram

*Deep sequencing

APOBEC hypermutation filter

>15% frequency reported

‡

Baseline Resistance-Associated Substitutions & FDA Snapshot Outcome

White K, et al . CROI 2018. Boston, MA. Poster 532

Resistance Class

Number of Participants, n (%)

B/F/TAF

n=634

Week 48

HIV-1 RNA <50 c/mL

With Data 634 (100%) 576/634 (91%)

Primary INSTI-R 6 (1.0%) 6/6 (100%)

T97A 5 (0.8%) 5/5 (100%)

Q148H (+G140S) 1 (0.2%) 1/1 (100%)

Primary NRTI-R 16 (2.5%) 14/16 (88%)

Any TAM 16 (2.2%) 14/16 (88%)

Primary NNRTI-R 76 (12%) 68/76 (90%)

K103N/S 41 (6.5%) 38/41 (93%)

E138A/G/K/Q 24 (3.8%) 21/24 (88%)

Primary PI-R 16 (2.5%) 15/16 (94%)

Studies 1489 & 1490: B/F/TAF vs DTG-containing Regimens in Treatment-Naïve Adults

‡B/F/TAF Patient With Transmitted Resistance: Baseline

White K, et al . CROI 2018. Boston, MA. Poster 532

‡B/F/TAF Patient with Transmitted Resistance: Baseline

(2.5 – 10)

Baseline Genotype:NRTI: K70RNNRTI: K103NPI: noneINSTI: G140S, Q148H

This is the first case of an ART-naïve patient with transmitted integrase resistance (G140S + Q148H) on

B/F/TAF

Virologic suppression was rapidand maintained from Week 4 to 96

3 8 0 -1 4 8 9 -1 6 2 7

B /F /T A F

V is it D a te (W e e k s )

Pla

sm

a H

IV-1

RN

A (

co

pie

s/m

L)

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6

1 0

1 0 0

1 0 0 0

1 0 0 0 0

1 0 0 0 0 0

1 0 0 0 0 0 0

50

‡

Baseline Resistance Data

Andreatta K, et al . CROI 2018. Boston, MA. Poster 506

Resistance Class

Number of Participants, n (%)

B/F/TAF

n=572

PR/RT Baseline Data 405 (71%)

Historical Genotype 280 (49%)

Baseline DNA Genotype 149 (26%)

IN Baseline Data 170 (30%)

Historical Genotype 23 (4%)

Baseline DNA Genotype 149 (26%)

Studies 1844 & 1878: Suppressed Adults Switched from ABC/3TC/DTG or Boosted PI

‡

Baseline Resistance-Associated Substitutions & FDA Snapshot Outcome

Andreatta K, et al . CROI 2018. Boston, MA. Poster 506

Resistance Class

Number of Participants, n (%)

B/F/TAF

n=572

Week 48

HIV-1 RNA <50 c/mL

Primary INSTI-R 1 (1.0%) 1/1 (100%)

T97A 1 (1.0%) 1/1 (100%)

Primary NRTI-R 52 (13%) 49/52 (94%)

K65R 5 (1%) 5/5 (100%)

M184V/I 30 (7%) 28/30* (93%)

Any TAM 29 (7%) 28/29 (97%)

Primary NNRTI-R 73 (18%) 71/73 (97%)

K103N/S 46 (11%) 44/46 (96%)

Primary PI-R 25 (6%) 25/25 (100%)

Studies 1844 & 1878: Suppressed Adults Switched from ABC/3TC/DTG or Boosted PI

• M184V/I: 1 discontinued with HIV-1 RNA <50 c/mL at Week 4 and 1 had rebound at Week 8 and no detectable BIC in the plasma

‡

4030 Study Design

Study 4030: B/F/TAF vs DTG + F/TAF or F/TAF in Suppressed Adults

Phase 3, randomized, double-blind, multicenter, active-controlled study

Primary Endpoint

• HIV-1 RNA ≥50 copies/mL at Week 48 by modified FDA-defined snapshot algorithm

(4% non-inferiority margin)

Treatment Naïve Patients

Study 102 and 103

HIV-Suppressed Adults

DTG + F/TDF or F/TAF

HIV-1 RNA < 50 c/mL

eGFRCG ≥ 30 mL/min

Primary Endpoint

1:1

Week 48

B/F/TAF QD

B/F/TAF Placebo QD

DTG + F/TAF Placebo QD

DTG + F/TAF QD

N=260

N=260

Key inclusion criteria• Any NRTI, NNRTI or PI resistance are permitted

• HIV-1 <50 c/mL ≥ 6 months if documented or suspected NRTI resistance• HIV-1 <50 c/mL ≥ 3 months if no NRTI resistance suspected or documented

• No documented resistance to INSTI or confirmed virologic failure (2 consecutive HIV-1 RNA ≥ 50 c/mL after achieving < 50 c/mL while on an INSTI-containing regimen)

• HBV and/or HCV coinfections allowed

‡

ClinicalTrial.gov: NCT03110380

‡

Conclusions

▪ ARV-naïve: Treatment with B/F/TAF, DTG/ABC/3TC, or DTG + F/TAF was highly efficacious through Week 48 – Rapid viral load suppression by Week 4

▪ Pre-existing drug resistance did not affect efficacy outcome– One patient with transmitted INSTI resistance at G140S+Q148H treated with

B/F/TAF achieved HIV-1 RNA was < 50 copies/mL at Week 4 and maintained suppression through Week 96

▪ ARV Suppressed Switch: Switch to B/F/TAF from DTG +ABC/3TC or Boosted PI was highly efficacious through Week 48

▪ Pre-existing drug resistance did not affect efficacy outcome– High maintenance of suppression with M184V/I or 1-2 TAMs

▪ No patient developed resistance to study drugs on B/F/TAF or a DTG-based regimen

▪ Further studies of bictegravir and B/F/TAF in patients with virologic resistance are warranted

‡

Acknowledgements

▪ Patients and their families

▪ Study Investigators and Site Staff

▪ Gilead Sciences

– B/F/TAF Team, Erin Quirk, Hal Martin, Devi Sengupta, Hiba Graham, Sean Collins, Huyen Cao, Tariro Makadzendge

– Clinical Virology: Rima Acosta, Kristen Andreatta, Madeleine Willkom, Danielle Porter, Nicolas Margot

▪ Seq-IT: Martin Daümer, Alex Thielen

▪ Monogram: Tim Persyn

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