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Introduction to new drugs African Treatment Advocacy Training

Introduction to new drugs African Treatment Advocacy Training. 31 May 2007 Simon Collins www.i-Base.info. Overview Introduction HIV lifecycle and drug families History of ARV drug approval Stages of research and access New drugs for 2007-8 Specific drugs.

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Introduction to new drugs African Treatment Advocacy Training

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  1. Introduction to new drugsAfrican Treatment Advocacy Training 31 May 2007 Simon Collins www.i-Base.info

  2. Overview • Introduction • HIV lifecycle and drug families • History of ARV drug approval • Stages of research and access • New drugs for 2007-8 • Specific drugs

  3. To get most out of treatment:“when you make a choice (this includes changing or not changing treatment)… remember to look forward”

  4. • risk vs benefit in short term• risk vs benefit in long term• timeline for newer drugs• timeline for new strategies Looking forward

  5. 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

  6. HIV life cycle Aim to understand:• drugs only work on active cells • different targets• some target have no drugs

  7. 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

  8. 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 24 approved ARVs in US/Europedifferent access in Western countries

  9. 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 24 approved ARVs in US/Europedifferent access in Western countries

  10. 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

  11. ARV approval timeline (FDA*) delavirdine** nelfinavir saquinavir (Fortovase) ** atazanavir, fosamprenavir, FTC 3TC, saquinavir (invirase) efavirenz, abacavir darunavir AZT ddI 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 amprenavir** d4T T-20 ddC** tenofovir tipranavir, lopinavir/r (Meltrex) indinavir, ritonavir, nevirapine * FDA often ~ 6 months before Europe ** drugs/formulations no longer used

  12. Projected pipeline in 2003 fosamprenavir CCR5 inhibitors: maraviroc aplaviroc vicriviroc (??) Nelfinavir (625mg) Atripla? TMC-125 capravirine (vasculitis) tipranavir Zerit XR ? 2006 2007 2008 2005 2003 2004 Fuzeon (T-20) FTC TMC-114 Integrase: raltegravir elvitegravir DAPD (lens problems) Reverset atazanavir Meltrex ritonavir (non-refrigerated)

  13. In practice - many failed fosamprenavir CCR5 inhibitors: maraviroc aplaviroc vicriviroc (??) Nelfinavir (625mg) Atripla? TMC-125 capravirine (vasculitis) tipranavir Zerit XR ? 2006 2007 2008 2005 2003 2004 Fuzeon (T-20) FTC TMC-114 DAPD (lens problems) Integrase: raltegravir elvitegravir Reverset atazanavir Meltrex ritonavir (non-refrigerated)

  14. • 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) Recent promising failures Development stopped after clinical studies due to toxicity (T), efficacy (E) or formulation (F)

  15. Timeline for developing a drug Phase 1: single dose HIV-negative Phase 3: efficacy and safety Phase 4: long-term safety identify compounds/molecules ~ 10yrs Pre-clinical: Animal and test tube Phase 2: dose finding HIV-positive Expanded access (EAP) / named-patient programmes (NPP)

  16. 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 Long-term risk unknown Delayed access Early access Balance

  17. 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

  18. Drug pipeline for 2007/8 • raltegravir • maraviroc• TMC-125 (rilpivirine)• Atripla (fixed dose efavirenz+tenofovir+FTC)Later drugs include TMC-278 (NNRTI), elvitigravir Integrase)

  19. 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

  20. raltegravir Markowitz THLB0214

  21. raltegravir Markowitz THLB0214

  22. raltegravir: Common (≥5%) side effects 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

  23. 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

  24. maraviroc Table 1: Virologic and immunologic responses at week 24 As no progression of HIV, questions importance of tropism test???

  25. 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

  26. 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

  27. www.i-Base.info simon.collins@i-Base.org.uk Thank you…

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