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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 • • • • • • • • • • • • • 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 • • • • • • • • • • • • 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 • • • • • • • • • • • • • 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 • • • • • • • • • • • • 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 • • • • • • • 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) • • • • • • • • 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 • • • • • • • • • 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