1 Depletion of naïve CD4+T cell compartment by immune hyperactivation can be rapidly reversed by AntiViral- HyperActivation 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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1 Depletion of naïve CD4+T cell compartment by immune hyperactivation can be rapidly reversed by AntiViral- HyperActivation Limiting Therapeutics (AV-HALTs)
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1
Depletion of naïve CD4+T cell compartment by immune hyperactivation
can be rapidly reversed by AntiViral- HyperActivation Limiting Therapeutics
(AV-HALTs)
D.V. Baev, E. Katabira, R. Maserati, P. Cahn, D. De Forni, B. Poddesu, M.R. Stevens, F. Lorion behalf of the VS411 Study Team
Oral agents combining antiviral and immunomodulating properties to
both
reduce viral load and
decrease immune-activation
AntiViral -HyperActivation Limiting Therapeutics
ViroStatics AV-HALTs
VS411: Proof of Concept
2nd generation AV-HALTs: To be developed
Why decrease immune activation?
AV-HALTsA New Class of Antiretroviral Drugs
3
Scientific Rationale behind AV-HALTS
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
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
11Viral load was suppressed below 50 copies/ml in only two individuals
VS411: Phase II [HALT] ResultsComparison of VS411 200/900 to HUNT et al. 2003
12Hunt P, et al. JID 2003;187:1534-1543
8%
4%1%
20-
10-
0-
30-
Day 0 Day 28
6.7%4.3%
Per
cen
tag
e o
f A
ctiv
ated
CD
4+ c
ells
CD
38+/H
LA
-DR
+
Per
cen
tag
e o
f A
ctiv
ated
CD
4+ c
ells
CD
38+/H
LA
-DR
+
20-
10-
0-
30-
VS411, 28 daysddI 200mg / HU 900mg
P =.001
HAART, 21 monthsVL <1,000
CD4+ T lymphocytes
Naïve – but not Central Memory – CD4 T Cell Depletion Correlates with CD4 T Cell Activation
13
0 2 4 6 8 10 12 14 16 18 200
102030405060708090
100
f(x) = − 2.70802556822812 x + 51.3895784266075R² = 0.231621238803075
m
CD
4+ N
aïve
0 2 4 6 8 10 12 14 16 18 200
102030405060708090
100
CD
4+ C
M
Naïve Central Memory (CM)
0 2 4 6 8 10 12 14 16 18 200
0.51
1.52
2.53
3.54
4.55
f(x) = 0.185339803313403 x + 0.108114991211517R² = 0.16263246877592
% CD4+ CD38+HLA-DR+
% K
i-67+
CD
4+ N
aïve
Tota
l P
rolif
erat
ing
0 2 4 6 8 10 12 14 16 18 200
2
4
6
8
10
12
14
16
% CD4+ CD38+HLA-DR+
% K
i-67+
CD
4+ C
M
Reversion of Naïve CD4 T Cell Depletion by AV-HALTs
14
Naïve, Change from Baseline CM, Change from Baseline
0 2 4 6 8 10 12 14 16
-30-20-10
010203040
f(x) = 1.38884754 x − 4.35956464R² = 0.13289792033515
% c
hang
e CD
4+ N
aive
0 2 4 6 8 10 12 14 16
-40-30-20-10
010203040
% c
hang
e C
D4+
CM
0 2 4 6 8 10 12 14 16
-7-6-5-4-3-2-1012
f(x) = − 0.150335945 x + 0.346472219R² = 0.0966308943033439
% CD4+ CD38+HLA-DR+
% c
hang
e Ki
-67+
CD
4+ N
aïve
0 2 4 6 8 10 12 14 16
-12-10
-8-6-4-20246
% CD4+ CD38+HLA-DR+
% c
hang
e K
i-67+
CD
4+ C
M
Tota
l P
rolif
erat
ing
% CD4+ CD38+HLA-DR+ % CD4+ CD38+HLA-DR+
Screening for Second-Generation AV-HALTs
In vitroClinical Proof of Concept
Prediction
Compound 1
Compound 2
Compound 3
AV-HALT profile• AV efficacy• HALT efficacy• Toxicity
Following VS411Pathway
Viral Load CD4
Hyperactivation
ComparatorPrototype
Clinical
Screening
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Viral Load CD4
Hyperactivation
2nd generation
IdealAV-HALT
VS411 combines low doses of two drugs (didanosine and hydroxyurea) to approach the criteria for an Ideal AV-HALT
An ideal AV-HALT would have:- Low mitochondrial and cellular toxicity- Little if any apopototic effect (cell death)- Activity in both activated and resting T helper cells, and- Limit, but not completely block, cell proliferation
(Lack of)Cell toxicity
(Lack of)Apoptotic
effect
Antiproliferative capacity
Antiviral effect in resting/stimulated cells
Antiviral effectin activated cells
(Lack of)Mitochondrial
Toxicity
IdealAV-HALT
VS411
VS1-002
% c
om
pa
red
to
n
ot
tre
ate
d c
on
tro
l
020406080100
VS1-002 provides both antiviral and hyper-activation reducing activity comparable to VS411 with:
- a long patent life - less potential toxicity - in a single molecule
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Measures of Toxicity
Measures of Activity
VS2-091 and VS2-102 approach the criteria of an Ideal AV-HALT
At nanomolar concentrationsIn a single molecule
VS2-091VS2-102
Screening for Second-Generation AV-HALTs
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
Thank you to the Study Subjects, Investigators and the ViroStaticsTeam
ViroStaticsPorto Conte, Italy Princeton, New Jersey Montreal, Canada17