When we feel emotions or think about various things, “neurotransmitters” pass between neurons in the brain to transmit information. There are various types of neurotransmitters, including γ-aminobutyric acid (GABA), which has an anti-stress effect, and serotonin, which brings mental stability. When the neurotransmitters are out of balance, people can easily become stressed, irritable, and have other mental alterations. We have discovered the possibility that pyridoxamine (RS8001), a type of vitamin B6, can improve the balance of these substances and have been working to develop a therapeutic drug that can help women with mental health care.

Background of RS8001 development and the safety

The neurotransmitters GABA and serotonin have an amino group in their chemical structure. RS8001 (pyridoxamine), We develop a type of water-soluble vitamin B6 (pyridoxamine) that also has an amino group in its structure. Therefore, biochemical and animal studies suggest that pyridoxamine is utilized to produce GABA and serotonin and also inhibit the degradation of the neurotransmitters, resulting in the increment of these neurotransmitters in the brain. In fact, animals (rats) treated with pyridoxamine proved to be more stable in response to excitation and stimulation (stress). Pyridoxamine is a nutrient found in regular food and has been shown to be highly safe even when administered in large doses, but it is an unapproved medicine in developed countries, including Japan.

As society becomes more complex, many people live under stress, but compared to physical illnesses, medical treatment for mental illnesses is still insufficient. Medicines that control and regulate neurotransmitters may be useful in the treatment of such diseases. Today, women are expected to play an active role in society, and mental health care for women is an extremely important issue in society. We have been engaged in the research and development of the drug for the treatment of premenstrual syndrome/premenstrual dysphoric mood disorder, which makes social life difficult for women of reproductive age, and menopausal disorders during the menopause.

Therapeutic for premenstrual syndrome

with psychiatric symptoms /premenstrual dysphoric disorder

Premenstrual Syndrome (PMS) is a disorder specific to women of reproductive age in which psychological and physical symptoms persist for 3 to 10 days before menstruation and then lessen or disappear with the onset of menstruation. More severe psychological symptoms are classified as premenstrual dysphoric disorder (PMDD), which is now generally considered to be a continuum of PMS. Currently 70-80% of women of reproductive age have some symptoms related to PMS during premenstrual period. When such symptoms affect their daily and social life, they are eligible for the treatment. Studies in Japan have reported that the frequency of PMS with the difficulties in social life is 5.4% and that of PMDD is 1.2%. Antidepressants (SSRIs) and low-dose pills have been used for the treatments, but they are not widely used in Japan due to side effects and resistance among women in general.

We have been conducting a Phase II investigator-initiated clinical trial of pyridoxamine for PMS/PMDD in collaboration with Kinki University, Tohoku University, Tokyo Medical and Dental University, Tokyo Women’s Medical University, and others (placebo lead-in* double-blind, placebo-controlled, three-arm comparative study; target number of patients: 105). This clinical trial has been adopted by the Japan Agency for Medical Research and Development (AMED) for the “Cyclic Innovation for Clinical Empowerment (CiCLE)” project in FY2019 with Renascience as the representative organization. We started the clinical trial in November 2020, earlier than originally planned, but the number of patient visits decreased due to the impact of the spread of novel coronavirus infection, so we have added 5 private facilities so far to promote the enrollment, created in-hospital posters and educational booklets, conducted webinars for pharmacists by the coordinating physician. As a result, the target number of the enrollment was achieved in September 2023. Interim evaluations by the AMED have determined that the project should be continued. A co-development and option agreement was signed in December 2019 with ASKA Pharmaceuticals, an specialty pharmaceutical company for gynecology.

*Placebo lead-in method: Placebos do not contain active ingredients but may improve disease symptoms due to psychological effects (placebo effect). Therefore, we have adopted a study design in which subjects are asked to take a placebo for a certain period of time before receiving the active drug, and subjects with a large placebo effect are not asked to participate in the study.

Therapeutic for menopausal disorder

Menopausal disorders are caused by the decrease in female hormone secretion and various psychological and social stresses during the perimenopausal period and involves various symptoms such as hot flashes (e.g., upper body flushing, glowing, sweating), mental symptoms (depression, anxiety, and insomnia), and physical symptoms (fatigue and joint pain), which interfere with daily life. Hormone replacement therapy, which supplements female hormone in small doses, is a typical drug therapy, but its use in Japan is limited to about 2% of the patients due to concerns about adverse events such as breast cancer.

Our collaborators at Tokyo Medical and Dental University discovered that hot flashes and depression, the two major symptoms of menopausal women, were more severe in those with low vitamin B6 intake in the study on the relationship between various menopausal symptoms and nutrient intake, suggesting that vitamin B6 supplementation may alleviate these symptoms.

Therefore, we have been conducting a clinical study of RS8001 (pyridoxamine) as a treatment for hot flashes and depression in menopausal disorder. In December 2021, we signed a collaboration agreement with Tokyo Medical and Dental University. In March 2023, this project was selected for the AMED’s “Practical Research Project for Comprehensive Support of Women’s Health (the representative organization: Tokyo Medical and Dental University)”. This clinical research has been conducted in a double-blind design employing a placebo lead-in method with the aim of eliminating the placebo effect as much as possible.

Percentage of menopause disorder patients with hot flashes and depression