Compelling preclinical proof

From safety to biodistribution to drug delivery; studies to date are robust and informative.

Safety

In an 18 day mouse study, the XACTTM group, dosed every three days for a total of 6 XACT administrations, demonstrated no observed toxicity.

Maximum tolerated dose study:

  • MTD = 70 mg/kg
  • The maximum tolerated dose was 180% higher than the dose used in the previous, successful safety study
  • XACT has potential use in a broad range of drug delivery applications – i.e. less potent drugs requiring a higher dose volume

Biodistribution

Biodistribution In Vivo

Biodistribution in vivo

  • XACT Initial clearance occurs through the kidney
  • Liver hypothesized to be primary site of later clearance
  • After culmination of the 21-day study, 55.3% of XACT is eliminated via urine and feces

Untargeted XACT biodistribution

  • Studies reveal varied uptake by organs, low, medium, high
  • All organs, except bone, demonstrate continued clearance
  • Observations of bone uptake have led us to expand our bone-borne disease application studies

Untargeted XACT Biodistribution

Biodistribution In Vitro

Biodistribution in vitro

XACT has demonstrated intracellular penetration within minutes. XACT distributes within the cell and naturally localizes in the nucleus, nucleoli, and the actin cytoskeleton. This repeated success has been demonstrated in human fibroblasts and MCF10A Breast Cancer cells.

Well tolerated in multiple cell lines

  • During in vitro efficacy tests, XACT is typically <0.1 mg/mL, cytotoxicity is not observed
  • Certain cell lines respond differentially to XACT offering further selectivity of action
  • Per ISO10993-5-2009:8.5.1, XACT has only slight (Grade 1) toxicity at relevant conc.

Well Tolerated in Multiple Cell Lines

Routes of Administration

Routes of administration

  • Changing routes of administration alters biodistribution
  • SubQ and IM offer lowest liver retention

Drug delivery

Proof of concept: efficacy

  • XACT+Doxorubicin is as potent against Raji B Lymphoma as Dox alone
  • All mice given XACT+Dox reach endpoint without clinical signs of cancer
  • 22% in the Dox arm die due to drug-induced toxicity and all mice in Dox arm have 10-20% weight loss

Proof of Concept: Efficacy

  • In a Solid Tumor Model of Metastasis, XACT enhances Dox performance
  • XACT enhances Dox ability to slow disease progression, limiting clinical indications
  • XACT decreases drug dosing/toxicity-associated weight loss

Proof of Concept: Efficacy

Intracellular Delivery of Peptide

Intracellular delivery of peptide

  • KLAKLAK is a pro-apoptotic peptide which is cell membrane impermeable
  • XACT binds to KLAKLAK with high affinity and transports it across the membrane where it is released triggering apoptosis
siRNA Delivery

siRNA delivery

  • XACT binds ~10-100 siRNA per tube
  • GFP-loaded XACT introduced to MM.1S cells strongly expressing GFP knockdown gene expression ~10%
  • Liposome-driven siRNA transport is comparable to XACT when used per manufacturer’s suggestion
Drug Loading

Drug loading

  • Small molecules may be loaded across the tube’s surfaces
  • Covalent or non-covalent binding to the exterior
  • Multiple functionalities available for targeting moiety attachment
Dosing

Dosing

  • Target and direct XACT to potentially lower size of effective dose and adverse events
  • Loading optimization accomplished by altering the chemistry of the tubes or enhancing the interactions between tube and cargo

Controlled release

Release Kinetics

Release kinetics

  • XACT has demonstrated controllable, sustained release over 7+ days utilizing GRAS recipients
  • Local release can be stimulated with MRI and NIR
pH Controlled Release

pH controlled release

  • Loading and release can be controlled with pH and temperature
  • Increased shelf stability
  • Enables control over unloading event
  • Optimized for different chemistries
Circulation Times

Circulation times

  • Blood circulatory times can be changed by altering surface chemistry
  • Modifying circulation time allows for control of system absorption
  • Customized chemistry to direct and retain XACT carrier where desired
Enhanced PK Performance

Enhanced PK performance

  • Standard of care, doxorubicin, can be enhanced using XACT-based delivery
  • Increases early plasma availability
  • Doubles the AUC vs. free drug
  • Stabilizes doxorubicin in the liver