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Sequoia Pharmaceuticals Presents In Vitro and First-in-Human Data Supporting Further Development of SPI-256, a Novel Investigational Protease Inhibitor

WASHINGTON, Oct. 26 /PRNewswire/ -- Sequoia Pharmaceuticals presented positive results today from two studies on SPI-256, a novel investigational HIV protease inhibitor (PI). One study based on an in vitro analysis demonstrates that the mode of interaction of SPI-256 with HIV protease provides a rationale for its high potency and high genetic barrier to resistance. The second study conducted in healthy volunteers demonstrates that SPI-256 is generally safe and well tolerated in humans and is amenable to boosting by pharmacokinetic enhancers (PKEs). The data were presented at the 48th annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/46th annual Infectious Diseases Society of America (IDSA) joint meeting held in Washington, D.C.

"Two ongoing significant needs in contemporary HIV therapy are: new agents that have activity against mutant virus and also have a high genetic barrier to developing resistance; and new agents that can boost the pharmacokinetic levels of existing drugs," said Martin Markowitz, MD, professor and clinical director at the Aaron Diamond AIDS Research Center. "These data on SPI-256 look very promising and address the need for new agents with activity against protease inhibitor-resistant virus as well as the development of resistance. I look forward to further advancements and innovations in HIV that will address our needs in the treatment community from a resistance, as well as a PK, point of view."

Data on SPI-256 at this conference

Discovery and in vitro activity of SPI-256

Scientists from Sequoia Pharmaceuticals presented their structure-based approach that led to the development of SPI-256. Prior to discovering SPI-256, Sequoia scientists examined three-dimensional structures of wild-type and drug-resistant mutant HIV proteases bound to selected inhibitors. By analyzing these structures, the Sequoia scientists were able to identify a subset of main-chain and active-site atoms of HIV protease representing a conserved atomic substructure that cannot be altered by mutations. This conserved substructure then served as the target for a series of protease inhibitors in development at Sequoia. SPI-256 emerged from this series of protease inhibitors as the lead candidate and was advanced to clinical studies.

In vitro activity data were also presented in this poster. These data demonstrated how the structural design elements of SPI-256 present a high genetic barrier to the emergence of resistant strains of HIV. Additionally, the unique structural properties of SPI-256 explain its high potency when tested against a panel of 50 viral strains in a PhenoSense (TM) assay. In this analysis, SPI-256 achieved potency levels 4- to 50-fold higher than currently approved front-line protease inhibitors when tested in wild-type HIV strains.

SPI-256 also exhibited an excellent resistance profile against multi-drug resistant (MDR) isolates. In an analysis of 11 "worst case scenario" MDR isolates (defined as 6 primary PI mutations and FC>50), SPI-256 retained low nanomolar activity against most MDR isolates and mean IC50 at least an order of magnitude lower than that for atazanavir, lopinavir, amprenavir, tipranavir and other reference PIs and was better than or comparable with darunavir.

Furthermore, an additional analysis demonstrated that SPI-256 possesses a high barrier to resistance. Through in vitro resistance selection experiments, when scientists at Sequoia attempted to propagate HIV in the presence of SPI-256, the drug posed a markedly higher barrier to developing resistance than atazanavir and lopinavir. Resistance to SPI-256 required the accumulation of multiple primary protease mutations.

"There is a compelling need for new protease inhibitors that potently subdue prevalent strains of HIV and which impede the development of new multi-drug resistant strains, without conferring toxicity," said John Erickson, PhD, cofounder and chief scientific officer of Sequoia. "To address this need, we designed our protease inhibitor using a structure-based approach that targets highly conserved regions of the protease enzyme while minimizing interactions with regions of the enzyme that are highly malleable and thus susceptible to mutations."

First-in-human data with SPI-256

The primary objective of this Phase 1; randomized, double-blind, placebo-controlled, single- and escalating-dose crossover study was to evaluate the safety, tolerability and pharmacokinetics of single, ascending doses of SPI-256 administered alone or in combination with 100mg ritonavir (RTV) in healthy volunteers.

Data were presented on 59 healthy volunteers who took a single dose of SPI-256 (150mg, 450mg, 600mg, 900mg, or 1200mg) alone in Phase 1 of the study (n=38); in Phase 2 of the study, 37 subjects took either a single dose of SPI-256 (150mg, 450mg, 900mg) in combination with 100mg of RTV or received a single dose of 1200mg of SPI-256 with a high-fat meal.

SPI-256 demonstrated that it was generally safe and well tolerated in this healthy volunteer population. Adverse events (AEs) were reported by approximately half of subjects, although most were judged to be unrelated or unlikely to be related to study drug. In Phase 1 of the study, three subjects reported a total of 8 AEs possibly related to study drug. In Phase 2 of the study, two subjects reported one AE each that was possibly or definitely related to study drug.

Peak exposure to SPI-256 given alone was dose proportional over the range of 150 to 1200mg. In addition, a single dose of SPI-256 achieved sufficient plasma concentration to suggest the potential of once- or twice-daily dosing regimens in treatment-naive or -experienced patients.

When combined with ritonavir, SPI-256 levels were markedly elevated. This finding suggests that SPI-256 may be amenable to boosting with Sequoia's own pharmacokinetic enhancer, SPI-452, which is also undergoing evaluation in human clinical trials.

"The emergence of our first clinical candidate is an important milestone for Sequoia and indicative of the tremendous progress we've made during the past 12 months," said Steve Skolsky, president and chief executive officer of Sequoia. "We're very pleased at the speed with which we have brought our drug candidates to human trials, following the successful filing of two investigational new drug applications in 2007, one for SPI-256, and a second for our proprietary pharmacokinetic enhancer, SPI-452."

About Sequoia Pharmaceuticals, Inc.

Sequoia Pharmaceuticals discovers and develops unique antiviral drugs that potently inhibit the most prevalent form 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 NCE's 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 (PKEs) which have potential application in a wide range of therapy 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.

SOURCE Sequoia Pharmaceuticals
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