RIBOZYME AND OMICS

PIPELINE

RZ-001

Hepatocellular Carcinoma(HCC)

Global market growth is expected from USD 650 m. in 2018 to USD 5.6 bn. In 2028
Market Size (hepatocellular carcinoma)
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Global market is growing at around 20% annually

Market for targeted therapies
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The market share of sorafenib is expected to continue to decline from 2020

Market for Immunotherapies
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The market share of various anti-cancer drugs is expected to increase

Medical unmet needs
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    High mortality rate
    Major cause of death, 50% of the cases diagnosed: Advanced HCC (Stage III or IV, Vascular invasion)
    90% or more advanced HCC patients survived for less than a year have liver cirrhosis.
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    Lack of effective therapies
    First line targeted therapy : Sorafenib, Lenvatinib, Avastin+Tecentriq
    Second line therapy : Regorafenib, Nivolumab, Cabozantinib
    Low survival benefit (a few months), side effects, resistance induction, low cure rates, liver failure, metastasis
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    In need of new therapies
    Therapies for alleviation of liver cirrhosis and minimization of side effects on non-cancerous liver cells
    Liver cancer specific gene therapy for failure in standard treatments
    Therapies effective on carcinomas with different genetic characteristics
Advanced HCC therapies and side effects
Drug Efficacy / Side effect
Sorafenib

Cure rate: 0%, Partial response rate: 2%, 2-3 months survival difference compared to control group

Side effects: hand-foot syndrome, diarrhea, hypertension, gastrointestinal perforation, bleeding, etc.
Regorafenib (2017)

Second line therapy after Sorafenib treatment

Cure response: 11%, Response rate: 79% or more, low survival benefit, resistance induction
Nivolumab (2017)

Second line therapy after Sorafenib treatment

Cure response: 19%, immune-mediated side effects
Lenvatinib (2018)

New first line therapy

Hypertension, diarrhea, hepatic encephalopathy, Lack of proper second line therapy
Development of innovative therapies with higher cure response and survival rate and fewer side effects / combinantion treatment
Telomerase – targeted molecule for liver cancer treatment
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Useful targeted molecule for developing liver cancer therapies : hTERT

hTERT
Telomerase
Ribonucleoprotein enzyme that maintains the protective telomere structures (telomeric repeat (TTAGGG)) in eukaryotic chromosome
Selective expression in highly proliferative cells (bone marrow stem cells, germ cells…) and 90% or more of cancer cells Activated in most stages of liver cancer
Regulation of gene expression involved in cancer cell growth & progression
Related with drug-resistance through telomere-(in)dependent manner
TERT expression: Prognostic factor for TPP and OS after TACE (Cancers 2021)
TERT promoter mutation

Activated in the majority of HCCs, most frequently with TERT promoter mutation, although variable among HCC.

Nat. Commun. 2013

Relapse Rate and Survival Rate Prognostic Factors

TERT overexpression is significant prognostic factor for late IHR in HCC treated with curative resection and survival duration.

Sci. Rep. 2017

Telomerase – Limitations of existing targeted cancer therapy approaches
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In need of multifunctional TERT-targeted therapy due to the limitation of TERT inhibition
In need of HCC-specific therapies that can minimize dysfunction of normal liver cell
Advantages of technology
  • Improved HCC specificity

    HCC-selective expression of therapeutic RNA through specific replacement of hTERT RNA with therapeutic RNA

  • Multiple antitumor effects

    Removal of cancer cell hTERT RNA and simultaneous expression of therapeutic RNA

  • hTERT targeting

    Effective application to heterogenous cancer cells through targeting hTERT expressed in 80 ~ 90% of HCC

  • Improved anticancer efficacy

    Use of HSVtk as therapeutic gene: Cnacer regression, bystander effect, and cancer immunity induction

  • Indication expansion

    Indication expansion for various carcinomas. Modular engineering
    Application to various diseases

RNA replacement enzyme vector-based cancer therapy (1st indication: Advanced HCC, RZ-001)
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Adenovirus
ds linear DNA virus
Not require host replication / integration for expression
Infects nearly all mammali an cells at all stages of the cell cycle
High infection efficiency