Nuevos fármacos · 10.00 h Presentación de la jornada Dr Bonaventura Clotet 10.15 h Resumen I:...

10.00 h Presentación de la jornada Dr Bonaventura Clotet

10.15 h Resumen I: Infecciones oportunistas, tumores y VHB/C. Comorbilidad Dr Josep Ma Miró

10.45 h Resumen II: Nuevos enfoques terapéuticos y preventivos Dr Daniel Podzamczer

11.15 h Resumen III: Nuevos fármacos Dr Pere Domingo

11.45 h Resumen IV: Vacunas Dr Felipe García

12.15 h Coffee-Break

12.45 h Resumen V: Complicaciones del tratamiento y de la propia infección Dra Eugènia Negredo

13.15 h Resumen VI: Avances en investigación básica. Resistencias. Erradicación Dr Javier Martínez-Picado.

13.45 h Resumen VII: Interacciones farmacológicas y farmacocinética Dr Esteve Ribera

14.15 h “Los top 10 del CROI” Dr Josep M Llibre

14.45 h Discusión conjunta

15.00 h Clausura de la jornada Dr Josep M Gatell

15.15 h Almuerzo

UPDATE. 20 th CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS

Barcelona, 11 de marzo 2013Auditori de La Pedrera Passeig de Gràcia, 92

Con el apoyo de:

Organiza:

www.flsida.org

Con la colaboración:

Nuevos fármacos Pere Domingo

Malalties Infeccioses Hospital de la Santa Creu i Sant Pau

Barcelona [email protected]













15.15 h Almuerzo



Con el apoyo de:

Organiza:

www.flsida.org


Fármaco Compañía Familia Nº abstract

Inh. maduración DPH Pharma Inh. maduración 105

BMS-626529 BMS Inh. unión 542

LEDGIN U. Leuven INI 547

TAF Gilead ITIAN 99LB, 540

MK-1439 MSD ITINAN 100

Dolutegravir ViiV INI 554

Quad Gilead Combo 553

Cenicriviroc Tobira CCR5 106LB













15.15 h Almuerzo



Con el apoyo de:

Organiza:

www.flsida.org


Compara've Study of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate, Each with

Elvitegravir, Cobicistat, and Emtricitabine, for HIV Treatment

A Zolopa,1* R Or'z,2 P Sax,3I Brar,4 R Elion,5 H Wang,6 C Callebaut,6 S Ramanathan,6 M Fordyce,6 S McCallister6

1Stanford Univ, Palo Alto, CA, US (Presen'ng Author); 2Orlando Imm Ctr, Orlando, FL, US; 3Brigham and

Women’s Hosp, Harvard Med Sch, Boston MA, US; 4Henry Ford Hosp, Detroit, MI, US; 5George Washington Univ Hosp, Washington DC, US; 6Gilead Sci, Foster City, CA, US

20th Conference on Retroviruses and Opportunis'c Infec'ons

March 5, 2013 Paper # 99LB

A Zolopa, et al., CROI 2013; Paper # 99LB

Tenofovir Alafenamide (TAF) Next Genera'on Prodrug of Tenofovir

Confiden'al

TDF TFV TAF

N

N

N

N

NH2

OPO

OO

O

O

O

OO

O

N

N

N

N

NH2

OPO

HOOH

N

N

N

N

NH2

OPO

NH OO

O

Tenofovir Disoproxil Fumarate Tenofovir Tenofovir Alafenamide

Lymphoid Cells

TFV

Plasma

TFV-MP

TFV-DP

TAF

TDF/TFV

Gut

TDF

Cathepsin A

TFV

TAF TAF


•  TAF is a prodrug of tenofovir (TFV) with increased delivery to lymphoid cells and hepatocytes

•  Rela=ve to TDF 300 mg, TAF 25 mg has1: –  Increased an'-‐HIV-‐1 ac'vity in Phase 1 –  Increased intracellular TFV-‐DP levels by ~7-‐fold –  Decreased circula'ng plasma TFV levels by ~90% –  Lower levels of TFV in kidney and bone 'ssue expected

•  TAF formulated into a single tablet regimen as E/C/F/TAF

–  Elvitegravir 150mg –  Cobicistat 150mg –  FTC (emtricitabine) 200mg –  TAF 10mg

•  TAF 10mg in E/C/F/TAF has PK comparable to TAF 25mg alone2

–  COBI ↑ TAF levels ~2.2-‐fold

Tenofovir Alafenamide (TAF) Background (formerly GS-‐7340)

1P Ruane, et al. CROI 2012; Paper # 103

2S Ramanathan, et al. IWCPHT 2012; Abstract O_13


E/C/F/TAF QD

E/C/F/TDF (STB) Placebo QD Treatment-naive subjects (n=150)!

E/C/F/TDF (STB) QD

E/C/F/TAF Placebo QD

Week 48!

Randomized 2:1 Stratification by HIV RNA >/≤100,000

Treatment Arm 1 (n=100)

Treatment Arm 2 (n=50)

Primary endpoint!--Proportion with HIV-1 RNA < 50 at Week 24 (Snapshot)

Phase 2 Study Design GS-‐US-‐292-‐0102

Randomized, placebo-controlled, double-blind study


Baseline Characteris=cs GS-‐US-‐292-‐0102 – Week 24 Analysis

Characteristic E/C/F/TAF (n=112)

STB (n=58)

Age (years), Median 34 38

Male 96% 98%

White Race 67% 69%

Black Race (or African Descent) 30% 28%

Other Race 3% 3%

Hispanic or Latino Ethnicity 22% 19%

Asymptomatic HIV Infection 88% 91%

HBsAg, HCVAb Seropositive 0, 0 0, 0

HIV-1 RNA (log10c/mL), Median 4.55 4.58

> 100,000 c/mL 17% 28%

CD4 count (cells/mm3), Median 385 397

≤ 200 13% 19%

Estimated GFR (mL/min), Median – Cockcroft-Gault 115.2 113.3


Subject Disposi=on GS-‐US-‐292-‐0102 – Week 24 Analysis

Week 24 data, n (%) E/C/F/TAF (n=112)

STB (n=58)

Suppressed to < 50 copies/mL 97 (86.6%) 52 (89.7%)

Not suppressed 15 (13.4%) 6 (10.3%)

-- Never suppressed to <50 2 (1.8%) 3 (5.2%)

-- Suppressed with blip or rebound at W24 5 (4.5%) 3 (5.2%)

-- Discontinued due to adverse event* 4 (3.6%) 0

-- Data unavailable** 4 (3.6%) 0

*Coxsackie (1), MAC/CMV (1), Acute promyelocytic leukemia (1), flushing/photosensitivity (1)

**Lost to Follow-up (1), Administrative (1), Viral load collected outside window (2)

Weighted difference: -4.9% (95%CI, -15.7 to 5.9), p=0.36

FDA Snapshot


Virologic Response (M=F, ITT) GS-‐US-‐292-‐0102 – Week 24 Analysis

0

10

20

30

40

50

60

70

80

90

100

2

E/C/F/TAF (n=112) STB (n=58)

4 8 12 16 24

% Sub

jects H

IV-‐1 RNA <50 c/mL (M

=F, ITT)

Time (Weeks)

E/C/F/TAF 87.5%

STB 89.7%

♦  Mean change from baseline CD4+ cell count: –  E/C/F/TAF, +163 cells/μL –  STB, +177 cells/μL (p = 0.76)


Interim Resistance Analysis GS-‐US-‐292-‐0102– Week 24 Analysis

•  3 subjects met protocol-‐specified criteria for resistance analysis

–  Confirmed >400 copies/mL of HIV-‐1 RNA at Week 24 or the discon'nua'on visit

–  E/C/F/TAF arm (n=1) •  1 subject with Week 24 rebound

–  No resistance detected

–  STB arm (n=2) •  1 subject with persistent viremia

–  NRTI resistance (M184V + K70E) –  No EVG resistance

•  1 subject with late rebound –  No resistance detected


Adverse Events GS-‐US-‐292-‐0102 – Week 24 Analysis

Adverse Events occurring in at least 5% of subjects in E/C/F/TAF

E/C/F/TAF (n=112)

STB (n=58)

Any AE 91 (81%) 47 (81%)

Nausea 20 (18%) 7 (12%)

Diarrhea 13 (12%) 7 (12%)

Fatigue 13 (12%) 5 (9%)

Headache 11 (10%) 6 (10%)

Upper Respiratory Tract Infection 8 (7%) 7 (12%)

Flatulence 6 (5%) 2 (3%)

♦  More than 90% of AEs in both arms were Grade 1 or 2 ♦  There were no treatment-‐related SAEs in either arm


Grade 3 or 4 Lab Abnormali=es GS-‐US-‐292-‐0102 – Week 24 Analysis

Maximum Toxicity Grade Post-Baseline, n (%)

E/C/F/TAF (n=112)

STB (n=58)

Any G3 or G4 abnormality 19 (17%) 8 (14%)

LDL 7 (6%) 2 (3%)

Neutropenia 5 (5%) 1 (2%)

White Blood Cells 1 (1%) 0

Amylase 2 (2%) 1 (2%)

Creatine Phosphokinase 6 (5%) 2 (3%)

Glucose 0 1 (2%)

Total cholesterol 1 (1%) 0

Triglycerides 1 (1%) 1 (2%)

♦  There were more subjects with neutropenia in the E/C/F/TAF arm at baseline


Fas'ng Metabolic Assessments GS-‐US-‐292-‐0102– Week 24 Analysis

Assessment (median increase) E/C/F/TAF (n=112)

STB (n=58) p-value

Total Cholesterol (mg/dL) 31 15 <0.001

LDL (mg/dL) 17 4 0.001

HDL (mg/dL) 6 2 0.007

TC:HDL ratio 0.1 0.1 0.47

Triglycerides (mg/dL) 24 21 0.48

Fasting serum glucose (mg/dL) 3 3 0.78


Median Change in Serum Crea=nine GS-‐US-‐292-‐0102 – Week 24 Analysis

0 12 24-0.2

-0.1

0.0

0.1

0.2

E/C/F/TAF

STB

Time (Weeks)

Med

ian

(Q1,

Q3)

cha

nge

from

base

line

Ser

um C

reat

inin

e (m

g/dL

)

0.09

0.06

0.11 0.12 0.10 0.12 0.08

0.05 0.08 0.06

0.08 0.07

♦  Change in serum crea.nine at Week 24 –  E/C/F/TAF: 0.07 mg/dL –  STB: 0.12 mg/dL (p=0.02)

p = 0.02

4


0 12 24-30

-20

-10

0

10

20 E/C/F/TAF

STB

Time (Weeks)

Med

ian

(Q1,

Q3)

cha

nge

from

bas

elin

eeG

FR C

ockr

oft-G

ault

(mL/

min

)

Median Es=mated GFR (Cockcroc-‐Gault) GS-‐US-‐292-‐0102 – Week 24 Analysis

-‐7.2 -‐6.4 -‐6.3 -‐5.1 -‐7.7 -‐4.9 -‐9.4 -‐10.6

-‐7.1 -‐10.5 -‐11.6 -‐11.8 p= 0.04

♦  Change in eGFR at Week 24 –  E/C/F/TAF: -‐4.8 mL/min –  STB: -‐11.8 mL/min (p=0.04)

4


Poten=al Markers of Renal Tubulopathy GS-‐US-‐292-‐0102 – Week 24 Analysis

Test E/C/F/TAF (n=112)

STB (n=58)

Serum phosphate (mg/dL) Normal 2.0 – 2.2 1.5 – 2.0 <1.5

109 (98%) 1 (0.9%) 1 (0.9%)

0

54 (93%) 3 (5.2%) 1 (1.7%)

0

Fractional excretion of PO4 change from baseline 1.5 2.6

Glycosuria (dipstick) 0 1+ 2+ or higher

110 (99%) 1 (0.9%)

0

58 (100%)

0 0

Proteinuria (dipstick) 0 1+ 2+ or higher

97 (87%)

12 (10.8%) 3 (2.7%)

46 (79%)

11 (19.0%) 1 (1.7%)

♦  No renal AEs or discon.nua.ons occurred ♦  No cases of proximal renal tubulopathy seen


0 12 24

-2

0

2

Time (Weeks)

Mea

n %

cha

nge

in B

MD

0 12 24

-2

0

2

Time (Weeks)M

ean

% c

hang

e in

BM

D

Percent Change in Bone Mineral Density (DEXA) GS-‐US-‐292-‐0102 – Week 24 Analysis

SPINE

♦  Propor.on of subjects with no decrease in BMD –  Spine: E/C/F/TAF, 38%; STB, 12% –  Hip: E/C/F/TAF, 41%; STB: 23%

HIP

-‐ 0.8

-‐ 2.5

-‐ 0.3

-‐ 2.0 p = 0.002 p < 0.001


Summary GS-‐US-‐292-‐0102 – Week 24 Analysis

•  Treatment-‐naïve pa'ents given either E/C/F/TAF or STB had high levels of virologic suppression through 24 weeks

–  No resistance to E/C/F/TAF occurred

•  Pa'ents who received E/C/F/TAF had a significantly smaller increase in serum crea'nine

–  Changes in crea'nine occurred in first 4 weeks –  No renal discon'nua'ons and no tubulopathy seen in either arm –  Mechanism underlying difference in lower crea'nine change is under inves'ga'on

•  Pa'ents who received E/C/F/TAF had a significantly smaller decrease in bone mineral density of hip and spine

•  Two confirmatory Phase 3 studies are currently underway

–  Proac've efforts to increase par'cipa'on of women

•  Related Abstracts: #529 TAF PK in renal impairment; #540 TAF not OAT substrate

20 20

Safety and Antiviral Activity of MK-1439, a Novel Non-Nucleoside Reverse Transcriptase

Inhibitor (NNRTI), In Treatment-Naïve HIV-Infected Patients

Matt S. Anderson1, Jocelyn Gilmartin1, Martine Robberechts2, Inge De Lepeleire2, Ernestina Tetteh1, Ying Guo1,

Dirk Schürmann3, Frank Wagner4, John A. Wagner1, Joan R. Butterton1

1Merck Sharp & Dohme Corp., Whitehouse Station, NJ USA 2MSD Belgium, Brussels, Belgium

3Charité - Universitätsmedizin Berlin, Berlin, Germany 4Charité - Research Organisation, Berlin, Germany

Conference on Retroviral and Opportunistic Infections (CROI 2013) Paper # 100; Session 26. ART: New Agents and New Insights; 05-Mar-13

21

MK-1439 Phase Ib METHODS - Study Design

•  Double-blind, randomized, placebo-controlled, multiple panel study •  ClinicalTrials.gov identifier: NCT01466985

•  ART-naïve, HIV-1 infected patients •  MK-1439 administered as monotherapy once daily for 7 days •  Patients offered 10 days of SOC starting on Day 8 (during MK-1439

washout)

•  These doses span the range under study in Phase 2b (25, 50, 100, 200 mg)

•  ClinicalTrials.gov identifier: NCT01632345

Panel N Treatment A N=6 MK-1439 25 mg qd x 7 days

N=3 placebo to MK-1439 25 mg qd x 7 days B N=6 MK-1439 200 mg qd x 7 days

N=3 placebo to MK-1439 200 mg qd x 7 days

Anderson, M., et al., CROI 2013; Paper #100

22

MK-1439 Phase Ib RESULTS – Study Population •  ART-naïve, HIV-1 infected patients •  Open to males and females – only males enrolled •  23 – 45 years; BMI 20.6 – 35 kg x m2 •  Screened for health status •  Medical history and examination •  Prior ART exposure

•  ART-naïve OR ≤ 30 days of an investigational ART (not an NNRTI) OR ≤ 60 days of combination ART (not an NNRTI)

•  No concomitant medications •  Laboratory

Biochemistry, hematology within normal limits CD4+ count > 200 /µL Serology HIV infection with plasma viral load ≥ 104 copies/mL HCV, HBSAg neg


23

MK-1439 Phase Ib RESULTS - Safety

Unblinded Clinical Adverse Events (AEs) •  13 of the 18 patients reported 21 non-serious clinical AEs •  The most common AEs (i.e., ≥ 2 reports) were

–  headache (5), diarrhea (3), nausea (2), common cold (2), sore throat (2), night sweats (2)

•  3 AEs were considered "possibly" or "probably" related to study drug (night sweats, headache, and loss of appetite), of which two (headache, and loss of appetite) were reported by subjects dosed with MK-1439. •  All clinical AEs were mild or moderate in intensity and of limited duration •  One serious AE was reported

–  Increase in LFTs concurrent with acute HCV infection, judged as probably not related to study drug


24

MK-1439 Phase Ib RESULTS – Plasma HIV RNA

Similar HIV-RNA decline for both doses vs. placebo at 7 days: l  1.37 log10 copies/mL at 25 mg daily dose

l  1.26 log10 copies/mL at 200 mg daily dose


25

MK-1439 Phase I and Phase Ib CONCLUSIONS In HIV-1 infected male patients, •  MK-1439 was generally well tolerated with no clinically significant trends or signals apparent in vital sign measurements, laboratory findings, or ECGs •  MK-1439 pharmacokinetics in HIV-1 infected patients are generally similar to that observed in healthy normal subjects and are consistent with qd dosing •  Similarly robust antiviral activity against HIV-1 was observed with 25 and 200 mg QD doses, that provided a C24hr of 14- and 87-fold above the protein adjusted IC95 of wild-type virus, without evidence for the emergence of viral resistance


DTG treatment response by subgroups


AEs leading to withdrawal

Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF

Integrated Week 96 Analyses

A Zolopa1, JK Rockstroh2, C Orkin3, H.J. Stellbrink4, S Walmsley5, D Cooper6,

L Zhong7, M Fordyce7, MS Rhee7, J Szwarcberg7

1Stanford University, Palo Alto, CA, US; 2University of Bonn, Bonn, Germany; 3Barts and the London NHS Trust, London, UK; 4ICH Study Center, Hamburg, Germany;

5Toronto General Hospital, Toronto, Canada; 6St Vincent's Hospital, Sydney, Australia; 7Gilead Sciences, Foster City, CA, US

20th Conference on Retroviruses and Opportunistic Infections

March 3-6, 2013, Atlanta, GA Poster #: 553

Study Design Study 102 and 103

Randomized, double-blind, double dummy, active-controlled study Treatment Naïve Patients with HIV-1 RNA ≥ 5000 c/mL

Any CD4 cell count, eGFR ≥ 70 mL/min

Studies to be continued blinded through Week 192

ATR Placebo QHS STB QD

ATV/r + TVD Placebo QD STB QD

STB Placebo QD ATV/r + TVD QD

Study 102

(n=700)

Study 103

(n=700)

1:1

1:1

STB Placebo QD ATR QHS

Week 48 Primary Endpoint

Week 96 Secondary Endpoint

Baseline Characteristics Combined Study 102 and 103 Characteristic STB

(n=701) ATR

(n=352) ATV/r + TVD

(n=355) Age (years), Mean 38 38 39 Male 90% 90% 89% Non-White 34% 36% 22% Black or African Descent 25% 26% 13% Asymptomatic HIV Infection 82% 84% 83% HBV : HCV Seropositive * 1% : 5% 3% : 4% 2% : 3% HIV-1 RNA (log10c/mL), Median 4.78 4.78 4.86

> 100,000 to 400,000 c/mL 31% 25% 32% > 400,000 c/mL 8% 8% 8%

CD4 count (cells/mm3), Mean 377 382 375 < 50 3% 2% 1% 50 – 200 11% 13% 10% 201 – 350 33% 27% 35% > 350 53% 58% 54%

GFR (mL/min), Median (Cockcroft Gault) 114 114 115 *Positive HBV surface antigen or HCV antibody

15% Discontinued (n=55)


STB Randomized and Treated

(n=701)

ATR Randomized and Treated

(n=352)

Adverse event 4% 7% 6%

Lost to follow-up 4% 5% 3%

Lack of efficacy 1% 1% 0.3%

Non-compliance 2% 2% 2%

Withdrew consent 1% 2% 3%

Investigator discretion 1% 0 1%

Pregnancy 1% 0 0.3%

Protocol violation 0.3% 0 0

Death 0.1% 0.3% 0


Subject Disposition Combined Study 102 and 103 – Week 96

ATV/r + TVD Randomized and Treated

(n=355)

Efficacy Endpoint: HIV-1 RNA <50 c/mL Study 102 – Primary (Week 48) and Secondary (Week 96)

9%5%6%7%

84%88%

11%9%8%7%

82%84%

0

20

40

60

80

100

W48 W96 W48 W96 W48 W96

Virologic Success Virologic Nonsuppression

No data

Perc

enta

ge o

f sub

ject

s (%

) STB (n=348) ATR (n=352) 95% CI for Difference

Favors ATR Favors STB

W48

0 -12%

-1.6 8.8

3.6

W96 -2.9 8.3 2.7

12%

Virologic success (HIV-1 RNA <50 c/mL) as defined by FDA Snapshot algorithm

Efficacy Endpoint: HIV-1 RNA <50 c/mL Study 103 – Primary (Week 48) and Secondary (Week 96)

90%83%

5% 7% 5%10%

87%82%

5% 7% 8% 10%

0

20

40

60

80

100

W48 W96 W48 W96 W48 W96

Virologic Success Virologic

Nonsuppression

No data

Perc

enta

ge o

f sub

ject

s (%

) STB (n=353) ATV/r + TVD (n=355) 95% CI for Difference

Favors ATV/r + TVD Favors STB

W48

0 -12%

-2.1 7.5

2.7

W96 -4.5 6.7

1.1

12%

1 1

Virologic success (HIV-1 RNA <50 c/mL) as defined by FDA Snapshot algorithm

Difference in Efficacy by Subgroup Combined Study 102 and 103 – Week 96

Differences in Percentages (95% CI)

OVERALL

Age <40 years

≥40 years

Sex

Male

Female

Race White

Non-White

Baseline HIV-1 RNA ≤100,000 c/mL >100,000 c/mL

Baseline CD4 count

≤350 cells/mm3

>350 cells/mm3

Study Drug Adherence*

<95% ≥95%

Favors STB Favors Comparator

-25 -20 -15 -10 -5 0 5 10 15 20 25

* Pill count

8 16 24 32 40 48 72 960

100

200

300STBATR

BL

ATV/r + TVD

60 84 Week

+275

+273

STB (n=) 701 686 673 660 654 653 659 653 630 627 623 ATR (n=) 352 339 325 322 317 314 315 312 311 302 302 ATV/r+TVD (n=) 355 336 325 333 326 319 321 321 317 312 315

Cha

nge

in C

D4

(cel

ls/m

m3 )

, M

ean

(95%

CI)

+261

Change from Baseline in CD4 Cells Combined Study 102, 103 – Week 96

+223

+206

+211

Emergent Resistance Through Week 96 Combined Study 102, 103 – Week 96

STB (n=701)

ATR (n=352)

ATV/r + TVD (n=355)

Wk48 Wk96 (Δ) Wk48 Wk96 (Δ) Wk48 Wk96 (Δ)

Emergent Resistance, n 13 (1.9%) +3 (+0.4%) 8 (2.3%) +2 (+0.6%) 0 0

Primary INSTI-R 11 (1.6%) +3 (+0.4%) 8 (2.3%) +2 (+0.6%) 0 0 or NNRTI-R E92Q 8 +1 K103N 7 +2 or PI-R, n N155H 3 +2 K101E 0 +3

Q148R 3 0 V108I 2 0 T66I 2 0 Y188F/H/L 1 +1

M230L 0 +2 V90I 0 +1 G190A 1 0 P225H 0 +1

Primary NRTI-R, n 12 (1.7%) +3 (+0.4%) 2 (0.6%) +1 (+0.3%) 0 0 M184V/I 12 +3 M184V/I 2 +1 K65R 4 +1 K65R 2 +1

Summary of Adverse Events Combined Study 102, 103 – Week 96

STB (n=701)

ATR (n=352)

ATV/r + TVD (n=355)

Adverse Event W48 W96 (Δ) W48 W96 (Δ) W48 W96 (Δ)

Any Grade 93% +3% 95% +2% 94% +3%

Related to study drug 46% +1% 67% +1% 57% +3%

Grade 2 to 4 56% +9% 55% +9% 62% +9%

Led to study drug DC 4% +1% 5% +2% 5% +1%

SAE 10% +3% 7% +3% 9% +5%

Death, n 1 0 2 0 3 0

Common Neuropsychiatric AEs (All Grades) Study 102 and 103 – Week 96

Abnormal Dreams Dizziness

Patie

nts

with

AE

(%)

Weeks Weeks

STB (n=701) ATR (n=352)

Bar: Incident events Line: Ongoing events in the window (prevalence)

ATV/r + TVD (n=355)

0

5

10

15

20

25

24 48 72 960

5

10

15

20

25

24 48 72 96

5% 1%

14%

4% 1%

14%

1% 2%

5%

1% 1%

4%

Most were Grade 1 (STB vs ATR vs ATV/r+TVD):

Abnormal dreams: 94% vs 86% vs 93% Dizziness: 91% vs 86% vs 85%

AEs Leading to Study Drug Discontinuation Study 102 and 103 – Week 96

STB (n=701)

ATR (n=352)

ATV/r + TVD (n=355)

Adverse Event* W48 W96 (Δ) W48 W96 (Δ) W48 W96 (Δ)

Renal events 1.0% +0.4%^ 0 0 0.3% +0.3%^

Fatigue 0.3% 0 0.3% +0.3% 0.6% 0

Nausea 0.3% 0 0 0 1.1% 0

Hepatitis C 0.3% 0 0 +0.3% 0 +0.3%

Pyrexia 0.3% 0 0.3% 0 0 0

Burkitt’s lymphoma 0.1% +0.1% 0 0 0 0

Diarrhea 0.3% 0 0 0 0.3% 0

Rash events 0.1% 0 1.1% 0 1.1% 0 * >1 patients in STB

No cases of proximal tubulopathy between W48 and W96 ^3 STB and 1 ATV/r+TVD patients with isolated Cr elevation without

proximal tubulopathy between W48 and W96

0 24 48 72 96-0.2

-0.1

0.0

0.1

0.2

0.3

0.4

-10

0

10

20

30

Week

( µmol/L)

Changes in Serum Cr from Baseline and Week 4 Studies 102 and 103 – Week 96

Change from BL in Serum Cr (mg/dL) (Median [IQR])

Change from Wk 4 in Serum Cr (mg/dL) (Median [IQR])

STB ATV/r + TVD ATR

0 24 48 72 96-0.2

-0.1

0.0

0.1

0.2

0.3

0.4

-10

0

10

20

30

Week

( µmol/L)

0.13 0.08 0.01

0.03 0.04

0.01

0.13 0.08

0.01 0.04 0.04

0.02

Change from Baseline in Fasting Lipids Study 102 and 103 – Week 96

0

5

10

15

20

25

0.0

0.2

0.4

0.6

Med

ian

Cha

nge

at W

k 96

(mg/

dL) (mm

ol/L)

Total Cholesterol

LDL HDL Triglycerides

ATV/r + TVD STB

(P=0.001)*

(P=0.064)*

(P=0.002)*

* STB vs ATR

(P=0.003)^

0

5

10

15

20

25

0.0

0.2

0.4

0.6

Med

ian

Cha

nge

at W

k 96

(m

g/dL

) (mm

ol/L)

ATR

12

18

8

12

16

11

6 8

5 4

8

16

^ STB vs ATV/r+TVD

No difference in change in TC to HDL ratio at Week 48 or 96

Changes in Bone Mineral Density Study 103 – Week 96

0 24 48 72 96-8

-6

-4

-2

0

2

4

STBATV/r + TVD

Week0 24 48 72 96

-8

-6

-4

-2

0

2

4

STBATV/r + TVD

Week

Change in Hip BMD (%) Mean (95% CI)

(n=120)

Change in Spine BMD (%) Mean (95% CI)

(n=120)

-3.30 -3.54 (P=0.21) (P=0.049)

-2.54 -1.96

-3.87

-3.05

-4.19

-3.16

(P=0.11) (P=0.069)

Adverse Event STB

(n=353) ATV/r + TVD

(n=355)

W48 W96 (Δ) W48 W96 (Δ)

Fracture events, (n) 3 (1%) +1 (+0.3%)* 6 (2%) +8 (+2%)*

*Through Week 96, P=0.029

Conclusions Study 102 and 103 – Week 96 ♦  STB had robust and durable efficacy through Week 96

–  Comparable to ATR and ATV/r + TVD –  Consistent across wide ranges of viral load and CD4

l  CD4<50: small sub-group, high baseline HIV-1 RNA, suboptimal adherence

♦  STB associated with low rates of resistance

♦  STB was well-tolerated through Week 96 –  Relative to Week 48:

l  No new cases of proximal tubulopathy l  No further increases in serum creatinine

♦  Overall efficacy, safety, and tolerability support the use of STB as a first line regimen in treatment naïve HIV patients

Week 24 Primary Analysis of Cenicriviroc vs Efavirenz, in Combination

with FTC/TDF, in Treatment-naїve HIV-1 Infected Adults with CCR5-tropic virus

(Study 652-2-202; NCT01338883)

Joseph Gathe1, Jerry Cade2, Edwin DeJesus3, Judith Feinberg4, Jay Lalezari5, Javier O. Morales‑Ramίrez6, Anthony Scarsella7,

Michael Saag8, Melanie Thompson9, Eric Lefebvre10 1Therapeutic Concepts, Houston, TX, US; 2Nevada AIDS Res Ed Society, Las Vegas, NV, US; 3Orlando Immunology Ctr, Orlando, FL, US; 4Univ Cincinnati, Cincinnati, OH, US; 5Quest Clin Res, San Francisco, CA, US; 6Clin Res P.R., Inc., San Juan, Puerto Rico; 7Pacific Oaks Med Grp, Beverly Hills, CA, US; 8Univ Alabama at Birmingham, Birmingham, AL, US; 9AIDS Res Consortium of Atlanta, Atlanta, GA, US; 10Tobira Therapeutics Inc., San Francisco, CA, US

CVC Study 202

Cenicriviroc (CVC) Characteristics •  Oral CCR5/CCR2 receptor antagonist

−  In vitro protein-adjusted IC90 against HIV clinical isolates = 0.25 nM

−  Inhibits binding of MCP-1 to CCR2 at 5.9 nM (IC50)

•  Once-daily dosing −  Long plasma t½ = 30–40 hours

•  Low drug–drug interaction potential −  Metabolized via CYP3A4 and CYP2C8 −  Not a known CYP inducer or inhibitor

•  Additive to synergistic antiviral activity in vitro with −  NRTIs, NNRTIs, PIs and INSTIs

46

CVC Study 202

Design: Phase 2b, Randomized, Double-Blind, Double‑Dummy, Dose-Finding Study

47

Subjects (N=143) •  Tx-naїve adults •  CCR5-tropic only HIV

(genotype and phenotype) •  HIV RNA ≥1000 copies/mL •  CD4+ cell count ≥200 c/mm3

•  No primary NRTI/NNRTI resistance

•  Stratified by baseline viral load (< or ≥100 000 copies/mL)

R 2:2:1

CVC 100 mg + FTC/TDF + EFV placebo

EFV 600 mg + FTC/TDF + CVC placebo

CVC 200 mg + FTC/TDF + EFV placebo

Primary analysis Week 24

Final analysis Week 48

Primary endpoint: Subjects (%) with HIV-1 RNA <50 copies/mL at Week 24 in the ITT population (FDA Snapshot algorithm)

CVC Study 202

48

Baseline characteristics CVC 100 mg (N=59)

CVC 200 mg (N=56)

EFV (N=28)

Male 92% 100% 89%

Mean age, years (min–max) 36 (19–63) 36 (21–57) 32 (19–49) Race

Caucasian 58% 64% 64%

Black/African American 41% 23% 32%

Ethnicity

Hispanic 12% 32% 36%

Mean HIV-1 RNA, log10 copies/mL 4.43 4.59 4.47

Mean CD4 cells/mm3 (min–max) 414 (188–749) 410 (77–1090) 359 (191–641)

Baseline HIV-1 RNA copies/mL ≥100 000 17% 25% 14%

Demographics and Baseline Characteristics

CVC Study 202

HIV-1 RNA <50 copies/mL (ITT-FDA Snapshot) Su

bjec

ts w

ith H

IV-1

RN

A

<50

copi

es/m

L, %

(±SE

)

20

40

60

80

100

BL 4 12 24 Weeks

76% 73% 71%

CVC 100 mg

0 3 11 25 37 44 42 45 2 2 4 17 28 33 40 41 0 4 5 12 16 18 19 20

1 2 8 16 20

CVC 200 mg EFV

CVC 100 mg (N=59) CVC 200 mg (N=56)

EFV (N=28) 49

CVC Study 202

Category CVC 100 mg (N=59)

CVC 200 mg (N=56)

EFV (N=28)

Virologic success (HIV-1 RNA <50 copies/mL) 76% 73% 71%

Virologic non-responsea 12% 14% 4%

No virologic data in Week 24 window 12% 13% 25%

Discontinued for reasons other than AEb 10% 11% 7%

Discontinued due to AE 0% 2% 18%

Missing data in window but on study 2% 0% 0%

Week 24 Virologic Outcomes (ITT-FDA Snapshot)

50

aIncludes subjects who discontinued prior to Week 24 for lack or loss of efficacy, subjects who had ≥50 copies/mL in the Week 24 window and subjects who changed therapy in a manner not permitted per protocol prior to Week 24 bOther reasons include: withdrew consent, lost to follow-up, moved, etc.

CVC Study 202

Week 24 Virologic Outcomes by Stratification (ITT-FDA Snapshot)

51

Category

Baseline HIV RNA (copies/mL) <100 000 ≥100 000

CVC 100 mg (N=49)

CVC 200 mg (N=42)

EFV (N=24)

CVC 100 mg (N=10)

CVC 200 mg (N=14)

EFV (N=4)

Virologic success 80% 81% 71% 60% 50% 75%

Virologic non-response 10% 10% 0% 20% 29% 25%

No virologic data in Week 24 window 10% 9% 29% 20% 21% 0%

Discontinued (Other) includes: consent withdrawn, non-compliance, lost to follow-up, other reasons

CVC Study 202

Emerging Resistance and Tropism Change in Subjects with Protocol-Defined Virologic Failure

52

CVC 100 mg (N=59)

CVC 200 mg (N=56)

EFV (N=28)

Protocol-defined virologic failure,a n (%) 7 (12%) 9 (16%) 3 (11%) Paired data available for testing of resistance-associated mutations (RAMs), n 7 9 3

Virologic resistance, n No NRTI/NNRTI RAMs 4 2 2 NRTI RAMsb (M184I and/or V) 3 2 0 NNRTI RAMsb (V108I/V or I) 0 2 0 Amplification not successful 0 3 1

Paired data available for viral tropism testing, n 4 2 1 Tropism change (D/M), n 0 1c 0

aHIV-1 RNA <1 log10 copies/mL below baseline at Week 4 (unless viral load <50 copies/ml); HIV-1 RNA <1 log10 above nadir value at Week 4; HIV-1 RNA >400 copies/mL between Week 12 and 24; HIV-1 RNA >50 copies/mL between Week 24 and 48 (with HIV-1 RNA >400 copies/mL at the second visit); HIV-1 RNA ≥50 copies/mL after confirmed suppression to <50 copies/mL (with HIV-1 RNA >400 copies/mL at the second visit); bIAS-USA 2011 list; cShowed a dual/mixed (R5X4) phenotype at early termination

CVC Study 202

58 53 55 54 53 52 56 55 49 56 53 55 54 53 53 51 50 46 28 25 26 24 23 22 21 22 21

CVC 100 mg (N=59)

EFV (N=28) CVC 200 mg (N=56)

CD4+ Counts Changes from Baseline

53

BL 4 12 24

Mea

n ch

ange

from

bas

elin

e in

C

D4

cell

coun

t, m

m3 (

±SE)

50

100

200

147

170

135

1 2 8 16 20

150

CVC 200 mg

Weeks

CVC 100 mg EFV

CVC Study 202

Treatment-Emergent Adverse Events

54

Adverse events CVC

100 mg (N=58)

CVC 200 mg (N=57)

EFV (N=28)

Mean duration of intake of study medication, weeks (SE)

33.5 (1.78)

35.1 (1.86)

28.7 (3.21)

AEs by worst grade severity Grade 3 2% 4% 11%

Grade 4 0% 0% 0%

AEs leading to discontinuation

0% 2% 18%

Serious AEs 0% 0% 0%

Deaths 0% 0% 0%

All available data at analysis cut-off date were included

CVC Study 202

Grade 2 or Higher Treatment-Related AEs

55

Adverse eventsa

(incidence ≥5%)

CVC 100 mg (N=58)

CVC 200 mg (N=57)

EFV (N=28)

Any Grade ≥2 AE 9% 9% 32%

Nausea 0% 4% 7%

Abnormal dreams 2% 0% 11%

Rash events 2% 0% 7%

Insomnia 0% 0% 7%


aOnly clinical AEs shown in table

CVC Study 202

aPercentages are based on the number of subjects with available data for a given laboratory assessment

Grade 3 or 4 Laboratory Abnormalities

56

Laboratory Parametera CVC

100 mg (N=58)

CVC 200 mg (N=57)

EFV (N=28)

All Grade 3 or 4 laboratory abnormalities 9% 19% 7%

CPK increased 3% 14% 0%

Phosphate decreased 3% 4% 4%

Fibrinogen decreased 0% 4% 0%

Neutrophils decreased 2% 0% 4%

AST increased 2% 0% 0%

Prothrombin time/INR increased 2% 0% 0%


CVC Study 202

Fasting Lipid Changes from Baseline

57

Total cholesterol

Mea

n ch

ange

from

ba

selin

e, m

g/dL

(±SE

)

4

Mea

n ch

ange

from

ba

selin

e, m

g/dL

(±SE

)

Triglycerides

Mea

n ch

ange

from

ba

selin

e, m

g/dL

(±SE

)

HDL cholesterol

Mea

n ch

ange

from

ba

selin

e, m

g/dL

(±SE

)

CVC 100 mg CVC 200 mg EVF 600 mg

-40

-20

0

20

40

-40

-20

0

20

40

12 24 Weeks

4 12 24

4 12 24 Weeks

Weeks

LDL cholesterol

Weeks -20

-10

0

10

20

-20

-10

0

10

20

4 12 24

CVC Study 202

MCP-1 Changes from Baseline

55 51 47 54 50 44 28 22 21

58

12

Mea

n ch

ange

from

bas

elin

e in

M

CP-

1 le

vels

,a ng

/L (±

SE)

CVC 100 mg CVC 200 mg

EFV

CVC 200 mg

24 BL

CVC 100 mg

EFV

Weeks

aResults are based on the number of subjects with available data for a given laboratory assessment

CVC Study 202

aResults are based on the number of subjects with available data for a given laboratory assessment

sCD14 Changes from Baseline

55 51 47 54 50 44 28 22 21

59

Mea

n ch

ange

from

bas

elin

e in

sC

D14

leve

ls,a

x 10

6 ng

/L (±

SE)

EFV

12 24 BL



EFV

Weeks

CVC Study 202

Week 24 Primary Analysis: CVC Summary

•  Similar % of subjects with VL <50 copies/mL in all treatment arms

•  One subject with VF had viral tropism switch

•  Generally well tolerated −  Few AEs Grade ≥3 −  One discontinuation due to AE

•  Reduced total and LDL cholesterol

•  Dose-dependent increases in MCP-1 −  Suggests potent CCR2 blockade

•  Effect on sCD14 merits further evaluation

•  Efficacy and safety support Phase 3 development

60

CVC Study 202

CVC Study 202

“….for it is no more than a dream remembered, a Civiliza=on gone with the wind….”


TFV Plasma and TFV-‐DP Intracellular Levels GS-‐US-‐292-‐0102 – Week 24 Analysis

E/C/F/TAF ♦  PBMC TFV-‐DP exposure was 5.3-‐fold

higher (90% CI: 2.9 to 9.6) ♦  Plasma TFV exposure (AUCtau) was 91%

lower

Plasma TFV PK Mean (%CV)

E/C/F/TAF (n=19)

STB (n=7)

Ctrough (ng/ml) 11.4 (17.9) 82.8 (26.6)

AUCtau (ng*hr/ml) 326.2 (14.8) 3795.2 (21.9)

WK 4 or 8 TFV-DP AUC0-24h from QUAD and E/C/F/TAF

QUAD

E/C/F/TAF 10

mg0

10

20

X

~5XMean with SD

TFV-

DP

(µM

*h) 5.3X

PBMC TFV-‐DP AUC0-‐24h at Week 4 or 8

X

65

MK-1439 BACKGROUND

MK-1439 is a next generation NNRTI, currently in Phase 2b study with potential for: Enhanced safety, tolerability and potency

–  Once-daily dosing –  Low rates of CNS toxicity –  Enhanced potency against select NNRTI resistance mutations

§  ≤ 3 fold potency shift against the most prevalent transmitted NNRTI mutant viruses (K103N, Y181C, G190A) [Feng M, ICAAC 2012]

Potential advantages of a next generation NNRTI: • Improved safety / tolerability profile • Minimal interactions: enhanced compatibility with concomitant medications • Potential for greater treatment efficacy / durability

Nonclinical Pharmacology • Potent and selective inhibitor of reverse transcriptase

–  IC95 ~19 nM (50% human serum) • Eliminated primarily by oxidative metabolism (CYP3A4/5)

–  Does not inhibit or significantly induce drug-metabolizing CYP enzymes • Good Preclinical Safety Profile

–  6 month Safety Assessment study in rats and 9 months in dogs: no significant adverse antemortem or postmortem findings


66

MK-1439 Phase I - Pharmacokinetics

Single doses up to 1200 mg: •  AUC and Cmax increase in a slightly less than dose proportional

manner •  Plasma concentrations decline in a single exponential phase with t½

of ~11 to 16 hours •  MK-1439 is rapidly absorbed with a Tmax of ~1 to 2 hour •  Minimal food effect (high-fat meal): GMR AUC0-∞ (fed/fasted)=1.33 •  Renal excretion represents <10% of the total clearance Multiple doses up to 750 mg once daily: •  Data consistent with single dose PK •  Steady state achieved by Day 7 with once daily dosing •  AUC0-24hr, Cmax, and C24hr accumulation ratios were 1.2 to 1.4 •  12 mg dose gives C24 hr exceeding the serum adjusted IC95 of wild-

type virus


67

MK-1439 Phase I - Safety

•  Approximately 140 subjects (92 young male, 12 young female, 12 elderly female, 12 elderly male and 12 young male HIV-1 infected) have received at least one dose or more doses of MK-1439

•  MK-1439 has been generally well tolerated administered as single doses up to 1200 mg, and as multiple doses up to 120 mg qd x 14 d, and 750 mg qd x 10 d

•  No clinically significant drug related abnormalities have been observed in CBC, urinalysis, ECG, and physical exams

•  No rash events temporally related to MK-1439 •  No significant CNS events associated with MK-1439 dosing •  All clinical AEs resolved and were generally mild to moderate in intensity •  Two SAEs reported, each judged probably not drug related:

–  This study: Increase in LFTs concurrent with acute HCV infection. –  Sarcoidosis reported in healthy volunteers after administration of MK-1439 750 mg qd x 7d


68

MK-1439 Phase Ib RESULTS - Pharmacokinetics

•  N = 6 patients per dose •  Pharmacokinetic profiles are comparable to healthy volunteers •  Steady state C24hr concentrations exceeded the serum adjusted IC95 of wild-type

virus by 14-fold (25 mg) and 87-fold (200 mg) •  C24hr accumulation ratio of 1.5- to 1.6-fold

Time (hr)Day 1

0 6 12 18 24

MK-

1439

Pla

sma

Con

cent

ratio

n (n

M)

10

100

1000

10000

Time (day)Days 3-6

(pre-dose troughs)

3 4 5 6

Time (hr)Day 7

0 12 24 36 48 60 72 84 96 108 120

Panel A: 25 mg QD for 7 daysPanel B: 200 mg QD for 7 days

Serum adjusted IC95 (19 nM) for WT virus

Mean Plasma Concentration Profiles for MK-1439 Following Administration to HIV-1 Infected Patients


69


Pharmacokinetic Parameters for MK-1439 in HIV-1 Infected Patients

MK-1439 Dose (mg) Day N AUC0-24hr

a (µM•hr)

Cmaxa

(nM) C24hr

a (nM)

Tmaxb

(hr) Effective t1/2

c (hr)

25 1 6 8.31 ± 1.14 686 ± 89.6 171 ± 47.8 1.5 (1 - 2) --

25 7 6 11.5 ± 3.00 845 ± 202 267 ± 109 1 (1 - 2) 10 – 16 hr

Accumulation Ratiod 7/1 6 1.36 (1.19 -

1.82) 1.21 (0.967 -

1.72) 1.51 (1.22 - 2.26) -- --

200 1 6 40.8 ± 8.01 2790 ± 480 1030 ± 373 2 (1 - 4) --

200 7 6 63.6 ± 15.8 4320 ± 365 1650 ± 696 2 (1 - 4) 10 – 16 hr


1.95) 1.56 (1.34 - 2.00) 1.60 (1.06 - 1.90) -- --

aArithmetic mean ± SD; bMedian (min - max); cHarmonic mean ± pseudo SD; dDay 7/1 GMR (min, max) calculated by PPDM

•  MK-1439 plasma pharmacokinetics in HIV-1 infected patients are similar to those in healthy subjects


70






a (µM•hr)

Cmaxa

(nM) C24hr

a (nM)

Tmaxb

(hr) Effective t1/2

c (hr)

25 1 6 8.31 ± 1.14 686 ± 89.6 171 ± 47.8 1.5 (1 - 2) --

25 7 6 11.5 ± 3.00 845 ± 202 267 ± 109 1 (1 - 2) 10 – 16 hr


1.82) 1.21 (0.967 -

1.72) 1.51 (1.22 - 2.26) -- --

200 1 6 40.8 ± 8.01 2790 ± 480 1030 ± 373 2 (1 - 4) --

200 7 6 63.6 ± 15.8 4320 ± 365 1650 ± 696 2 (1 - 4) 10 – 16 hr


1.95) 1.56 (1.34 - 2.00) 1.60 (1.06 - 1.90) -- --


71






a (µM•hr)

Cmaxa

(nM) C24hr

a (nM)

Tmaxb

(hr) Effective t1/2

c (hr)

25 1 6 8.31 ± 1.14 686 ± 89.6 171 ± 47.8 1.5 (1 - 2) --

25 7 6 11.5 ± 3.00 845 ± 202 267 ± 109 1 (1 - 2) 10 – 16 hr


1.82) 1.21 (0.967 -

1.72) 1.51 (1.22 - 2.26) -- --

200 1 6 40.8 ± 8.01 2790 ± 480 1030 ± 373 2 (1 - 4) --

200 7 6 63.6 ± 15.8 4320 ± 365 1650 ± 696 2 (1 - 4) 10 – 16 hr


1.95) 1.56 (1.34 - 2.00) 1.60 (1.06 - 1.90) -- --


72

Background Study 102 and 103

Elvitegravir (EVG)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir DF (TDF) (STB) have been co-formulated as the first integrase inhibitor-containing single tablet regimen

•  EVG (150 mg) is a potent once-daily HIV integrase inhibitor •  COBI (150 mg) is a pharmacoenhancer designed to have no activity against

HIV •  FTC/TDF (200/300 mg) is a preferred first line NRTI combination1-3

STB demonstrated noninferiority to two guideline preferred regimens in treatment naive patients with durable efficacy through 96-week4-8

•  vs efavirenz (EFV)/FTC/TDF (ATR) •  vs atazanavir boosted by ritonavir (ATV/r) + FTC/TDF (TVD)

STB is approved in the US (Aug 27, 2012) 1. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf 2. Thompson et al, JAMA, 2010;304(3):321-333

3. EACS Guidelines. Version 6.0 - October 2011 4. Cohen C et al. AIDS 2011; 25: F7-12

5. Sax P et al. Lancet 2012; 379; 2439-2448 6. DeJesus E et al. Lancet 2012; 379; 2429-2438

7. Zolopa A et al. JAIDS 2013 [Epub] 8. Rockstroh J et al. JAIDS 2013 [Epub]

Efficacy by Baseline HIV-1 RNA Subgroups Combined Study 102 and 103 – Week 96

Viro

logi

c Su

cces

s* a

t Wk

96 (%

)

8580

8781 83 8384

79 83

0

20

40

60

80

100

HIV-1 RNA (c/mL)

368/433

191/236

172/214

89/ 112

47/ 54

24/ 29

100

80

60

40

20

0 ≤100,000 >400,000 >100,000 to 400,000

Virologic success (HIV-1 RNA <50 c/mL) as defined by FDA Snapshot algorithm p value for all comparison vs. STB: non-significant (> 0.05)

179/214

72/ 87

24/ 29

STB (n=701) ATR (n=352) ATV/r + TVD (n=355)

Efficacy by Baseline CD4 Subgroups Combined Study 102 and 103 - Week 96

Subgroup of CD4 < 50 (n=30)

♦  11/19 STB with virologic success. 8 were non-success (all with VL > 100 K c/mL, 4 with suboptimal adherence)

♦  5/6 ATR with virologic success. 1 was non-success (VL > 100 K c/mL, suboptimal adherence)

♦  5/5 ATV/r + TVD with virologic success

7884 86

80 80 8285 81 82

0

20

40

60

80

100

CD4 (cells/mm3)

>50 to ≤200 >350

100

80

60

40

20

0

Viro

logi

c Su

cces

s* a

t Wk

96 (%

)

61/ 78

36/ 45

29/ 34

196/ 234

77/ 96

100/ 124

319/ 370

169/ 205

158/ 192

>200 to ≤350

STB (n=701) ATR (n=352) ATV/r + FTC/TDF (n=355)

Virologic success (HIV-1 RNA <50 c/mL) as defined by FDA Snapshot algorithm p value for all comparison vs. STB: non-significant (> 0.05)

Suboptimal adherence defined as < 95%

Efficacy by Adherence * Combined Study 102, 103 – Week 96

Viro

logi

c Su

cces

s* a

t Wk

96 (%

)

72

89

63

89

7685

0

20

40

60

80

100

HIV-1 RNA (c/mL)

100

80

60

40

20

0

* Pill count Virologic success (HIV-1 RNA <50 c/mL) as defined by FDA Snapshot algorithm p value for all comparison vs. STB: nonsignifican t (> 0.05)

<95% ≥95%

134/ 187

54/ 86

78/ 103

453/ 511

233/ 263

214/ 251


Common Adverse Events Combined Study 102, 103 – Week 96

Adverse Event *

STB (n=701)

ATR (n=352)

ATV/r + TVD (n=355)

W48 W96(Δ) W48 W96(Δ) W48 W96(Δ) Diarrhea 22% +3% 19% +5% 27% +4% Nausea 20% +1% 14% +1% 19% +2% Rash events 17% +4% 28% +3% 18% +5% Upper respiratory infection 15% +6% 11% +6% 16% +4% Headache 15% +2% 10% +2% 12% +3% Fatigue 13% +1% 13% +2% 13% +3% Depression 8% +3% 11% +3% 6% +5% Insomnia 8% +2% 14% +2% 5% +2% Nasopharyngitis 7% +3% 5% +3% 8% +3% Abnormal dreams 9% +0.1% 27% +1% 4% +0.3% Sinusitis 6% +2% 8% +3% 5% +3% Dizziness 6% +1% 24% +1% 7% +1% Ocular icterus 0.3% 0 0 0 14% 0

* >10% of patients in any group

Common Gastrointestinal AEs (All Grades) Study 102 and 103 – Week 96

Diarrhea Nausea

Patie

nts

with

AE

(%)

Weeks Weeks


0

5

10

15

20

25

24 48 72 960

5

10

15

20

25

24 48 72 96

Bar: Incident events Line: Ongoing events in the window (prevalence)

5%

9%

5% 4%

9% 5%

3%

4% 4%

4%

4% 3%

Most were Grade 1 (STB vs ATR vs ATV/r+TVD)

Diarrhea:74% vs 73% vs 68% Nausea: 85% vs 81% vs 85%

Grade 3 or 4 Laboratory Abnormalities Study 102 and 103 - Week 96

Grade 3-4 Lab Abnormalities*

STB (n=701)

ATR (n=352)

ATV/r + TVD (n=355)

W48 W96 W48 W96 W48 W96 Creatine Kinase 5% +1% 11% +3% 7% +3%

Hematuria 3% +0.3% 1% +1% 2% +1%

Amylase 2% +1% 2% 0 4% +1%

AST 2% +0.3% 3% +2% 4% +2%

ALT 1% +0.4% 3% +1% 2% +1%

Neutropenia 1% +0.4% 3% +0.3% 2% 0

GGT 1% +0.1% 5% +2% 1% +1%

Hypercholesterolemia 1% +0.5% 2% +1% 0% +1%

Lipase 1% +0.3% 1% +0.3% 2% +1%

Glycosuria 1% +0.3% 1% +1% 1% +1%

Hyperglycemia 1% +0.3% 0.3% +0.3% 1% +1%

Hyperbilirubinemia 1% +0.1% 0 +0.3% 58% +7%

Hypertriglyceridemia 0.2% 0 1% +1% 1% +0.3% * ≥ 1% in any treatment group at Week 96

CVC Study 202

Treatment arm

CVC 50 mg

CVC placebo

EFV 600 mg

EFV placebo

FTC/TDF (Truvada®)

Blinded: Taken with breakfast

Blinded: Taken on empty stomach at bedtime

Open-label: At anytime

CVC 100 mg

CVC 200 mg

EFV

79

Dosing Instructions of Blinded Study Drugs

CVC Study 202

Week 24 PK/PD Efficacy Analyses

80

CVC Exposure Quartiles: Modeled Cmin

20

40

60

80

100

Subj

ects

, %

Q1 (13.2–40.1)

Q2 (40.1–70.8)

Q3 (70.8–141)

Q4 (141–400)

Cmin range, ng/mL

83%

17%

91%

9%

88%

12%

100%

0%

CVC Study 202

Future Directions

•  CVC formulation optimized −  Single tablet available

−  Fixed-dose combinations underway

•  Interaction study results of CVC with EFV, ATV/r and DRV/r −  Submitted to conferences for first half of 2013

•  Proposed Phase 3 trials −  CVC with guideline preferred agents in novel combinations

−  Effect on inflammatory and metabolic parameters

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