1. Introduction to new drugs: I-Base training London - May 2007 Introduction to new drugs African Treatment Advocacy Training 31 May 2007 Simon Collins www.i-Base.info

2. 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

3. 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”

4. 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

5. 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

6. Introduction to new drugs: I-Base training London - May 2007 HIV life cycle Aim to understand:drugs only work on active cellsdifferent targetssome target have no drugs

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

8. Drug timeline Aim to understand:new drugs will comesome new drugs may failsome drugs will stop being usedsome existing drugs will improve formulations

9. 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

10. 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

11. 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

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

13. Introduction to new drugs: I-Base training London - May 2007 20032004 2005 2006 20072008 Fuzeon (T-20) FTC Zerit XR atazanavir tipranavir DAPD (lens problems) capravirine (vasculitis) ? TMC-114 fosamprenavir Nelfinavir (625mg) CCR5 inhibitors: maraviroc aplaviroc vicriviroc (??) Reverset Meltrex ritonavir (non-refrigerated) Projected pipeline in 2003 Integrase: raltegravir elvitegravir Atripla? TMC-125

14. Introduction to new drugs: I-Base training London - May 2007 20032004 2005 2006 20072008 Fuzeon (T-20) FTC Zerit XR atazanavir tipranavir DAPD (lens problems) capravirine (vasculitis) ? TMC-114 fosamprenavir Nelfinavir (625mg) CCR5 inhibitors: maraviroc aplaviroc vicriviroc (??) Reverset Integrase: raltegravir elvitegravir Meltrex ritonavir (non-refrigerated) In practice - many failed Atripla? TMC-125

15. 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

16. 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

17. 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

18. Introduction to new drugs: I-Base training London - May 2007 Drug pipeline for 2007/8 Aim to understand:some new drugs will comesome new drugs may failsome drugs will stop being usedsome improved formulations

19. Introduction to new drugs: I-Base training London - May 2007 Drug pipeline for 2007/8 raltegravirmaravirocTMC-125 (rilpivirine)Atripla (fixed dose efavirenz+tenofovir+FTC) Later drugs include TMC-278 (NNRTI), elvitigravir Integrase)

20. 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

21. Introduction to new drugs: I-Base training London - May 2007 Markowitz THLB0214 raltegravir

22. Introduction to new drugs: I-Base training London - May 2007 Markowitz THLB0214 raltegravir

23. Introduction to new drugs: I-Base training London - May 2007 raltegravir: Common (≥5%) side effects MK 0518 (all doses) +TDF/FTC N=160 (%) Efavirenz +TDF/FTC N=38 (%) Nausea 1113 Headache 924 Dizziness 826 Diarrhea 711 Insomnia 711 Abnormal dreams 618 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

24. 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

25. 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 Placebo + OBT n = 58 MVC QD + OBT n = 57 MVC BID + OBT n = 52 Mean decrease in HIV-1 RNA (log 10 c/mL)*-0.97-0.91-1.20 Treatment diff (MVC-OBT) in HIV-1 RNA decrease (log 10 c/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/mm 3, mean) All treated patients with D/M-tropic HIV-1+36 (n=58)+60 (n=57)+62 (n=52) Mean CD4 change (cells/mm 3, 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???

26. 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 400mg800mgcontrol Mean VL change (log)-0.88 *-1.01 * -0.14 Mean CD4 change+58+61+13 VL failure9%9%78% Med. duration of Rx (wks)48 wks48 wks18 wks * P <0.05 compared to control

27. 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

28. Introduction to new drugs: I-Base training London - May 2007 www.i-Base.info simon.collins@i-Base.org.uk Thank you…