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Introduction to new drugs
African Treatment Advocacy Training
31 May 2007
Simon Collins
www.i-Base.info
Introduction to new drugs: I-Base training
London - May 2007
Overview
• Introduction
• HIV lifecycle and drug families
• History of ARV drug approval
• Stages of research and access
• New drugs for 2007-8
• Specific drugs
Introduction to new drugs: I-Base training
London - May 2007
To get most out of treatment:
“when you make a choice
(this includes changing or not
changing treatment)…
remember to look forward”
Introduction to new drugs: I-Base training
London - May 2007
Looking forward
• risk vs benefit in short term
• risk vs benefit in long term
• timeline for newer drugs
• timeline for new strategies
Introduction to new drugs: I-Base training
London - May 2007
Even if nothing in UK
changes…
- Current drugs and knowledge could keep 90%
of HIV+ people alive for the next 20-30 years
(even if there was no further research)
- Limitations include:
- i) whether +ve people get access to those
treatments and that knowledge
- ii) whether they understand what leads to longterm or short-term treatment response
- Iii) whether they get treated with the best care
Introduction to new drugs: I-Base training
London - May 2007
HIV life cycle
Aim to understand:
•
drugs only work on active cells
•
different targets
•
some target have no drugs
Introduction to new drugs: I-Base training
London - May 2007
Introduction to new drugs: I-Base training
London - May 2007
Drug timeline
Aim to understand:
•
new drugs will come
•
some new drugs may fail
•
some drugs will stop being used
•
some existing drugs will improve
formulations
Introduction to new drugs: I-Base training
London - May 2007
24 approved ARVs in US/Europe
different access in Western countries
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AZT 1987
ddI 1991
ddC 1992
d4T 1994
3TC 1995
saquinavir (invirase) 1995
indinavir 1996
ritonavir 1996
nevirapine 1996
delavirdine 1997
nelfinavir 1997
saquinavir (Fortovase) 1997
efavirenz 1998
Introduction to new drugs: I-Base training
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abacavir 1998
amprenavir 1999
lopinavir 2000
tenofovir 2001
T-20 2003
atazanavir 2004
fosamprenavir 2004
FTC 2004
tipranavir 2005
Meltrex Kaletra 2006
Atripla 2006 (US)
darunavir 2007
London - May 2007
24 approved ARVs in US/Europe
different access in Western countries
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AZT 1987
ddI 1991
ddC 1992
d4T 1994
3TC 1995
saquinavir (invirase) 1995
indinavir 1996
ritonavir 1996
nevirapine 1996
delavirdine 1997
nelfinavir 1997
saquinavir (Fortovase) 1997
efavirenz 1998
Introduction to new drugs: I-Base training
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abacavir 1998
amprenavir 1999
lopinavir 2000
tenofovir 2001
T-20 2003
atazanavir 2004
fosamprenavir 2004
FTC 2004
tipranavir 2005
Meltrex Kaletra 2006
Atripla 2006 (US)
darunavir 2007
London - May 2007
Co-Formulations and combinations
US/Europe
Generic (via India etc)
• AZT+3TC (Combivir)
• AZT+3TC+abacavir
(Trizivir)
• abacavir+3TC (Kivexa)
• tenofovir+FTC (Truvada)
• lopinavir/r (Kaletra)
• Atripla
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Introduction to new drugs: I-Base training
AZT+3TC
d4T+3TC
AZT+3TC+abacavir
AZT+3TC+nevirapine
d4T+3TC+nevirapine
Kaletra (lopinavir/r)
ddI+3TC+efavirenz KIT
London - May 2007
ARV approval timeline (FDA*)
delavirdine**
nelfinavir
saquinavir
(Fortovase) **
AZT
ddI
3TC,
saquinavir efavirenz,
abacavir
(invirase)
atazanavir,
fosamprenavir,
FTC
darunavir
lopinavir/r**
85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07
ddC** d4T
* FDA often ~ 6 months before Europe
** drugs/formulations no longer used
Introduction to new drugs: I-Base training
amprenavir**
indinavir,
ritonavir,
nevirapine
tenofovir
T-20
tipranavir,
lopinavir/r
(Meltrex)
London - May 2007
Projected pipeline in 2003
fosamprenavir
CCR5 inhibitors:
maraviroc
Nelfinavir
aplaviroc
Atripla?
(625mg)
capravirine vicriviroc (??)
TMC-125
tipranavir (vasculitis)
Zerit XR
2003
Fuzeon
2004
2005
FTC
(T-20)
atazanavir
2006
2007
TMC-114
DAPD
(lens problems)
Reverset
2008
Integrase:
raltegravir
elvitegravir
Meltrex ritonavir
(non-refrigerated)
Introduction to new drugs: I-Base training
London - May 2007
?
In practice - many failed
fosamprenavir
CCR5 inhibitors:
maraviroc
Nelfinavir
aplaviroc
Atripla?
(625mg)
capravirine vicriviroc (??)
TMC-125
tipranavir (vasculitis)
Zerit XR
2003
Fuzeon
2004
2005
FTC
(T-20)
atazanavir
2006
2007
TMC-114
DAPD
(lens problems)
Reverset
2008
Integrase:
raltegravir
elvitegravir
Meltrex ritonavir
(non-refrigerated)
Introduction to new drugs: I-Base training
London - May 2007
?
Recent promising failures
Development stopped after clinical studies due to
toxicity (T), efficacy (E) or formulation (F)
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dOTC - monkeys died
DPC-681- toxicity
DPC-684 - toxicity
DPC 961- suicidal paients
emivirine (MKC442) - efficacy
MK914 - kidney toxicity
nelfinavir 625mg form. (2004)
d4T ER - formulation (2004)
• DAPD, amdoxovir (2004)
Introduction to new drugs: I-Base training
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DMP450 - efficacy
TMC 126 - dropped
TMC 120 - dropped
DPC 817- toxicity
adefovir - kidney toxicity
lodenesine - liver toxicity
capravirine - efficacy (2005)
aplaviroc - liver toxicity
reverset - pancreatic tox (2006)
London - May 2007
Timeline for developing a drug
identify
compounds/
molecules
Phase 1:
single dose
HIV-negative
Phase 3:
efficacy and
safety
Phase 4:
long-term
safety
~ 10yrs
Pre-clinical:
Animal and
test tube
Introduction to new drugs: I-Base training
Phase 2:
dose finding
HIV-positive
Expanded
access (EAP) /
named-patient
programmes
(NPP)
London - May 2007
Risk and benefit of shorter
drug development
Get to use treatment earlier
Option of better drugs
May not have choice to wait
Less experience and data
Early access
Long-term risk unknown
Delayed access
Balance
Introduction to new drugs: I-Base training
London - May 2007
Drug pipeline for 2007/8
Aim to understand:
•
some new drugs will come
•
some new drugs may fail
•
some drugs will stop being used
•
some improved formulations
Introduction to new drugs: I-Base training
London - May 2007
Drug pipeline for 2007/8
•
raltegravir
•
maraviroc
•
TMC-125 (rilpivirine)
•
Atripla (fixed dose efavirenz+tenofovir+FTC)
Later drugs include TMC-278
(NNRTI), elvitigravir Integrase)
Introduction to new drugs: I-Base training
London - May 2007
Merck’s integrase inhibitor: raltegravir
• Raltegravir is an HIV integrase (integrase is 3-step process
and it blocks the final step, where the viral DNA is spliced
into the CD4-cell DNA)
• In treatment naïve patients with HIV RNA ≥ 5000 copies/ml
and CD4 ≥ 100/mm3, raltegravir studied at four dose levels
for 24 weeks:
• had potent antiretroviral activity
• 85-95% with HIV RNA < 50 copies/mL
• achieved viral suppression faster than EFV
• was generally well tolerated
Markowitz THLB0214
Introduction to new drugs: I-Base training
London - May 2007
raltegravir
Change From Baseline
in HIV RNA (Log
10 Copies/mL)
Protocol 004: HIV RNA Change from Baseline*
(log10 copies/mL) (95% CI)
0
Markowitz THLB0214
-1
-2
-3
0
MK-0518 100mg
MK-0518 200mg
MK-0518 400mg
MK-0518 600mg
Efavirenz
2
4
8
12
W eek
16
24
38
40
40
39
37
39
40
41
38
38
39
40
41
38
38
39
40
41
38
37
39
40
41
38
38
39
40
41
38
37
*assay LoQ 400 copies/mL
Introduction to new drugs: I-Base training
m518p4rna6 Aug. 10, 2006
IAC 2006 Abs# THLB0214
London - May 2007
raltegravir
Percent of Patients with
HIV RNA <50 copies/mL
Protocol 004: Percent (95% CI) of Patients
with HIV RNA < 50 copies/mL (NC=F)
100
Markowitz THLB0214
80
60
*
40
*
20
0
0
MK-0518 100mg
MK-0518 200mg
MK-0518 400mg
MK-0518 600mg
Efavirenz
2
4
8
12
Week
16
24
39
40
41
40
38
39
40
41
40
38
39
40
41
40
38
39
40
41
40
38
39
40
41
40
38
39
40
41
40
37
* P < 0.001 for MK-0518 at each dose vs. EFV
Introduction to new drugs: I-Base training
m518p4.r50.5 Aug. 3, 2006
IAC 2006 Abs# THLB0214
London - May 2007
raltegravir: Common (≥5%) side effects
MK 0518 (all doses)
+TDF/FTC
N=160 (%)
Efavirenz
+TDF/FTC
N=38 (%)
Nausea
11
13
Headache
9
24
Dizziness
8
26
Diarrhea
7
11
Insomnia
7
11
Abnormal dreams
6
18
Flatulence
6
-
Additional AEs seen at ≥ 5% in efavirenz group:
Fatigue (5%)
Nightmare (11%)
Disturbance in attention (5%)
Vomiting (8%)
Lethargy (5%)
Malaise (8%)
Anxiety (5%)
Introduction to new drugs: I-Base training
* With TFV/3TC
London - May 2007
maraviroc
• Double-blind placebo controlled study in 190
mixed/dual tropic patients
• Randomised to optimised background regimen
(OBT), plus either maraviroc once-daily (n=63), vs
maraviroc twice daily (n-61) or placebo (n-60).
• Over 90% patients were PI-experienced
• 50-60% currently using T-20
• Baseline CD4 count <100 cells/mm3
• Baseline viral load > 5logs respectively
Introduction to new drugs: I-Base training
London - May 2007
maraviroc
Table 1: Virologic and immunologic responses at week 24
All treated patients with D/M-tropic HIV-1
Mean decrease in HIV-1 RNA (log10c/mL)*
Placebo
OBT
+
MVC
OBT
QD
+
MVC BID + OBT
n = 52
n = 58
n = 57
-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 (%)
24.1
24.6
30.8
HIV RNA < 50 c/mL (%)
15.5
21.1
26.9
-0.89
-1.26
-1.44
+36 (n=58)
+60 (n=57)
+62 (n=52)
-104 (n=2)
+48 (n=12)
+33 (n=12)
Mean decrease in HIV-1 RNA in pts using T-20
Mean CD4 change (cells/mm3, mean)
All treated patients with D/M-tropic HIV-1
Mean CD4 change (cells/mm3, mean)
Pts with only X4-tropic HIV-1 detectable at time of
virologic failure
As no progression of HIV, questions importance of tropism test???
Introduction to new drugs: I-Base training
London - May 2007
etravirine (TMC-125)
Phase II study in 199 treatment experienced patients with documented NNRTI
resistance and 3 or more primary PI mutations.
Randomised to TMC125 (400 mg or 800 mg bid) with an investigator selected
background, or standard-of-care control regimen.
Median baseline CD4 - 100 cells/mm3; viral load 4.7 log copies/mL
Table 1: Results of etravirine (TMC-125) at 48-weeks
400mg
800mg
control
Mean VL change (log)
-0.88 *
-1.01 *
-0.14
Mean CD4 change
+58
+61
+13
VL failure
9%
9%
78%
Med. duration of Rx (wks)
48 wks
48 wks
18 wks
* P <0.05 compared to control
Introduction to new drugs: I-Base training
London - May 2007
Why “a little is not a good thing”
• Different to other treatment - against
‘common sense’ - ie for headache, heart
disease, high blood pressure, pain relief etc but similar to TB
• Resistance is permanent: loss of treatment
options (current and future)
• Difference between 1 year and 20+ years
• Transmission risk, resistance
• Time needed to explain difficult ideas
Introduction to new drugs: I-Base training
London - May 2007
www.i-Base.info
[email protected]
Thank you…
Introduction to new drugs: I-Base training
London - May 2007