News/Press

February 9, 2009

Sequoia Pharmaceuticals presents proof of clinical concept of SPI-452, a novel pharmacokinetic enhancer

 

MONTREAL (Feb. 9, 2009) — 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.

 

October 26, 2008

Sequoia Pharmaceuticals presents in vitro and first-in-human data supporting further development of SPI-256, a novel investigational protease inhibitor

 

WASHINGTON, D.C. – 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, DC.

“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 PhenoSenseTM 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-naïve 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.

 

December 6, 2007

Sequoia Pharmaceuticals Files Second IND in One Year

Novel Drug to Enhance the Pharmacokinetic Properties of Co-Administered Therapeutics.

 

Sequoia Pharmaceuticals, Inc. announced today that is has filed its second Investigational New Drug application (IND) with the FDA for 2007. This is a request to begin clinical trials in humans. The subject of this IND is a drug which is designed to improve the effectiveness of other, co-administered drugs. It is also expected to reduce intra-patient variability with respect to how quickly co-administered therapeutics are eliminated from the body.

The benefits are expected to be a decreased pill burden for the patient and a more predictable dosing regimen for the prescribing physician.

This drug, SPI-452, is designed to permit less-frequent dosing of a co-administered therapeutic, and has no other known activity

Sequoia’s first IND, for a novel HIV protease inhibitor, was filed in January 2007. Phase 1 clinical trials continue to yield favorable results.

Steve Skolsky, CEO, said “I am impressed with the accomplishments of the teams at Sequoia. To have discovered and developed two drug candidates within five years of founding and to file two INDs in one year is an impressive demonstration of the commitment and capability of the entire organization. We look forward to advancing both drugs through early development.”

 

October 29, 2007

Sequoia Pharmaceuticals, Inc. announced today the appointment of Steven D. Skolsky as its President and Chief Executive Officer. He will also serve as a member of the Board of Directors. 

“Sequoia is pleased to have recruited such an outstanding, talented leader as Steven Skolsky,” said Chris Mirabelli, Chairman of the Board of Sequoia Pharmaceuticals.  “Steve has an impressive record of success within the pharmaceutical industry.  The combination of his leadership and management experience, as well as his business acumen, makes Steve uniquely qualified to lead us through the exciting times ahead.”

“Sequoia possesses an extraordinary scientific pedigree, and a very attractive research portfolio. I am honored to have the opportunity to lead Sequoia, and to build on its outstanding technological progress as we move towards commercialization”, said Mr. Skolsky.

Mr. Skolsky brings over twenty-five years of U.S. and international experience in the pharmaceutical and biotechnology arena.   He most recently served as chief executive officer of Trimeris, a biotechnology company specializing in HIV therapeutics. Previously Mr. Skolsky had a distinguished career at GlaxoSmithKline where he served as GSK’s Senior Vice President of Global Commercial Strategy responsible for world-wide clinical development and product strategy. He also served as managing director of GSK’s operations in Australia and New Zealand and previously was Vice President of Sales and Marketing of the HIV/Oncology Division at Glaxo Wellcome.  He is a graduate of the University of North Carolina at Chapel Hill.

 

June 2007

Sequoia Pharmaceuticals has initiated Phase 1 Clinical Trials on its novel HIV protease inhibitor, and these trials are progressing exceptionally well.

 

January 20, 2007

Sequoia Pharmaceuticals, Inc. announced today that is has raised $35 million in a Series C financing that will be used to further develop its pipeline candidates for the treatment of drug resistant HIV infection, including the company’s two lead clinical candidates, an HIV protease inhibitor as well as a novel therapeutic agent: a pharmacokinetic enhancer.