PPI-461- Presidio Announces Proof-of-Concept Data And Initiation of Clinical Testing For PPI-668

Presidio Pharmaceuticals, Inc. Announces Clinical Proof-of-Concept Data for its First HCV NS5A Inhibitor, PPI-461, and Initiation of Clinical Testing for its Second-Generation NS5A Inhibitor, PPI-668.

SAN FRANCISCO, Nov 04, 2011 (BUSINESS WIRE) -- Presidio Pharmaceuticals, Inc. today announced progress with its HCV antiviral drug discovery and development programs. A primary company objective is to advance multiple potent and safe inhibitors that target multiple HCV proteins and provide pan-genotypic coverage, as we believe such combination therapies will more adequately address the global medical need in the future. To that end, the company intends to bring 2 or 3 of its novel HCV NS5A inhibitors through early clinical development (Phase 1b/2a), with subsequent Phase 2-3 clinical evaluation of such NS5A candidates in suitable combination regimens with other HCV antivirals through corporate partnering or intercompany collaborations.

In support of this corporate strategy, in addition to the NS5A program, Presidio has intensified its efforts on an internal research program to discover potent, pan-genotypic inhibitors of the HCV polymerase. In recent months a lead series of non-nucleosidic HCV polymerase inhibitors was identified that inhibits all of the major HCV genotypes at low nanomolar concentrations and exhibits potential for once- or twice-daily oral dosing in humans. Presidio's goal is to nominate a candidate for clinical development later this year.

At this week's meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco this week, Presidio will have 2 scientific presentations on its first generation NS5A inhibitor, PPI-461, reporting clinical and virologic data from the recently concluded Phase 1b clinical proof-of-concept trial of PPI-461. In addition, Presidio is announcing the initiation of Phase 1 clinical evaluation of PPI-668, its next-generation NS5A inhibitor with enhanced potency against HCV genotypes 3 and 6, supporting our emphasis on combinations that possess strong pan-genotypic coverage.

PPI-461 and PPI-668 are novel HCV NS5A inhibitors, discovered at Presidio, which exhibit highly potent and selective activity against the major HCV genotypes in laboratory assays. Inhibitors of the HCV NS5A protein represent a promising new class of HCV antivirals that are mechanistically distinct from HCV agents that target the viral protease or polymerase. Laboratory data and emerging clinical data suggest that NS5A inhibitors can potentially be used in combination with any of these other HCV agents to achieve better treatment efficacy in hepatitis C patients and combat the emergence of viral resistance.

PPI-461 - Phase 1b Proof-of-Concept Clinical Results

Jacob P. Lalezari, M.D. (Quest Clinical Research) will present the results of an international Phase 1b trial of PPI-461. Dr. Lalezari's oral presentation, entitled, "A Dose-Ranging Trial of PPI-461, a Potent New Pan-Genotypic HCV NS5A Inhibitor, in Patients with HCV Genotype-1 Infection," is scheduled for 5:30 PM on Sunday, November 6, 2011 in AASLD Parallel Session #12. The presentation reflects the final results of a Phase 1b dose-ranging trial conducted at medical centers in the U.S., England and Denmark. The key findings of the study are that hepatitis C (genotype-1) patients dosed once daily for 3 days with PPI-461 (50, 100 or 200 mg/day) consistently showed rapid, profound reductions in serum HCV RNA levels. The 100 and 200 mg/day doses showed similar efficacy, while efficacy with the 50 mg dose was appreciable, but somewhat lower. Mean maximal HCV RNA reductions for the 100 and 200 mg/day doses, during the 3-day treatment period, were 3.6 log10 IU/mL. At those dose levels, 11 of 12 patients achieved a 3 to 4 log10 (99.9-99.99%) reduction in HCV RNA levels in the first 1-2 days of treatment; the 12th patient also had a marked HCV RNA reduction (2.6 log10, 99+%). Similar to the results in the previous Phase 1a dose-ranging trial in healthy volunteers, PPI-461 was well tolerated in the Phase 1b trial, with no appreciable pattern of treatment-related (drug vs. placebo) or dose-related clinical adverse effects or laboratory abnormalities.

A second AASLD presentation will be a poster by company scientists and academic collaborators entitled, "Resistance Monitoring of HCV Patients Treated for Three Days with the NS5A Inhibitor PPI-461 Reveals Rapid Emergence of Resistant HCV Variants," during the Saturday, November 5, 2011, afternoon poster session. This presentation summarizes the results of comprehensive resistance analysis of patient samples obtained during the PPI-461 Phase 1b trial. Resistant HCV variants were evident in most patients by the end of treatment, as expected when NS5A inhibitors (or other direct-acting HCV antivirals) are used as monotherapy, further supporting the need to use HCV inhibitors in combination to maximize viral clearance and avoid the emergence of resistance.

PPI-688 Advances to Phase 1 Trial

A second-generation NS5A candidate from Presidio's internal research program, PPI-668, has successfully completed preclinical evaluations and has begun Phase 1 clinical testing in a two-part Phase 1 study. In this combined Phase 1a-1b study, volunteer dose-ranging assessments (Part I) will be followed directly by dose-ranging assessments in hepatitis C patients (Part II). In the currently ongoing Part I dosing of healthy volunteers, the first two doses of PPI-668 have been well-tolerated and the pharmacokinetic data to date indicate that, after relatively low oral doses of PPI-668, the volunteers in this study achieved substantial peak and trough plasma concentrations that far exceed the concentrations of PPI-668 needed to inhibit HCV replication in vitro. It is anticipated that data providing an initial assessment of the antiviral effect of PPI-668 in HCV patients will be obtained in the next several months. This Phase 1a-1b study is targeted for completion by early 2Q2012.

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 serious, global viral infections. For more information, please visit our website at: www.presidiopharma.com .

SOURCE: Presidio Pharmaceuticals, Inc.

    
     Presidio Pharmaceuticals, Inc.
     H. Daniel Perez, M.D., 415-655-7560
     President & Chief Executive Officer
     dperez@presidiopharma.com
  

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

AASLD:PPI-461 NS5A Inhibitor with Pan-Genotype Activity

Presidio Pharmaceuticals, Inc. to Present First Clinical Data for PPI-461, a New HCV NS5A inhibitor, at the American Association for the Study of Liver Diseases (AASLD) Meeting, Supporting Initiation of a Trial in Hepatitis C Patients

Oct 27

SAN FRANCISCO--(BUSINESS WIRE)--Presidio Pharmaceuticals, Inc. announced today that Nathaniel Brown, M.D., Chief Medical Officer, will present a late-breaker poster, “Safety and Pharmacokinetics of PPI-461, a Potent New Hepatitis C virus (HCV) NS5A Inhibitor with Pan-Genotype Activity” at the 61st AASLD meeting in Boston, MA, on November 1, 2010. The presentation provides the results of the first clinical trial of PPI-461, and will be available for review from 8:00A to 5:00P (EDT) in Exhibit Hall C at the Hynes Convention Center.

“Safety and Pharmacokinetics of PPI-461, a Potent New Hepatitis C virus (HCV) NS5A Inhibitor with Pan-Genotype Activity”
PPI-461

PPI-461 is a novel and promising NS5A inhibitor that interferes with HCV replication. Discovered at Presidio, PPI-461 exhibits highly potent and selective activity against all seven major HCV genotypes in laboratory assays. Inhibitors of the HCV NS5A protein represent a promising new class of HCV antivirals that are mechanistically distinct from HCV agents that target the viral protease or replicase (polymerase). Laboratory data suggest that NS5A inhibitors can potentially be used in combination with any of these other HCV agents, to achieve better efficacy in hepatitis C patients and combat the emergence of antiviral resistance.

About the Phase 1a Trial Results

The data to be reported at the AASLD meeting are the results of a Phase 1a dose-ranging trial of PPI-461 in healthy volunteers completed this year. This trial assessed the safety and pharmacokinetics of five different oral dosing regimens for PPI-461: four single doses (20, 50, 100, and 200 mg), and a multi-dose regimen (200 mg daily for five days). A total of 40 subjects participated in the study, with eight subjects in each of the five dosing groups.

As indicated in the LB-12 abstract, now viewable on the AASLD meeting website (AASLD.org), all PPI-461 dose regimens were well tolerated. All subjects completed the study, and there were no patterns of clinical adverse events or laboratory abnormalities associated with administration of PPI-461. The pharmacokinetic results indicated that all subjects rapidly achieved substantial blood levels of PPI-461, which far exceeded the concentrations of PPI-461 needed to inhibit HCV (genotypes 1-7) in the laboratory. For PPI-461 doses of 50 mg or more, all subjects achieved blood levels of PPI-461 that would be expected to inhibit HCV replication for 24 hours or longer. This profile suggests that PPI-461 may be effective when administered to hepatitis C patients at relatively low oral doses on a once-daily dosing schedule, which would facilitate its convenient use in future co-formulated combination therapies. Additional details of the Phase 1a results will be given with the November 1 presentation at AASLD.

First Study of PPI-461 in Hepatitis C Patients Underway

Based on the encouraging Phase 1a results, Presidio has initiated a Phase 1b proof-of-concept clinical trial of PPI-461 in hepatitis C patients. This dose-ranging trial will evaluate the safety, pharmacokinetics and antiviral efficacy of PPI-461 in previously-untreated patients with HCV genotype-1 infection.

“We are pleased to begin initial assessments of the tolerance and antiviral efficacy of PPI-461 in patients with chronic hepatitis C, following the encouraging results of the recent Phase 1a study,” said Nathaniel Brown, M.D., Chief Medical Officer. “HCV-related mortality and severe debilitation are projected to increase continually in the coming years, so there is an urgent need for improved therapies for hepatitis C.”

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 more information, please visit our website

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