ISSN 2644-2345
MARCH - 2022

APAC SPECIAL

STARTUPCITY.COM

JAPANESESTARTUPSEDITION

CHORDIA USES RNA DEREGULATIONSTRESS TO TREAT CANCERS

Normal Cells
C h orCancer Cells
with RNA
Deregulation Stressdianeeli
Pipeline
Chordia Pip

Cell Survival

Cell DeathRNA DEREGULATION STRESS,NEW HALLMARKS OF CANCER

A Better Tomorrow ThroughInnovative Therapy

$15

COV

ERWE AIM TO DEVELOP
LIFE-CHANGINGTREATMENTS
FOR CANCER BY
GENERATING SMALLMOLECULE MEDICINESTHAT PREVENT
OR MODIFY RNA
DEREGULATION

Dr. Daisuke Morishita,

CTO of Chordia TherapeuticsSTO

R

YtOP

JAPANESE
Startups in APAC - 2022

CHORDIA

THERAPEUTICS
INC.

ATomorrow
BetterThroughInnovativeTherapy

Two decades ago, Douglas Hanahan
and Robert Weinberg publishedtheir influential review: The
Hallmarks of Cancer–a study thatproved to be groundbreaking inunderstanding cancer’s common
traits and the rational design and manufacturing ofdrugs. This review organized the complexities ofcancer into six major hallmarks: self-sufficiency ingrowth signals, insensitivity to anti-growth signals,
evading apoptosis, limitless replicative potential,
sustained angiogenesis, and tissue invasion andmetastasis. In addition to these original six hallmarks,scientists have since identified equally prevalent
hallmarks, referred to as stress phenotypes of cancer.
Although these cancer phenotypes are not responsiblefor initiating tumorigenesis, they are common
characteristics across several types of tumors. Now, anovel hallmark of cancer, RNA deregulation, has been
newly proposed as another indication of cancer within
this group of stress phenotypes. However, exploiting
and leveraging RNA deregulation in cancer therapy isuncharted territory for most drug manufacturers andpharmaceuticals. Chordia Therapeutics aims to bringthis technology into the limelight.
Driven by science and new-age research indeveloping the next generation of small-molecule
inhibitors for cancer treatment, Chordia Therapeutics
is a Japanese startup that has developed drugs that

WE ARE ADVANCING DRUG
DEVELOPMENT QUICKLYAND STEADILY BY MAKING
THE BEST USE OF THE
FLEXIBILITY OF A LEAN
ORGANIZATION, A BROAD
NETWORK OF EXPERIENCED
PROFESSIONALS, AND OUR
ACCUMULATED R&D WISDOMoverload RNA deregulation stress by changing RNA splicing
to initiate the death of cancer cells. The company’s innovations
are powered by the experience of its highly skilled teamthat is constantly developing First-in-Class small-molecule
anticancer drugs with modern mechanisms of action.

RNA Deregulation–a Novel Strategy for Cancer Therapy“We aim to develop life-changing treatments for cancer bygenerating small-molecule medicines that prevent or modify
RNA deregulation,” says Dr. Daisuke Morishita, CSO of Chordia
Therapeutics. RNA stress is caused by gene mutations of proteinsand the abnormality of molecules and nucleic acid sequences
brought about by enzyme inactivity. The Chordia pipeline is built
on the team’s expertise in RNA deregulation.
The team is developing pipelines that target splicing (CLKinhibitors), transcription (CDK12 inhibitors), tRNA recruitment(GCN2 inhibitors), RNA degradation (undisclosed information)and generate aberrant RNA that creates additional stress incancer cells. Additionally, Chordia collaborates with academic
researchers to analyze innovative next-generation sequencing
and gene-editing systems. Proactive research allows the team tothoroughly understand neoplastic disease states involving RNA
deregulation, expediently drive the discovery of new therapeutictargets, and better define patient selection strategies.

Drugs that Indirectly Eliminate Cancer Cells
Currently, no FDA-approved drugs inhibit transcription, splicing,degradation, or tRNA recruitment, allowing Chordia’s assets tobecome first-in-class drugs. First-in-class drug discovery may

prove to be highly effective in patients who have not responded
to previous therapies and help pharma organizations massively
increase their revenue since it is the only drug of its kind on themarket.
Chordia’s first-in-class drug, CTX-712, targets cancer cellswith a splicing factor (SF) mutation; this drug kills cancer cells
when they exhibit splicing vulnerability as a CLK inhibitor. CTX712 dephosphorylates serine and arginine-rich (SR) proteins
and induces, primarily, skipped exon types of splicing changes
which generate RNA deregulation stress. “Although CTX-712
has proven to be efficacious against a wide range of cancers in
non-clinical studies, we found that CTX-712 selectively inducescell death, particularly for cancers with genetic mutations inSplicing factors,” says Dr. Morishita. It is an orally available,
selective, small-molecule inhibitor of CDC-like kinase (CLK).
CTX-712 inhibits RNA splicing to generate RNA deregulationstress, which causes cancer cell death and tumor growth inhibitionin multiple preclinical models. In its preclinical research trials,
CTX-712 demonstrated prowess against a wide variety of cancer
cells and exhibited a good safety profile. The drug is now in its
Phase 1 trial, conducted at several research centers, including theNational Cancer Center Hospital in Japan, and has commenced
a new chapter in cancer therapy development as it is one of thefirst therapies to explore the targeting of RNA deregulation stress.
Chordia Therapeutics also engaged in a licensing agreement
for preclinical asset CTX-177, a selective small-molecule

inhibitor of mucosa associated lymphoidtissue lymphoma translocation protein
1 (MALT1), with Ono Pharmaceuticalin December 2020. Ono Pharmaceuticalis the developer of Opdivo and is aleading global oncology player, and theorganization’s interest in Chordia’s drug
development is a testament to the highvalue of Chordia’s assets. The contract
will fund the company JPY 3.3 billion at
the start of CTX-177’s Phase 1 clinical
trial, JPY 49.6 billion if subsequent certain
development and commercial milestones
are achieved.
Additional compounds in preclinicaldevelopment include CTX-439—a firstin-class inhibitor of cyclin-dependent
kinase12(CDK12)—andCRD1968099, which inhibits general control
nonderepressible 2 (GCN2). These orally
available compounds increase RNA
deregulation stress by interfering withRNA transcription and tRNA recruitment,
respectively, and have shown anticancer
effects in preclinical models as a single
reagent, as well as in a combination
therapy with other medications. Chordia isproceeding with these preclinical pipelines
and will soon begin clinical trials.

A Company Backed by
Decades of Pharma
ResearchBranching
outfrom
Takeda Pharmaceutical in
November 2017, Chordia
Therapeutics has quickly
matured into a clinicalstage biotech company
engaged in researching anddeveloping novel therapies
for cancers with high unmet
medical needs. “In orderto develop next-generation
anticancer drugs based on
definite scientific evidence,
we focused on RNA controlabnormalities found as
new features of cancer andobtained exclusive licensing rights fromTakeda for four non-clinical anticancer
drug candidate programs,” says Dr. Hiroshi
Miyake, CEO of Chordia, and Site Headof Oncology Research for Japan at Takeda
Pharmaceutical. Dr. Morishita also spent adecade at Takeda Pharmaceutical, working
on oncology therapeutic areas, especiallyin cancer-related RNA networks. During
his ten years as the representative ofindustry-academia collaboration programsin Takeda, Dr. Morishita took the leadin the drug discovery research of CTX177. He then translated and passed his
knowledge onto the teams at Chordia tocontinue this research.
Chordia’s expertise as an innovative
drug manufacturer stems from its
dedication to swift R&D derived fromquick decision-making and gratitude
to its external partners who support
the company. “We are advancing drug
development quickly and steadily bymaking the best use of the flexibilityof a lean organization, a broad networkof experienced professionals, and ouraccumulated R&D wisdom,” adds Dr.
Miyake.

A Vision for a Bright Future in Oncology
As the development of genetic analysis
technology and its application in medical

treatment advances, experts anticipate
that drug manufacturers and healthcare
practitioners will focus on previously
overlooked patient groups and diseases.
Compounding the knowledge gleaned
from these studies, organizations canthoroughly analyze the relationshipbetween gene mutations of patientsand their symptoms and will, inturn, optimize therapies. Chordia
Therapeutics is already several steps
ahead of contemporary organizations
since the team not only foresees thistrend but has also taken steps to actualize
it with their out-of-the-box research
on RNA deregulation. Furthermore, torealize personalized medicine, Chordia
strives to create efficient R&D processes
in collaboration with stakeholders invarious fields including universities,
othercompanies,
hospitals,
andinvestors. Staying true to the company’s
name (derived from the word ‘chord,’which signifies a pleasant sound whenmusical notes are played synchronously),
Chordia is harmonizing their energy andpassion for science with collaborators,
supporters, and stakeholders to enable
the discovery of innovative drugs.