IT-139: A Novel GRP78 Inhibitor


✔  Clinically-validated with manageable toxicity
 

✔  Targets critical proliferation and survival pathway
 

✔  Reduces resistance to other anti-cancer agents


STRATEGIC OVERVIEW


  • Moderate-risk, high-reward development program
  • Clinical-stage with favorable safety and toxicity profile
  • Potential synergy with wide variety of existing agents
    • Platinum-based Antineoplastics
      • Platinol® (cisplatin or CDDP)
      • Paraplatin® (carboplatin)
      • Eloxatin® (oxaliplatin)
    • PD-1 Checkpoint Inhibitors
      • Merck's Keytruda® (pembrolizumab)
      • BMS's Opdivo® (nivolumab)
    • CTLA-4 Checkpoint Inhibitors
      • BMS's Yervoy® (ipilimumab)
    • Chemotherapy
      • Gemzar® (gemcitabine)
      • Taxotere® (docetaxel)
      • Taxol® (paclitaxel)
      • Adriamycin® (doxorubicin)
      • Adrucil® (fluorouracil or 5-FU)
      • Tarceva® (erlotonib)
      • Nexavar® (sorafenib)
      • Afinitor® (everolimus)

GRP78


Role of er chaperones and upr in tumorigenesis and anticancer therapies

  1. The Endoplasmic Reticulum (ER), shown below, is a highly dynamic and complex organelle that plays a vital role in lipid synthesis, calcium storage, protein folding and processing
  2. Due to poor vascularization and resulting hypoxia, glucose deprivation, and low pH, the tumor microenvironment triggers ER stress and the accumulation of unfolded or misfolded proteins
  3. This accumulation results in the Unfolded Protein Response (UPR), including up-regulation of pro-survival GRP78
  4. IT-139, an ‘anti-austerity’ therapy, inhibits GRP78, interrupting this pro-survival response, resulting in an apoptotic cascade in stressed cells (but not unstressed cells)
 

Critical Role of GRP78 in the UPR

  • If one thinks of the ER as a factory, GRP78 are forklifts (‘chaperones’) that manipulate (‘fold’) and move goods (‘proteins’) around
  • ER stress triggers the UPR, causing additional GRP78 to besynthesized and thus allowing a greater volume of proteins to be (re)folded and transported
  • Inhibiting GRP78 effectively blocks the signal that ‘more forklifts are necessary’
  • Without additional GRP78, unfolded or misfolded proteins rapidly accumulate in the ER, quickly resulting in an apoptotic cascade (cell death
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About glucose-regulated protein 78kDa (GRP78)

  • Master regulator of endoplasmic reticulum (ER) stress
    • Critical proliferation, survival and resistance pathway
    • Overexpressed in cancer cells relative to normal cells due to hostile conditions in the tumor microenvironment
  • Inhibiting GRP78 should increase the efficacy and safety of existing anti-cancer drugs
 

er stress / grp78 as a critical target

 

Mechanism of action


DRUG PRODUCT


IT-139

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  • IT-139 is a lyophilized powder of sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)], administered via infusion
  • API synthesis and drug product formulation utilize high-yield, scalable processes

INTELLECTUAL PROPERTY


  • Robust patent protection
    • 16 Families
    • 42 Active patents
    • 18 Pending patents

Key Patents


PRECLINICAL DATA


It-139's Effect on Protein Levels Limited to Cancer Cells

 

IT-139 Inhibits Metastasis

 

IT-139 Decreases Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma

 

IT-139 Exhibits Profound Synergy in combination with Cisplatin and Oxaliplatin


CLINICAL DATA


IT-139-01 Clinical study in solid tumors

 

Phase 1 Safety

 

Phase 1 Results in Colorectal Cancer (CRC)


DEVELOPMENT STRATEGY


Target Indications

 

About Metastatic Melanoma

  • Melanoma is less common, but more aggressive and deadlier than other forms of skin cancer, with more than 232K people worldwide diagnosed each year and a steadily increasing incidence over the past 30 years
  • 76K patients diagnosed and 10K deaths annually in the U.S.
  • A V600 mutation of the BRAF protein occurs in approximately half of melanomas
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  • When diagnosed early, melanoma is generally curable, but metastatic melanoma has a poor prognosis
  • 5-yr survival rate of only 17% for metastatic melanoma
  • Eligible for both Breakthrough Therapy and Orphan Drug Designations
 

IT-139-02 Clinical Study in Solid Tumors


LICENSING OPPORTUNITIES


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  • Seeking development and commercialization partners with the capital and expertise to advance development in both core and non-core indications for IT-139
    • Phase 2 results in Metastatic Melanoma expected in 2H18
  • Open to discuss:
    • Exploratory / pilot studies in combination with existing agents
    • Worldwide license by indication
    • Geographic license by indication

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  • Pancreatic Cancer
  • Colorectal Cancer
  • Lung Cancer
  • Osteosarcoma
  • Gastroesophageal Cancer
  • Breast Cancer
  • Prostate Cancer
  • Liver Cancer
  • Other Solid Tumors

Licensing Contact

E. Russell McAllister

Chief Financial Officer
russell.mcallister@intezyne.com

O: 813.910.2120
C: 415.794.2686