December 24, 2019

BrightPath Concludes Agreements with Osaka University,BIKEN Foundation and Teikyo University for
Development of TLR9 Agonist Lipid-Nucleic Acid as Immuno-stimulator
Tokyo, December 24, 2019 — BrightPath Biotherapeutics Co., Ltd. (an immuno-oncologycompany) has concluded the following agreements with Osaka University, the Research
Foundation for Microbial Diseases of Osaka University (“BIKEN Foundation”) and Teikyo
University, aiming at the clinical development of a TLR9 agonist lipid-nucleic acid drug as animmuno-stimulator with anti-tumor effects (the “Drug”).
•Joint R&D agreement for development of a process for manufacturing the Drug,
between BrightPath and Osaka University•Agreement for the grant of license for manufacturing the Drug, among BrightPath,
BIKEN Foundation, Osaka University and Teikyo University

While using immune checkpoint inhibitors, as typified by PD-1 blockade, is becoming apromising option in cancer treatment, their response rates still remain unsatisfactory, except
in cases of specific types of cancer. Immune checkpoint inhibitors are drugs that help “releasethe brakes” on immune cells capable of attacking cancer cells. However, this function cannot
produce sufficient anti-tumor effects by merely releasing the brakes when tumors are
immunologically silent (“cold tumors”). The term “cold tumors” refers to a condition where
there are no immune cells within the tumor or where immune cells are not ready to attack
cancer cells while they exist in the tumor. This is regarded as a major factor for low response
rates of immune checkpoint inhibitors. A big challenge in cancer immunotherapies is to makecold tumors hot, i.e., to infiltrate immune cells into tumors and enable them to attack cancer
cells. To this end, researchers and pharmaceutical companies around the world arestruggling to make progress through various approaches.
TLR9 (toll-like receptor 9) is a receptor protein expressed on endosomes in specific types ofcells of the innate immune system, and has the ability to detect viruses and other foreign
invaders. In the context of cancer treatment, TLR9 agonists are considered to stimulate
immune responses by triggering signaling through cytokines produced from cells of theinnate immune system and helping activate T-cells to attack cancer cells (in other words, toconvert “cold” tumors into “hot” ones). In the US, TLR9 agonists have already been approved

for use as hepatitis B vaccines. TLR9 agonists as a cancer therapeutic drug are currently
under clinical development mostly in the US and are demonstrating certain clinical efficacy
in their early phase trials. However, most of those TLR9 agonists are subject to a restrictionthat requires direct administration into tumor cells, resulting from the nature of their drug
formulation. This restriction poses some big challenges. First, TLR9 agonists are applicableand effective only for accessible cancer. Second, TLR9 agonists cannot be directly
administered to visually undetectable tumors (for example, small metastases may beoverlooked). Third, invasive procedures are required to administer TLR9 agonists into theaffected area, which increases the physical burden on the patient (resulting in limitation on
the number of administrations).
Dr. Taiki Aoshi (*1), Dr. Takashi Matsuzaki (*2), Dr. Shohei Koyama (*3), Dr. Ryo Suzuki (*4)
and others have overcome these challenges and succeeded in developing an intravenously
administered drug. With a focus on nucleic acids, which are the active ingredient of TLR9agonists, they propose to embed those nucleic acids in lipids. This can enhance the stabilityof TLR9 agonists in the patient’s blood and make it unnecessary to limit the number ofadministrations, unlike the case of direct administration to tumors.
Under circumstances where clinical concepts of TLR9 agonists are to be demonstrated, webelieve that a superior format for delivery of TLR9 agonists adopted for the Drug willassuredly bring differentiation to the Drug, even with lower development risks.
BrightPath is committed to pushing this development project forward, aiming to launch aclinical trial for the Drug in fiscal 2021.
*1: Associate Professor, Vaccine Dynamics Project, Research Institute for Microbial Diseases,Osaka University*2: Specially Appointed Associate Professor, Cardiovascular Medicine, Graduate School ofMedicine, Osaka University*3: Assistant Professor, Respiratory Medicine and Clinical Immunology, Graduate School ofMedicine, Osaka University*4: Professor, Laboratory of Drug and Gene Delivery Research, Faculty of Pharma-Science,
Teikyo University

BrightPath
BrightPath is a clinical stage biopharmaceutical company focused on the development ofnovel cancer immunotherapies able to transform cancer treatment for progressive orrefractory cancers that cannot be treated using conventional standard therapies. In addition
to its cancer peptide vaccines currently in clinical trials in the United States, BrightPath isactively involved in developing cell therapies, immunomodulatory antibodies and new drugs
targeted toward cancer-specific neoantigens.

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