Introduction to new drugs: I-Base training London - May 2007

Introduction to new drugsAfrican Treatment Advocacy Training

31 May 2007Simon 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-20tenofo

vir

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 13Headache 9 24Dizziness 8 26Diarrhea 7 11Insomnia 7 11Abnormal 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 +13VL 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

simon.collins@i-Base.org.uk

Thank you…