Dose-Ranging Trial of PPI-461, a Potent New Pan-Genotypic HCV NS5A - - PowerPoint PPT Presentation

Dose-Ranging Trial of PPI-461, a Potent New Pan-Genotypic HCV NS5A Inhibitor, in Patients with HCV Genotype-1 Infection

• J. Lalezari1, K. Agarwal2, G. Dusheiko3,
• A. Brown4, N. Weis5, P. Christensen6, A. Laursen7,
• D. Asmuth8, P. Vig9, E. Ruby9, N. Huang9, Q. Huang9,
• R. Colonno9, G. Harding10 and N. Brown9

1Quest Clinical Research (San Francisco, CA, U.S.A.), 2Kings College Hospital (London,

U.K.), 3Royal Free Hospital (London, U.K.), 4Imperial College Healthcare (London, U.K.),

5Hvidovre Hospital (Copenhagen, Denmark), 6Odense University Hospital (Odense,

Denmark), 7U. Hospital of Arhus (Arhus, Denmark), 8University of California-Davis Medical Center (Sacramento, CA, U.S.A.), 9Presidio Pharmaceuticals (San Francisco, CA, U.S.A.), 10Smerud Medical Research International (Oslo, Norway)

HCV NS5A Inhibitors

Optimized Inhibitors Characteristics PPI-461

Potent in vitro activity (sub nM) HCV g1a EC50 = 0.21 nM HCV g1b EC50 = 0.01 nM Broad-spectrum activity vs. all major HCV genotypes EC50s vs. HCV g2-g7 range from 0.01 nM to 9.3 nM Additive to synergistic activity with

• ther classes of HCV inhibitors

Additive/synergistic with PIs, Nucs, NNucs, cyclophilins and IFN No cross-resistance with other classes of inhibitors Low dose, once-daily (QD) dosing in humans Dose proportional plasma levels >>HCV EC50s with QD dosing Well tolerated, with minimal side effects All doses (20-200 mg QD) 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/m2
• Screen ALT
• Hgb >11 g/dL (females), >12 g/dL (males)
• WBC >4,000/mm3 , ANC >1,800/mm3
• Platelets > 100,000/mm3
• Total Bilirubin <2.0 mg/dL; albumin >3.4 g/dL; creatinine WNL

Patient Demographics & Baseline Disease Features

*TaqMan v2.0 PCR assay

Parameter (Screen Values) 50 mg (N=6) 100 mg (N=6) 200 mg (N=6) Placebo (N=6) Age (range) 57 (41-64) 45 (21-54) 51 (36-60) 42 (31-55) Gender (%M) 100% 100% 83% 100% BMI (kg/m2) 24 26 24 26 HCV RNA* (log10 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

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

• r 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

* Includes pegIFN/RBV-attributed AEs; most AEs during follow-up period

† Number of affected patients in the dose group

AE Term 50 mg (N=6) 100 mg (N=6) 200 mg (N=6) Placebo (N=6) Headache 2† 2 2 Flu-like illness 3 1 2 Myalgia 1 1 1 2 Arthralgia 1 1 1 Fatigue 2 1 Dry skin 1 1 1 gamma-GTP 1 1 WBC or ANC 1 1 Pruritus 1 1 Pyrexia 1 1

PPI-461 Pharmacokinetics

• Dose proportional PK
• Rapid absorption: Tmax = 1-2 hr
• T1/2 = 7-9 hr
• Cmax levels

100 mg: 1,282 ng/mL (1,740 nM) 200 mg: 1,950 ng/mL (2,346 nM)

>>> HCV EC50s for g1-7

• Cmin levels

100 mg: 105 ng/mL (142 nM) 200 mg: 206 ng/mL (280 nM) > HCV EC50s for g1-7 3000 2500 2000 1500 1000 500 10 8 6 4 2 20 16 12 24 Time (hr) Plasma Concentration (ng/mL) 50 mg 100 mg 200 mg

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)

1.0 2.0 3.0 4.0 18 60 6 30 54 48 24 12 72 Time (hr) HCV RNA Log10 IU/mL Decline 50 mg (5/6)* 100 mg (6/6) 200 mg (6/6) 36 42 66 Placebo (6/6) Mean Maximal HCV RNA Drop (log10 IU/mL) 3.10 3.65 3.62 0.09

* Excludes 1 patient with pre-existing linked resistance substitutions

HCV RNA Responses - Individual Patients

Maximal HCV RNA Reduction During 3-Day Rx (log10 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 log10 (>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 (Emax
• 14/18 patients on active treatment were HCV-g1a, 4 were g1b

– Good efficacy vs. both HCV-g1 subtypes (1a and 1b)

• 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 log10) 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

Resistance Monitoring

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

• ther 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

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Questions & Discussion