Drug Development

Compound
Name
Target
Indication
Pre-
clinical
Clinical
phase
Partner
1
2a
2b
3
RBM-
007
FGF2
Wet Age-related
Macular
Degeneration
(wet AMD)
AJU pharma

RBM-007 for Wet Age-related Macular Degeneration (wet AMD)

Description/Summary

Age-related macular degeneration (AMD) causes damage to the macula located at the center of the retina of the eye and vision loss. The estimated number of patients with AMD is 196 million and is expected to increase to 288 million by 2040 in the world. AMD is a leading cause of blindness in people over the age of 60. There are 2 types of AMD: dry and wet. In wet AMD, new and abnormal blood vessels grow uncontrollably under the macula, causing swelling, bleeding and/or fibrosis. This usually leads to severe and rapid loss of vision.
Currently approved therapies for wet AMD, intravitreal injections of anti-VEGF drugs, have shown visual benefits for wet AMD patients. However, one-third of patients exhibit incomplete response to therapy, and over the extended management course can lose vision, with the formation of submacular fibrosis as one risk factor.
RBM-007 is a novel oligonucleotide-based aptamer with potent anti-FGF2 (fibroblast growth factor 2) activity. FGF2 is implicated in not only angiogenesis but also fibrosis in several diseases including wet AMD. The dual action of RBM-007 (anti-angiogenic and anti-scarring) holds promise as an additive or alternative therapy to anti-VEGF treatments for wet AMD.
RIBOMIC has conducted Phase 1 and 2 clinical trials of RBM-007 (umedaptanib pegol) in the US and successfully shown the safety and the POC (Proof of Concept) in wet AMD medication.

Publications

Dual therapeutic action of a neutralizing anti-FGF2 aptamer in bone diseases and bone cancer pain
Jin, L., Nonaka, Y., Miyakawa, S., Fujiwara, M., Nakamura, Y.
Mol Ther 24(11): 1974-1986 (2016). doi: 10.1038/mt.2016.158

Anti-angiogenic and anti-scarring dual action of an anti-fibroblast growth factor 2 aptamer in animal models of retinal disease
Matsuda, Y., Nonaka, Y., Futakawa, S., Imai, H., Akita, K., Nishihata, T., Fujiwara, M., Ali, Y., Bhisitkul., R.B., Nakamura, Y.
Mol. Ther. Nucl. Acids, 17(9): 819-828 (2019). doi: 10.1016/j.omtn.2019.07.018

Multiple therapeutic applications of RBM-007, an anti-FGF2 aptamer.
Nakamura, Y.
Cells 2021, 10, 1617. doi: 10.3390/cells10071617

Safety and tolerability of intravitreal umedaptanib pegol (anti-FGF2) for neovascular age-related macular degeneration (nAMD): a phase 1, open label study.
Pereira, D.S., Akita, K., ・・・ Nakamura, Y.
Eye, published online: 01 December 2023.

Clinical proof of concept for anti-FGF2 therapy in exudative age-related macular degeneration (nAMD): phase 2 trials in treatment-naive and anti-VEGF pretreated patients.
Pereira, D.S., Maturi, ・・・ Nakamura, Y.
Eye, published online: 30 November 2023.

RBM-
007
FGF2
Achon
droplasia
AMED
(grant support)

RBM-007 for Achondroplasia

Description/Summary

Achondroplasia (ACH) is a rare disease that causes short stature (adult height of approximately 130 cm for males and approximately 125 cm for females) with short limbs. There is no effective treatment available, and this disease is designated as an intractable disease by the Ministry of Health, Labour and Welfare. This disease results mainly from a genetic defect in FGFR3 (fibroblast growth factor type 3 receptor). This genetic change causes the receptor to be overly active to growth factors such as FGF2, which leads to reduced growth of chondrocytes, resulting a short stature. ACH occurs in a frequency of 1 in approximately 25,000 normal live births and is estimated to affect approximately 250,000 people worldwide.
RBM-007 demonstrates therapeutic effects by inhibiting the binding of FGF2 to FGFR3 in a study using an animal model of ACH and patient-derived iPS (induced pluripotent stem) cells.

Public Supports

FY 2015 to 2017
Japan Agency for Medical Research and Development (AMED)
Project Promoting Support for Drug Discovery
Support Program for Orphan Drug prior to the Designation
FY 2018 to 2020
Japan Agency for Medical Research and Development (AMED)
Project Promoting Support for Drug Discovery
Practical Research Project for Rare / Intractable Diseases
FY 2021 to 2023
Japan Agency for Medical Research and Development(AMED)
Project Promoting Support for Drug Discovery
Support Program for Orphan Drug prior to the Designation

Publications

Dual therapeutic action of a neutralizing anti-FGF2 aptamer in bone diseases and bone cancer pain
Jin, L., Nonaka, Y., Miyakawa, S., Fujiwara, M., Nakamura, Y.
Mol Ther 24(11): 1974-1986 (2016). doi: 10.1038/mt.2016.158

RNA aptamer restores defective bone growth in FGFR3-related skeletal dysplasia
Kimura, T., Bosakova, M., Nonaka, Y., Hruba, E., Yasuda K., Furakawa, S., et al.
Science Translational Medicine??05 May 2021: Vol. 13, Issue 592, eaba4226
doi: 10.1126/scitranslmed.aba4226

Multiple therapeutic applications of RBM-007, an anti-FGF2 aptamer.
Nakamura, Y.
Cells 2021, 10, 1617. doi: 10.3390/cells10071617

RBM-
011
IL-21
Pulmonary
Arterial
Hypertension
AMED(grant support),
National
Cerebral
and
Cardiovascular
Center
(collaboration)

RBM-011 for Pulmonary Arterial Hypertension

Description/Summary

Pulmonary arterial hypertension (PAH) is a designated incurable disease that leads to right heart failure due to increased pulmonary arterial pressure by stenosis or occlusion of the pulmonary arteries. The estimated number of patients is approximately 75,000 in Japan, the United States and major European countries. The currently available drugs have only a major effect on the relaxation of the pulmonary artery smooth muscle, and no therapeutic drug has been developed whose main function is to suppress the hyperplasia of the pulmonary artery.
IL-21 is known to promote the proliferation of pulmonary artery smooth muscle cells and promote PAH pathology. RBM-011 is a promising candidate to provide a new treatment of PAH by inhibiting the action of IL-21.

Public Supports

FY 2018 to 2019
Japan Agency for Medical Research and Development (AMED)
Project Promoting Support for Drug Discovery
Practical Research Project for Rare / Intractable Diseases
FY 2020 to 2022
Japan Agency for Medical Research and Development (AMED)
Project Promoting Support for Drug Discovery
Practical Research Project for Rare / Intractable Diseases
RBM-
006
Auto
taxin
Proliferative
Vitreoretinopathy
Nihon University
(collaboration)

RBM-006 for Proliferative Vitreoretinopathy

Description/Summary

Proliferative vitreoretinopathy (PVR) is a disease in which fibrosis of retinal pigment epithelial (RPE) cells leads to the formation of a proliferative membrane in the vitreous cavity, often resulting in severe visual impairment such as retinal detachment and blindness. Currently no effective preventive measures in PVR exist.
Autotaxin is an enzyme that synthesizes the lipid mediator lysophosphatidic acid (LPA). Increased levels of LPA and autotaxin have been observed in several diseases caused by tissue fibrosis.
RBM-006 is an aptamer that inhibits autotaxin and has been shown to have excellent PVR prophylaxis effect in animal model studies.
collaboration with Professor Osamu Nureki, Department of Biological Sciences, Graduate School of Science, The University of Tokyo and others.

Publications

Structural basis for specific inhibition of autotaxin by a DNA aptamer
Kato, K., Ikeda, H., Miyakawa, S., Futakawa, S., Nonaka, Y., Fujiwara, M., Okudaira S, Kano K, Aoki, J., Morita, J., Ishitani, R., Nishimasu, H., Nakamura, Y., Nureki, O.
Nature Struct Mol Biol 23: 395-401 (2016). doi: 10.1038/nsmb.3200

Effect of Anti-Autotaxin Aptamer on the Development of Proliferative Vitreoretinopathy
Hanazaki, H., Yokota, H., Yamagami, S., Nakamura, Y., Nagaoka, T.
Int. J. Mol. Sci. 24, 15926 (2023).

RBM-
003
Chymase
Heart
failure
Osaka
Medical
College
(collaboration)

RBM-003 for Heart Failure

Description/Summary

Immediately after myocardial infarction, chymase is secreted from mast cells and the sites of tissue damage, such as myocardial cells. Angiotensin II is then activated to cause adverse effects on the myocardium. RBM-003 is an inhibitor of chymase and has been found to induce significant improvement in cardiac function in an experiment using an animal model of acute myocardial infarction.

Publications

A chymase inhibitory RNA aptamer improves cardiac function and survival after myocardial infarction
Jin, D., Takai, S., Nonaka, Y., Yamazaki, S., Fujiwara, M., Nakamura, Y.
Mol Ther Nucleic Acids, 14: 41-51 (2019). doi: 10.1016/j.omtn.2018.11.001.

RBM-
010
ADAMTS5
Osteo
arthritis

RBM-010 for Osteoarthritis

Description/Summary

RBM-010 is a promising candidate to provide a new treatment of osteoarthritis by inhibiting the action of ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5), which is one cause of the progression of osteoarthritis.
Osteoarthritis is a disease that, for a variety of reasons, causes pain and swelling in joints in the knees, legs, arms, shoulder and other parts of the body and eventually results in the deformation of joints. The only treatments are drugs to reduce pain and swelling and joint replacement surgery. There are no drugs that can cure this disease.
There are more than 25 million people in Japan and more than 240 million people worldwide, who suffer from osteoarthritis. The number of people with this disease is expected to continue to grow as the world’s population ages. (Source: The Journal of Bone and Mineral Metabolism 2009, 27(5), 620-8/Osteoarthritis Cartilage, 2018 March; 26(3): 319-325)

RBM-
009
ST2
Severe
asthma

RBM-009 for Severe asthma

Description/Summary

Severe asthma is defined as asthma that requires treatment with high-capacity inhaled steroids plus other long-term control medications. Patients with severe asthma have a reduced quality of life due to frequent shortness of breath and dyspnea, which significantly interfere with daily activities and sleep.
There are a certain number of patients with severe asthma who are poorly controlled or refractory to the standard therapies described above, and some of them suffer asthma attacks and even asthma death despite treatment.
In addition to inhaled steroids and bronchodilators, several antibody drugs have recently been approved and used in the treatment of severe asthma, but some patients with severe asthma cannot be controlled even with these antibody drugs, creating unmet medical needs.

Development of separating agents

Compound
Name
Target
Application
Discovery
Product
Commer-
cialization
RBM-
101
IgG
Affinity purification of
human IgG and
Fc-fusion proteins

RBM-101 IgG aptamer

Description/Summary

RBM-101 is an aptamer binds to the constant region Fc of human immunoglobulin IgG. Manufacturing therapeutic antibodies involves isolation and purification currently using a Protein A/G that binds to the Fc region. Elution requires acidic conditions and quality of the antibody may be impaired during acidic elution step. On the other hand, RBM-101 can purify therapeutic antibodies under neutral condition without degenerating them. In addition, it is durable in alkaline and acidic conditions and not degraded by nucleases. Such durability has been proven in collaboration with EVEC, Inc.

Public Supports

2014
The Small and Medium Enterprise Agency
Supplementary Budget Project Subsidy for Innovation of Manufacturing, Business, and Services

Publications

Alkaline-tolerant RNA aptamers useful to purify acid-sensitive antibodies in neutral conditions
Inomato, E., Tashiro, E., Miyakawa, S., Nakamura, Y., Akita, K.
Biochimie (Special Issue on Aptamer Technology and Applications), 145(2):113-124 (2018). doi: 10.1016/j.biochi.2017.10.025.

Conformational plasticity of RNA for target recognition as revealed by the 2.15 Å crystal structure of a human IgG-aptamer complex
Nomura, Y., Sugiyama, S., Sakamoto, T., Miyakawa, S., Adachi, H., Takano, K., Murakami, S., Inoue, T., Mori, Y., Nakamura, Y., Matsumura, H.
Nucl Acids Res 38(21): 7822?7829 (2010). doi: 10.1093/nar/gkq615.

Structural and molecular basis for hyperspecificity of RNA aptamer to human immunoglobulin G
Miyakawa, S., Nomura, Y., Sakamoto, T., Yamaguchi, Y., Kato, K., Yamazaki, S., Nakamura, Y.
RNA 14: 1154-1163 (2008). doi: 10.1261/rna.1005808.