Abstract
Abstract 2051
Eukaryotic translation initiation factor 5A (eIF5A) has been implicated in the regulation of cell proliferation, inflammation, differentiation, and apoptosis and is the only known protein to be post-translationally modified with a hypusine residue. Both hypusinated eIF5A and deoxyhypusine synthase, the enzyme that mediates eIF5A hypusination, have been identified as markers of neoplastic growth and metastasis. Accumulation of unmodified eIF5A is generally only observed during apoptosis and mutants of eIF5A that cannot be hypusinated (eIF5AK50R) are pro-apoptotic. In vitro cell studies and in vivo xenograft models have demonstrated that simultaneous small interfering RNA (siRNA)–mediated suppression of native eIF5A expression and over-expression of eIF5AK50R potently induces apoptosis in multiple cancer cell types, including myeloma, and inhibits human myeloma tumor growth in murine xenograft models. SNS01-T is a nanoparticle comprising: 1) a plasmid encoding the pro-apoptotic eIF5AK50R driven by a B cell specific promoter; 2) an siRNA that inhibits pro-survival hypusine-eIF5A expression; and 3) a polymer that assembles the nucleic acids into a nanoparticle. Pharmacokinetic, pharmacodynamic, biodistribution, and toxicology studies have been conducted with SNS01-T to support studies in multiple myeloma patients.
The pharmacokinetics and biodistribution of SNS01-T were evaluated in mice using RT-qPCR to assess the distribution and persistence of plasmid DNA and siRNA. Toxicology includes acute and 6-week studies with twice weekly administration of SNS01-T in male and female mice and dogs. Clinical signs, hematology, histopathology, clinical pathology, pharmacokinetics, and serum cytokines were measured. SNS01-T reached all tissues examined including the bone marrow. No evidence of accumulation of the plasmid or siRNA was observed and levels declined rapidly after the end of treatment. Toxicological findings of SNS01-T administration in mice at 0.25 and 0.5 mg/kg for 6 weeks included clinical signs limited to the injection site, increases in organ weight, increases in IFN-g and GRO, and hematological changes, that could not be attributed solely to the test article. Toxicological findings of SNS01-T administration in beagles at 0.375 and 0.75 mg/kg for 6 weeks included a dose-dependent increase in incidences of clinical signs, resulting in a NOAEL of 0.375 mg/kg.
A multiple ascending dose Phase 1b/2a open-label study has been initiated to evaluate the safety and tolerability of six weeks of twice-weekly administration of SNS01-T by intravenous infusion in patients with relapsed or refractory multiple myeloma. Approximately 12–15 patients are being enrolled and administered escalating doses of SNS01-T (Table 1). The patient starting dose is based upon the lower dose evaluated in the mouse toxicology study (0.25 mg/kg). The initial dosage in the clinical study was selected by reducing by a factor of 20 to 0.0125 mg/kg. The primary safety endpoints are the frequency, severity, and duration of treatment-related adverse events in patients following treatment with SNS01-T. Although safety is the primary endpoint of this study, efficacy is being evaluated by time to progression and by changes in values of the following biomarkers: monoclonal (M) protein, hemoglobin, bone marrow plasma cell percentage, plasma cell labeling index, C-reactive protein, and free light chain. Pharmacokinetics of SNS01-T are being assessed by monitoring levels of pExp5A pDNA and eIF5A siRNA in the blood and bone marrow by RT-qPCR. Immunogenicity of SNS01-T is also being assessed in patient samples by monitoring induction of pro-inflammatory cytokines and antibodies to SNS01-T. It is expected that results from the first group of patients will be presented.Table 1:Dose Escalation Schedule by GroupGroupNumber of PatientspExp5A pDNA DoseeIF5A siRNA DoseTotal Nucleic Acid Dose (SNS01-T)130.0083 mg/kg0.0042 mg/kg0.0125 mg/kg230.0333 mg/kg0.0167 mg/kg0.05 mg/kg330.1333 mg/kg0.0667 mg/kg0.2 mg/kg43–60.25 mg/kg0.125 mg/kg0.375 mg/kg
Disclosures:
Dondero: Senesco Technologies Inc.: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Thompson:Senesco Technologies Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
Multiple Myeloma in Horses, Dogs and Cats: A Comparative Review Focused on Clinical Signs and Pathogenesis