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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

Sunday, October 26, 2008 General News J E 4
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WASHINGTON, Oct. 26 Sequoia Pharmaceuticals presentedpositive results today from two studies on SPI-256, a novel investigationalHIV protease inhibitor (PI). One study based on an in vitro analysisdemonstrates that the mode of interaction of SPI-256 with HIV proteaseprovides a rationale for its high potency and high genetic barrier toresistance. The second study conducted in healthy volunteers demonstrates thatSPI-256 is generally safe and well tolerated in humans and is amenable toboosting by pharmacokinetic enhancers (PKEs). The data were presented at the48th annual Interscience Conference on Antimicrobial Agents and Chemotherapy(ICAAC)/46th annual Infectious Diseases Society of America (IDSA) jointmeeting held in Washington, D.C.

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

Data on SPI-256 at this conference

Discovery and in vitro activity of SPI-256

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

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

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

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

"There is a compelling need for new protease inhibitors that potentlysubdue prevalent strains of HIV and which impede the development of newmulti-drug resistant strains, without conferring toxicity," said JohnErickson, PhD, cofounder and chief scientific officer of Sequoia. "To addressthis need, we designed our protease inhibitor using a structure-based approachthat targets highly conserved regions of the protease enzyme while minimizinginteractions with regions of the enzyme that are highly malleable and thussusceptible 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 toevaluate the safety, tolerability and pharmacokinetics of single, ascendingdoses 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 ofSPI-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 ofSPI-256 (150mg, 450mg, 900mg) in combination with 100mg of RTV or received asingle dose of 1200mg of SPI-256 with a high-fat meal.

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

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

When combined with ritonavir, SPI-256 levels were markedly elevated. Thisfinding suggests that SPI-256 may be amenable to boosting with Sequoia's ownpharmacokinetic enhancer, SPI-452, which is also undergoing evaluation inhuman clinical trials.

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

About Sequoia Pharmaceuticals, Inc.

Sequoia Pharmaceuticals discovers and develops unique antiviral drugs thatpotently inhibit the most prevalent form of viruses and prevent the emergenceof drug-resistant viruses. Sequoia's core expertise of structure- andtarget-based design facilitates the efficient discovery of multiple NCE's witha small team of discovery scientists. Its current drug pipeline focuses onHIV/AIDS and HCV-induced hepatitis. Sequoia is also developing a uniqueseries of pharmacokinetic enhancers (PKEs) which have potential application ina wide range of therapy areas, including use in combination with currentlymarketed and experimental antiviral therapies.

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

SOURCE Sequoia Pharmaceuticals
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