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Current second-line treatment

Clinical development programme for Second-Line treatment Anton Pozniak World AIDS Conference, July 2014. Current second-line treatment. WHO standard: 2 new NRTIs plus LPV/r or ATV/r Efficacy of LPV/r + 2NRTIs in EARNEST and SECOND-LINE studies ? Use PI/r with Integrase Issues:

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Current second-line treatment

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  1. Clinical development programmefor Second-Line treatmentAnton PozniakWorld AIDS Conference, July 2014

  2. Current second-line treatment • WHO standard: 2 new NRTIs plus LPV/r or ATV/r • Efficacy of LPV/r + 2NRTIs in EARNEST and SECOND-LINE studies • ? Use PI/r with Integrase • Issues: • overlapping NRTI resistance • pill count, • twice daily (LPV/r), • NRTI safety • Cost versus first-line treatment

  3. What do the patients look like?Baseline characteristics- Earnest(at randomisation / switch to second-line) Note: n(%) or median (IQR)

  4. VL suppression at 96 weeks PI/RAL vs PI/NRTI P=0.36 P=0.87 P=0.97 P=0.88

  5. First-line to second Line First-line First-line Second-line Second-line TDF/3TC/DTG TDF/3TC/EFV400 or NRTI /NNRTIs PI/r+NNRTI DRV/r +DTG VF VF Option 2 Option 1

  6. OPTION 1Pill A to Pill B – two single tablet regimens? Pill A TDF/3TC/EFV400 $100 Pill B DRV400/r/DTG $250 Two pills, used in sequence Simple treatment rule – task shifting No overlapping drug resistance Mass generic production for Universal Access Low cost: $100 and $250 per person-year

  7. Data for low dose DRV/rPhase 2 trials: %HIV RNA >1 log reduction at Week 24, by dose and baseline DRV resistance DRV FC <4 (sensitive) DRV FC >4 (resistant) 400/100 800/100 400/100 600/100 OD OD BID BID 400/100 800/100 400/100 600/100 OD OD BID BID DRV/r dose group DRV/r dose group Katlama C et al AIDS 2007, 21: 395-402 Haubrich et al AIDS 2007, 21: F11-F18

  8. No PK/PD relationship ODIN trial: HIV RNA <50 copies/mL at Week 48, treatment experienced, DRV sensitive patients DRV/r 800/100 mg OD +2NRTIs, by DRV Cmin p=0.004, inverse correlation HIV RNA <50 c/mL (%) Week 48 Quartile of DRV Cmin Kakuda et al, HIV11, Glasgow 2012 [abstr P072]

  9. DRV/r 600/100 OD + 2NRTIs: 12 naïve patients ___________________________________________________________________________ Patient RNA BL RNA FU Time DRV Cmin ___________________________________________________________________________ Naïve 85,501 <50 20 months 2866 Naïve 115,853 <50 19 months 3140 Naïve 334,500 <50 10 months 3627 Naïve 154,000 <50 24 months 2553 Naïve 87,350 <50 18 months 3824 Naïve 88,110 <50 19 months 1700 Naïve 34,793 <50 12 months 1268 Naïve 4,526 <50 18 months 3732 Naïve 235,520 <50 20 months 2019 Naïve 7,251 <50 15 months 2818 Naïve 63,244 <50 16 months 4562 Naïve 397,932 <50 5 months no data ____________________________________________________________________ ___________________________________________________________________ Lanzafame et al, EACS, Brussels 2013 [abstr PE8/11]

  10. DRV/r 600/100 OD+2NRTIs: 7 pre-treated patients ___________________________________________________________________________ Prior ARV’sRNA BL RNA FU Time DRV Cmin ___________________________________________________________________________ TDF/FTC/FPV/r 33,250 <50 55 months 2143 ZDV/3TC/TDF 15,226 <50 55 months 4518 TDF/FTC/FPV/r 586 <50 43 months 844 TDF/FTC/ATV/r 8,450 <50 38 months no data TDF/FTC/LPV/r 11,426 <50 38 months no data TDF/FTC/FPV 119 <50 22 months no data TDF/FTC/FPV/r 112 <50 20 months no data ____________________________________________________________________ ___________________________________________________________________ Lanzafame et al, EACS, Brussels 2013 [abstr PE8/11]

  11. DRV600. Study Design W48 Randomisation 1 : 1 Open-label N = 50 100 HIV+ adults On 2 NRTIs + DRV 800mg qd > 4 weeks HIV-1 RNA < 50 c/mL > 3 months No history of prior virologic failure to PI-based ART N = 50 • Study endpoints • The proportion of patients with HIV-1 RNA <50 c/mL at w48 (ITT). Non inferiority if lower limit of the 95% CI for d < -15%, 80% power • Changes in CD4+ T cell count • Changes in DRV Ctrough in plasma • The proportion of patients with AEs during follow-up • The economic cost derived from ARV drugs

  12. Results w48 Non inferiority of DRV/r 600/100 mg QD 94% 96% 94% 90% ITT Observed data 50 50 49 48 -15% 0 95% CI for the difference ITT -4.0 (-12.9; 4.9) Observed data -2,2 (-9.6; 5.2)

  13. Clinical experience with DRV/r + DTG • There is no effect of DTG on DRV/r PK FDA label • DRV/r 600/100 BID lowers DTG Cmin by 38%. This is not considered clinically significant, given the 50mg OD dose of DTG used FDA label. • DRV/r + integrase proof of principle: NEAT (DRV/r + RAL vs DRV/r + TDF/FTC) CROI 2014 • DRV/r + DTG was the most common combination used in the SAILING trial. Lancet 2013, 382, 700-708 • In the SAILING trial, 72 patients treated with DRV/r + DTG + NRTIs with no primary PI mutations: HIV RNA <50 copies/mL at Week 48 in 69%, versus 70% for DRV/r + RAL + NRTIs.

  14. Pill A, Pill B: Phase 2B-Dose ranging study TDF/FTC + DRV/r 800/100 OD Treatment naive DTG + DRV/r 800/100 OD DTG + DRV/r 400/100 OD SL2: Second-line, 2 drugs Randomised, 48 weeks 24 week interim justifies progression of programme

  15. Pill A, Pill B: Phase 3 -pivotal study 2NRTI + PI/r (Control) NNRTI experienced n=1050 (350 per arm) DTG + DRV/r 800/100 OD DTG + DRV/r 400/100 OD Randomised, 96 weeks Africa, Asia

  16. Phase 3 study – design • Inclusion: HIV RNA >1000 on two visits while taking NNRTI based treatment • Primary endpoint: HIV RNA >1000 on two visits, 96 week follow up • Recruitment: Africa, SE Asia, E Europe • Statistics: powered to demonstrate non-inferiority for DRV/r + DTG versus control arm.

  17. Clinical development programmefor Second-Line treatment Need for FDC second line pill Low dose Darunavir and DTG attractive option as no overlapping resistance Co formulated as STR so easy to take Components well tolerated Cost savings Can Task shift Phase 2b into phase 3 for patient safety

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