introduction to new drugs: i-base training london - may 2007 introduction to new drugs african...
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Introduction to new drugs: I-Base training London - May 2007
Introduction to new drugsAfrican 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
• risk vs benefit in short
term
• risk vs benefit in long
term
• timeline for newer drugs
• timeline for new
strategies
Looking forward
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 long-term 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 timelineAim 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• 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
• 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
Introduction to new drugs: I-Base training London - May 2007
24 approved ARVs in US/Europe
different access in Western countries• 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
• 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
Introduction to new drugs: I-Base training London - May 2007
US/Europe
• AZT+3TC (Combivir)• AZT+3TC+abacavir (Trizivir)
• abacavir+3TC (Kivexa)
• tenofovir+FTC (Truvada)
• lopinavir/r (Kaletra)
• Atripla
Generic (via India etc)
• AZT+3TC• d4T+3TC• AZT+3TC+abacavir• AZT+3TC+nevirapine• d4T+3TC+nevirapine• Kaletra (lopinavir/r)
• ddI+3TC+efavirenz - KIT
Co-Formulations and combinations
Introduction to new drugs: I-Base training London - May 2007
85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07
AZT ddI
d4T
3TC,saquinavi
r (invirase)
indinavir,ritonavir,nevirapine
delavirdine**
nelfinavirsaquinavir (Fortovase)
**
T-20
tenofovir
ddC**
efavirenz,
abacavir
amprenavir**
lopinavir/r**
atazanavir,fosamprenav
ir,FTC
tipranavir,
lopinavir/r
(Meltrex)
* FDA often ~ 6 months before Europe
** drugs/formulations no longer used
ARV approval timeline (FDA*)
darunavir
Introduction to new drugs: I-Base training London - May 2007
2003 2004 2005 2006 2007 2008
Fuzeon
(T-20)
FTC
Zerit XR
atazanavir
tipranavir
DAPD (lens
problems)
capravirine
(vasculitis) ?
TMC-114
fosamprenavir
Nelfinavir(625mg)
CCR5 inhibitors:maraviroc aplavirocvicriviroc (??)
Reverset
Meltrex ritonavir (non-refrigerated)
Projected pipeline in 2003
Integrase:raltegravirelvitegravir
Atripla?
TMC-125
Introduction to new drugs: I-Base training London - May 2007
2003 2004 2005 2006 2007 2008
Fuzeon
(T-20)
FTC
Zerit XR
atazanavir
tipranavir
DAPD (lens
problems)
capravirine
(vasculitis) ?
TMC-114
fosamprenavir
Nelfinavir(625mg)
CCR5 inhibitors:maraviroc aplavirocvicriviroc (??)
Reverset
Integrase:raltegravirelvitegravir
Meltrex ritonavir (non-refrigerated)
In practice - many failed
Atripla?
TMC-125
Introduction to new drugs: I-Base training London - May 2007
• 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)
• 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)
Development stopped after clinical studies due to toxicity (T), efficacy
(E) or formulation (F)
Recent promising failures
Introduction to new drugs: I-Base training London - May 2007
Timeline for developing a drug
~ 10yrs
identify compounds/molecules
Pre-clinical:
Animal and test tube
Phase 3: efficacy and safety
Expanded access (EAP) / named-patient programmes (NPP)
Phase 2: dose finding HIV-positive
Phase 1: single dose HIV-negative
Phase 4: long-term safety
Introduction to new drugs: I-Base training London - May 2007
Risk and benefit of shorter drug development
Early access
Balance
Delayed access
Get to use treatment earlier
Option of better drugs
May not have choice to wait
Less experience and data
Long-term risk unknown
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
• 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
Merck’s integrase inhibitor: raltegravir
Markowitz THLB0214
Introduction to new drugs: I-Base training London - May 2007
IAC 2006 Abs# THLB0214
Protocol 004: HIV RNA Change from Baseline*(log10 copies/mL) (95% CI)
0 2 4 8 12 16 24Week
-3
-2
-1
0
Change From Baseline in HIV RNA (Log
10
Copies/mL)
m518p4rna6 Aug. 10, 2006
MK-0518 100mg 38 39 39 39 39 39 25MK-0518 200mg 40 40 40 40 40 40 27MK-0518 400mg 40 41 41 41 41 41 27MK-0518 600mg 39 38 38 38 38 38 28Efavirenz 37 38 38 37 38 37 26
*assay LoQ 400 copies/ mL
Markowitz THLB0214
raltegravir
Introduction to new drugs: I-Base training London - May 2007
IAC 2006 Abs# THLB0214
Protocol 004: Percent (95% CI) of Patients with HIV RNA < 50 copies/mL (NC=F)
0 2 4 8 12 16 24Week
0
20
40
60
80
100
Percent of Patients withHIV RNA <50 copies/mL
*
*
m518p4.r50.5 Aug. 3, 2006
MK-0518 100mg 39 39 39 39 39 39MK-0518 200mg 40 40 40 40 40 40MK-0518 400mg 41 41 41 41 41 41MK-0518 600mg 40 40 40 40 40 40Efavirenz 38 38 38 38 38 37
* P < 0.001 for MK -0518 at each dose vs. EFV
Markowitz THLB0214
raltegravir
Introduction to new drugs: I-Base training London - May 2007
raltegravir: Common (≥5%) side effectsMK 0518 (all
doses) +TDF/FTC N=160 (%)
Efavirenz+TDF/FTCN=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:Nightmare (11%)Vomiting (8%)Malaise (8%)
Fatigue (5%)Disturbance in attention (5%)Lethargy (5%)Anxiety (5%)
* With TFV/3TC
Introduction to new drugs: I-Base training 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
maravirocTable 1: Virologic and immunologic responses at week 24
All treated patients with D/M-tropic 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
Treatment diff (MVC-OBT) in HIV-1 RNA decrease (log10c/mL) (97.5% CI
+0.06 (-0.53, +0.64)
-0.23(-0.83, +0.36)
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 pts using T-20
-0.89 -1.26 -1.44
Mean CD4 change (cells/mm3, mean)
All treated patients with D/M-tropic HIV-1
+36 (n=58) +60 (n=57) +62 (n=52)
Mean CD4 change (cells/mm3, mean)
Pts with only X4-tropic HIV-1 detectable at time of virologic failure
-104 (n=2) +48 (n=12) +33 (n=12)
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-weeks400mg 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 wks18 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
Thank you…