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.

SUSHI Study
Our company founded RIBOMIC USA Inc. (a wholly owned subsidiary of our company) in August 2017 in Berkeley, California, for the purpose of conducting clinical studies with RBM-007 in subjects with AMD in the United States. We entered a phase I/IIa study in the United States in October 2018 and successfully completed in June 2019.

This clinical study is conducted as phase I/IIa study (referred to as SUSHI study) with patients because it involves an injection into the vitreous body, an organ of the eye, and thereby the phase I studies in healthy volunteers (studies designed to determine the safety or pharmacokinetics of investigational drugs) are not applicable. This phase I/IIa study is an open label, non-controlled, dose-escalating study assessing the safety, tolerability, and bioactivity of a single intravitreal injection of RBM-007 in nine subjects with refractory wet AMD.

Three doses (0.2, 1, 2 mg) were injected to test eyes. A single intravitreal injection of RBM-007 was well tolerated in patients with wet AMD unresponsive to prior anti-VEGF therapy. Moreover, RBM-007 showed evidence for bioactivity even after single injection. These results strongly suggest that FGF2 is involved in wet AMD independently or cooperatively with VEGF.

TOFU Study
Following the successful completion of phase 1/2a (SUSHI) study, we entered the phase 2 (TOFU) study in December 2019. This is a multicenter, active-controlled, double masked study assessing the safety, efficacy and durability of four monthly intravitreal (IVT) injections of RBM-007 monotherapy, and four monthly RBM-007 injections in combination with Eylea® dosed at every other month, compared to Eylea® monotherapy dosed at every other month in approximately eighty-one subjects with exudative age-related macular degeneration (AMD).

RAMEN Study
Following the excellent progress of the TOFU study, we newly initiated an open-label extension study (named RAMEN) in October 2020. The study design allows eligible 40 subjects who have completed the ongoing phase 2 double-masked TOFU Study to receive additional four monthly treatments of RBM-007. RAMEN is designed to provide long-term safety and efficacy feedback for the original trial outcomes as well as evaluate additional treatment effects. The trial extension is important since additional doses and treatment times will allow us to further evaluate structural changes in fibrosis.

TEMPURA Study
In July 2021, a phase 2 investigator sponsored trial (IST) - named ‘TEMPURA Study’ - was initiated for wet AMD. The TEMPURA IST (NCT04895293) is being conducted by Dr. Raj K. Maturi M.D. P.C at the Midwest Eye Institute, Indiana. The open labelled clinical trial is enrolling patients with intraretinal or subretinal edema due to previously untreated neovascular AMD. The study has been designed to assess the safety and efficacy of intravitreal injections of RBM-007 in treatment naïve patients. Dr. Maturi commented “Excited to see the potential benefits of new mechanism of action in wet AMD”.

References

  

Achondroplasia

Achondroplasia 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 achondroplasia 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 achondroplasia 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 achondroplasia.

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). The study design is single-site, open-label, single or two times administration, dose-escalating with sequential cohorts of 0.1 mg/kg, 0.3 mg/kg and 1.0 mg/kg.

[Information of the clinical study with RBM-007 in Japan]

References