Phase 2 of new ARVs Fostemsavir - PowerPoint Presentation

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Phase 2 of new ARVs

Fostemsavir

,

prodrug

of

temsavir

(

attachment inhibitor)

AI438011 Study

TAF (TFV

prodrug

)

Study 292-0102

Study 299-0102

Doravirine (non nucleoside reverse transcriptase inhibitor)

MK1439007 Study

Cabotegravir (integrase inhibitor)

LATTE Study

BMS-955176 (maturation inhibitor)

AI468002 Study

Design

Objective

Primary endpoint : non inferiority of D/C/F/TAF at W24: % HIV RNA < 50 c/

mL

by intention to treat, snapshot analysis (lower margin of the 2 sided 95% CI for the difference = -12%)

Secondary endpoints : HIV RNA < 50 c/mL at W48, safety, tolerability

D/C/F/TAF STR 800/150/200/10 mg QDDRV 400 mg x 2 + COBI + F/TDF placebos QD

DRV 400 mg x 2 + COBI 150 mg + F/TDF 200/300 mg QDD/C/F/TAF STR QD placebo

Randomisation*2 : 1Double-blind

Adults ≥ 18 yearsARV-naïve HIV RNA > 5,000 c/mLCD4 cell count > 50/mm3eGFR ≥ 70 mL/minSensitive to DRV, FTC and TDF

* Randomisation was stratified by HIV RNA (< or > 100,000 c/mL) and race (black or nonblack)

Study GS-US-299-0102: D/C/F/TAF QD STR vs DRV + COBI + F/TDF QD

N = 50

N = 100

W24

W48

Mills A,

JAIDS 2015; 69: 439-45

GS-US-299-0102

D =

darunavir

; C =

cobicistat

; F = FTC

D/C/F/TAF

N = 103

DRV + COBI

+ F/TDF

N = 50

Median age, years

31

36

Female

8%6%

Black

35%

34%

HIV RNA (log

10

c/

mL

), median

4.7

4.6

HIV RNA > 100,000 c/

mL

22%

14%CD4 cell count (/mm3), median368433CD4 < 200 per mm310.7%20%eGFR (Cockroft-Gault), mL/min, median116110Discontinuation by W4819 (18%)8 (16%)For investigator’s discretion10For adverse event22Lost to follow-up / Withdrew consent10 / 44 / 2Non-compliance20

Baseline characteristics and patient disposition

Study GS-US-299-0102: D/C/F/TAF QD vs DRV + COBI + F/TDF QD

Mills A, JAIDS 2015; 69: 439-45

GS-US-299-0102

Response to treatment

HIV RNA < 50 c/

mL

, ITT, snapshot analysis

D/C/F/TAF

DRV + COBI + F/TDF

171/196174/19596/112

104/117703/753680/75025

50

1007574.8

74.0%

Adjusted

difference(95% CI)

= 3.3% (- 11.4 ; 18.1)

76.7

84.0

Primary analysis, W24

(Overall)

0

W48

Adjusted

difference

(95% CI)

= -6.2% (- 19.9 ; 7.4)D/C/F/TAFDRV + COBI+ F/TDFVirologic failure16%12%No data8%4%Outcome at W48D/C/F/TAFDRV + COBI+ F/TDFW24+ 186+ 139W48+ 231+ 212p : not significantCD4/mm3 responseStudy GS-US-299-0102: D/C/F/TAF QD vs DRV + COBI + F/TDF QDMills A, JAIDS 2015; 69: 439-45GS-US-299-0102

Study GS-US-299-0102: D/C/F/TAF QD

vs

DRV + COBI + F/TDF QD

D/C/F/TAF

N = 103

DRV + COBI + F/TDF

N = 50

Virologic failure6 (5.8%)

2 (4%)

No emergence of resistance to TDF, FTC or DRVCriteria for resistance testing

Confirmed virologic failure : 2 consecutive HIV RNA > 50 c/mL and an HIV RNA > 400 c/mL at or after W8

Second, confirmatory, sample, tested for resistance

Resistance data at week 48

Mills A, JAIDS 2015; 69: 439-45

GS-US-299-0102

D/C/F/TAF

DRV + COBI + F/TDF

Grade 3-4 AE

6.8%

8.0%

AEs (all grades) in ≥ 10% of patients in either group

Diarrhea

21.4%

26%

Upper respiratory tract infection

15.5%

14%

Fatigue

13.6%

18%

Nausea

12.6%

10%

Rash

11.7%

8%

Flatulence

4.9%

12%Pain in extremity7.8%10%Vitamin D deficiency1.9%10%Vomiting3.9%10%Serious AEs4.9%4.0%AE leading to discontinuationN = 2Rash;Substance dependanceN = 2Worsening of diarrhea ;Proximal renal tubulopathyStudy GS-US-299-0102: D/C/F/TAF QD vs DRV + COBI + F/TDF QDAdverse events by W48Mills A, JAIDS 2015; 69: 439-45GS-US-299-0102

Renal outcome at W48

D/C/F/TAF

DRV + COBI + F/TDF

P

Mean (95% CI) change from baseline

in

creatinine

, mg/dL

+ 0.06 (0.04 - 0.08)

+ 0.09 (0.05 - 0.14)0.053Median decrease in

eGFR (

Cockroft-Gault),

mL/min

-2.9

-10.6

0.017

Median change in urine retinol binding protein/

creatinine

ratio, mg/g

+ 9%

+ 54%

0.003

Median change in urine beta-2

microglobulin/creatinine ratio, mg/g-42%+2.3%0.002Median change in urine albumin/creatinine ratio, mg/g-13.1%-22.6%0.17Median change in urine protein/creatinine ratio, mg/g-8.22%-27.52%0.19Median change in fractional excretion of phosphates+ 2.4%+ 1.8%nsEmergent dipstick proteinuria32%34%nsStudy GS-US-299-0102: D/C/F/TAF QD vs DRV + COBI + F/TDF QDMills A, JAIDS 2015; 69: 439-45GS-US-299-0102

Mean

percentage

change

from

baseline in bone mineral density (DEXA)

Total hipLumbar spineBone sub-study outcome at W48

D/C/F/TAFDRV + COBI + F/TDF

P

BMD decline > 3% in hip18.3%61.7%

< 0.001

BMD decline > 3% in lumbar spine

32.5%

55.3%

0.002

P1NP (bone formation) increase

+ 4.7%

+ 52.5%

< 0.001

CTx

(bone

resorption

) increase

+ 23.2%+ 74.4%< 0.001P1NP : pro-collagen Type 1 N-terminal propeptide ; CTx : C-terminal telopeptideStudy GS-US-299-0102: D/C/F/TAF QD vs DRV + COBI + F/TDF QDMills A, JAIDS 2015; 69: 439-45GS-US-299-0102D/C/F/TAFDRV + COBI + F/TDFW24W48W24W48-0,53-0,84-2,09-3,82-1,09-1,57-3,82-3,62P < 0,001P = 0,003P < 0,001P < 0,001

Median change in fasting metabolic parameters at Week 48

D/C/F/TAF

DRV + COBI + F/TDF

P

Total cholesterol, mg/dL

+ 40

+ 5

< 0.001

LDL-cholesterol, mg/

dL

+ 26

+ 4

< 0.001

HDL-cholesterol, mg/dL

+ 7

+ 3

0.009

Total cholesterol:HDL-cholesterol ratio

0.0

-0.2

0.15

Triglycerides, mg/dL

+ 29

-50.007Serum glucose, mg/dL+ 5+ 70.33Initiation of lipid lowering agent by W486.8%8%Study GS-US-299-0102: D/C/F/TAF QD vs DRV + COBI + F/TDF QDMills A, JAIDS 2015; 69: 439-45GS-US-299-0102

Study GS-US-299-0102: D/C/F/TAF QD

vs

DRV + COBI + F/TDF QD

Mills A, JAIDS 2015; 69: 439-45

GS-US-299-0102

Conclusion

D/C/F/TAF had significantly improved renal and bone safety parameters than DRV + COBI + F/TDF in antiretroviral-naïve, HIV-1 infected subjects : Less proteinuriaLess change in hip and spine BMDStudy limitationsSmall sample sizeEach participant had to take 5 tablets (double-blind) not optimal for patient’s adherence and retention in the studyFew women enrolled

This D/C/F/TAF STR offers a promising option for initial HIV treatment, withThe high barrier to resistance of DRVAnd the potential for improved long-term renal and bone safety with TAF