The research plan for a tooth regeneration treatment drug (commonly known as a "tooth regrowth drug") for congenital edentulism being carried out by the Medical Research Institute Kitano Hospital (Kita-ku, Osaka City, Director: Daisuke Hata; hereinafter referred to as "Kitano Hospital"), a public interest incorporated foundation, and its affiliated groups, was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) on March 25, 2024. Following this, an investigator-initiated clinical trial will now begin in cooperation with Kyoto University Hospital (Sakyo-ku, Kyoto City, Director: Akifumi Takaori).

History and background leading up to the clinical trial

Congenital anedentulism typically involves the absence of six or more teeth (incidence rate: 0.1%), and many of the causative genes are shared between mice and humans. Because patients with congenital anedentulism experience edentulism during childhood, when the jawbone is still developing, dentures and dental implants are difficult to treat. Furthermore, oral frailty (a decline in eating function) develops during the growth period, adversely affecting growth through atrophy of the jawbone that supports the teeth. The only existing treatments available are replacement teeth using dentures or dental implants after reaching adulthood, and the development of tooth regeneration therapy as a radical treatment has been strongly desired.

In May 2007, this research group discovered that mice lacking the USAG-1 protein gene developed supernumerary teeth, demonstrating that tooth number can be increased by a single protein molecule. Furthermore, in July 2019, they confirmed that tooth formation was restored by crossbreeding a mouse model of congenital edentulism with a mouse model of supernumerary teeth lacking the USAG-1 gene. They also demonstrated that local administration of USAG-1 siRNA (a nucleic acid formulation) to a mouse model of congenital edentulism restored congenitally missing teeth, demonstrating the validity of USAG-1 as a target for congenital edentulism. Based on these results, the research group developed a neutralizing antibody targeting USAG-1, acquired intellectual property rights, and established TreGem BioPharma Co., Ltd. (Kamigyo-ku, Kyoto City, Representative Director: Honoka Kihaya) in May 2020 as a research project.

The USAG-1 protein shares high amino acid homology (97%) among different animal species, including humans, mice, and beagles, and in December 2021, we demonstrated that a single intraoral and intravenous administration of the protein can restore missing teeth in model mice and beagles. Based on these results, we selected the human anti-USAG-1 antibody "TRG035" as our final development candidate.

Clinical trial plan

The development of this therapeutic drug, "TRG035," which aims to regenerate missing or damaged teeth, is a world first, and no similar technology exists in other countries at present. Therefore, we first received face-to-face advice from the Pharmaceuticals and Medical Devices Agency (PMDA) for its regulatory science strategy consultation service to determine the safety, pharmacokinetic, and pharmacological test items required for conducting clinical trials, and began preclinical trials in April 2022.

We have now completed the nonclinical studies and face-to-face consultation with the PMDA required for the first-in-human (FIH) trial, and finalized the protocol outline. Based on this, we plan to conduct the FIH trial in healthy volunteers at the Kyoto University Hospital Department of Early Medical Development [Next Generation Medicine and iPS Cell Therapy Research Center (Sakyo Ward, Kyoto City, Director: Manabu Muto; hereafter, "Ki-CONNECT")] to confirm the safety of TRG035 in humans and identify the appropriate dosage. This clinical trial is being prepared in collaboration with Kitano Hospital, TreGem BioPharma Co., Ltd., and the Japan Agency for Medical Research and Development (AMED).

Future developments

Following the FIH trial, a Phase IIa trial (P IIa trial) is planned to be conducted at Kitano Hospital for patients with congenital edentulism who have six or more congenitally missing teeth (oligodontia, incidence 0.1%), a condition for which there is a significant medical need. Once the efficacy of this trial has been confirmed, we will consider expanding the trial to patients with milder congenital partial edentulism who have one to five congenitally missing teeth (hypodontia, incidence 10%), a condition which also involves the congenital absence of permanent teeth but is believed to be driven primarily by environmental rather than genetic factors.

In Japan, the prevalence of tooth loss is extremely high, at over 58 million patients, primarily elderly people, and there are high hopes for dental regenerative medicine using TRG035 for acquired tooth loss as well. In response to this, we are planning a treatment in the future to regenerate the "third teeth" after permanent teeth through local administration.

Recently, there has been growing interest in preemptive medicine (preventive medicine) aimed at extending healthy life expectancy in a super-aging society. Diet has been highlighted as a way to improve oral frailty, a precursor to general frailty (a state of physical and mental decline due to aging), and the importance of teeth has been reaffirmed. Going forward, we aim to regenerate third teeth in response to common acquired tooth loss due to caries, periodontal disease, trauma, etc., thereby enabling elderly people to eat with their own teeth and leading to a fundamental improvement in oral frailty.

P IIa trial to be conducted at Kitano Hospital after the FIH trial

The expected subjects of the clinical trial areThose aged 2 to 7 years old who are born with four or more congenitally missing teeth"is.

We are currently building a research and development system aimed at practical application in Japan, and have already begun collecting data on clinical trial subjects. If you or a family member falls into any of the following categories, please contact us using the inquiry form below as there is a possibility that you may have congenital edentulism.

Contact for inquiries regarding this matter

We do not accept telephone inquiries from the general public. Please be sure to use the dedicated form.

Inquiries from the public regarding FIH exams

Kyoto University Hospital Inquiry consultation form

Inquiries from the public regarding the P IIa test

Kitano Hospital Congenital Anedentulism Special Site Inquiry form

Media Inquiries

Kitano Hospital Public Relations Department