Transcript Nuevos fármacos

Nuevos fármacos
Pere Domingo
Malalties Infeccioses
Hospital de la Santa Creu i Sant Pau
Barcelona
[email protected]
Fármaco
Compañía
Familia
Nº abstract
RS-788
RFS Pharma
ITIAN
489
Elvucitabina
Achillion Ph
ITIAN
511
Boehringer I.
Inh cápside
50
BioAlliance Ph
Integrasa
492
GSK
Integrasa
55
Merck Res Labs
CCR5
54LB
Gilead
Varios
58LB
TBR 652
Tobira Ther
CCR5
53
Lectina banana
U. Michigan
Microbicida
487
QNL111
S/GSK1349572
Vicriviroc
Quad
Fármaco
Compañía
Familia
Nº abstract
RS-788
RFS Pharma
ITIAN
489
Elvucitabina
Achillion Ph
ITIAN
511
Boehringer I.
Inh cápside
50
BioAlliance Ph
Integrasa
492
GSK
Integrasa
55
Vicriviroc
Merck Res Labs
CCR5
54LB
TBR 652
Tobira Ther
CCR5
53
Gilead
Varios
58LB
U. Michigan
Microbicida
487
QNL111
S/GSK1349572
Quad
Lectina banana
Análogos de
nucleósidos
Elvucitabina
A Phase II, randomized, double-blind trial at 16 sites in the United States and 3
sites in India.
Primary endpoint: proportion of subjects with HIV-1 RNA levels < 50 copies/mL at
Week 12.
Secondary endpoints at Weeks 12, 24, 48 and 96 included:
• Change in HIV-1 RNA level from Baseline
• Proportion of subjects with HIV-1 RNA levels < 400 copies/mL
• Proportion of subjects with HIV-1 RNA levels < 50 copies/mL (Weeks 24, 48, 96)
• Time to occurrence of less than 400 copies/mL and less than 50 copies/mL
• Change in CD4 count from Baseline
DeJesus E, et al. CROI. 2010. # 511
Diseño
DeJesus E, et al. CROI. 2010. # 511
Situación de los pacientes
DeJesus E, et al. CROI. 2010. # 511
Eficacia (< 50 copias/ml)
DeJesus E, et al. CROI. 2010. # 511
Eficacia (< 400 copias/ml)
DeJesus E, et al. CROI. 2010. # 511
Eficacia: disminución de carga viral
DeJesus E, et al. CROI. 2010. # 511
Eficacia: en tratamiento
DeJesus E, et al. CROI. 2010. # 511
Eficacia: incremento de CD4
DeJesus E, et al. CROI. 2010. # 511
Efectos adversos
DeJesus E, et al. CROI. 2010. # 511
Fracasos virológicos
DeJesus E, et al. CROI. 2010. # 511
Conclusiones
DeJesus E, et al. CROI. 2010. # 511
Antagonistas de
CCR5
TBR-652
• Oral CCR5 receptor antagonist
– In vitro protein-adjusted EC50 = 0,29 nM (clinical isolates)
• Plasma t ½ = 35-40 hours
• Once-daily dosing
• Metabolized by CYP and non-CYP pathways
• Neither CYP inducer nor inhibitor
• Additive or synergistic activity with other ART
classes in vitro
• Oral bioavailability of current formulation enhanced
by food
Palleja S, et al. CROI. 2010. Abstract 51
TBR-652: CCR2 characteristics
• CCR2 activity: IC50 = 5.9 nM
• CCR2 is a chemokine receptor found on the cell surface of
monocytes, dendritic celles (immature) and memory T cells
• Monocyte chemoatractant protein 1 (MCP-1) is the primary
ligand for CCR2
• CCR2 has been associated with and studied in a variety of
inflammation-associated diseases:
– Atherosclerosis
– Metabolic syndrome/insulin resistance
• To date no significant safety signals have been identified
with CCR2 antagonists
Palleja S, et al. CROI. 2010. Abstract 51
Protocol designTBR-652-201
• Evaluate antiviral potency, safety, tolerability, PK,
and CCR2 activity
– Randomized, double-blind, placebo-controlled doseescalating study in HIV-infected subjects with:
•
•
•
•
CD4 ≥ 250 cells/mm3
HIV-1 RNA > 5000 copies/ml
CCR5-tropic virus
Treatment experienced, no HIV treatment for ≥ 6 weeks
– 5 dose cohorts
• TBR-652 (≥ 8): 25, 50, 75, and 150 mg (F1 formulation)
• TBR-652 (n = 10): 100 mg (F2 formulation)
• PBO (n = 2)
– 10-day monotherapy
– MCP-1 measured on day 1 and 10
Thompson M, et al. CROI. 2009. Abstract 571a
Phase 3 Trials of Vicriviroc in TreatmentExperienced Subjects Demonstrate Safety but
Not Significantly Superior Efficacy over
Potent Background Regimens
J. Gathe,1 R. Diaz,2 G. Fätkenheuer,3
J. Zeinecker,4 C. Mak,5 R.A. Vilchez,5 W. Greaves,5
S. Kumar,5 C. Onyebuchi,5 L.M. Dunkle5
1Therapeutic
Concepts PA, Houston, Texas; 2Federal University of São Paulo, São
Paulo, Brazil; 3University of Cologne, Koln, Germany; 4Institute of Infectious
Diseases and Molecular Medicine, Cape Town, South Africa; 5Merck, Kenilworth,
New Jersey
VICTOR-E3 & 4:
Phase 3 Trial Design
• VICTOR-E3 and 4 were identically designed, randomized, double-blind,
placebo-controlled, 48-week multicenter Phase 3 studies
• Subjects were ART-experienced with:
– Documented resistance to ≥2 then available drug classes (NRTI, NNRTI,
or PI) or ART experience of at least 6 months
• MITT population = 721 of 857 enrolled subjects
– R5 subjects enrolled based on Trofile
– Confirmed by Trofile ES at study conclusion (blinded)
Treatmentexperienced
R5-HIV only
Total N =721
VCV 30 mg + OBT
Placebo + OBT
2:1
Week 24
Interim analysis
Week 48
Final analysis
• Primary endpoint: % HIV RNA <50 copies/mL at 48 weeks
Baseline Characteristics (MITT)
VICTOR-E3
VICTOR-E4
VCV
Control
VCV
Control
252
123
234
112
43 (0.6)
44 (0.9)
43 (0.6)
44 (0.8)
White, n (%)
163 (65%)
85 (69%)
121 (52%)
67 (60%)
Female , n (%)
85 (34%)
37 (30%)
66 (28%)
22 (20%)
Mean baseline HIV RNA, log10
(SE)
4.5 (0.1)
4.8 (0.1)
4.5 (0.1)
4.5 (0.1)
Mean CD4 count, cells/mm3 (SE)
246 (11.9)
221 (17.1)
273 (11.3)
287 (18.0)
OSS ≤2, n (%)
106 (42%)
54 (44%)
70 (30%)
31 (28%)
OSS ≥3, n (%)
141 (56%)
67 (54%)
152 (65%)
78 (70%)
Raltegravir in OBT regimen, n
(%)
95 (38%)
47 (38%)
59 (25%)
31 (28%)
Darunavir in OBT regimen, n (%)
94 (37%)
51 (41%)
90 (38%)
46 (41%)
N
Age, years (SE)
Disposition at 48 Weeks
Pooled VICTOR-E3 & 4 (MITT)
VCV
(N=486)
Control
(N=235)
Completed 48 weeks, n (%)
368 (75)
183 (78)
Total discontinuations, n (%)
118 (24)
52 (22)
Investigator-defined treatment
failure
54 (46)
31 (60)
Adverse Event
17 (14)
4 (8)
Lost-to-follow-up
17 (14)
7 (13)
Administrative
30 (25)
10 (19)
Pooled Efficacy (VICTOR-E3 & 4)
MITT Population
VCV
Control
486
235
HIV RNA <50 at week 48, n (%)
313 (64%)
145 (62%)
HIV RNA <400 at week 48, n (%)
352 (72%)
166 (71%)
Mean change in CD4, cells/mm3 (SE)
+138 (7.3)
+129 (9.4)
Overall N = 721
Virologic Response by OSS
% HIV RNA <50 c/mL
100%
80%
VCV
Control
70%
65%
60%
55%
61%
40%
20%
0%
n=176
n=85
≤2*
n=293
n=145
≥3
Overall Sensitivity Score (No. of Active Drugs in Background)
*Pre-specified subset; not adjusted for multiple analyses; Odds Ratio 1.9, P = 0.02.
Phenotypic Sensitivity Scores in
Recent HIV Trials
• PSS = total number of phenotypically active drugs in background
regimen
• Most vicriviroc trial participants had fully active background regimens
– In the MITT population, 461 (64%) of patients had ≥3 active drugs in OBT
70
PSS
PSS
PSS
PSS
67%
60
50
40
37%
30
29%
31% 30%
26% 25%
20
16%
19%
12%
10
0
=0
=1
=2
≥3
<1%
4%
Vicriviroc
Phase 3
Maraviroc
Phase 3
Raltegravir
Phase 3
Schering-Plough Corp. Data on file; Fätkenheuer G, et al. NEJM 2008; Steigbigel RT, et al. NEJM 2008.
Protocol-Defined Virologic Failures
VCV
N=486
Control
N= 235
Total
N= 721
71 (15%)
38 (16%)
109 (15%)
PDVFs with DM/X4 virus
9/71 (13%)
1/38 (3%)
10/109 (9%)
PDVFs with VCV resistance*
(R5 virus only)
3/71 (4%)
0/38
3/109 (3%)
PDVFs with OBT resistance
14/71 (20%)
8/38 (21%)
22/109 (20%)
Protocol-defined virologic
failures (PDVF)
*Resistance = relative MPI <94%.
Resistance in Virologic Failures
• Frequency of OBT resistance similar in
VCV and Control arms (~20%)
– Affected one or several drugs in OBT
– NRTI resistance was most commonly
observed
– PI/r next most frequent
– Raltegravir resistance infrequent (~3%)
Common Adverse Events
All Treated Subjects
Adverse
events
≥5%
VCV-treated
patients
adjusted
total
exposure
Adverse
events
in in
≥5%
of of
VCV-treated
patients
adjusted
forfor
total
exposure
VCV (n = 568)
Years of exposure = 455
Control (n = 285)
Years of exposure = 227
Number (%)
Rate*
Number (%)
Rate*
55 (10)
12
26 (9)
11
Any TEAE
477 (84)
105
247 (87)
109
Diarrhea
133 (23)
29
61 (21)
27
Nausea
88 (15)
19
19 (7)
8
Headache
69 (12)
15
42 (15)
19
Nasopharyngitis
48 (8)
11
21 (7)
9
Influenza
40 (7)
9
20 (7)
9
URTI
37 (7)
8
20 (7)
9
Vomiting
34 (6)
7
12 (4)
5
Insomnia
30 (5)
7
15 (5)
7
Back pain
27 (5)
6
17 (6)
8
Rash
27 (5)
6
12 (4)
5
26 (5)
6
18 (6)
8
LPV/r
Any SAE
*Per 100
patient years, all treated subjects.
Cough
Events of Interest
All Treated Subjects
VCV n=568
Yrs of Exposure = 455
Control n=285
Yrs of Exposure = 227
Number (%)
Rate*
Number
(%)
Rate*
218 (38)
48
118 (41)
52
0
0
1 (1)
<1
7 (1)
2
4 (1)
2
Hepatocellular injury
57 (10)
13
25 (9)
11
Dyslipidemia
33 (6)
7
21 (7)
9
131 (23)
29
69 (24)
30
HSV infection
37 (7)
8
23 (8)
10
Ischemic cardiovascular event
2 (1)
<1
3 (1)
1
Population
Any adverse event
Seizure
Malignancy
URI
*Per 100 patient years, normalized by exposure; all treated subjects.
Summary and Conclusions
• VCV was well tolerated in both phase 3 studies
• VCV did not meet the primary efficacy endpoint in
these trials
– OBT in these trials included more potent
antiretroviral drugs than in the VCV Phase 2 trial or
Phase 3 trials of recently approved HIV drugs
– 64% of subjects had ≥3 fully active drugs in their
OBT
• Resistance to VCV was observed very infrequently
Implications
• For subjects with 2 or fewer available
active drugs, VCV provided additional
opportunity to achieve full viral
suppression (<50 copies/mL)
• With the success of recently available
therapies for treatment-experienced
subjects, new agents will require novel
study designs to demonstrate efficacy
Inhibidores de la
Integrasa
What Attributes Make a Next
Generation HIV Integrase Inhibitor?
Differentiation in four key areas was viewed necessary:
1. Dose: Unboosted, low mg doses desirable to facilitate FDC
regimens. Less drug advantageous for patients (e.g., toxicity,
exposure, variability)
2. Dosing interval: Q24hr dosing considered a must, patient
convenience critical for compliance, long term durability.
Potential for forgiveness is also an important consideration.
3. Resistance profile: Superior resistance profile against INI
mutants
4. Barrier to resistance: Should show higher potential barrier to
resistance (time and nature of selected mutants)
S/GSK1349572 engineered to deliver these attributes
Most raltegravir- and elvitegravir-resistant mutants
are susceptible to S/GSK1349572
100
IC50 Fold Change
90
80
ELV
RAL
572
70
60
50
40
30
20
10
0
Integrase Mutants
(shaded mutants observed in clinic with RAL or ELV failure )
Seki T, et al. CROI 2010, Friday poster abstract J-122.
Mean Change from Baseline in HIV-1 RNA
(log10 copies/mL)
S/GSK1349572:
Attributes of a Next Generation INI
Dosing period
Follow-up period
0.5
0.0
-0.5
-1.0
-1.5
-2.0
2 mg
10 mg
50 mg
PBO
-2.5
1 2 3 4
(BL)
7 8 9 1011
14
Day
1.Lalezari J. et al. IAS 2009, Cape Town, abstract TUAB105.
2.Min S, et al. IAS 2009, Cape Town, abstract WEPEA099.
3.Song I, et al. IAS 2009, Cape Town, abstract WEPEB250.
4.Sato A, et al. IAS 2009, Cape Town, abstract WEPEA097.
5.Underwood M, et al. IAS 2009, Cape Town, abstract WEPEA098.
6.Seki T, et al. CROI 2010, Poster abstract J-122.
21
(FU)
• Only once daily, unboosted INI
in clinical development1
• Low PK variability and
predictable exposure-response
relationship with a low mg
dose2,3
• Unprecedented antiviral activity
in a ph2a study1
• Superior in vitro resistance
profile with potential for higher
genetic barrier to resistance4,5,6
The Single-Tablet, Fixed-Dose Regimen of
Elvitegravir/GS-9350/Emtricitabine/Tenofovir DF (Quad)
Achieves a High Rate of Virologic Suppression
and
GS-9350 is an Effective Booster
Calvin Cohen1, David Shamblaw2, Peter Ruane3, Richard Elion4, Edwin DeJesus5,
Hui C. Liu6, Lijie Zhong6, David Warren6, Brian P. Kearney6, and Steven L. Chuck6
1Community
Research Initiative of New England, Boston, MA; 2San Diego, CA;
3Los Angeles, CA; 4Whitman Walker Clinic, Washington, D.C.;
5Orlando Immunology Center, Orlando, FL; and 6Gilead Sciences, Foster City, CA
CROI 2010
Background
• Boosted elvitegravir 150 mg is a potent, once-daily HIV
integrase inhibitor
• GS-9350 is a CYP3A inhibitor that lacks anti-HIV
activity
• GS-9350 150 mg boosts EVG or atazanavir (ATV)
equivalently to ritonavir 100 mg
• Elvitegravir (EVG)/GS-9350/Emtricitabine
(FTC)/Tenofovir Disoproxil Fumarate (TDF) has been
co-formulated in one tablet (“Quad”)
Design of the Two Phase 2
Studies
Comparison
Quad + EFV/FTC/TDF placebo
n = 48
Eligible Subjects
2:1
Treatment-naïve
HIV RNA ≥5,000 copies/mL
CD4 cells >50 cells/mm3
No Resistance to
NRTIs
NNRTIs
PIs
HBV- and HCV-negative
EVG/GS-9350
vs.
EFV/FTC/TDF + Quad placebo
n = 23
Efavirenz
GS-9350 + RTV placebo
ATV + FTC/TDF
n = 50
GS-9350
2:1
vs.
RTV + GS-9350 placebo
ATV + FTC/TDF
n = 29
RTV
• Randomization was stratified by HIV RNA (≤ or > 100,000 copies/mL)
• Primary Endpoint: Proportions with HIV RNA < 50 copies/mL at Week 24
• 48-week trials
Baseline Characteristics
Quad
n=48
EFV/FTC/TDF
n=23
GS-9350
n=50
RTV
n=29
36
35
37
34
Male
92%
91%
94%
86%
Race
White
Black
69%
25%
78%
22%
62%
36%
55%
28%
HIV RNA
Mean, log10 copies/mL
>100,000 copies/mL
4.59
23%
4.58
22%
4.56
24%
4.69
38%
CD4 cells/mm3, median
354
436
341
367
AIDS
6%
4%
16%
10%
Age, mean years
Quad vs. EFV/FTC/TDF
Primary Endpoint: Percentage with
HIV RNA < 50 copies/mL (ITT M=F)
Percentage with
HIV RNA <50 copies/mL
100
90%
83%
80
Quad
EFV/FTC/TDF
60
Week 24 stratum-weighted difference
+5% (95% CI: -11.0% to 21.1%)
40
20
0
0
4
8
12
16
Week
20
24
GS-9350 vs. RTV with ATV + FTC/TDF
Primary Endpoint: Percentage with
HIV RNA < 50 copies/mL (ITT M=F)
Percentage with
HIV RNA < 50 copies/mL
100
86%
84%
80
RTV
GS-9350
60
Week 24 stratum-weighted difference
-1.9% (95% CI: -18.4% to 14.7%)
40
20
0
0
4
8
12
16
Week
20
24
Disposition of Subjects
Randomized
Never dosed
Discontinued Study Drugs
before Week 24
Adverse Event
Lost to Follow up
Investigator’s Discretion
Withdrew Consent
Subjects on Study Drugs
through Week 24
aProtocol
Quad
EFV/FTC/TDF
GS-9350
RTV
48
23
56
6a
29
3 (6%)
3 (13%)
4 (8%)
3 (10%)
0
2
1
0
1
1
0
1
2
1
1
0
1
1
0
1
45 (94%)
20 (87%)
46 (92%)
26 (90%)
violation (n=4); withdrew consent (n=2); these 6 subjects are excluded from all ITT analyses
Quad vs. EFV/FTC/TDF
Percentage with HIV RNA < 50
copies/mL (ITT M=E)
Percentage with
HIV RNA <50 copies/mL
100
96%
95%
Quad
EFV/FTC/TDF
80
Week 24
Median ∆
CD4 cells
60
40
20
0
0
4
8
12 16
Week
20
Quad
+123
EFV/FTC/TDF
+124
24
At Week 24: 3 subjects had HIV RNA > 50 copies/mL but < 400 copies/mL
At Week 32: 3 of the 3 subjects had HIV RNA <50 copies/mL
GS-9350 vs. RTV with ATV + FTC/TDF
Percentage with HIV RNA < 50
copies/mL (ITT M=E)
Percentage with
HIV RNA <50 copies/mL
100
96%
91%
RTV
GS-9350
80
Week 24
Median ∆
CD4 cells
60
40
20
0
0
4
8
12 16
Week
20
GS-9350
+206
RTV
+190
24
At Week 24: 5 subjects had HIV RNA > 50 copies/mL
At Week 32: 3 of the 5 had HIV RNA < 50 and 1 had 59 copies/mL; 1 virologic failure
Summary of TreatmentEmergent Adverse Events
Quad
n=48
EFV/FTC/TDF
n=23
GS-9350
n=50
RTV
n=29
Adverse Events related to
Randomized Drug,
Grades 1-4
17 (35%)
13 (57%)
10 (20%)
7 (24%)
Grade 3/4 Adverse Events
0
2 (9%)
2 (4%)
0
Adverse Events leading to
discontinuation of study drug
0
1 (4%)
2 (4%)
1 (3%)
Serious Adverse Events
(none related to study drugs)
1 (2%)
1 (4%)
0
1 (3%)
Adverse Events >5% Related to Randomized
Drug in Any Treatment Group
Quad
n=48
EFV/FTC/TDF
n=23
GS-9350
n=50
RTV
n=29
5 (10%)
8 (35%)
0
0
0
3 (13%)
0
0
Fatigue
4 (8%)
3 (13%)
1 (2%)
2 (7%)
Somnolence
2 (4%)
2 (9%)
0
0
Headache
2 (4%)
2 (9%)
1 (2%)
0
Diarrhea
4 (8%)
1 (4%)
3 (6%)
3 (10%)
Nausea
2 (4%)
1 (4%)
5 (10%)
1 (3%)
Abnormal Dreams,
Nightmares
Dizziness
Treatment-Emergent Laboratory Abnormalities
Grades 2-4 Occurring in >5% of Any Treatment Arm
Quad
n=48
EFV/FTC/TDF
n=23
GS-9350
n=50
RTV
n=29
0
0
40/49 (82%)
25 (86%)
Amylase
2 (4%)
2 (10%)
6 (12%)
2 (7%)
Neutrophils, decreased
3 (7%)
2 (10%)
1 (2%)
1 (3%)
Cholesterol*, total
4 (9%)
2 (10%)
3 (6%)
0
Proteinuria
1 (2%)
2 (10%)
2 (4%)
0
Bilirubin, total
*Similar small median increases in cholesterol, LDL, HDL, triglycerides
between arms in each study
Other Treatment-Emergent
Laboratory Abnormalities
Quad
n=48
EFV/FTC/TDF
n=23
GS-9350
n=50
RTV
n=29
ALT
Grades 2-4
0
0
1 (2%)
1 (3%)
AST
Grades 2-4
0
0
0
1 (3%)
Hypophosphatemia
(All were Grade 1)
0
0
1 (2%)
1 (3%)
1 (2%)
0
6 (12%)
0
Creatinine
(All were Grade 1)
Small Increases in Serum Creatinine
Affected Estimated GFR (Cockcroft-Gault)
Quad
n=48
EFV/FTC/TDF
n=23
∆ Mean Serum
Creatinine
Baseline to Week 24
+0.14 mg/dL
+0.04 mg/dL
∆ Mean eGFR*
Baseline to Week 24
-18 mL/min
-7 mL/min
-15 mL/min
-14 mL/min
Mean eGFR*
At Week 24
111 mL/min
126 mL/min
102 mL/min
111 mL/min
*Estimated GFR by Cockcroft-Gault
GS-9350
n=50
RTV
n=29
+0.18 mg/dL +0.14 mg/dL
Renal Study of GS-9350 Without ARVs in Healthy Volunteers
200
20
Actual GFR
(mL/min; Iohexol)
Placebo
GS-9350 150 mg
30
(mL/min; Cockcroft-Gault)
Mean Change Estimated GFR
GS-9350 Alters Estimated GFR—Not
Actual GFR
150
10
100
0
-10
-20
50
Dosing
0
-30
0
•
•
•
7
Day
GS-9350
Placebo
n=12
n=12
14
Study of GS-9350 (no ARVs) in healthy volunteers
– Administered GS-9350 or placebo for 7 days
– Measured serum creatinine and iohexol clearance concurrently
GS-9350 is associated with lower estimated GFR
– Onset in days, reversible in days
GS-9350 has no effect on actual GFR
GS-9350 Does Not Affect Actual GFR
But Can Increase Serum Creatinine
• Creatinine is excreted primarily by glomerular
filtration but ~10-15% by active tubular
secretion
• GS-9350 may inhibit tubular secretion of
creatinine
– Similar to the over-the-counter medicine,
Cimetidine
Conclusions from Phase 2 Studies
• Quad (vs. EFV/FTC/TDF)
– Efficacy met criteria for non-inferiority (90% vs. 83%)
– Fewer study drug-related adverse events (particularly CNS)
• GS-9350-boosted ATV (vs. RTV-boosted ATV) + FTC/TDF
– Similar efficacy
– Similar safety and tolerability
• Results support proceeding to Phase 3 studies
The generic name of GS-9350 is cobicistat
Funny how the new things
are the old things
Rudyard Kipling (1865-1936)