Technology

Problems to be solved

  • Even today, Parkinson‘s disease and Alzheimer’s disease are difficult to treat effectively but the drug discovery has repeatedly failed.
  • To avoid an additional failure, we need very strong clinical evidence for a new drug candidate.
  • We will tell you why our combination drug (febuxostat + inosine) is so promising.

Strong evidence for Alzheimer’s disease drugs from AI and cohort studies

  • Using AI (artificial intelligence), researchers from Cleveland Clinic and 5 US universities discovered atenolol, febuxostat and pioglitazone from all FDA-approved drugs as effective drugs for Alzheimer’s disease.
  • Big clinical data (over 7 million aged patients/year for 6 years) showed that febuxostat is the most effective to suppress Alzheimer’s disease.

Fig 6 Hazard ratios and 95% confidence interval (CI) for six cohort studies.

From Fang J et al. Artificial intelligence framework identifies candidate targets for drug repurposing in Alzheimer‘s disease. Alzheimers Res Ther. 2022 Jan 10;14(1):7)

Before their report, we had discovered this effect of febuxostat and patented combination drugs.

  • Using our unique drug discovery technology, we discovered the effect of febuxostat in 2015, and patented a combination drug of febuxostat and inosine, which is now in clinical development by us for the treatment of mitochondrial disease, Parkinson’s disease, and Alzheimer’s disease.
  • Due to the issues of patent expiration of each drug, we patented the combination drug with febuxostat and inosine that could be developed as a new drug.

How could we discover the effect of febuxostat before AI?

  • Interestingly around 10% of the body weight, genes and genetic diseases are occupied by “energy-related components”.
  • Thus even in common diseases, around 10% could be “energy-related“; however, no energy-related diseases are known in common diseases so far.
  • Then we found that Parkinson’s and Alzheimer’s diseases are caused by energy depletion and an effective treatment is energy enhancement.
  • We searched for effective methods to enhance energy (ATP) by integrating the data from genes, RNA, proteins, metabolites and patients.

Solutions

  • We found by our unique technology that XOR inhibitors including febuxostat, a gout drug, have mild ATP-enhancing effects.
  • Further, we found, by clinical trials, that the combination of febuxostat and inosine (SGC01) is a superior ATP enhancing drug to febuxostat alone in terms of efficacy and side effects.
  • Patents for the combination drugs have already been granted in U.S., Japan, China, and other countries around the world, eliminating competitors.

XOR inhibitor enhances ATP

  • Several animal experiments and clinical studies by others have shown that febuxostat, an XOR inhibitor, increases ATP and has organ-protecting effects via increasing hypoxanthine.
  • In the mouse model of ischemia-reperfusion injury of kidneys, unlike wild-type mice, neither ATP-enhancement nor nephroprotective effects occurred in HPRT-deficient mice that cannot utilize hypoxanthine (Fujii K, et al. JCI Insight. 2019 Nov 14;4(22)).
  • These results indicate that the beneficial effect of febuxostat is via hypoxanthine (Hx) elevation and Hx is the key compound.

Mechanism of the suppression of Alzheimer’s disease

  • Blood hypoxanthine (Hx) is the best biomarker for ATP enhancement therapy.
  • If so, hypoxanthine is further enhanced by adding inosine, a source of hypoxanthine, from outside the body.
  • The combination drug, unlike the XOR inhibitor alone, is a new drug and can recover development costs.

Combination drug of XOR inhibitor and inosine (new drug)

  • We predicted that the combination of an XOR inhibitor and inosine is a better ATP enhancer than the XOR inhibitor alone in terms of both efficacy and side effects.
  • Furthermore, the combination drug, unlike the XOR inhibitor alone, is a new drug and can recover development costs.

Combination of febuxostat and inosine (SGC01) proved higher efficacy and less side effects.

  • Synergistic effect of simultaneous administration of febuxostat and inosine on elevation of hypoxanthine (Kamatani N, et al. Gout and Nucleic Acid Metabolism 41, 171-181, 2017).
  • Simultaneous administration avoids the risk of hyperuricemia and hypouricemia caused by single administration (Kamatani N, et al. Gout and Nucleic Acid Metabolism 41, 171-181, 2017).

Efficacy and safety of the combined therapy confirmed in mitochondrial disease and Parkinson’s disease

  • We treated two patients with mitochondrial disease with SGC01 for two weeks, and observed marked improvement in essential biomarkers (Kamatani N et al. J Hum Genet. 2019;64:351-353 ）
  • We treated 26 patients with Parkinson’s disease with SGC01 for 2 months, and observed significant improvement in the primary endpoint (MS-UPDRS Part III; Watanabe H et al. Medicine. 99(35):e21576, August 28, 2020).

Market

  • The number of patients with mitochondrial disease is estimated to be 38,000 (based on genes) and 82,000 (based on diabetes) in US, and is increasing due to clinical sequencing.
  • The number of Parkinson’s disease patients in US is estimated to be a million（Yang, W et al. NPJ Parkinsons Dis. 6: 15, 2020), and is increasing because of aging.
  • The number of patients with Alzheimer’s disease is estimated to be 3.8 million in US, and increasing because of aging.
  • ATP enhancers cover a huge market.

Competing projects

  • Many companies are developing drugs for mitochondrial disease and Parkinson’s disease, but few have confirmed their effectiveness in clinical trials
  • None of the companies are developing combination drugs with XOR inhibitors and inosine.
  • Patents for combination drugs of febuxostat and inosine (SGC01) as well as other combinations (XOR inhibitor and hypoxanthine resource) have been granted in Japan, the U.S., China, and other countries around the world, making it possible to protect against other companies.
  • Since our drug development is based on human genetic and clinical data, the success rate is much higher than other drugs.
  • Mitochondria have more than 1,500 proteins, and a drug that replenish a component has only limited effect.

Providing value

  • For mitochondrial disease, which has more than 350 causative genes and does not have effective treatments, our ATP-enhancer is a breakthrough that could bring well-being to many patients with the genetic disease.
  • While all existing drugs for Parkinson’s disease are temporary symptomatic remedies, this combination drug is the first disease-modifying drug (improves the course of the disease).
  • There is no drug that suppresses Alzheimer’s disease, and the oral drug will be an epoch-making new drug.
  • While our drug uses two widely used compounds and therefore has a high success rate, it can be developed as a new drug.