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Sequoia Pharmaceuticals Presents Proof of Clinical Concept of SPI-452, a Novel Pharmacokinetic Enhancer
Date:2/9/2009

MONTREAL, Feb. 9 /PRNewswire/ -- Sequoia Pharmaceuticals presented positive results today from two phase 1 studies in healthy volunteers and preclinical studies on SPI-452, a novel pharmacokinetic enhancer (PKE) with no inherent antiviral activity. Pharmacokinetic enhancers increase drug levels of co-administered agents through inhibition of cytochrome P450 (CYP)-mediated drug metabolism. These increased drug levels can lead to improved efficacy, reduced pill burden, and reduced daily dosing. Because of the risk of developing drug resistance, there is a need for new PKEs that have no antiviral activity. The only currently available PKE for use in HIV therapy is ritonavir, a protease inhibitor that has inherent antiviral activity. SPI-452 was designed to be a potent inhibitor of CYP3A enzymes with no antiviral activity and an improved safety profile; thereby, enhancing treatment options for patients who would benefit from a PKE given as a stand-alone agent or as part of a fixed-dose combination. These data were presented at the 16th Conference on Retroviruses and Opportunistic Infections on Monday, February 9, 2009, in Montreal, Canada.

Pharmacokinetic data from a 2-week, repeat-dose, proof-of-clinical-concept study and a single ascending-dose, first-time-in-human study conducted in healthy volunteers demonstrated that SPI-452 substantially enhanced the exposures of three currently approved HIV protease inhibitors (PIs). SPI-452 was generally safe and well tolerated, with few side effects. Furthermore, there were no statistically significant changes in triglyceride and low- density lipoprotein (LDL) cholesterol levels in subjects receiving SPI-452 compared with placebo, which may indicate that SPI-452 has a favorable lipid profile, an attribute that is in increasing demand in the treatment of HIV. These first-time-in-human and proof-of-clinical-concept data support the further investigation of SPI-452 and validate the Sequoia PKE development program.

"In the HIV community and the clinical arena at large, there is a compelling need for novel agents that enhance the pharmacokinetic profiles of existing drugs in order to increase efficacy, reduce pill burden, and decrease frequency of dosing for patients," said Martin Markowitz, MD, clinical director at the Aaron Diamond AIDS Research Center and an Aaron Diamond professor at Rockefeller University. "Sequoia Pharmaceuticals' PKE development program has demonstrated significant progress toward fulfilling the unmet medical need for a safe and well tolerated PKE that potently enhances the pharmacokinetics of target compounds without the risk of promoting the emergence of resistant mutants due to its lack of antiviral activity."

Data on SPI-452 at this conference

Study 0452-002: Proof of Clinical Concept

Study 0452-002 was designed to evaluate the pharmacokinetic profile of multiple doses of SPI-452 and to establish proof of clinical concept of the pharmacokinetic enhancement ability of SPI-452 when combined with either of 2 currently marketed HIV protease inhibitors, darunavir or atazanavir. Sixty- seven healthy volunteers were enrolled in this randomized, placebo-controlled, repeat- and escalating-dose trial. Before administering SPI-452, subjects received a single dose of darunavir (600 mg), atazanavir (300 mg) or placebo in order to establish PI plasma concentration levels. After a 7 day washout period, subjects were randomized to 15 days of SPI-452 (25 mg, 50 mg, or 200 mg) once daily or placebo. On day 15, subjects also received, once again, either darunavir, atazanavir or placebo co-administered with the final dose of SPI-452. On day 16 subjects received darunavir, atazanavir or placebo only.

Pharmacokinetic results of SPI-452 co-administered with darunavir and atazanavir demonstrated that SPI-452 significantly increased the minimum plasma concentrations (Cmin) at 12 and 24 hours up to 37-fold of darunavir and up to 13-fold of atazanavir. SPI-452 given alone demonstrated that steady- state drug levels were achieved by day 14 and that SPI-452 levels increased slightly greater than linearly with dose. SPI-452 was generally safe and well tolerated when dosed up to 200 mg once daily for 15 days. No subjects withdrew from the study because of study drug, and no serious adverse events (AEs) were reported. AEs were usually mild in severity with no pattern of body-system AEs. The most common AEs reported were headache, nausea/emesis and diarrhea. Furthermore, there were no statistically significant changes in triglyceride and LDL cholesterol levels in subjects receiving SPI-452 compared with placebo, which may indicate that SPI-452 has a favorable lipid profile.

"SPI-452 represents an extremely promising PKE with the unique ability to boost levels of protease inhibitors without conferring any inherent antiviral activity, a distinguishing feature that would allow SPI-452 to be combined with PIs in HIV or HCV treatment," said Joseph Eron, MD, professor and director of the AIDS Clinical Trial Unit and Center for AIDS Research at the University of North Carolina at Chapel Hill. "These data support the further development of SPI-452 as a potential alternative to ritonavir."

Study 0452-001: First Time in Humans

Results were also presented from an earlier first-time-in-human study where fifty-eight healthy volunteers took part in a randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerability and pharmacokinetics of single, ascending doses of SPI-452 administered alone and in combination with 1000 mg of saquinavir (SQV). In part 1 of the study, subjects received single doses of SPI-452 (25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 600 mg). In part 2, subjects received SPI-452 (50 mg or 200 mg) and SQV (1000 mg), SQV (1000 mg) alone or placebo.

Pharmacokinetic results from this study demonstrated that SPI-452 increased mean exposure levels of saquinavir which was early validation that SPI-452 was a potent pharmacokinetic enhancer. Co-administration of SPI-452 and SQV did not alter SPI-452 exposure. SPI-452 was generally safe and well tolerated in single, ascending doses of 25 mg to 600 mg and in single-dose combination with 1000 mg of SQV. No subjects withdrew from the study because of study drug, and no serious AEs were reported. Adverse events were usually mild in severity. The most common AEs reported were headache and pharyngitis.

Preclinical Evaluation

The ability of SPI-452 to inhibit CYP3A and the metabolism of HIV PIs was assessed using liver microsomes or cryopreserved hepatocytes. In these in vitro studies, SPI-452 inhibited the metabolism of all HIV PIs and one investigational HCV PI tested in human liver microsomes and primary hepatocytes similar to ritonavir. In addition, SPI-452 demonstrated no inherent antiviral activity, nor did it affect the antiviral potency of these HIV PIs in in vitro cell assay.

The ability of SPI-452 to enhance the pharmacokinetic exposure of three co-administered HIV PIs (saquinavir, lopinavir and atazanavir) was evaluated in a series of single-dose in vivo animal studies. SPI-452 consistently and significantly enhanced the systemic exposure of the co-administered HIV PIs comparable with ritonavir.

"We are very encouraged by the significant pharmacokinetic enhancing ability of SPI-452 combined with its positive safety and tolerability profile," said John Erickson, PhD, cofounder and chief scientific officer of Sequoia. "The data we have collected from multiple studies on SPI-452 strongly support the continued human testing of SPI-452 and its development as a stand- alone agent or component of a fixed-dose combination, and they validate the direction and course of our PKE development program."

About Sequoia Pharmaceuticals Inc.

Sequoia Pharmaceuticals discovers and develops unique antiviral drugs that potently inhibit the most prevalent forms of viruses and prevent the emergence of drug-resistant viruses. Sequoia's core expertise of structure- and target- based design facilitates the efficient discovery of multiple NCEs with a small team of discovery scientists. Its current drug pipeline focuses on HIV/AIDS and HCV-induced hepatitis. Sequoia is also developing a unique series of pharmacokinetic enhancers that have potential application in a wide range of therapeutic areas, including use in combination with currently marketed and experimental antiviral therapies.

Sequoia Pharmaceuticals has two investigational new drug applications (INDs) filed with the Food and Drug Administration. The first IND is for SPI- 256, an HIV protease inhibitor in phase 1 clinical development. The second IND is for SPI-452, a pharmacokinetic enhancer in phase 1 clinical development.


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