Recently, Sumitomo Pharma of Japan and Racthera jointly announced that they have submitted allogeneic iPS cell-derived dopaminergic neural progenitor cells (generic name:) to the regulatory authorities. Application for production and marketing authorization of raguneprocel, which is used to improve the motor function of patients with advanced Parkinson's disease during the "critical stage". This milestone event marks that the clinical transformation of stem cell regenerative medicine therapy in the treatment of neurological diseases has entered a critical stage, and it is expected to bring the first radical therapy that addresses the problem from the pathological mechanism level to approximately 10 million Parkinson's disease patients worldwide.

Parkinson's disease (PD) is a common neurodegenerative disorder. With the acceleration of population aging, it is estimated that the number of global patients will exceed 25 million by 2050. The core pathological feature of Parkinson's disease is the gradual loss of dopamine-producing neurons in the brain, leading to motor dysfunction. Traditional treatment mainly relies on levodopa drugs, but long-term use can lead to fluctuations in therapeutic effects and complications such as dyskinesia. Especially for patients in the middle and advanced stages, off-stage movement disorders seriously affect the quality of life.

The marketing application of raguneprocel this time is based on the data from the investigator-Initiated Clinical Study (IIT) led by Kyoto University Hospital. The trial results were published in the top international journal Nature in April this year. In the Phase I/II open-label trial conducted in Japan, after 7 patients with moderate to severe Parkinson's disease (aged 50-69 years) received unilateral or bilateral putamen transplantation, a 24-month follow-up showed that:

• In terms of safety: No serious adverse events occurred. All 73 adverse events were mild to moderate. MRI monitoring did not detect excessive graft growth, and 18F-FLT PET imaging confirmed no tumorigenic proliferation.

• In terms of effectiveness: The transplanted cells can survive for a long time and produce dopamine, and the motor symptoms of patients are improved, especially more significantly in the high-dose group. Specifically, among the 6 patients evaluated for therapeutic effect, the average improvement in the MDS-UPDRS III score of 4 patients at the critical stage was 9.5 points (20.4%), and the improvement in the opening stage score of 5 patients was 4.3 points (35.7%). The Hoehn-Yahr stages of 4 patients improved, among which 1 improved by 2 grades. 18F-DOPA PET imaging showed that the average dopaminergic functional signal in the transplantation area was enhanced by 44.7%, and it reached 63.5% in the high-dose group.

As the world's first Parkinson's disease iPS cell therapy to enter the marketing application stage, the research and development process of raguneprocel (DSP-1083) carries significant expectations in the field of regenerative medicine. The core principle of this therapy is to induce pluripotent stem cells (ipscs) to differentiate into dopaminergic neural progenitor cells. After transplantation, they can further mature into functional dopamine neurons in the patient's brain, making up for the neuronal deficiency in the substantia nigro-striatum pathway of Parkinson's disease patients and fundamentally improving motor function disorders.

As early as 2017, the iPS cell therapy research jointly conducted by Sumitomo Pharmaceutical and Kyoto University was included in the SAKIGAKE priority review system of Japan's Ministry of Health, Labour and Welfare. This channel is specifically established for innovative therapies with significant clinical advantages, aiming to accelerate the clinical application of breakthrough medical technologies. This iPS cell therapy has achieved multiple breakthroughs in technology: Using clinical-grade iPS cell lines provided by the CiRA Foundation, combined with the differentiation technology of Kyoto University and Eisai's patented purification process, the purity of dopaminergic progenitor cells in the final product reaches 60%, and it does not contain serotonergic neurons (which can avoid the graft-induced movement disorder caused by traditional fetal tissue transplantation)。

It is worth mentioning that raguneprocel's international layout is advancing simultaneously. In June this year, Sumitomo Pharmaceutical transported live cells derived from iPS cells manufactured in Osaka to the United States. On the 25th of the same month, they were successfully transplanted into patients. This was the first time that Japan had transplanted related cells overseas, and it also accumulated more clinical data for this production and marketing license application.

Looking globally, the field of iPS cell therapy for Parkinson's disease is showing a vigorous development trend. Aspen Neuroscience, an American company, follows the autologous iPS route. Its product pipeline, ANPD001, reprograms the patient's own skin cells to avoid immune rejection and was granted FDA Fast Track designation in 2023.

In China, related enterprises are also actively making plans and promoting clinical research on iPS cell therapy for Parkinson's disease. In April this year, the "NCR201 Injection", a treatment product derived from iPS cells and dopaminergic neural precursor cells (iDAP) developed by Zhongsheng Suyuan, was approved for clinical trials for the treatment of Parkinson's disease. In June, NCR201 was administered to the first patient with early-onset Parkinson's disease (EOPD). The patient was able to get out of bed and move around on the day of the operation after waking up, and could talk freely without any adverse reactions. Seven days after the operation, a CT re-examination showed no intracranial edema or hemorrhage, and the researcher judged that all aspects were in good condition. The patient was discharged smoothly. Prior to this, preliminary clinical data showed that significant therapeutic effects were observed in many PD subjects after administration of NCR201 injection:

• After half a year of treatment, the average daily time of Good ON (onset without troublesome movement disorder) of the patients improved by 89.5% compared with the baseline. • Many patients have achieved a breakthrough effect of "disappearance of the critical stage". The maximum improvement in the MDS-UPDRS III score during the critical period was 52.9%. The Hoehn-Yahr stage decreased by up to 2 grades within half a year, achieving disease reversal.

Vice President Shi Jiong of the First Affiliated Hospital of University of Science and Technology of China pointed out, "NCR201, by precisely supplementing dopaminergic neurons, may achieve a transformation from symptomatic treatment to disease course modification, which is particularly significant for early-onset patients - these patients have a disease course of several decades, and the long-term complications of traditional drug treatment are more prominent."

From Sumitomo Pharmaceutical's submission of the world's first iPS cell therapy marketing application to Zhongsheng Suyuan's breakthrough exploration of NCR201 in early-onset Parkinson's disease, regenerative medicine is rewriting the treatment rules for neurodegenerative diseases. We believe that with the acceleration of industrialization and the accumulation of clinical evidence, the dawn of a "cure" for Parkinson's disease is beginning to emerge - this neural regeneration revolution led by stem cells will eventually unlock the imprisoned bodies of millions of patients.