Proton pump inhibitors (PPIs) inhibit H⁺, K⁺-ATPase, an enzyme which is the final step of gastric acid secretion and is selectively located in the gastric parietal cells. PPIs block the enzyme in a covalent and irreversible binding manner, thus providing better efficacy than previous pharmacological agents such as antacids and histamine H₂ receptor antagonists. Although PPIs have been the first-line therapeutic option for acid related diseases (ARDs), there are several limitations to their efficacy, i.e. short half-life in blood, insufficient acid suppression especially at night, necessity of repeated dosages for full action, and large variation in efficacy among patients due to CYP2C19 polymorphism. To overcome these shortcomings, we performed a high-throughput random screening using in-house chemical libraries and further lead optimization to look for the most relevant clinical candidate compounds. As the results of these researches, we discovered vonoprazan fumarate, a novel gastric acid antisecretory agent which inhibits H⁺, K⁺-ATPase in a reversible and K⁺-competitive manner. Vonoprazan exerted a more potent and longer lasting inhibitory effect than lansoprazole on gastric acid secretion in preclinical studies, presumably by its high accumulation profile in the gastric parietal cells. It also exhibited a rapid onset of action and prolonged inhibition of intragastric acidity in humans and showed remarkable effects on multiple ARDs including erosive esophagitis and Helicobacter pylori eradication. Vonoprazan fumarate was approved in 2014 for clinical use in Japan. Vonoprazan is a new therapeutic option which can potentially improve outcomes compared with conventional PPI-based treatments for ARDs.

Overactive bladder (OAB) is defined as urgency, with or without urge incontinence, usually with frequency and nocturia. Antimuscarinic drugs are often prescribed as a standard care; however, the treatment discontinuation due to the adverse events including dry mouth and constipation has been an issue. Taking these situations into account, we considered that a novel OAB drug having a different mechanism from antimuscarinics fills the unmet medical need. It has been known that, during bladder filling, activation of sympathetic nerves results in bladder smooth muscle relaxation via the β-adrenergic receptor (AR) stimulation. In 1999, three Japanese groups independently provided evidence for the existence of β₃-AR in human bladder smooth muscles and some of these groups showed that β₃-AR activation is mainly involved in the relaxation induced by β adrenergic stimulation. Therefore, we conducted pharmacological research focusing on β₃-AR as a novel target molecule for the treatment of OAB. A selective β₃-AR agonist mirabegron showed the relaxant effect in rat bladder smooth muscle and decreased resting intravesical pressure in anesthetized rats. Mirabegron also improved storage function in a rat detrusor overactivity model. Furthermore, in vitro isometric contraction study using human bladder tissues was conducted to predict the clinical efficacy and mirabegron showed the relaxant effect in human bladder smooth muscle. In clinical studies with OAB patients, mirabegron demonstrated promising efficacy and tolerability. These pharmacological evidences contributed to the approval of mirabegron as a first-in-class drug for OAB treatment in Japan ahead of other countries.

GPR119 (G-protein coupled receptor 119) has been shown to be highly expressed in the lower small intestinal and colorectal L-cells and pancreatic β-cells, and mediates intracellular cAMP concentration, glucagon like peptide (GLP-1) secretion, and glucose stimulated insulin secretion (GSIS). As the next generation for the treatment of type 2 diabetes mellitus (T2DM), GPR119 agonist has been intensively studied by pharmaceutical companies and a lot of patents have been applied by them. In such highly competitive condition, biological differentiation and to find an advantage among GPR119 agonists were necessary to proceed the candidate compound in further clinical investigation. Firuglipel (DS-8500a) is an orally available GPR119 agonist synthesized in DAIICHI SANKYO CO., LTD (DS). It was originated from DS-chemical library and optimized in the aspect of bioavailability and safety. Firuglipel had a higher intrinsic activity (IA) of the production of intracellular cAMP in human GPR119 expressing CHO-K1 cells than those of other GPR119 agonists studied. The level of IA in each GPR119 agonist was correlated with the existence of agonist conformer. In parallel with the study for the differentiation from other GPR119 agonists, we compared firuglipel with dipeptidyl peptide-4 (DPP-4) inhibitor in NONcNZO10/LtJ mice and evaluated their combination in streptozotocin (STZ) treated C57BL/6J mice to clarify future positioning among anti-diabetics therapy. These pharmacological studies illustrated here can draw out a clinical value of compound and expected to lead the production of first-in-class agent in pharmaceutical companies.

The global population is aging rapidly and, in Japan, the number of elderly has been steadily rising. It is important to shrink the gap between the average lifespan and the number of years people can expect to remain healthy. This links with improving the quality of life for the elderly and reducing social welfare spending. Maintaining motor function is believed to be a key to extending the number of years a person remains healthy, but recent years have seen a rise in locomotive syndrome. Decreases in muscle mass with age, and the deterioration in motor functions leads to sarcopenia. However, there is a dearth of medicines for increasing muscle mass or muscular strength. In this study, we used non-human primates (NHPs), which have similar anatomical features to humans and have advanced functional differentiation between the fore- and hindlimbs, to examine a highly accurate method of measuring muscle mass using Magnetic Resonance Imaging (MRI) and compared it to Dual Energy X-ray Absorptiometry (DXA) usually used in clinical settings. The results showed that both MRI and DXA provided high repeatability. Furthermore, correlation analysis between the amount of excised muscle for measurement and the results from MRI and DXA showed a high correlation at all sites examined, with the correlation coefficient higher for MRI than for DXA. We expect that the establishment of a highly accurate method for measurement of muscle mass using MRI and DXA will give impetus to the development of drugs that target muscle mass.

A number of promising compounds developed in rodent arthritis models lack efficacy in clinical osteoarthritis (OA) pain. To enhance successful translation of preclinical findings, a nonhuman primate (NHP) model of knee OA was developed and characterized using behavioral assessments designed for use in the NHP. A unilateral medial meniscectomy (MMx) was performed and animals underwent an exercise regimen. Decreased ipsilateral knee pressure threshold, pressure “hyperalgesia”, and decreased ipsilateral weight bearing, suggestive of pain at rest were observed. The sensitivity of the pain-related behaviors to pharmacological manipulation was evaluated. A single dose of the opioid morphine reduced pain-related behaviors. Likewise, the serotonin-norepinephrine reuptake inhibitor duloxetine reduced pain-related behavior, and efficacy was similar to that of morphine. By contrast, the anticonvulsant pregabalin did not significantly affect pain-related behavior. Repeated dosing with the non-steroidal anti-inflammatory drug (NSAID) diclofenac reduced pain-related behaviors whereas repeated dosing with the NK₁ receptor antagonist aprepitant did not. The drug effects observed in the NHP OA model mirror the efficacy observed clinically.

Retinal diseases such as glaucoma, diabetic retinopathy, age-related macular degeneration and retinitis pigmentosa are the major causes of blindness. However, these pathological mechanisms remain to be elucidated, and development of new therapeutic agents has been desired. A large number of experimental animal models using rodents (rats and mice) have been used for the evaluations of the pathogenesis and novel therapeutic candidates in retinal diseases. However, the anatomy of the retina in rodents is different from that in humans, as rodents have no macular. Conversely, non-human primates have macular similar to humans, and therefore rhesus and cynomolgus monkeys are widely used as experimental animal models of retinal diseases. Here, we will introduce non-human primate models of retinal diseases and their pharmacological approaches, with a focus on our research findings.

Nusinersen (Spinraza^®) was approved as Japan’s first antisense oligonucleotide (ASO) drug for treatment of SMA (spinal muscular atrophy) patients with a deletion or mutation of the survival motor neuron (SMN) 1 gene and ≥1 copy of the SMN2 gene. Nuseinersen is a fully modified 2'-O-(2-methoxyethyl) (2'-MOE) ASO designed to bind the SMN2 pre-mRNA and alter splicing, such that a mature mRNA is produced and is translated as full-length SMN protein. In 4 types of mouse SMA disease models, treatment with nusinersen improved the form of the neuromuscular junction, increased myofiber size, improved righting reflex and grip, and prolonged survival. The efficacy of nusinersen was verified in 2 multinational, randomized, double-blind, sham-controlled clinical studies in SMA patients with differing ages of onset and ages (ENDEAR study and CHERISH study), and improvement and maintenance of motor function by nusinersen were demonstrated regardless of the type of SMA. Moreover, both studies showed that greater efficacy may be obtained with early initiation of nusinersen treatment. Therefore, treatment with nusinersen should be started as early as possible to delay or halt progression of the disease and maximize therapeutic effect. As nusinersen is the only ASO currently available for SMA, it will be widely used, therefore we will expect that nusinersen will contribute to improve patients’ QOL and reduce the burden of caregivers and the healthcare system by improving motor function of patients with SMA.