Press Release
April 11, 2024
Dear All
University of Yamanashi
Alivexis, Inc.
Joint Research on Novel Anti-Allergic Disease Drug Candidate Published byAlivexis, Inc. and University of Yamanashi

Alivexis, Inc., and the University of Yamanashi announce the publication of a joint research article
entitled “A highly selective KIT inhibitor MOD000001 suppresses IgE-mediated mast cell activation”,
published in JACI: Global, an open-access online journal from the American Association of Allergy,
Asthma and Immunology (AAAAI).
The research, led by Associate Professor Yuki Nakamura and Professor Atsuhito Nakao of theDepartment of Immunology, Graduate School of Medicine, University of Yamanashi, incollaboration with Alivexis, was performed on a new small molecule compound, MOD000001, toinvestigate its use as a treatment for allergic diseases, including hay fever, asthma, and chronic
hives. This compound targets a cellular receptor molecule called KIT, thereby suppressing theactivation and reducing the number of mast cells, which are the root cause of allergy symptoms. In
the published study, administration of MOD000001 not only suppressed mast cell activation butalso reduced the survival of mouse and human primary mast cells and alleviated symptoms in amouse model of skin allergic reaction. Currently, Alivexis is further optimizing similar compounds
for early clinical application as an oral anti-allergy medication. The paper was published in JACI:
Global on April, 2nd.
Summary
Background:
Allergic diseases such as hay fever (allergic rhinitis), asthma, food allergies, atopic dermatitis, andhives (urticaria) occur when a particular type of immune cell known as mast cells are activated byallergens in the environment. Mast cells then release molecules including histamine, triggering
inflammation, itching, and other allergic symptoms. Existing anti-allergic drugs such as
antihistamines and corticosteroids target and inhibit the reaction against these molecules. However,these treatments only provide symptomatic relief because they do not directly inhibit the activationof mast cells by allergens, thus allergic symptoms return quickly after stopping medication.
Mast cell activity and survival are regulated by a receptor molecule called KIT, which is expressedon the surface of mast cells. The research groups at University of Yamanashi and Alivexis
hypothesized that specific suppression of KIT function would reduce the activity and number ofmast cells in the body, potentially leading to the development of a new anti-allergic medication.
Since the number of mast cells are increased in the nasal mucosa, bronchi, skin, and intestines ofpatients with allergic diseases, reducing the number of mast cells in those tissues could achievestrong and long-lasting relief of allergy symptoms. Although several KIT inhibitors have beendeveloped to date for the treatment of diseases such as leukemia and cancer, these drugs are nothighly specific to KIT and come with many side effects.

Results of this study:
The research group used a proprietary drug discovery platform, which includes molecular dynamics
simulations using state-of-the-art supercomputers, to accurately and rapidly perform compound
selection through predicting binding affinity of the compounds to target proteins, and subsequently
identified several small molecule compounds that selectively bind to the KIT receptor. Through invitro experiments, they further identified MOD000001 as a strong selective inhibitor of KIT enzyme
activity, which plays an important role in the activity and the survival of mast cells.
Further studies using mouse bone marrow-derived mast cells and peripheral blood hematopoietic
stem cell-derived human mast cells showed that MOD000001 significantly and specifically inhibitedthe activation and the survival of mast cells induced by SCF (a molecule that binds to and activates
the KIT receptor) and allergens, as well as the migration activity of mast cells. In addition, studies
using a mouse model of chronic urticaria showed that oral administration of MOD000001
significantly alleviated allergy-induced urticaria. Furthermore, long-term oral administration of
MOD000001 was confirmed to reduce the number of mast cells in mouse skin. No adverse effects
were observed in mice treated with MOD000001 even for a long period of time.
Significance of this study’s results:
Until now, treatments for allergic diseases have mainly focused on the mediator molecules ofallergic reaction produced by immune cells such as mast cells, rather than directly targeting mastcells themselves. Therefore, MOD000001 can be considered as a compound which tackles allergy
in a new and distinct way. Since this compound has higher specificity for KIT than currently available
KIT inhibitors, it is expected to have a better safety profile. Additionally, since MOD000001 affects
the mast cell survival mechanism, the number of mast cells in the body should decrease, resulting
in a more potent and sustained reduction in allergic reactions, anti-allergic effects in patients who
do not respond to existing drugs, and reduction in the dosage of existing anti-allergy drugs.
Alivexis, Inc. has already identified and is evaluating optimized oral KIT-specific inhibitors basedon MOD000001, aiming for early clinical application as anti-allergy drugs. In addition to deliveringa new allergy therapy, they are also considering the possible application to other diseases thatinvolve mast cells, such as cancer, arteriosclerosis, fibrosis and others.
[Publication Information]
JACI: Global (Open access journal of the American Academy of Allergy, Asthma & Immunology)[Title]A highly selective KIT inhibitor MOD000001 suppresses IgE-mediated mast cell activation[Authors]
Yuki Nakamura, PhD,1 Takeo Urakami, PhD,2 Kayoko Ishimaru,1Nguyen Quoc Vuong Tran, PhD,1 Takafumi Shimizu, MS,2 William Sinko, PhD,2 Taisuke Takahashi,PhD,2 Sivapriya Marappan, PhD,3 Kishore Narayanan, PhD,3 Ramulu Poddutoori, PhD,3,6 YohTerada, PhD,2 and Atsuhito Nakao, MD, PhD.1,4,5
1. Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
2. Alivexis, Inc., Tokyo, Japan.
3. Aurigene Oncology Ltd, Bangalore, India.
4. Yamanashi GLIA Center, University of Yamanashi, Yamanashi, Japan.
5. Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan
6. Currently affiliated with Syngene International Limited, Bangalore, India

[DOI] https://doi.org/10.1016/j.jacig.2024.100249[Reference diagram]

Novel highly selective KIT inhibitor
MOD000001

Long-term p.o. for 7wks

VehicleMOD000001

PCA reaction
Hair

Hair

Surface

Surface

Epidermis

Epidermis

Mast cell
Dermis

DermisSubcutaneous fat

Subcutaneous fat

Mast cell numbers

Thenovel
KIT-specificinhibitor
MOD000001
strongly suppresses
allergic reactions even with a single oral
dose. When orally administered to micefor 7 weeks, as shown in the figure, thenumber of mast cells in the skinsignificantly decreases. Furthermore,
the PCA reaction (a mouse model ofhives, which evaluates the intensity ofplasma leakage (symptoms) caused byallergen-induced mast cell activation bymeasuring the amount of blue dyeleakage administered intravenously
prior to mast cell activation. A darker
shade of blue indicates stronger
symptoms) is alleviated.

<Contact Information for R&D>
Department of Immunology, Faculty of Medicine,
University of Yamanashi
Professor

Atsuhito Nakao

TEL ：+81-55-273-9542
E-mail：anakao@yamanashi.ac.jp
Alivexis, Inc. Research and Development
TEL ：+81-3-6868-4547
E-mail：info@alivexis.com<Contact Information for public information>
Alivexis, Inc. Business Administration
TEL ：+81-3-6868-4547
E-mail：info@alivexis.com