Dose-Ranging Trial of PPI-461, a Potent New Pan-Genotypic HCV NS5A Inhibitor, in Patients with HCV Genotype-1 Infection J. Lalezari 1 , K. Agarwal 2 , G. Dusheiko 3 , A. Brown 4 , N. Weis 5 , P. Christensen 6 , A. Laursen 7 , D. Asmuth 8 , P. Vig 9 , E. Ruby 9 , N. Huang 9 , Q. Huang 9 , R. Colonno 9 , G. Harding 10 and N. Brown 9 1 Quest Clinical Research (San Francisco, CA, U.S.A.), 2 Kings College Hospital (London, U.K.), 3 Royal Free Hospital (London, U.K.), 4 Imperial College Healthcare (London, U.K.), 5 Hvidovre Hospital (Copenhagen, Denmark), 6 Odense University Hospital (Odense, Denmark), 7 U. Hospital of Arhus (Arhus, Denmark), 8 University of California-Davis Medical Center (Sacramento, CA, U.S.A.), 9 Presidio Pharmaceuticals (San Francisco, CA, U.S.A.), 10 Smerud Medical Research International (Oslo, Norway)
HCV NS5A Inhibitors Optimized Inhibitors Characteristics PPI-461 HCV g1a EC 50 = 0.21 nM Potent in vitro activity (sub nM) HCV g1b EC 50 = 0.01 nM Broad-spectrum activity vs. all EC 50 s vs. HCV g2-g7 range major HCV genotypes from 0.01 nM to 9.3 nM Additive/synergistic with PIs, Nucs, A dditive to synergistic activity with NNucs, cyclophilins and IFN other classes of HCV inhibitors No cross-resistance with other classes of inhibitors Low dose, once-daily (QD) Dose proportional plasma levels dosing in humans >>HCV EC 50 s with QD dosing Well tolerated, with All doses (20-200 mg QD) minimal side effects well-tolerated in healthy volunteers
PPI-461 Phase 1b Trial in Patients • Treatment-naïve HCV-g1 patients, 3-day treatment period – Consistent with regulatory guidance (FDA, EMA) for 1st trial of new DAA • Randomized, blinded, sequential dose escalation design – Sequential cohorts of 8 patients – Randomized 6:2 (active PPI-461 capsules vs. matching placebo) – Double-blind – PPI-461 doses: 50, 100 and 200 mg QD x 3 days – 14 day follow-up after 3-day treatment period – Initiation of follow-on pegIFN/RBV allowed, anytime post-treatment • Serial Assessments – Safety (clinical symptoms/signs; blood counts, chemistries, UAs) – PPI-461 plasma levels over time (pharmacokinetic analyses) – Serum HCV RNA levels by quant PCR (TaqMan™ v2.0) at each visit, with intensive assessment of HCV RNA in first 30 hr of treatment
PPI-461 Phase 1b Trial Key Entry Criteria • Age 18-65, Male or Female • Chronic Hepatitis C, genotypes 1a or 1b, treatment-naive � No cirrhosis, no signs of decompensated liver disease • HCV Ab positive, HCV RNA ������� 10 IU/mL at Screen (TaqMan v2.0) • HIV Ab negative, HBsAg negative • No confounding medical conditions • BMI 18-32 kg/m 2 • Screen ALT ��������� • Hgb >11 g/dL (females), >12 g/dL (males) • WBC >4,000/mm 3 , ANC >1,800/mm 3 • Platelets > 100,000/mm 3 • Total Bilirubin <2.0 mg/dL; albumin >3.4 g/dL; creatinine WNL
Patient Demographics & Baseline Disease Features Parameter 50 mg 100 mg 200 mg Placebo (Screen Values) (N=6) (N=6) (N=6) (N=6) Age (range) 57 (41-64) 45 (21-54) 51 (36-60) 42 (31-55) Gender (%M) 100% 100% 83% 100% BMI (kg/m 2 ) 24 26 24 26 HCV RNA* (log 10 IU/mL) 6.97 6.50 6.86 6.36 Median ALT (IU/L) 83 125 71 86 Median AST (IU/L) 52 65 59 64 * TaqMan v2.0 PCR assay
PPI-461 Safety Results • All doses well-tolerated (50, 100 and 200 mg QD x 3 days) – All patients completed study treatment and all evaluations – No premature discontinuations or dose modifications – No pattern of treatment-related (PPI-461 vs. placebo) or dose- related clinical adverse effects (AEs) or laboratory abnormalities – Scattered grade 1-2 lab abnormalities, with no persistent changes or patterns of change for any lab parameter during study Rx • Typical IFN/RBV-related AEs & lab abnormalities noted during 2-week post-treatment period – Seen in patients who received follow-on pegIFN/RBV (12 of 24 patients received pegIFN/RBV) – Flu-like symptoms, myalgia, etc.; ��������������������� etc.
Adverse Events Occurring in ����������� Overall Study Period*, Decreasing Order of Frequency Regardless of Attributability to Study Drug 50 mg 100 mg 200 mg Placebo AE Term (N=6) (N=6) (N=6) (N=6) Headache 2 † 0 2 2 Flu-like illness 3 1 0 2 Myalgia 1 1 1 2 Arthralgia 1 1 0 1 Fatigue 2 0 0 1 Dry skin 1 1 0 1 gamma-GTP � 0 1 0 1 WBC or ANC � 0 1 0 1 Pruritus 1 1 0 0 Pyrexia 0 1 0 1 * Includes pegIFN/RBV-attributed AEs; most AEs during follow-up period † Number of affected patients in the dose group
PPI-461 Pharmacokinetics 3000 • Dose proportional PK Plasma Concentration (ng/mL) 2500 • Rapid absorption: T max = 1-2 hr • T 1/2 = 7-9 hr 2000 • C max levels � 100 mg: 1,282 ng/mL (1,740 nM) 1500 � 200 mg: 1,950 ng/mL (2,346 nM) � >>> HCV EC 50 s for g1-7 • C min levels 1000 200 mg � 100 mg: 105 ng/mL (142 nM) 100 mg 50 mg � 200 mg: 206 ng/mL (280 nM) 500 � > HCV EC 50 s for g1-7 0 0 2 4 6 8 10 12 16 20 24 Time (hr) PPI-461 plasma levels continuously exceed HCV inhibitory concentrations at 100-200 mg QD
PPI-461 Antiviral Efficacy by Dose Group (During 3-Day Treatment Period) 0 Mean Maximal HCV RNA Drop (log 10 IU/mL) HCV RNA Log 10 IU/mL Decline Placebo (6/6) 0.09 1.0 50 mg (5/6)* 3.10 100 mg (6/6) 3.65 2.0 200 mg (6/6) 3.62 3.0 4.0 0 6 12 18 24 30 36 42 48 54 60 66 72 Time (hr) * Excludes 1 patient with pre-existing linked resistance substitutions
HCV RNA Responses - Individual Patients Maximal HCV RNA Reduction During 3-Day Rx (log 10 IU/mL) Dose/Patient 1 2 3 4 5 6 50 mg 0.4 (1b)* 2.5 (1a) 2.8 (1a) 3.3 (1a) 3.4 (1a) 3.5 (1b) 100 mg 2.6 (1a) 3.7 (1a) 3.7 (1a) 3.8 (1b) 4.0 (1a) 4.1 (1b) 200 mg 3.3 (1a) 3.4 (1a) 3.5 (1a) 3.7 (1a) 3.8 (1a) 4.0 (1a) • Patient 1* (50 mg) was fully resistant at baseline due to presence of 4 linked NS5A-specific resistance substitutions • Rapid response: 11/12 pts in 100-200 mg dose groups had >3 log 10 (>99.9%) HCV RNA drop by Day 2, 1 pt with 2.6 log drop (99.7%) • Similar efficacy for 100 and 200 mg doses (E max ������������ • 14/18 patients on active treatment were HCV-g1a, 4 were g1b – Good efficacy vs. both HCV-g1 subtypes (1a and 1b)
Resistance Monitoring • Comprehensive analysis of patients’ serum samples – Clonal and Population sequencing of HCV NS5A gene in patients’ HCV RNA at Baseline and during treatment – Population phenotypes determined for all PPI-461 treated patients at Baseline and Day 3 • Key results – NS5A resistance substitutions detectable in 5 patients at Baseline • Apart from Pt #1 in 50 mg cohort, 4 other patients had single substitutions expressing low level resistance at Baseline • All 4 had multi-log HCV RNA drops (2.6 to 4.1 log 10 ) by Day 2-3 – NS5A resistance substitutions detectable after 3 days of PPI-461 monotherapy in 17/18 of the PPI-461 dosed patients Detailed results of resistance studies presented in Poster # 356
PPI-461 Phase 1b Conclusions • PPI-461 well-tolerated at all dose levels (50-200 mg/d x 3 days) • PK results support once-daily dosing • Rapid and consistent efficacy (maximal response at ������������ – Mean maximal HCV RNA reductions 3.6 log for 100 and 200 mg QD – Similar efficacy in HCV g1a and g1b patients • Marked HCV RNA responses in 17/18 active-dosed patients – 1 patient in 50 mg group had pre-existing, high-level resistance – Occasional non-responding patients also reported in monotherapy trials for other NS5As (BMS-790052, GS-5885), and for other DAAs (telaprevir, etc) – 4 patients with low-level Baseline resistance had multi-log responses • Rapid enrichment of pre-existing resistant variants, similar to data reported for BMS-790052 and HCV protease inhibitors – NS5A inhibitors need to be used in combination with SOC or other DAAs Pan-genotypic potency, rapid efficacy, good tolerance, and QD dosing support PPI-461 as a good candidate for future HCV combination therapies
Questions & Discussion 13
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