Hope for a treatment for 'multiple‐system atrophy', an intractable neurological disease: The University of Tokyo demonstrates efficacy of high‐dose coenzyme Q10 supplementation in an investigator‐initiated clinical trial

A research team led by Project Associate Professor Jun Mitsui of the Graduate School of Medicine at the University of Tokyo, Project Professor Shoji Tsuji of the Graduate School of Medicine at the University of Tokyo (also a professor at the Institute of Medical Genomics of the International University of Health and Welfare) and Director Takashi Moritoyo of the Clinical Research Promotion Center at the University of Tokyo Hospital demonstrated the efficacy of high‐dose coenzyme Q10 (ubiquinol) supplementation for treating multiple system atrophy (MSA), an intractable neurological disease, in an investigator‐initiated clinical trial. In the randomized double‐blind trial, which included 139 patients with MSA from 13 institutions in Japan, the ubiquinol treatment group showed a significant decrease in disease progression compared with that in the placebo group. The finding is expected to contribute to new drug development for MSA and was published in the international scientific journal eClinicalMedicine.

MSA is a progressive neurological disease with an average age of onset of the mid‐50s and is registered as a designated intractable disease. The disease mostly occurs sporadically and is characterized by a variety of combinations of autonomic symptoms, cerebellar ataxias (unstable walking, difficulty in speech), parkinsonism (stiffness, tremor, slow movement of limbs) and other issues. The number of patients with MSA in Japan is estimated to be around 12,000. Based on epidemiological studies in Japan, 50% of patients require a walker in 3 years from the onset and a wheelchair in 5 years from the onset.

In a previous study of national survey data, the research team identified two families with familial MSA. With the families' cooperation, a causative gene, COQ2, was identified in both families. COQ2 encodes a biosynthetic enzyme of coenzyme Q10. The team revealed that the level of coenzyme Q10 in the cerebellum of patients with MSA was significantly decreased. Although each allele of COQ2 is inherited from each parent, the team found that both alleles in patients with MSA were variant, which contributed to the onset of MSA. In sporadic MSA, 9.1% of the patients had a variant in one allele, with an odds ratio of 2.9 compared to healthy individuals; this variant was shown to be a risk factor for MSA. Coenzyme Q10 is involved in adenosine triphosphate (ATP) production in mitochondria, and its compound itself is involved in scavenging of reactive oxygen species.

The research team further reported that the levels of coenzyme Q10 in the plasma, cerebrospinal fluid, and cerebellum specimens were decreased in patients with sporadic MSA who did not have the variant. The same results were reported previously by other research groups worldwide.

Based on these previous findings, the research team conducted an investigator‐initiated clinical trial and examined whether high‐dose coenzyme Q10 supplementation could slow the progression of MSA. First, a randomized double‐blind phase 1 trial was conducted to investigate the safety and pharmacokinetics of orally administered coenzyme Q10 (900, 1200, or 1500 mg) in healthy Japanese males. The safety of coenzyme Q10 was compared with that of a placebo, and the levels of coenzyme Q10 in the plasma and cerebrospinal fluid were measured. The results indicated that coenzyme Q10 was safe and confirmed that the group administered 1500 mg achieved the highest plasma concentration.

In the current phase 2 trial, the research team examined the efficacy and safety of coenzyme Q10 among patients. Specifically, in 2018, 139 patients with sporadic MSA from 13 institutions in Japan participated in the study, and 131 patients who met the inclusion criteria were randomly assigned to the coenzyme Q10 (1500 mg/day) or placebo group. The patients were assessed after 48 weeks of oral supplementation. As the primary outcome measure, motor functions in MSA (UMSARS part 2) were assessed. As secondary outcome measures, limitation in activities of daily living (e.g., UMSARS part 1), cerebellar motor impairment (SARA) and the time required to walk 10 meters were assessed.

Participants had an average age of 60 years and were in an early stage of MSA at approximately 3 years after treatment initiation. The average decrease in the primary outcome measure UMSARS part 2 score was 7.1 in the placebo group, whereas this value was 5.4 in the coenzyme Q10 group (progression suppressed by approximately 25%). In secondary outcome analyses, although the activities of daily living did not improve significantly, the progression of cerebellar motor impairment and deterioration in the time required to walk 10 meters were significantly reduced in the coenzyme Q10 group compared with those in the placebo group. These results remained significant when the patients were stratified based on their characteristics.

Although the effect of coenzyme Q10 was not associated with MSA disease duration, Q10 is expected to be effective even when administered after disease onset. The most common adverse events and adverse effects were digestive symptoms such as vomiting and diarrhea, none of which was serious. Given that the reduction in the deterioration of motor functions reassessed in UMSARS part 2 remained significant at four weeks after the end of the study treatment, coenzyme Q10 supplementation appears to be a disease‐modifying therapy rather than a symptomatic therapy. The research team will further consult with the Pharmaceuticals and Medical Devices Agency (PMDA) to pursue a phase 3 trial or drug development in cooperation with industry.

Journal Information
Publication: eClinicalMedicine
Title: High‐dose ubiquinol supplementation in multiple‐system atrophy: a multicentre, randomised, double‐blinded, placebo‐controlled phase 2 trial
DOI: 10.1016/j.eclinm.2023.101920