press release
June 26, 2012, 6:00 a.m. EDT
Presidio Pharmaceuticals Successfully Completes Phase 1 Proof-of-Concept for PPI-668, its Potent HCV NS5A Inhibitor, in Hepatitis C Patients with Genotype-1 Infection
A protocol amendment has been completed to explore the pan-genotypic clinical efficacy of PPI-668 in HCV genotype-2a/3a patients. Recruitment is currently underway for this added cohort
SAN FRANCISCO, Jun 26, 2012 (BUSINESS WIRE) -- Presidio Pharmaceuticals, Inc. announced today successful completion of Phase 1b clinical testing of its lead HCV NS5A inhibitor in patients with HCV genotype-1 infection, with positive efficacy and safety observations supporting advancement of PPI-668 to Phase 2 combination studies.
The randomized, blinded Phase 1b trial of PPI-668 involved sequential cohorts of treatment-naive HCV genotype-1 patients who received oral doses of PPI-668 of 40, 80, 160 or 240 mg, once daily for three consecutive days. Within each 10-patient cohort, patients were randomized 8:2 to PPI-668 or placebo.
In all of the Phase 1b dose cohorts, PPI-668 was well tolerated with no serious or severe adverse events, no premature treatment discontinuations and no apparent pattern of treatment-related clinical side effects or laboratory abnormalities.
The Phase 1 clinical results indicate that PPI-668 had a favorable pharmacokinetic (PK) profile that included rapid achievement of high (micromolar) plasma levels, prolonged maintenance of potentially effective levels between doses, and achievement of steady-state pharmacokinetics after the first dose.
The Phase 1b efficacy observations indicated consistently rapid, marked reductions in patients' serum viral load (HCV RNA levels), that were dose-related. Patients' HCV RNA reductions typically exceeded 3 log10 IU/ml (99.9%) by Day 2. During the 3-day treatment period, mean maximal HCV RNA reductions for the 4 dosing groups were:
-- 3.2 log10 IU/mL in the 40 mg dose group
-- 3.5 log10 IU/mL in the 80 mg dose group
-- 3.5 log10 IU/mL in the 160 mg dose group
-- 3.7 log10 IU/mL in the 240 mg dose group
There was only one minimal-responder in the trial. A patient in the 240 mg dose group was found to be fully resistant at baseline with 100% of this patient's pre-treatment HCV RNA containing 3 genetically linked NS5A resistance mutations. This patient was excluded from the efficacy analysis of the 240 mg cohort, since he was pre-resistant and could not contribute to dose-response inferences.
Five other patients with detectable resistance mutations at baseline, including those harboring the relatively common L31M variant, responded well to PPI-668 treatment, with multi-log HCV RNA reductions.
A protocol amendment has been completed to explore the pan-genotypic clinical efficacy of PPI-668 in HCV genotype-2a/3a patients. Recruitment is currently underway for this added cohort.
"The rapid 3.5 to 3.7 log10 HCV RNA reductions observed with PPI-668 at the three higher dose levels and the encouraging safety profile support advancement of PPI-668 to Phase 2 combination studies with other promising HCV antiviral agents," said Nathaniel A. Brown, M.D., Presidio's Chief Medical Officer. "The PK profile of PPI-668 appears to be a major factor in its efficacy profile, with rapid achievement of potentially effective plasma levels and with inter-dose plasma concentrations exceeding those needed to inhibit both wild-type HCV and many naturally-occurring HCV variants."
Detailed results of the completed trial are expected to be presented at a scientific meeting in the fall of 2012.
About Hepatitis C
Chronic hepatitis C is a progressive inflammatory liver disease caused by chronic infection with the hepatitis C virus (HCV). Approximately 170 to 200 million persons have chronic HCV infection worldwide, resulting in more than 350,000 deaths annually.
The current standard treatment for patients with hepatitis C genotype-1 infection in the United States and several other countries is combined administration of pegylated-interferon-alfa, ribavirin, and an HCV protease inhibitor. This treatment is characterized by incomplete efficacy and severe side effects in some patients.
There is a continuing need for all oral, more consistently effective and better tolerated antiviral combinations for HCV infection, regardless of HCV genotype, patient genetic factors, or disease stage.
About Presidio
Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company focused on the discovery and development of novel oral antiviral therapeutics. 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
dperez@presidiopharma.com
Copyright Business Wire 2012
Showing posts with label PPI-668. Show all posts
Showing posts with label PPI-668. Show all posts
Tuesday, June 26, 2012
Monday, January 9, 2012
Hepatitis C-Presidio Phase 1a dose-ranging assessment of PPI-668 completed
SAN FRANCISCO -- (BUSINESS WIRE) -- Presidio Pharmaceuticals, Inc. announced today the successful completion of a Phase 1a dose-ranging assessment of PPI-668, a potent, pan-genotypic second-generation hepatitis C virus (HCV) NS5A inhibitor, in healthy volunteers and subsequent advancement to a Phase 1b assessment of the dose-related efficacy in hepatitis C patients.
The Phase 1a dose-ranging assessment of PPI-668 was conducted with 32 healthy volunteers in New Zealand. The trial was a randomized, double-blind, placebo-controlled assessment of the safety and pharmacokinetics of three oral doses of PPI-668, initially assessed as single doses and subsequently as a multi-day regimen, in which the highest PPI-668 dose was given once daily for five successive days. The trial results indicated that all dose regimens of PPI-668 were well-tolerated. There were no serious or severe clinical adverse events, no patterns of treatment-related adverse events or laboratory abnormalities, and all subjects completed the trial successfully.
Pharmacokinetic (PK) analyses of subjects’ plasma samples in the Phase 1a trial indicated that substantial blood levels of PPI-668 were rapidly and consistently achieved and dose proportional. PPI-668 plasma concentrations were orders of magnitude above those shown to inhibit HCV replication in vitro and were maintained at predicted effective concentrations for more than 24 hours. These PK results support once-daily dosing for PPI-668 in future studies. Also important was the observation that in the 5-day multi-dose regimen, steady-state PK was achieved rapidly (by Day 2), with no evidence of subsequent accumulation or changes in the clearance profile of PPI-668.
“These first clinical data for PPI-668 indicate excellent tolerance in healthy subjects for up to five days,” said Nathaniel A. Brown, M.D., Presidio’s Chief Medical Officer. “Equally important, the pharmacokinetic profile of PPI-668 is very encouraging, suggesting that effective plasma concentrations can be obtained with relatively low, once-daily doses of PPI-668 - which will facilitate co-formulation of PPI-668 with other HCV antivirals in future combination therapies for hepatitis C.”
Patient screening for the Phase 1b evaluation of PPI-668 in hepatitis C patients has begun in New Zealand and the United States and will soon include Australia. Dosing of the first cohort of hepatitis C patients will begin this week. Presidio expects to have results regarding the antiviral efficacy of PPI-668 in HCV patients in the second quarter of 2012.
In a second HCV research program focused on inhibitors of the HCV NS5B polymerase, Presidio has discovered a lead chemical series of non-nucleosidic NS5B inhibitors with potent activity against all major HCV genotypes. Preclinical profiling is ongoing with a goal of nominating a candidate for clinical development in the coming months.
With its novel NS5A and NS5B inhibitors, Presidio’s objective is to provide two complementary HCV antivirals that will be appropriate for broad use in optimized future combination therapies for patients with HCV infection. Presidio anticipates that such therapies will have a convenient oral dosing regimen (once or twice daily), will exhibit rapid pan-genotypic efficacy and will be well-tolerated.
ABOUT HEPATITIS C AND NS5A INHIBITORS
Chronic hepatitis C is a persistent, potentially progressive inflammatory liver disease caused by chronic infection with the hepatitis C virus (HCV). Worldwide there are an estimated 130 to 170 million persons with chronic HCV infection. There are 7 major genotypes (strains) of HCV, which have differing geographic distributions. Globally, about 40-60% of patients are infected with HCV genotype-1, with the remaining patients infected with HCV genotypes 2 through 7.
Patients with advanced hepatitis C can develop potentially fatal liver failure or liver cancer, and hepatitis C is estimated to account for over 350,000 deaths per year worldwide (WHO estimate). The current standard-of-care treatment for hepatitis C in the United States, for patients with HCV genotype-1 infection, is combined administration of pegylated-interferon, ribavirin, and first-generation HCV protease inhibitors. This multi-drug treatment is characterized by incomplete efficacy for HCV genotype-1 patients, variations in efficacy according to patients’ underlying human genetic factors, no established efficacy for patients infected with other HCV genotypes, substantial tolerance issues, and dosing inconveniences. Thus, there is a continuing need for more consistently effective and better tolerated HCV inhibitors that can be orally administered in future combination therapies for hepatitis C patients worldwide, regardless of HCV genotype, patient genetic factors, or disease stage.
Inhibitors of the HCV NS5A protein represent an exciting, relatively new class of HCV inhibitors that, when optimized, exhibit potent activity across all HCV genotypes, with a mechanism that is distinct from other classes of HCV antivirals, which commonly target the HCV protease or polymerase. PPI-668 is a novel, optimized, second-generation HCV NS5A inhibitor, which exhibits highly potent and selective activity against all HCV genotypes in replicon assays, with favorable toxicology and pharmacology profiles in preclinical assessments.
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 hepatitis C virus (HCV). For more information, please visit our website at: www.presidiopharma.com.
Friday, November 4, 2011
PPI-461- Presidio Announces Proof-of-Concept Data And Initiation of Clinical Testing For 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
Subscribe to:
Posts (Atom)