nuevos fármacos antiretrovirales - fls-science.com · dtg and abc/3tc jean-michel molina, 1...

Nuevos fármacos

antiretrovirales

Pere Domingo

Malalties Infeccioses

Hospital de la Santa Creu i Sant Pau

Institut del Recerca del HSCSP

Universitat Autonòma de Barcelona

[email protected]

Vacas flacas/lineales

INsTI

Bictegravir switch (Study 380-1844 ) #A022

Bictegravir swicth women (#500)

Bictegravir in adolescents (#844)

ITINAN

Switch a RPV/F/TAF (#504)

Doravirina, Drive-Ahead (#491)

ITIAN

EFdA (MK-8591)(#26, #89LB)

Anticuerpos monoclonales

Ibalizumab (# 561)

ARVs long acting

Implante SC (TAF, #486)

Nanoformulados

MVC, #48, #483

FTC, #484

CBV+RPV, #485

DRV/r, #480

3D (LPV, EFV, TFV) #487

4D (LPV/r, 3TC, TFV) #488

Switch to Bictegravir/F/TAF From DTG and ABC/3TC

Jean-Michel Molina,1 Douglas Ward,2 Indira Brar,3 Anthony Mills,4 Hans Jürgen Stellbrink,5 Luis

López-Cortés,6 Peter Ruane,7 Daniel Podzamczer,8 Cynthia Brinson,9 Joseph Custodio,10 Hui Liu,10

Kristen Andreatta,10 Hal Martin,10 Andrew Cheng,10 Erin Quirk10

1Hôpital Saint Louis, Paris, France; 2Dupont Circle Physicians, Washington DC; 3Henry Ford Hospital, Detroit, MI; 4Southern

California Men’s Medical Group, Los Angeles, CA; 5ICH Study Center, Hamburg, Germany; 6Unidad Clínica de Enfermedades

Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla,

Spain; 7Peter J. Ruane, MD Inc., Los Angeles, CA; 8Hospital Universitari de Bellvitge, Barcelona, Spain; 9Central Texas Clinical

Research, Austin, TX; 10Gilead Sciences, Inc., Foster City, CA

CROI 2018, Abstract 022 March 4–7, 2018 Boston, MA

Study 380-1844: Design

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

(NCT02603120): North America, Europe, Australia

Primary endpoint: proportion with HIV-1 RNA ≥50 copies/mL at Week

48

– Noninferiority margin of 4% based on FDA snapshot algorithm

8 *Could be components of single-tablet regimen. OLE, open label extension.

Week 0 48

HIV-suppressed adults on regimen

containing DTG, ABC & 3TC*

HIV-1 RNA <50 copies/mL for ≥3 mo

eGFRCG ≥50 mL/min

No active HBV infection

No known resistance to study drugs

DTG/ABC/3TC placebo qd

B/F/TAF 50/200/25 mg qd

B/F/TAF Placebo qd

DTG/ABC/3TC 50/600/300 mg qd

n=282

n=281

Primary Endpoint

1:1

OLE B/F/TAF

OLE B/F/TAF

Baseline Characteristics Study 380-1844

B/F/TAF

n=282

DTG/ABC/3TC

n=281

Median age, years (range) 47 (21-71) 45 (20-70)

Male, % 88 90

Race, %

White 73 73

Black or African descent 21 22

Hispanic/Latino Ethnicity, % 16 19

Median CD4 cell count, cells/µL

(IQR) 732 (554,936) 661 (478,874)

Median eGFRCG, mL/min (IQR) 101(84,119) 101(85,122)

Virologic Outcome at Week 48 Study 380-1844

Switching to B/F/TAF was noninferior to remaining on DTG/ABC/3TC

10

Treatment Difference in RNA ≥50, % (95.002% CI)

-1.0 2.8

0.7

-4% 4%0

Favors

B/F/TAF

Favors

DTG/ABC/3TC

1.1

93.6

5.30.4

95.0

4.6

0

20

40

60

80

100

HIV-1 RNA

<50 c/mL

HIV-1 RNA

≥50 c/mL

No Virologic

Data

3

282

1

281

264

282

267

281

13

281

15

282

DTG/ABC/3TC (n=281)

B/F/TAF (n=282)

Virologic Outcome

Pa

tie

nts

, %

p=0.59

p=0.62

Virologic Outcome at Week 48 Study 380-1844

Switching to B/F/TAF was noninferior to remaining on DTG/ABC/3TC

No participant developed treatment-emergent resistance

11

Treatment Difference in RNA ≥50, % (95.002% CI)

-1.0 2.8

0.7

-4% 4%0

Favors

B/F/TAF

Favors

DTG/ABC/3TC

1.1

93.6

5.30.4

95.0

4.6

0

20

40

60

80

100

HIV-1 RNA

<50 c/mL

HIV-1 RNA

≥50 c/mL

No Virologic

Data

3

282

1

281

264

282

267

281

13

281

15

282

DTG/ABC/3TC (n=281)

B/F/TAF (n=282)

Virologic Outcome

Pa

tie

nts

, %

p=0.59

p=0.62

Adverse Events Leading to Study Drug Discontinuation Study 380-1844

2 deaths occurred in the B/F/TAF arm, unrelated to study medication:

– Male, 71 years old: sudden death, atherosclerotic CVD on autopsy

– Female, 46 years old: alcohol and opioid toxicity

12

*Not considered related to study treatment by investigator.

Patients, n (%)

B/F/TAF

n=282

DTG/ABC/3TC

n=281

Overall 6 (2) 2 (1)

Headache 2 1

Vomiting 1 0

Cerebrovascular

accident 1 0

Abnormal dreams 1 0

Suicidal ideation* 1 0

Pruritis 0 1

Most Common Adverse Events Through Week 48 Study 380-1844

Patients, n (%)

B/F/TAF

n=282

DTG/ABC/3T

C

n=281

Any AE (all grades) 225 (79.8) 225 (80.1)

AEs occurring in ≥5% of patients

Upper respiratory tract infection 29 (10) 27 (10)

Nasopharyngitis 20 (7) 22 (8)

Headache 19 (7) 21 (7)

Diarrhea 24 (9) 14 (5)

Arthralgia 19 (7) 10 (4)

Insomnia 8 (3) 14 (5)

13

Study Drug-Related AEs Through Week 48 Study 380-1844

14

All Grades

B/F/TAF

n=282

DTG/ABC/3

TC

n=281 p-Value

Any study drug-related AE,

n (%) 23 (8) 44 (16) 0.01

Study drug-related AE in

≥1%, n (%)

Headache 7 (3) 8 (3)

Abnormal dreams 1 (<1) 5 (2)

Flatulence 0 5 (2)

Nausea 0 5 (2)

Diarrhea 2 (<1) 4 (1)

Fatigue 1 (<1) 3 (1)

Insomnia 0 3 (1)

p-value from Fisher exact test

Laboratory Abnormalities Through Week 48 Study 380-1844

No cases of rhabdomyolysis

All amylase elevations were transient and not associated with pancreatitis; 4/7

cases had normal lipase

Grade 3 and 4 ALT abnormalities were not study treatment related, did not result

in study drug interruption, and were associated with other AEs: acute HCV

infection (n=3), acute HAV infection (n=1), alcohol abuse (n=1), and NASH (n=1) 15

Grade 3 or 4 Lab Abnormalities,

n (%)

B/F/TAF

n=282

DTG/ABC/3TC

n=281

Any 47 (17) 32 (11)

in ≥ 2% of patients

LDL elevation 14 (5) 13 (5)

Increased amylase 7 (2) 0

ALT elevation 6 (2) 0

CK elevation 6 (2) 6 (2)

Fasting hyperglycemia 6 (2) 2 (<1)

Change in eGFRCG Over Time Study 380-1844

No discontinuations due to renal AEs and no cases of renal tubulopathy in

either arm 16 *From 2-sided Wilcoxon rank-sum test.

1.0 mL/min

-1.8 mL/min

p <0.001*

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e e

GF

RC

G,

mL

/min

(Q

1, Q

3)

Week

0

1 0

2 0

- 1 0

- 2 0

B / F / T A F

0 4 8 1 2 2 4 3 6 4 8

A B C / D T G / 3 T CB/F/TAF DTG/ABC/3TC

Changes in Quantitative Proteinuria at Week 48 Study 380-1844

17 *From 2-sided Wilcoxon rank-sum test for % change from baseline at Week 48 for each marker for treatment comparison.

14 20 21

9

29

17

-50

-25

0

25

50

75

100

-34

β2-microglobulin:CreatinineRetinol-Binding

Protein:Creatinine

Me

dia

n %

Ch

an

ge

Fro

m B

ase

lin

e (

Q1

, Q

3)

Albumin:Creatinine

B/F/TAF

DTG/ABC/3TC

6372

-6

-19-22 -20

66

-7

p=0.74*

Baseline 5.6 mg/g 5.4 mg/g

p=0.31* p=0.53*

8496

75

99 μg/g 96 μg/g 75 μg/g 77 μg/g

Changes in Spine and Hip BMD Through Week 48 Study 380-1844

18 *From ANOVA model for comparison of B/F/TAF vs DTG/ABC/3TC at Week 48.

B/F/TAF n=256

DTG/ABC/3TC n=262

244

253

233

244

256

265

246

253

229

242

-1

1

2

-2

0

0.30

0.16

0.69

0.42

HipSpine

-1

1

2

-2

0

Me

an

% C

ha

ng

e

Fro

m B

ase

lin

e(9

5%

CI)

WeekWeek

24 48 24 480 0

p=0.33*

p=0.47*

Fasting Lipid Changes at Week 48 Study 380-1844

19 *p-values from 2-sided Wilcoxon rank-sum test.

-1 0

-5

0

5

1 0

1 5

2 0

2 5

3 0

0

21

2

-1

-5

3

Total

Cholesterol

LDL

Cholesterol

TriglyceridesHDL

Cholesterol

B/F/TAF

DTG/ABC/3TC

113 118 49 48 111 111Baseline mg/dL 182 186

Media

n C

hange F

rom

Baseline, m

g/d

L*

0

p=0.77 p=0.42 p=0.13 p=0.028

3.7 3.8

0 0

Total

Cholesterol:HDL

p=0.56

Study 380-1844 Conclusions

Switching to B/F/TAF was non-inferior to remaining on

DTG/ABC/3TC

No treatment emergent resistance was observed in

either arm

B/F/TAF was well tolerated

– Adverse events were comparable between arms at Week

48

The lipid, bone and renal safety profiles of switching to

B/F/TAF were comparable to remaining on

DTG/ABC/3TC through 48 weeks of treatment

B/F/TAF offers an effective and safe alternative to

DTG/ABC/3TC

Study 380-1961: Switching to B/F/TAF in women (Kityo

et al. Poster 500)

20

Switching to B/E/TAF in Women

Kytio C, et al. #500

Disposition


Baseline characteristics


Virologic outcomes by FDA snapshot algorithm at week 48


Resistance


Adverse events


Grade 3-4 lab abnormalities


Changes in eGFRCG over time


Changes in quantitative proteinuria at week 48 by prior regimen


Changes in fasting lipids


Conclusions


INSTI-containing single-tablet regimen size

Gaur AH, et al. #844

Similar Efficacy and Safety By

Subgroup in DRIVE-AHEAD: DOR/3TC/TDF vs EFV/FTC/TDF

Orkin C, et al. #491

Baseline characteristics


Proportion of Participants with HIV-1 RNA <50 copies/mL Over Time (FDA

Snapshot Approach)


Efficacy by Subgroup: Baseline Clinical Characteristics (Observed

Failure Approach)


Efficacy by Subgroup: Demographic Factors (Observed Failure Approach)


Clinical Adverse Events (%) by Gender


Clinical Adverse Events (%) by Race/Ethnicity


Clinical Adverse Events (%) by Baseline CD4+ T-cell Count


Conclusions


Schematic representation of the mechanism of DNA polymerization

Sarafianos SG, et al. EMBO J. 2002

Step 1: Binding of DNA to free enzyme E [RT(apo)] with the

3′ primer end at the P site

Binding of dNTP to the N site to form an ‘open’ ternary

complex [open RT(ter)]

Formation of a ‘closed’ ternary complex

[closed RT(ter)] through conformational

change

Bond formation accompanied by release of

pyrophosphate to form the non‐translocated

complex N [RT(N)–dNMP]

Step 5: in processive synthesis, the primer translocates

from the N site to the P site

P = ‘priming’ site, N = nucleotide‐binding site


Chain terminator


Step 1: binding of DNA to free enzyme E [RT(apo)] with the




Formation of a ‘closed’ ternary complex

[closed RT(ter)] through conformational

change

Bond formation accompanied by release of

pyrophosphate to form the non‐translocated

complex N [RT(N)–dNMP]

Step 5: in processive synthesis, the primer translocates

from the N site to the P site




Step 1: binding of DNA to free enzyme E [RT(apo)] with the




Step 3: formation of a ‘closed’ ternary

complex [closed RT(ter)] through

conformational change

Step 4: bond formation accompanied by

release of pyrophosphate to form the

non‐translocated complex N [RT(N)–dNMP]

Step 5′: in non‐processive synthesis, DNA dissociates from

the enzyme


Multiple Daily Doses of MK-8591 as Low as 0.25 mg Are Expected to

Suppress HIV

Randolph P. Matthews1; Deanne Jackson Rudd1; Vanessa Lev'ine1; Sandra Zhang1; Laura Sterling2; Jay A. Grobler1; Ryan Vargo1; S. Aubrey Stoch1; Mar'ian

lwamoto1

MK-8591 (4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine, EFdA)

MK-8591 Demonstrates PK Suitable for Multiple Dosing Regimens and Has High

Antiviral Potency

Use of MK-8591 as a daily antiretroviral

MK-8591 PN009: Multiple daily Dose Study

After daily dosing, MK-8591 was generally well tolerated and demonstrated similar PK to predicted

MK-8591-TP achieves PK target on day 1 at 8,25 mg

MK-8591-TP QD PK in healthy adults

MK-8591-TP Levels Appear Sufficient at Steady State in Rectal and VaginaI

Tissue

Conclusions

LOW DOSE MK-8591 PROTECTS RHESUS MACAQUES AGAINST

RECTAL SHIV INFECTION

Rhesus macaques treated with 3.9 mg/kg MK-859I weekly and challenged intrarectally with low dose SHIV 109CP3 weekly were completely protected

Protection against infection

“The intelligent people are

full of doubt, while the

stupid are full of

confidence”

Charles Bukowski

(1888-1959)

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