EASL; Presidio's PPI-461, a novel HCV NS5A inhibitor preliminary results

Mar. 30, 2011 (Business Wire) -- Presidio Pharmaceuticals, Inc. announced today positive preliminary results from a Phase 1b clinical trial of PPI-461, a novel HCV NS5A inhibitor for the treatment of patients with chronic hepatitis C.


The PPI-461 phase 1b clinical trial reported here is a multiple ascending dose, randomized, blinded, placebo-controlled study in treatment-naïve adult hepatitis C patients with HCV genotype-1 infection; this trial is presently ongoing in the U.K., Denmark, and the United States. The study objectives are to assess the safety, tolerability, pharmacokinetics, and initial antiviral effects of PPI-461 during once-daily (QD) dosing at three dosing levels (50, 100, and 200 mg/day) for three days. Each dosing cohort

of 8 patients is randomized 6 (PPI-461):2 (placebo). Two dosing groups have completed study treatment to date; the third (200 mg) dosing group is ongoing.


The interim Phase 1b trial results indicate that PPI-461 has been well-tolerated, with no serious or severe adverse events and no modifications or premature discontinuations of study treatment. Among PPI-461 recipients there have been only transient clinical adverse events, of non-specific types commonly seen in clinical trials, with no dose-related or treatment-related patterns of specific adverse events or laboratory abnormalities.

Pharmacokinetic (PK) analyses of patients’ PPI-461 blood levels indicate that substantial blood levels of PPI-461 have been achieved rapidly and are dose proportional. Importantly, blood levels that are inhibitory for HCV replication have been maintained throughout the 24-hr inter-dose periods in the study patients.

Virologic data from the first two dosing groups indicate rapid and marked reductions in patients’ serum viral loads (HCV RNA levels), in both dosing groups, in the first two days of treatment. The 50 mg dosing group achieved a mean maximal HCV RNA reduction of 3.1 log10 IU/mL (5 of 6 patients), while the 100 mg group achieved a mean maximal HCV RNA reduction of 3.7 log10 IU/mL (6 of 6 patients). The mean maximal HCV RNA reduction for 4 Placebo treated patients was 0.3 log10 IU/mL. One patient in the 50 mg cohort had a negligible response to PPI-461(0.4 log10 IU/mL HCV RNA reduction). This patient entered the study with highly resistant virus, as evidenced by NS5A resistance substitutions (L31M, Y93N, L28F, R30N) detected at high levels in pre-treatment sera. Such a patient would be expected to have minimal efficacy with any NS5A inhibitor, since these agents share common key resistance mutations, as will be reported in a Presidio presentation at the 2011 annual meeting of the European Association for the Study of Liver Disease (EASL) in Berlin on April 2nd (R. Colonno et al., poster #1199).

Efficacy data for individual patients receiving active PPI-461 treatment in the first two dosing cohorts in the Phase 1b trial are presented in Table 1:

Table 1
HCV RNA Reduction log10 IU/mL

Dose\Patient .........1....... 2....... 3 .........4......... 5........ 6

50 mg,
.................... 0.4*......... 2.6 .....2.7..... 3.3 ....3.4..... 3.5

100 mg ..........2.6.......... 3.7..... 3.7..... 3.8..... 4.0..... 4.1



*Four NS5A-specific linked mutations in 100% of virus population at study entry ..

“These positive clinical data for PPI-461 in hepatitis C patients further support the inclusion of NS5A inhibitors in clinical development of novel combination therapies. Such future combination therapies are expected to substantially improve patient outcomes and should help stem the rising incidence of HCV-associated severe liver disease and premature mortality,” said Nathaniel A. Brown, M.D., Presidio’s Chief Medical Officer.


The final results of the completed Phase 1b trial of PPI-461 will be submitted for presentation at a scientific meeting later this year.

About Presidio’s HCV NS5A Inhibitors

Inhibitors of the HCV NS5A protein represent an exciting, highly potent class that is mechanistically distinct from other classes of direct-acting HCV antivirals that target the viral protease or replicase (polymerase).

PPI-461 is the first in a series of novel and selective HCV NS5A inhibitors discovered by Presidio Pharmaceuticals. Presidio’s NS5A candidates are selected from numerous internal discovery leads, based on their potent activity against all major HCV genotypes and their potential for once-daily dosing with good tolerance. A Presidio presentation at the 2011 annual meeting of EASL in Berlin on April 2nd (R. Colonno et al., Poster #1200) will highlight the preclinical profile of three other novel NS5A inhibitors in development by Presidio, which derive from distinct chemical series.

About Presidio
Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company dedicated to the discovery and development of small-molecule antiviral therapeutics for novel and validated targets. For more information, please visit our website at: http://www.presidiopharma.com/ .

Presidio Pharmaceuticals, Inc.

Omar K. Haffar, PhD, 415-655-7561

omar@presidiopharma.com