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AASLD 2011: New NS5A Inhibitor PPI-461 Shows Promising Safety and Efficacy in Brief Study

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Presidio's hepatitis C virus (HCV) NS5A inhibitor candidate PPI-461 demonstrated rapid and potent antiviral activity in a 3-day study, but resistance may be a problem, according to a study presented at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) this week in San Francisco.

Jay Lalezari from Quest Clinical Research in San Francisco and colleagues compared 3 once-daily doses of PPI-461 (50, 100, and 200 mg) vs placebo in 24 treatment-naive genotype 1 chronic hepatitis C patients. The drug was taken for 3 days, followed by a 14-day post-treatment observation period.

PPI-461 produced a "rapid onset of potent antiviral activity," Lalezari said. The 2 higher doses were more effective, with a maximal HCV RNA reduction of 3.6 log. All participants except 1 patient with multiple pre-existing resistance mutations showed marked HCV RNA decline. The drug appeared equally effective against subtypes 1a and 1b. PPI-461 was generally well-tolerated, with no discontinuations or dose modifications due to adverse events.

However, almost all patients who received PPI-461 developed resistance mutations over 3 days, as the drug killed off susceptible virus. While these data emphasize that NS5A inhibitors will need to be used with other direct-acting antivirals (DAAs) or interferon, PPI-462 is a "good candidate for future combination therapies," the researchers concluded.

Lalezari noted that Presidio is seeking partners to collaborate on development of PPI-461 in combination with other DAAs, but is not pursing evaluation with pegylated interferon plus ribavirin. The company has a second-generation NS5A -- PPI-688 -- now in the pipeline.

Below is an edited excerpt from a press release issued by Presidio describing its NS5A development program.

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, CA -- Nov. 4, 201 -- 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, MD (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-668 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.

Investigator affiliations:

Abstract 82: Quest Clinical Research and UCSF, San Francisco, CA; Kings College Hospital , London, UK; Royal Free Hospital, London, UK; Imperial College Healthcare , London, UK; Copenhagen University Hospital, Hvidovre, Denmark; Odense University Hospital, Odense, Denmark; University Hospital of Aarhus, Aarhus , Denmark; University of California Davis Medical Center, Sacramento, CA; Presidio Pharmaceuticals, San Francisco, CA; Smerud Medical Research International, Oslo, Norway.

Abstract 356: Presidio Pharmaceuticals, San Francisco, CA; Kings College Hospital, London, UK; Quest Clinical Research and UCSF, San Francisco, CA.

11/8/11

References

J Lalezari, K Agarwal, GM Dusheiko, et al. Dose-Ranging Trial of PPI-461, a Potent New Pan-Genotypic HCV NS5A Inhibitor, in Patients with HCV Genotype-1 Infection. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 82.

N Huang, Q Huang, M Lau, et al. Resistance Monitoring of HCV Patients Treated for 3 Days with the NS5A Inhibitor PPI-461 Reveals Rapid Emergence of Resistant HCV Variants. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 356.

Other Source

Presidio Pharmaceuticals. 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. Press release. November 4, 2011.