Pipeline
Age-related Macular Degeneration
Age-related macular degeneration (AMD) affects approximately 1% of individuals aged 50 years or older and is the leading cause of vision loss in Western countries. As at 2014, of the 135 million AMD sufferers worldwide, some 12.25 million patients resided in the United States (Reference 1).
Drugs that can inhibit abnormal retinal angiogenesis (anti-VEGF drugs, such as Lucentis® and Eylea®) are available for treatment of wet AMD and they constitute a market worth around one trillion yen. However, currently available drugs, which have been in practical use for around 10 years, have been found through follow-up research to have clinical issues:
- A significant number of patients do not benefit from currently available drugs (anti-VEGF drugs) (Reference 2).
- Even patients who have appeared to benefit from currently available drugs experience reduced efficacy after about two to three years and are again exposed to the risk of vision loss (Reference 3).
These factors are likely to involve retinal scarring (fibrosis) caused by lesions (Reference 4). Currently available drugs have no inhibitory effect on scarring.
Results from clinical studies on the effects of an anti-VEGF drug (generic name: ranibizumab; brand name: Lucentis®) on the visual acuity of patients with AMD (Reference 3)
[Green line] Results of visual acuity measurement following monthly injections over the first two years and vitreous injections at intervals of several months over the latter two years.
[Red line] Results of follow-up of visual acuity at or after four years. ETDRS Letters on the vertical line indicate increases (visual acuity gains) or decreases (visual acuity losses) in the number of lines of smaller letters that can be correctly discerned on an American-style visual acuity chart.
Our anti-FGF2 (fibroblast growth factor 2) aptamer, RBM-007 (Reference 5), inhibits not only angiogenesis but also scar formation in the retina. This dual action is a novel mechanism that currently available drugs do not have and is expected to provide a new therapeutic approach to patients who do not respond well to currently available drugs.
Three P2 clinical trials have been conducted in the USA to assess safety and efficacy of RBM-007 for wet AMD.
1.TOFU Study (Active-controlled, double masked trial)
https://clinicaltrials.gov/ct2/show/study/NCT04200248
2. RAMEN Study (Single-arm, open-label extension trial)
https://clinicaltrials.gov/ct2/show/NCT04640272
3. TEMPURA study (Investigator sponsored trial in treatment naïve wAMD patients).
https://clinicaltrials.gov/ct2/show/NCT04895293?term=NCT04895293&draw=2&rank=1
Throughout these studies, RBM-007 was well tolerated and no safety concerns were identified. The results indicated that RBM-007 is effective in treatment-naïve wet AMD, showing a clinical proof of concept for anti-FGF2 therapy in wet AMD, while less effective in long-term anti-VEGF pretreated wet AMD.
References
- Market Scope, 2014 Report on the Retinal Pharma & Biotech Market (data cited after modification).
- Ranibizumab versus verteporfin for neovascular age-related macular degeneration
- Fellow eye comparisons for 7-year outcomes in ranibizumab-treated AMD subjects from ANCHOR, MARINA,and HORIZON (SEVEN-UP Study)
- Fibrosis and diseases of the eye
- Anti-angiogenic and anti-scarring dual action of an anti-fibroblast growth factor 2 aptamer in animal models of retinal disease
Achondroplasia
Achondroplasia (ACH) is the most prevalent genetic form of dwarfism in humans, caused by activating mutation in FGFR3 tyrosine kinase. The clinical need for safe and effective inhibitor of FGFR3 is currently unmet, leaving ACH an incurable condition. We evaluated the RBM-007, a RNA aptamer developed to neutralize the FGFR3 cognate ligand, FGF2, for its activity against FGFR3 signaling in cartilage. In cultured chondrocytes and in cartilage xenografts derived from ACH iPS cells, RBM-007 rescued the proliferation arrest and aberrant chondrocyte differentiation and maturation in the growth plate cartilage. When delivered by subcutaneous injection, RBM-007 restored defective bone growth in mouse model to ACH.
Following these pre-clinical studies, in July 2020, we entered the phase 1 study to evaluate the safety, tolerability and pharmacokinetics of RBM-007 administered subcutaneously in healthy volunteers (24 subjects in total). This phase 1 study was completed in May 2021.
The Investigational New Drug (IND) applications for an observational study, an early Phase 2 study and an early Phase 2 extension study of ACH project has been approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. The purpose of the observational study is to obtain clinical basic data of ACH patients, including height growth velocity, and to select appropriate subjects for the early phase 2 study. These studies have been supported by Support Program for Orphan drug prior to the Designation of AMED (Agency for Medical Research and Development) until 2023.
[Information of the RBM-007 phase 1 study in Japan]
[Information of the RBM-007 early phase 2 observational study in Japan]
[Information of the RBM-007 early phase 2 study in Japan]
[Information of the RBM-007 early phase 2 extension study in Japan]