“One step further through precise gene-targeting”

siRNAgen Therapeutics Corporation focuses on the discovery and development of RNAi therapeutics through its own innovative SAMiRNA™ tech to maximize efficacy and minimize adverse effect

Our flagship drug: SAMiRNA-AREG (amphisiran)

*Amphisiran (SAMiRNA-AREG): is oligonucleotide DNA/RNA heteroduplex nanoparticles with hydrophilic PEG and hydrophobic hydrocarbon conjugation tail at each end targeting human amphiregulin-mRNA.
Reduced Areg (Amphiregulin) cellular synthesis leads to inhibition not only of EGFR cascade & TGF-β downstream crosstalk cellular pathway, but also juxtacrine (cell to cell) proliferative signaling pathway, resulting in anti-fibrotic & anti-proliferative effects.

M.O.A (Anti-fibrotic and Anti-proliferative)

Anti-fibrotics: Amphisiran™ knocks down AREG(amphiregulin), which stimulates fibroblast proliferation and myofibroblast trasformation not only from the surface EGFR but also downstream pathways.

Fig1. AR (amphiregulin) stimulates fibroblast proliferation and differentiation leading to fibrosis.
Korean K Intern Med. 2014;29(3):281-90 (Fig.2)

Amphiregulin (AREG) is a ligand of the epidermal growth factor receptor (EGFR), a widely expressed transmembrane tyrosine kinase, and a paracrine substance, with which engage in juxtacrine signaling synthesized as a membrane-anchored precursor protein. Alternatively, after proteolytic processing by cell membrane proteases, mainly TACE/ADAM17, AREG is secreted and behaves as an autocrine or paracrine factor. AREG gene expression and release is induced by a plethora of stimuli including inflammatory lipids, cytokines, hormones, growth factors and xenobiotics. Through EGFR binding AREG activates major intracellular signaling cascades governing cell survival, proliferation and motility. Physiologically, AREG plays an important role in the development and maturation of mammary glands, bone tissue and oocytes. Chronic elevation of AREG expression is increasingly associated with different pathological conditions, mostly of inflammatory and/or neoplastic nature.

Anti-fibrotics

Skin

Scarring

  • Is continuous overgrowth of collagen in the dermis resulting from on-going chronic wound healing process beyond repairing consequently results in scar formation in extreme cases-hypertrophic scars or keloids
  • Prevention or reduction of scar is a therapeutic challenge of unmet medical need

Market Potential

  • Global Scar Treatment Market is expected to reach USD 37.6 Billion by 2024 : VynZ Research

Target gene

Amphiregulin

Development Status

  • IND submission expected in 2021

Lung

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterized by worsening lung function and dyspnea

Market potential

  • The global idiopathic pulmonary fibrosis treatment market is expected to reach over 4.2 USD billion by 2026 : Source: Acumen Research and Consulting

Target gene

amphiregulin

Development state

  • Preclinical study on animal model finished in 2019 IND submission in 2021

RIPF

Radiation-induced pulmonary fibrosis (RIPF) is a side effect of lung damage caused by radiation therapy for lung cancer and breast cancer. Pathological characterization of RIPF includes excessive accumulation of extracellular matrix and myofibroblasts with scar formation, leading to disruption of pulmonary function.

Market potential

  • Medication for RIPF would improve breast and lung cancer therapy.
  • The global breast cancer and non-small cell lung cancer therapeutics market is estimated to reach USD 38.4 billion by 2025 and USD 22.4 Billion by 2027, respectively (Source: Grand View Research, Inc. and iHealthcareAnalyst, Inc.).

Target gene

amphiregulin

Development state

  • IND submission is scheduled in 2021

M.O.A of Amphisiran in mitigating ARDS development from COVID-19 induced ALI.

Amphisiran can inhibit fibroblast activation, myofibroblast differentiation, provisional ECM accumulation, and inflammatory hypersecretion in fibro-proliferative phase of ARDS by knocking down cellular Amphiregulin synthesis.

Acute respiratory distress syndrome (ARDS) represents a severe and rapid form of microvascular lung injury. Traditionally, ARDS is divided into three stages in which an initial inflammatory phase is followed by fibroproliferation, during which mesenchymal cells, in particular interstitial fibroblasts, migrate, replicate, and secrete extracellular matrix proteins such as collagen. Unabated, this process can lead to established interstitial and intra alveolar fibrosis, the final phase.

The fibroproliferative phase of acute respiratory distress syndrome (ARDS) has traditionally been regarded as a late event but recent studies that suggest fibroproliferation is an early response to lung injury and an important therapeutic target. The fibroblast is considered to be the major cell responsible for collagen synthesis in the lung and there is now considerable evidence to suggest that soluble mediators play a key role in fibroblast activation. (Fibroproliferation Occurs Early in the Acute Respiratory Distress Syndrome and Impacts on Outcome. American Journal of Respiratory and Critical Care Medicine. https://doi.org/10.1164/ajrccm.162.5.2001061) These include classical growth factors such as transforming growth factor-β1and proinflammatory cytokines, which had been reduced greatly by amphisiran administration in our preclinical studies.

Kidney

DKD (Diabetic Kidney Disease)

Diabetic Kidney Disease (Diabetic nephropathy) is kidney damage that results from having diabetes. Having high blood glucose levels due to diabetes can damage the part of the kidneys that filters your blood. The damaged filter becomes 'leaky' and lets protein into your urine.

Market potential

  • The global diabetic nephropathy market size will grow USD 1.75 billion during 2018-2022 :source: technavio

Target gene

amphiregulin

Development state

  • animal model study ongoing in 2020
  • Phase I will be commencing in 2020

Liver

Nonalcoholic steatohepatitis (NASH) is liver inflammation and damage caused by a buildup of fat in the liver and can get worse and cause scarring of the liver, which leads to cirrhosis. But the disease doesn't always get worse.

Market potential

  • The global Non-Alcoholic Steatohepatitis (NASH) drugs market is expected to reach US$61.60 billion in 2028, growing at a CAGR of 39.36%, for the duration spanning 2018-2028.Aug 29, 2019 : NEWS PROVIDED BY Research and Markets Aug 29, 2019

Target gene

amphiregulin

Development state

  • animal model study ongoing in 2020
  • IND submission scheduled in 2021
  • Uro-genital

    Senile Erectile Dysfunction

  • Heart

    Reactive fibrotic Heart Failure

  • Autoimmune

    Psoriasis

    Atopy

  • Anti-proliferative

    Amphisiran is effectively knocks down amphiregulin (which plays major role in cancer cell invasion and proliferation through cell to cell exosomal release) synthesis at mRNA level.

    Fig 2. A (amphiregulin) contained in EGFR-exosome might contribute to diverse cancer & inflammation phenomena.
    Fig 3. Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway.
    Taverna S1,2, Pucci M1, Giallombardo M1, Di Be. Sci Rep. 2017 Jun 9;7(1):3170

    Anti Cancer

    RIPF

    Radiation-induced pulmonary fibrosis (RIPF) is a side effect of lung damage caused by radiation therapy for lung cancer and breast cancer. Pathological characterization of RIPF includes excessive accumulation of extracellular matrix and myofibroblasts with scar formation, leading to disruption of pulmonary function.

    Market potential

    • Medication for RIPF would improve breast and lung cancer therapy.
    • The global breast cancer and non-small cell lung cancer therapeutics market is estimated to reach USD 38.4 billion by 2025 and USD 22.4 Billion by 2027, respectively (Source: Grand View Research, Inc. and iHealthcareAnalyst, Inc.).

    Target gene

    amphiregulin

    Development state

    • IND submission is scheduled in 2021

    Cancer

    Anti-proliferative effect of SAMiRNA-Areg will be explored on monoclonal antibody chemo-drug resistant, co-administering and mitigating acquired resistance and hostile TME.

    Development Status

    • finished human proof of concept (hPOC) in 2020 IIT will be commencing in late 2021

    Characteristics

    SAMiRNA-Areg showed superb anti-fibrotic effect in various animal models and extremely low toxicity without any off-target effects in GLP tox study.

    Additionally, it has good potential to be an anti-proliferative for cancer therapy as a sole and/or adjuvant agent, given the facts that amphiregulin exosomes increase cancer cell invasion and Areg (amphiregulin) also present in the tumor microenvironment (TME), which contributes to drug resistance.

    Given the facts that current monoclonal antibody (anti-proliferative) cancer drugs, eg Herceptin, have been not only shown to cause serious adverse effects, but also to develop drug resistance after continuous administration, by which cause alternative and downstream pathway potentiation, SAMiRNA-Areg is a promising substitute for this kind of cancer drugs in terms of inhibiting those pathways and “body-friendly’ nature of SAMiRNA (do not block our body’s own growth factor receptor forcefully, instead precisely targeting problematic protein synthesis at DNA level).

    AREG plays key role in fibrosis by stimulating myofibroblast differentiation and proliferation. It also involved in the cancer metastasis. SAMiRNA-AREG selectively delivered to inflamed fibrotic tissue and/or cancer tissue and knock down AREG mRNA more than 50% without innate immune stimulation.

    Amphisiran is self-micelle-forming nanoparticle being composed of a passenger strand with hydrophobic and hydrophilic conjugate-ligands at each end, and phosphorylated guide strand in the middle. SAMiRNA spontaneously forms nanoparticle by hydrophobic ligand-interaction and also spontaneously being cleaved by hydrophobic ligand at cell-entering.

    Amphisiran (FIC amphiregulin-targeting siRNA drug), which has anti-fibrotic and anti-proliferative effect with minimal adverse effect, is entering phase I stage with indication for IPF in 2020 and phase II study will be commencing in 2021 for the indication of RIPF (Radio Induced Pulmonary Fibrosis) aiming “orphan” drug designation from FDA after showing far better efficacy and toxicity profile than any other current (or under-developing) drugs in our pre-clinical studies including IPF, CKD, NASH.

    We are expecting that SAMiRNA-AREG not only mitigate RIPF, but also prevent cancer- metastasis and -drug resistance as well. Thus, most of cancer patients will get benefits from it.

    Summary of prioritized Indications

    Indications Key fx
    AB-01 Hypertrophied scar inc Keloid *20B USD market
    AB-02 Acne scar/Enlg pores *New market (Anti-ageing)
    AB-03 ILD inc IPF & RIPF * “Orphan” for IPF & RIPF
    AB-04 RIF (connective tissue) *FIC(First in class)
    Mandatory tx before Radio Therapy
    Indications Key fx
    AB-05 DNP(newly developed glomerular capillary hypertension and hyperfiltration among diabetic nephropathy with high Areg pts). *FIC for prevention of CKD (Slow down GFB destruction).
    *Companion S/Urinary Areg Diagnostics
    Urine Areg = prognostic to CKD & monitoring Tx response
    AB-06 NASH *Hindering fibrotic transformation of HSC
    AB-07 ARDS *”Breakthrough” for ARDS odds reduction of 28D mortality in ICU
    AB-08 Breast Cancer (HER2+) with high Areg *50% Br Ca pts show high Areg Will increase Herceptin sale X3(suscep, TME & resistance)
    AB-09 NSCLC *Prevention of bony mets & Reduce A/E

    Development Plan

    Review summary of Key journal regarding amphiregulin and cancer.

    Anti-proliferative

    • Amphiregulin Exosomes Increase Cancer Cell Invasion
      • CellPress, James N Higginbotham, Michelle Demory Beckler, Jonathan D.Gephart
      • https://doi.org/10.1016/j.cub.2011.03.043
    • Amphiregulin Is a Critical Downstream Effector of Estrogen Signaling in ERα-Positive Breast Cancer.
      • Cancer Res. 2015 Nov 15;75(22):4830-8. doi: 10.1158/0008-5472.CAN-15-0709. Epub 2015 Nov 2.
      • Peterson EA1, Jenkins EC1, Lofgren KA2, Chandiramani N1, Liu H1, Aranda E1, Barnett M1, Kenny PA3
    • An antibody to amphiregulin, an abundant growth factor in patients' fluids, inhibits ovarian tumors.
      • Oncogene. 2016 Jan 28;35(4):438-47. doi: 10.1038/onc.2015.93. Epub 2015 Apr 27.
      • Carvalho S1, Lindzen M1, Lauriola M1, Shirazi N1, Sinha S1, Abdul-Hai A2, Levanon K

    TME

    • Recent studies revealed that AREG is also present in the tumor microenvironment (TME) and contributes to therapeutic resistance.
      • Amphiregulin in Cancer: New Insights for Translational Medicine. Trends Cancer. 2016 Mar;2(3):111-113. Xu Q1, Chiao P2, Sun Y3.

    Acquired resist

    • Amphiregulin as a Novel Resistance Factor for Amrubicin in Lung Cancer Cells.
      • Anticancer Res. 2017 May;37(5):2225-2231.Tokunaga S1, Nagano T2, Kobayashi K1, Katsurada M1, Nakata K1, Yamamoto M1.
    • Amphiregulin confers trastuzumab resistance via AKT and ERK activation in HER2-positive breast cancer.
      • Kim JW, Kim DK, Min A, Lee KH, Nam HJ, Kim JH, Kim JS, Kim TY, Im SA, Park IA.
      • J Cancer Res Clin Oncol. 2016 Jan;142(1):157-65. doi: 10.1007/s00432-015-2012-4. Epub 2015 Jul 21