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Future Applications of Antiretroviral
Agents in Development
Kathleen E. Squires, MD
Professor of Medicine and Director
Division of Infectious Diseases
Jefferson Medical College
Philadelphia, PA
Antiretroviral Drug Development
Issues to Address
Current Limitations
• Adherence
• Toxicity
• Activity
• Resistance
Ideal Characteristics
• Improve convenience
• Improve tolerability
• Reduce toxicity
• Improve activity
– Wild-type virus
– Resistant virus
• Penetrate reservoirs
• Exploit new targets
Novel Agents in Clinical Development
Phase
Reverse
Transcriptase
Inhibitors
Protease
Inhibitors
Entry
Inhibitors
Integrase/
Maturation
Inhibitors;
Immunologics
II/III
Etravirine (TMC 125)
Darunavir
Maraviroc
Vicriviroc
MK-0518
II
BILR 355 BS
TNX-355
GS 9137
I/II
Amdoxovir
Apricitabine
Rilpivirine (TMC 278)
Brecanavir
AMD 070
PRO 542
Bevirimat
CTLA4-mAb
I
Fosalvudine
PPL-100
PRO 140
TAK 652
Preclinical
22
7
21
11
New Generation NNRTIs
Etravirine (TMC125)
• Novel NNRTI designed to have a high genetic barrier to
development of resistance[1]
• Potent in vitro antiviral activity against:
– Wild-type and NNRTI resistant HIV-1[2]
– Clinical isolates resistant against approved NNRTIs[2]
• In a 7-day clinical trial, TMC125 monotherapy produced a
median viral load change of –0.89 log10 copies/mL in patients
on failing NNRTI therapy[3]
• DUET 1 and 2 studies ongoing: etravirine vs placebo, with
DRV/r and OBR in patients with both NNRTI and PI resistance
• Expanded access just opened
1Vingerhoets
2Andries
J, et al. J Virol 2005 Oct;79(20):12773-12782.
K, et al. Antimicrob Agents Chemother 2004 Dec;48(12):4680–4686.
3Gazzard BG, et al. AIDS 2003 Dec 5;17(18):F49–F54.
TMC125-C223
Study Design
Active control*
N = 199
TMC125 400 mg BID + OBR†
TMC125 800 mg BID + OBR†
•
4 weeks
48 weeks
Screening
Treatment
Primary Objective:
–
Proportion of patients with ≥ 1 log10 reduction in HIV RNA from baseline
to Week 24
*Active control: best available regimen from licensed agents
†Optimized background regimen: investigator selected NRTIs ± LPV/r ± T-20
Cohen C, et al. 12th Annual Conference of BHIVA; Mar 29-Apr 1, 2006; Brighton, UK. Abstract P2.
TMC125-C223
Virologic Response* at Week 48
400 mg BID (n = 80)
800 mg BID (n = 79)
23%
22%
<50 copies/mL
0%
P < .001
P < .001
P = .036
P = .009
28%
30%
<400 copies/mL
8%
31%
34%
≥1 log reduction
in HIV RNA
Active control (n = 40)
P = .016
P = .004
8%
0
20
P-values versus active control
* Time-to-Loss of Virologic Response (TLOVR)
TMC125, Phase IIb formulation TF035
40
60
Percentage with response
80
100
Cohen C, et al, XVI International AIDS Conference; Aug
13-18, 2006; Toronto, Canada. Abstract TUPE0061.
TMC125-C223
Number of NNRTI Mutations and
Virologic Response at Week 48
Mean change in log10 VL
0
TMC125
800 mg
BID
n = 79
Active
control
n = 40
–0.14
Baseline NNRTI mutations
in TMC125 800 mg BID
0*
n = 14
1
n = 19
2
n = 16
–0.5
–1.0
3
n = 30
–0.54
–0.9
–1.01
–1.38
–1.5
–1.67
–2.0
• Patients discontinuing the trial for any reason had their VL response imputed as
no change from baseline (NC = F)
*All patients had NNRTI mutations from prior genotyping
TMC125, Phase IIb formulation TF035
Cohen C, et al. XVI International AIDS Conference;
Aug 13-18, 2006; Toronto, Canada. Abstract TUPE0061.
Baseline NNRTI Mutations Associated With
TMC125 FC >10 (Arbitrary Threshold)
• No single NNRTI mutation was associated with mean FC >10
(arbitrary threshold) to TMC125
• Frequency of combinations of NNRTI mutations associated with
mean TMC125 FC >10 was low (12%)
• Each of the following mutations, always in combination with up to four
other mutations, were associated with mean FC >10
– K101P, V179E, V179F, Y181I, Y181V, G190S, M230L
– For V179E, V179F, G190S, M230L: additional mutations always included
Y181C when FC >10
• These mutations were previously identified in vitro to be associated
with increased FC to TMC125
TMC125, Phase IIb formulation TF035
1. Cohen C, et al. XVI International AIDS Conference; Aug
13-18, 2006; Toronto, Canada. Abstract TUPE0061.
2. Vingerhoets J ,et al. J Virol. 2005 Oct;79(20):12773-82.
Targets for Antiretroviral Therapy
Attachment
Inhibitors,
Coreceptor
Antagonists
Fusion
Inhibitor
Entry
Inhibitors
NRTIs,
NNRTIs
PIs
Reverse
Transcriptase
Inhibitors
Integrase
Inhibitors
Protease
Inhibitors
Maturation
Inhibitors
HIV Entry Inhibitors
•
•
•
•
•
New class of therapy
Works early in life cycle of the HIV virus
Inhibits fusion of viral particle with cell
Subcutaneous injection
Potent antiviral, but need other active antivirals
for best effect
• Injection site reactions
Phase II Study of TNX-355
A Novel Entry Inhibitor
•
48-week phase II study
– 3-class experienced (n=82)
Treatment arms
– OBR vs. TNX-355 + OBR
• 15 mg/kg IV q2wks
• 10 mg/kg IV qwk x 8 wks, then
10 mg/kg q2wks
– CD4 response:
• OBR: +5 cells/mm3
• 10 mg/kg: +9 cells/mm3
• 15 mg/kg: +51 cells/mm3
•
•
Well tolerated, no serious ADR
related to drug, no ISRs
Results sustained to Wk 48
TNX-355 + OBR
Mean Change in HIV-1 RNA at
Week 24 (log10 copies/mL)
•
0
15
10
OBR
Alone mg/kg mg/kg
-0.20
-0.4
-0.8
-1.2
-0.95
(P = .003)
-1.16
(P < .001)
Norris D, et al. 45th ICAAC. Washington, DC, 2005. Abstract LB2-26
Tanox Inc. News Release May 2, 2006.
HIV Tropism and Disease Progression
R5
Mixed/Dual
↑ X4
Amount of Virus
CD4 Cell Count
Dual-tropic HIV
CXCR4tropic HIV
Limit of tropism
assay detection*
CCR5tropic HIV
Time
* Less than 10% of a tropism is not detectable with current tropism assay
Courtesy GSK interactive CD "Exploring an allosteric world: CCR5 entry inhibitors and HIV"
CCR5 Inhibitors in Development
Maraviroc
• Randomization of 80 HIV infected patients with CCR5 tropic virus
– CD4 >250 cells/mm3
– VL >5000 copies/mL
• Doses >100mg/d had > 1.0 log10
decrease
• Small  CD4 count with all doses
• 61/63 had CCR5 tropic virus at BL
remained CCR5 tropic at follow up
– 1 reverted to CCR5 topic at day 40
– 1 persisted >6 mo post study with no
evidence of clinical progression
Median VL Change From
BL (log10 copies/mL)
0.5
0
-0.5
-1.0
-1.5
Placebo 15
100 mg BID
Placebo 07
150 mg Fast
25 mg QD
150 mg Fed
50 mg BID
300 mg QD
100 mg QD
300 mg BID
Dosing
-2.0
0
5
10
15
20
25
30
35
40
Days
Fatkenheuer G et al. XV IAC. Bangcock, Thailand. Abstract TuPeB4489
Phase IIb Pilot Study Evaluating the Safety
of Maraviroc in Patients with Non-R5 HIV-1
OBT* + MARAVIROC (150 mg** BID)
Screening
and
randomization
OBT* + MARAVIROC (150 mg** QD)
OBT* + Placebo
4-6 Weeks
0
•
•
24
Primary
efficacy
endpoint
48 Weeks
Randomized, double-blind, placebo-controlled study
Selection criteria:
– D/M-tropic, X4-tropic or indeterminate tropism phenotype
– Antiretroviral experienced and/or multi-class resistance
– At least one active drug in OBT
*OBT = 3 to 6 ARVs (note PK boosting doses of RTV will not be counted as an ARV)
**150 mg maraviroc with PIs provides equivalent dose to 300 mg without PIs
Maraviroc: Efficacy Results
All treated patients with D/Mtropic HIV-1
Placebo +
OBT
n = 58
MVC QD +
OBT
n = 57
MVC BID +
OBT
n = 52
Mean decrease in HIV-1 RNA
(log10c/mL)*
-0.97
-0.91
-1.20
+0.06
(-0.53, +0.64)
-0.23
(-0.83, +0.36)
Treatment diff (MVC-OBT) in
HIV-1 RNA decrease
(log10c/mL) (97.5% CI)
HIV RNA < 400 c/mL (%)
HIV RNA < 50 c/mL (%)
24.1
15.5
24.6
21.1
30.8
26.9
Mean decrease in HIV-1 RNA
in patients using enfuvirtide**
(log10c/mL)
-0.89
-1.26
-1.44
OBT - optimized background therapy
D/M - dual/mixed tropic
*Primary endpoint
**LOCF
Mayer H, et al IAC 2006. Abstract THLB0215.
On the Horizon
Integrase Inhibitors
• Integrase inhibitors
– MK-0518
– GS 9137
Integrase Inhibitor (MK-0518)
Phase IIa 10-Day Dosing Study
• Phase IIa, placebo-controlled,
monotherapy study
Change in HIV RNA
at Day 10
(log10 copies/mL)
– 35 treatment-naïve patients
– Baseline HIV RNA
Placebo (n=7)
• 4.53 to 4.97 log10 copies/mL
-0.2
MK-0518
• MK-0518
(mg bid)
– Doses: 100, 200, 400, 600 mg bid
• At day 10
– HIV RNA <400 copies/mL: >50%
– No significant change in CD4 cell
count from baseline
– Most common adverse events
100 (n=7)
-1.9
200 (n=7)
-2.0
400 (n=6)
-1.7
600 (n=8)
-2.2
• Headache, fatigue, and dizziness
Morales-Ramirez JO, et al. EACS 2005. Abstract LBPS1/6.
MK-0518: Phase IIb
(Protocol 005)
• Multicenter, randomized,
double blind
Placebo
+ OBR
N = 43
N=167
VL ≥ 5000
CD4 ≥ 50
Resistant to ≥ 1
NRTI, NNRTI, PI
MK-0518 200mg bid
MK-0518 400mg bid
+ OBR
+ OBR
N = 40
N = 42
• Treatment arms similar at baseline
• Mean duration of HAART: 9-11 yrs
MK-0518 600mg bid
+ OBR
N = 42
• Mean VL: 4.6-4.8 log10 copies/mL
• Use of ENF in OBR: 33% to 38%
– Patients with no active PIs in OBR: 84% to 98%
– Mean CD4: 220-283 cells/mm3
Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB.
MK-0518
Virologic Suppression Through Week 16
Treatment†
MK-0518 200 mg BID
MK-0518 400 mg BID
n
25
28
% < 400 copies
84
73
MK-0518 600 mg BID
Placebo
28
27
67
24
CI = Confidence Interval.
† All subjects received OBT in addition to MK-0518 or placebo.
Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB.
MK-0518: Adverse Events
• ADRs: similar to placebo
• Most common ADR
– Diarrhea, nausea, fatigue, ISRs, headache, pruritus
– Occurring in >5% of 2 patients per arm
Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB.
MK-0518: Study Design
Potent Activity of Integrase Inhibitor in Treatment-Naive Patients
Part I Design
• 8 patients each received MK-0518 at 600, 400, 200, or 100 mg
bid or placebo for 10 days monotherapy
• 30 patients in addition each received one of the MK-0518
doses plus TFV+3TC, or efavirenz plus TFV+3TC, for a total of
38 patients in each arm
Part II Design
• Part I patients continued at same dose in Part II
~150 additional patients randomized for Part II
Endpoints
• HIV RNA and CD4 counts
MK-0518 vs Efavirenz
HIV RNA < 50 copies/mL at Week 24 (NC = F)
HIV RNA levels %
(95% CI)
Treatment (mg)
N
<400
copies/mL
<50 copies/mL
MK-0518 BID
100
18
89 (65, 99)
88 (64, 99)*
MK-0518 BID
200
18
100 (82, 100)
100 (82, 100)
MK-0518 BID
300
17
94 (71, 100)
94 (71, 100)
MK-0518 BID
400
17
100 (81, 100)
94 (70, 100)*
Efavirenz BID
600
15
93 (68, 100)
86 (57, 98)*
*One patient was excluded pending additional test results
Markowitz M, et al. IAC 2006. Abstract THLB0214.
Integrase Inhibitor (GS 9137)
10-Day Monotherapy Study
•
Change in
HIV RNA
at Day 10
Phase IIb, placebo-controlled,
monotherapy study
– 40 treatment-naïve and treatmentexperienced patients
– Baseline
• HIV RNA: 4.75 log10 copies/mL
• CD4: 442 cells/mm3
•
At day 10
– >1 log10 reduction in HIV RNA
• GS-9137: 83%
• Placebo: 0%
– No serious adverse events and no
study drug discontinuations
– Most common adverse events
• Fatigue, diarrhea, headache, nausea
(log10 copies/mL)
Placebo
-0.13
GS-9137
800 mg qd
-0.89*
200 mg bid
-1.44*
400 mg bid
-1.98*
800 mg bid
-1.78*
50 mg qd
+ RTV 100mg qd
-2.03*†
*P<0.01 versus placebo.
†P<0.05 versus 800 mg qd.
DeJesus E, et al. 13th CROI. Denver, 2006. Abstract 160LB.
Maturation Inhibitor
PA-457
• First maturation inhibitor
• Data from a double blind, placebo controlled single
dose study of 75mg, 150mg and 250mg and
placebo (all n=6); naïve or of-treatment for >4
weeks; two subjects had MDR
• Dose related response with median reduction at the
highest dose of -0.51 log10 and a greatest decline of
-0.73 log10. 8/12 in higher doses >0.3 log10
• Return to baseline was inhibited for at least 20 days
in the 250mg dose arm
Martin D, et al. CROI 2005. Abstract 159.
Maturation Inhibitor (PA-457)
Phase II Dosing Study
• Phase II, placebo-controlled,
monotherapy study
• HIV RNA: 4.73 log10 copies/mL
• CD4: 441 cells/mm3
• Oral doses of PA-457
– 25, 50, 100, 200 mg qd
• At day 11
– AUC and trough levels were
significantly associated with
antiviral response (P<0.01)
0.2
0.046
0
Log10 Copies/mL
– 32 treatment-naïve patients
– Baseline
Change in HIV RNA at Day 11
-0.2
-0.174
-0.4
-0.483
-0.6
-0.8
-1
-1.05
-1.2
25
50
100
PA-457 mg qd
200
Smith P, et al. 13th CROI. Denver, 2006. Abstract 52.
New Antiretroviral Agents
Conclusions
• Newer drugs are needed to improve
convenience, tolerability and activity (wild-type
and resistant virus)
• Promising agents are in development both in
existing classes (NNRTI, PI) and new classes
(e.g, entry and integrase inhibitors)
• Further basic and clinical research is needed