Alzheimer’s disease (AD) is the most common dementia in the world characterized by the neuropathological hallmarks consisting of an accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFT). There is no fundamental therapeutic treatment. We have developed a novel AD therapeutic candidate SAK3 which improves neuronal plasticity in the brain. SAK3 enhanced the acetylcholine release via T-type calcium channels. T-type calcium channels is highly expressed in neuro-progenitor cells in the hippocampal dentate gyrus. SAK3 enhanced the proliferation and differentiation of the neuro-progenitor cells, thereby improving depressive behaviors. The Cav3.1 null mice impaired the proliferation and differentiation of the neuro-progenitor cells. In addition, SAK3 activated CaMKII involving neuronal plasticity, thereby improving spine regeneration and proteasome activities impaired in AD related App^NL-F/NL-F knock-in mice. The improvement of the decreased proteasome activity through enhancement CaMKII/Rpt6 signaling by SAK3 treatment contributed to the amelioration of synaptic abnormalities and cognitive decline. The increased proteasome activity also accounted for inhibition of Aβ deposition. Taken together, the proteasome activation via enhancement of CaMKII/Rpt6 signaling is a new strategy for AD treatment, which rescues the AD pathology including cognitive impairments and Aβ deposition. SAK3 may be a new hopeful drug candidate rescuing dementia patients.

The treatment of diseases can be broadly classified into causal and symptomatic therapies. All the drugs currently on the market for Parkinson’s disease are symptomatic treatments. Levodopa, a dopamine precursor, is the mainstay of treatment for Parkinson’s disease to correct the malfunction of basal ganglia circuits caused by dopamine deficiency in the brain. In addition, dopamine agonists, anticholinergics, NMDA receptor antagonists, adenosine A2A receptor antagonists, COMT inhibitors, and MAO-B inhibitors have been marketed. With regard to the causal therapies, 57 out of 145 clinical trials for Parkinson’s disease registered on ClinicalTrials.gov in January 2020 were related to disease-modifying drugs. Anti-α-synuclein antibodies, GLP-1 agonists, and kinase inhibitors have been examined in clinical trials as disease-modifying drugs, but no drug has been obviously demonstrated to inhibit the progression of Parkinson’s disease to date. It is not easy to prove the beneficial results obtained from basic research in clinical trials. Especially for neurodegenerative disorders such as Parkinson’s disease, it is more difficult to demonstrate clinical efficacy of disease-modifying drugs because there is no useful biomarker to quantify the degree of neuronal degeneration in clinical practice. In addition, the difficulty of using placebos for long periods in a clinical trial also makes proper assessment difficult.

Major depressive disorder presents a substantial global health burden, and at least 30–40% of patients exhibit treatment resistance to antidepressants. Ketamine, an NMDA receptor antagonist, is used as an anesthetic agent. In 2019, the U.S. Food and Drug Administration (FDA) approved esketamine (the S-enantiomer of ketamine) as a therapeutic agent for treatment-resistant depression; however, this drug has reportedly been associated with serious side effects such as dissociative symptoms, thus limiting its clinical use as an antidepressant. Recently, various clinical studies have reported that psilocybin, the psychoactive substance found in magic mushrooms, has a fast-acting and long-lasting antidepressant effect in patients with major depressive disorder, including those resistant to conventional treatment. Furthermore, psilocybin is a psychoactive drug that is relatively harmless compared to ketamine and other similar substances. Accordingly, the FDA has designated psilocybin as a “breakthrough therapy approach” for the treatment of major depressive disorder. Additionally, serotonergic psychedelics such as psilocybin and lysergic acid diethylamide show some potential in the treatment of depression, anxiety, and addiction. The increased attention the use of psychedelics has attracted as a psychiatric disorder treatment approach is referred to as the “psychedelic renaissance”. Pharmacologically, psychedelics cause hallucinations by stimulating cortical serotonin 5-HT_2A receptors (5-HT2A), although whether 5-HT2A is responsible for the manifestation of their therapeutic effects remains unclear. Furthermore, it is unclear whether the hallucinations and “mystical experience” that the patients go through because of 5-HT2A activation by psychedelics is essential for the therapeutic effect of these substances. Future research should elucidate the molecular and neural mechanisms underlying the therapeutic effects of psychedelics. This review summarizes the therapeutic effects of psychedelics on psychiatric disorders such as major depressive disorder in clinical and pre-clinical studies, and discusses the possibility of 5-HT2A as a novel therapeutic target.

The monoamine hypothesis has been common hypotheses for the pathophysiology of major depressive disorder (MDD). Since mainstream antidepressants are selective serotonin (5-HT) reuptake inhibitors, hypo-serotonergic function has been implicated in the MDD. However, one-third of patients are refractory to the treatment with antidepressants. Tryptophan (TRP) is metabolized via the kynurenine (KYN) and 5-HT pathways. Indoleamine 2,3-dioxygenase 1 (IDO1) is the first metabolizing enzyme in the TRP-KYN pathway which is inducible by pro-inflammatory cytokines, involved depression-like behavior via 5-HT depletion due to decreased level of TRP in the 5-HT pathway. Kynurenine 3-monooxygenase (KMO) is the enzyme in the metabolism of KYN to 3-hydroxykynurenine. KMO deficiency increases level of kynurenic acid (KA), a KYN metabolite by kynurenine aminotransferases (KATs) and induces depression-like behavior. Interestingly, Chronic unpredictable mild stress (CUMS) is associated with a disruption of the hypothalamus-pituitary-adrenocortical (HPA) system and increases KA level with decreased KMO expression in the prefrontal cortex. The decrease of KMO may be related to the reduction in expression of microglia, since KMO is mainly found in microglia in the nervous system. CUMS increases KA level via alternation of enzymes from KMO to KAT. KA is α7 nicotinic acetylcholine receptor (α7nAChR) antagonist. Activation of α7nAChR by nicotine or galantamine attenuates CUMS-induced depression-like behaviors. Taken together, depletion of 5-HT by induction of IDO1 and α7nAChR antagonism by KA via decreased KMO expression cause depression-like behavior, suggesting that metabolic alterations in TRP-KYN pathway are highly involved in the pathophysiology of MDD. Therefore, TRP-KYN pathway is expected to be an attractive target for the development of novel diagnosis of MDD and antidepressants.

Our previous study has suggested that peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the pathophysiology of schizophrenia. In the current study, we screened and identified rare variants in the PPARA gene (encoding PPARα) of schizophrenia subjects. In vitro study showed that those variants decreased activities of PPARα as a transcription factor. Ppara KO mice exhibited a deficit in the sensorimotor gating function and schizophrenia-related histological abnormalities. RNA-seq analysis revealed that PPARα regulates the expression of synaptogenesis signaling pathway-related genes in the brain. Remarkably, treatment of mice with the PPARα agonist fenofibrate alleviated an NMDA receptor antagonist, phencyclidine (PCP)-induced spine pathology and reduced sensitivity to MK-801, another NMDA receptor antagonist. In conclusion, the current study further supports the idea that perturbation in the PPARα-regulated transcriptional machinery leads to a predisposition to schizophrenia, probably by affecting synapse physiology. This study also demonstrates that PPARα can serve as a novel therapeutic target for schizophrenia.

Schizophrenia affects approximately 24 million people worldwide. Existing medications for the treatment of schizophrenia work primarily by improving positive symptoms such as agitation, hallucinations, delusions, and aggression. They possess common mechanism of action (MOA), blocking to neurotransmitter receptors such as dopamine, serotonin, and adrenaline receptors. Although multiple agents are available for the treatment of schizophrenia, the majority do not address negative symptoms or cognitive dysfunction. In other cases, patients have drug-related adverse effects. The vasoactive intestinal peptide receptor 2 (VIPR2, also known as VPAC2 receptor) might be an attractive drug target for the treatment of schizophrenia because both clinical and preclinical studies have demonstrated a strong link between high expression/overactivation of VIPR2 and schizophrenia. Despite these backgrounds, the proof-of-concept of VIPR2 inhibitors has not been examined clinically. A reason might be that VIPR2 belongs to class-B GPCRs, and the discovery of small-molecule drugs against class-B GPCRs is generally difficult. We have developed a bicyclic peptide KS-133, which shows VIPR2 antagonist activity and suppresses cognitive decline in a mouse model relevant to schizophrenia. KS-133 has a different MOA from current therapeutic drugs and exhibits high selectivity for VIPR2 and potent inhibitory activity against a single-target molecule. Therefore, it may contribute to both the development of a novel drug candidate for the treatment of psychiatric disorders such as schizophrenia and acceleration of basic studies on VIPR2.

Discovery of RANKL (receptor activator of NF-κB ligand) had an impact on identification of the mechanisms regulating osteoclast differentiation and function, resulting in establishment of research field bridging bone biology and immunology (osteoimmunology), and development of a human anti-RANKL monoclonal antibody (denosumab). Denosumab has been clinically available for treatment of osteoporosis and cancer-induced bone diseases in many countries. Denosumab is a so-called blockbuster of which sales amount was 5.3 billion US dollars in 2021. I will discuss the intense competition between Amgen Inc. and us regarding discovery of RANKL. One of the recent topics is the identification of RANKL reverse signaling with a RANKL-binding peptide, W9 known as a RANKL antagonist. The RANKL reverse signaling stimulates differentiation of osteoblasts and bone formation. The findings revealed the RANKL-RANK (a receptor of RANKL) dual signaling in coupling between bone resorption and bone formation. Interestingly, W9 also stimulates differentiation of chondrocytes and repairs defect of articular cartilage regardless of RANKL. Identification of the mechanisms will be useful for development of pharmaceuticals treating osteoarthritis. I also suggest possible applications of anti-RANKL antibody (anti-RANKL) to the treatment of cancer patients. RANKL has an important role in development of medullary thymic epithelial cells (mTECs) establishing self-tolerance. Anti-RANKL potentiates anticancer immune responses thorough regeneration of tumor-reactive T-cells by inhibiting mTEC development. I expect the synergy of anti-RANKL and immune checkpoint inhibitors such as anti-CTLA-4 antibody and anti-PD-1 antibody for immuno-oncology. Several clinical trials are currently in progress. It is likely that cancers will not be incurable diseases in the near future.

RANKL is a bidirectional signaling molecule; activation of the RANKL reverse signaling is triggered by the cross-linking of multiple RANKL trimers to form a molecular cluster. In adults, RANKL is expressed primarily in bone tissue and the immune system. In bone tissue, the functions of RANKL forward and reverse signaling have been separately analyzed; the forward signaling is responsible for bone resorption by inducing the maturation of osteoclasts, while the reverse signaling is activated by vesicular RANK, one of the osteoclast-derived coupling factors, leading to the promotion of early osteoblast differentiation. In the immune system, RANKL is expressed on lymphocytes and the interaction with antigen-presenting cells such as RANK-expressing dendritic cells should result in the activation of both the forward and the reverse signaling, however, the discrimination of the function of each pathway has not been achieved yet. To activate RANKL reverse signaling, a multivalent protein construct of anti-RANKL single-chain Fv multimerized with peptide linkers would be effective, since this type of construct can induce cluster formation by cross-linking RANKL trimers. It was also found that the divalent construct with minimal molecular size can cross-link the RANKL trimer without affecting the forward signaling. On the other hand, the design of constructs to inhibit the activation of RANKL reverse signaling needs to be tested experimentally. Particularly, it may be necessary to obtain small molecules that act on the RANKL intracellular domain to achieve selective inhibition of the reverse signaling without affecting the forward signaling.

The cranium is a small portion of the body but has the most complex structure composed of more than 20 small parts. The cranium is a unique tissue that is equipped with teeth. Tooth misalignment is corrected by orthodontic treatment, in which bone surrounding the tooth root undergoes remodeling by applying special devices. There is a wider individual variation in the shape of the mandible, a component of the cranium, than other parts of the body, which is partly due to the difference of the mechanical loading onto the bone by mastication and occlusion. Thus, mechanical loading has crucial roles in cranial bone metabolism. It has been recently revealed that osteocytes have crucial functions in the regulation of remodeling of the jawbone and the alveolar bone, by producing cytokines IGF-1 and RANKL. The mechanisms by which osteocytes produce these cytokines upon mechanical stimuli are addressed in many studies. Insights obtained by these studies can be applied to orthodontic treatment in the future.

Periodontal disease is characterized by inflammation of the periodontal tissue and subsequent destruction of the alveolar bone. It is one of the most common infectious diseases in humans, being the leading cause of tooth loss in adults. Recently, it has been shown that the receptor activator of NF-κB ligand (RANKL) produced by osteoblasts and periodontal ligament fibroblasts critically contributes to the bone destruction caused by periodontal disease. Activation of the immune system plays an important role in the induction of RANKL during periodontal inflammation. Here we discuss the molecular mechanisms of periodontal bone destruction by focusing on the osteoimmune molecule RANKL.

Recently, the importance of safety assessment based on mechanism of action for drug discovery has been emphasized, and international organizations are increasingly requesting safety assessment using non-animal test methods (Hereafter referred to as alternative method) that are not based on animal experiments using human-derived cells or tissues. However, it is clear that the variety of phenomena captured in animal studies cannot be covered by a stand-alone alternative method, as has been developed in the past, and there are some cases that are not intended to assess human toxicity based on comparison with the data of animal experiments. Expectations are therefore growing for the use of the New Approach Method (NAM) in drug discovery. In this article, we summarize the current status of alternative methods for reproductive toxicity testing and the regulatory acceptance of safety assessments by the Microphysiological system (MPS) as examples regarding NAM.

On March 28th, 2022, asciminib hydrochloride (Scemblix^® Tablets 20 ‍mg/40 ‍mg), the world’s first tyrosine kinase inhibitor (TKI) specifically targeting the ABL myristoyl pocket (STAMP inhibitor), was approved for chronic myeloid leukemia (CML) resistant or intolerant to prior therapy. Asciminib specifically binds to the myristoyl pocket, an allosteric site of BCR::ABL1, and inhibits the ABL1 family molecules. In vitro and in vivo pharmacology studies demonstrated cell growth inhibition and antitumor effects of asciminib. The international phase I study for patients with chronic or accelerated phase CML investigated the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of asciminib monotherapy. However, the MTD was not reached, so and RDE was determined based on tolerability, safety, pharmacokinetics (PK) and preliminary efficacy data obtained by the time of the study. RDE was determined to be 40 ‍mg twice daily in chronic or accelerated phase CML without T315I mutation, and 200 ‍mg twice daily in chronic or accelerated phase CML with T315I mutation. The international phase III study for patients with chronic phase CML who were previously treated with ≥2 TKIs and resistant or intolerant to the recent treatment demonstrated the superiority of asciminib over bosutinib in achieving the primary endpoint of a major molecular response (MMR) at week 24. Regarding safety, the most common treatment-related adverse event in asciminib arm was thrombocytopenia, and others included neutropenia. Asciminib is expected to be a new treatment option for CML patients who have limited choices due to resistance or intolerance to previous therapies.

Nemolizumab (Mitchga^® syringes) is a biologic with a novel mechanism of action that was first approved in Japan in March 2022 for pruritus associated with atopic dermatitis (AD) only when existing treatments were insufficiently effective. Nemolizumab is a humanized antihuman interleukin-31 (IL-31) receptor A (IL-31RA) monoclonal antibody that targets the receptor for IL-31, the major pruritogen in AD. Nemolizumab inhibits IL-31 signaling and suppresses pruritus by competitively preventing IL-31 from binding to IL-31RA. In the phase III study, nemolizumab, 60 ‍mg, was administered subcutaneously once every 4 weeks, in combination with topical therapy, to patients aged 13 years or older who had AD and inadequately controlled moderate-to-severe pruritus. The efficacy of the treatment was verified by mean percentage change in the pruritus visual analogue scale score from baseline to 16 weeks. Skin symptoms and quality of life (QOL) were improved after 16 weeks. Furthermore, data for up to 68 weeks revealed continuous improvement and/or maintenance of itching, skin symptoms, and QOL. The most common adverse effects were worsening of AD, skin infection, and upper respiratory tract infection. Because skin symptoms may worsen during treatment with this product, patients must be monitored carefully and managed appropriately (e.g., by intensifying treatment with topical anti-inflammatory drugs or withdrawal of medication as needed). Nemolizumab effectively suppresses itching, the most distressing symptom of AD, and improves skin symptoms. It is also expected to help improve QOL, including sleep.

This review describes the pharmacological properties of nemolizumab, pharmacokinetics, efficacy and safety in clinical trials in Japan.