Transcript Slide 1

Depletion of naïve CD4+T cell
compartment by immune hyperactivation
can be rapidly reversed by AntiViralHyperActivation Limiting Therapeutics
(AV-HALTs)
D.V. Baev, E. Katabira, R. Maserati, P. Cahn,
D. De Forni, B. Poddesu, M.R. Stevens, F. Lori
on behalf of the VS411 Study Team
WELBX03
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AV-HALTs
AntiViral-HyperActivation Limiting Therapeutics
Anti
Viral Hyper
Activation
Limiting
Therapeutics
Oral agents combining antiviral and
immunomodulating properties to both
reduce viral load
and
decrease immune-activation
ViroStatics AV-HALTs
VS411: Proof of Concept
2nd generation AV-HALTs: To be
developed
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AV-HALTs
A New Class of Antiretroviral Drugs
Scientific Rationale
behind AV-HALTS
Why decrease immune activation?
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Dec 10, 1981
The first reports of what is now known as HIV-disease/AIDS indicated that the individuals’
immune systems were experiencing excessive activation despite low CD4+ cell counts
Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men:
evidence of a new acquired cellular immunodeficiency
MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan, RA Wolf, and A Saxon
An outbreak of community-acquired Pneumocystis carinii pneumonia:
initial manifestation of cellular immune dysfunction
H Masur, MA Michelis, JB Greene, I Onorato, RA Stouwe, RS Holzman, G Wormser, L Brettman, M Lange, HW Murray, and S Cunningham-Rundles
Table 3. Characterization of T-Lymphocyte Subsets
GROUP
LYMPHOCYTE SUBSET
LEU 1
LEU 2
LEU 3
LEU 3/
LEU 2
RATIO
T10
per cent lymphocytes reactive with monoclonal antibodies
Patients
1
2
3
4
Mean
± S.D.
Normal subjects
(n = 16 [mean
± S.D.])
45
47
49
67
52 *
± 10.1
71.0
± 10.0
57
52
57
47
53.3 †
± 4.7
28.0
± 8.0
0
0
10
2
3.0 †
± 4.76
46.0
± 12.0
59
59
79
81
69.5
± 12.1
15.0
± 6.6
0
0
0.18
0.04
0.05
± 0.08
1.6
± 0.74
T10 is now
known as CD38.
The CD38 protein is
a marker of cell
activation.
A 4- to 5-fold
increase above
healthy normals
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Why Decrease Immune Activation ?
HIV disease is driven by immune system hyperactivation
Immune hyperactivation is not normalized by HAART
Life Expectancy (years)
Probability of Survival
1.0
Population
Controls
0.7
5
 10 years 
Current HAART
(2000 – 2005)
0.5
0
Early HAART
(1997 – 1999)
0.2
5
0
Pre-HAART
(1995 – 1996)
Ι
Ι
Ι
Ι
Ι
Ι
Ι
Ι
Ι
25
70
30
35
40
45
50
55
60
65
Life Expectancy, years
Ι
Adapted from:
Lohse N et al. Ann Intern
Med 2007;146-95
The ViroStatics AV-HALT Drug
Development Program
Proving the AV-HALT concept in humans
and
Moving novel agents into clinical development
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AV-HALTs
Drug Development Program
Proof of Concept
Achieved in HIV/AIDS
First Generation AV-HALT
VS411
• Contained two readily available generic drugs
• One acted as an “AV” (didanosine)
• One acted as a “HALT” (hydroxyurea)
• Multinational Phase 2a Clinical Trial
AV-HALTs
Drug Development Program
Proof of Concept
Achieved in HIV/AIDS
First Generation AV-HALT
VS411
• AV-HALT properties proven
• AV:
• AV:
• HALT:
Viral load up to -1.8 logs,
CD4 cell counts up to +135 cells/mm3
- 30% hyperactivation decrease in only 28 days,
similar to what HAART achieves after months/years
VS411 Proof of Concept Phase 2a Trial
A 28-day Randomized, Double-blinded Study
58 ART naïve subjects (50% female; 50% black)
Safety - Viral Load Reduction – CD4+ Counts - Immunological Assays
Countries
Uganda 1
Argentina
Italy
2
3
Russia 4
Low
dose
ddI
High
Dose
ddI
Didanosine
Hydroxyurea
200 mg
300 mg
200 mg
600 mg
200 mg
900 mg
400 mg
300 mg
400 mg
600 mg
Investigators
1
Elly Katabira, MD
President - International AIDS Society
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Renato Maserati, MD;
Giancarlo Pasetti, MD (Pavia, Parma)
2
Safety precautions:
Standard didanosine
and hydroxyurea
dosages reduced by
one-half or more
Didanosine Cmax
blunted in Phase I
Pedro Cahn, MD
Past President - International AIDS Society;
Sergio Lupo, MD; Arnaldo Casiro, MD;
Jorge Contarelli (Buenos Aires, Rosario)
VS411 was safe and well tolerated, no SAE
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Aza Rakhmanova, MD;
Natalia Zakharova, MD (St. Petersburg)
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VS411: Phase II Study Results
CD4+ Increases up to +135 cells/mm3
Didanosine/
hydroxyurea
200mg/300mg
Didanosine/
hydroxyurea
200mg/600mg
Didanosine/
hydroxyurea
200mg/900mg
Didanosine/
hydroxyurea
400mg/300mg
Didanosine/
hydroxyurea
400mg/600mg
Mean Change
From Baseline
cells/mm3 OT
+ 71.9
+ 56.9
+ 95.7
+ 67.4
+ 50.7
Mean Change
From Baseline
cells/mm3 ITT
+ 48.0
+ 56.9
+95.7
+ 67.4
+ 50.7
Median Change
From Baseline
cells/mm3 OT
+ 24.0
+ 52.0
+ 135.0
+ 54.0
+ 67.0
Median Change
From Baseline
cells/mm3 ITT
+ 1.5
+ 52.0
+ 135.0
+ 54.0
+ 67.0
The “blunting” of CD4+ cell increases historically seen with the
didanosine/hydroxyurea combination was not seen with VS411
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VS411: Phase 2a Antiviral [AV] Results
Mean Viral Log Reduction (ITT)
Log10 reduction from baseline
DAY 14
200 mg ddI
300 mg HU
200 mg ddI
600 mg HU
200 mg ddI
900 mg HU
400 mg ddI
300 mg HU
400 mg ddI
600 mg HU
Lamivudine – 3TC
Day 12
Log10 reduction from baseline
DAY 28
200 mg ddI
300 mg HU
200 mg ddI
600 mg HU
200 mg ddI
900 mg HU
400 mg ddI
300 mg HU
400 mg ddI
600 mg HU
Tenofovir –
TDF
Day 21
Historical
nucleoside
analogue
comparators
Viral load was suppressed below 50 copies/ml in only two individuals
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VS411: Phase II [HALT] Results
HAART, 21 months
VS411, 28 days
VL <1,000
ddI 200mg / HU 900mg
30-
20
10
-
8%
4%
0-
1%
Percentage of Activated CD4+ cells
CD38+/HLA-DR+
Percentage of Activated CD4+ cells
CD38+/HLA-DR+
Comparison of VS411 200/900 to HUNT et al. 2003
30
20
-
P =.001
106.7%
4.3%
0-
Day 0
Day 28
CD4+ T lymphocytes
Hunt P, et al. JID 2003;187:1534-1543
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Naïve – but not Central Memory – CD4 T Cell
Depletion Correlates with CD4 T Cell Activation
Naïve
100
CD4+ Naïve
80
70
CD4+ CM
y = -2.708x + 51.39
R² = 0.23162
P = .001
90
Total
Central Memory (CM)
60
50
40
30
20
10
0
0
5
10
15
20
0
5
10
15
20
10
15
20
16
5
y = 0.1853x + 0.108
R² = 0.16263
P = .01
4
3
2
1
% Ki-67+ CD4+ CM
% Ki-67+ CD4+ Naïve
m
Proliferating
100
90
80
70
60
50
40
30
20
10
0
14
12
10
8
6
4
2
0
0
0
5
10
15
% CD4+ CD38+HLA-DR+
20
0
5
% CD4+ CD38+HLA-DR+
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Reversion of Naïve CD4 T Cell Depletion
by AV-HALTs
Naïve, Change from Baseline CM, Change from Baseline
y = 1.3888x - 4.3596
R² = 0.1329
P = .03
20
10
0
-10 0
10
20
40
20
% change
CD4+ CM
30
% change
CD4+ Naive
Total
40
0
0
10
20
-20
-20
-40
% CD4+ CD38+HLA-DR+
2
10
0
5
-2
-4
-6
-8
0
10
20
y = -0.1503x + 0.3465
R² = 0.09663
P = .04
% CD4+ CD38+HLA-DR+
% change
Ki-67+ CD4+ CM
% change
Ki-67+ CD4+ Naïve
Proliferating
-30
% CD4+ CD38+HLA-DR+
0
-5
0
10
20
-10
-15
% CD4+ CD38+HLA-DR+
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Screening for Second-Generation AV-HALTs
Clinical
Proof of Concept
In vitro
 Viral Load
 CD4
AV-HALT profile
• AV efficacy
• HALT efficacy
• Toxicity
Comparator
Prototype
 Hyperactivation
Compound 1
Clinical
2nd
generation
 Viral Load
 CD4
Prediction
Following VS411
 Hyperactivation
Pathway
Compound 2
Compound 3
Screening
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Screening for Second-Generation AV-HALTs
(Lack of)
Mitochondrial
Toxicity
(Lack of)
Apoptotic
effect
Measures of Activity
Antiviral effect
in activated cells
% compared to
not treated control
Measures of Toxicity
(Lack of)
Cell toxicity
100
80
60
40
20
0
Antiproliferative
capacity
Antiviral effect
in resting/stimulated cells
Ideal
VS2-091
AV-HALT
VS2-102
VS411
VS1-002
An ideal AV-HALT would have:
VS1-002 provides both antiviral and hyper-activation reducing activity
- Low
mitochondrial
cellular toxicity
VS2-091
andand
VS2-102
approachtothe
criteria
of an Ideal AV-HALT
comparable
VS411
with:
-
combines
low
doses of two drugs (didanosine and
- Little VS411
if any apopototic
effect (cell
death)
nanomolar
concentrations
in both activated
and
resting
T helper
and for an- Ideal
a- Activity
longhydroxyurea)
patent
life to
-Atless
potential
toxicity
in a single
molecule
approach
thecells,
criteria
AV-HALT
- Limit, but not completely block, cell
proliferation
In a single molecule
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Thank you to the Study Subjects,
Investigators and the ViroStaticsTeam
There are two kinds of people:
those who do the work,
and those who take the credit
Try to be in the first group. There is less
competition there…
Indira Gandhi
ViroStatics
Porto Conte, Italy
Princeton, New Jersey
Montreal, Canada
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