Development of Mecasin, a drug for a rare disease, Lou Gehrig's disease (ALS)

 

Since 2007, the Rare Diseases Europe (EURORDIS) designated the last day of February—either the 29th or 28th—as World Rare Disease Day, based on the “rare” date of February 29, which comes every four years. Events related to this day are held in about 80 countries to raise the awareness of rare and incurable diseases and help the patients in need. Rare disease refers to an incurable disease which only a few suffer from. It either has no cure or its diagnosis and treatment are unclear. Up to now, the number of rare diseases reported by the World Health Organization (WHO) is 7,000, and there are as many as 250 million patients worldwide. 

In Korean Medicine, the treatment for rare and incurable diseases is handled in various medical books, including the Yellow Emperor's Classic of Medicine, It has achieved performance in treating various rare and incurable diseases—including the Lou Gehrig's disease—to deal with the discomforts arising from rare diseases and delay progression of the disease, and therefore, improve highly their quality of life through preventing progress, relieving symptoms and increasing physical strength.

 Lou Gehrig's disease, which is one of the rare and incurable diseases, is a progressive motor neuron disease and the most destructive and aggressive disease1) with an average life span of three to four years from the date of onset and one and a half years from the date of diagnosis. The disease, also called as amyotrophic lateral sclerosis (ALS), is the most common form of progressive motor neuron diseases. It is the most rapidly progressing neurodegenerative disease which shows gradual and severe muscle weakness due to degenerative changes in cerebral cortex, brain stem and spinal motor nerves, and eventually death from respiratory muscle paralysis (see Figure 1).

1. Gordon PH etc. Progression in ALS is not linear but is curvilinear. J Neurol, 2010;257(10):1713-7.

Figure 1. Degenerative changes of lower motor neurons observed during special MRI scan

 The only treatment medicine for ALS used today is Riluzole, a glutamic acid inhibitor, the only drug approved by the FDA (and by the Ministry of Food and Drug Safety (MFDS) of Korea.) Although daily oral administration of 100mg of Riluzole is recognized for its short life extension effect2) of about two months, serious side effects such as drug-induced hepatitis, neutropenia, and interstitial lung disease (ILD) have been reported3).

 

2. Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 ;4(3):191-206.

3. Drug manufacturing (import) item authorization change order classification No. 119. Riluzole single drug (oral). Pharmaceutical Management Division, Ministry of Food and Drug Safety (MFDS). 2009.

 Therefore, in order to make a difference from the existing Riluzole as a drug for ALS, a research team in Wonkwang University has developed a drug that suppresses disease progression and improves symptoms; a drug that has long-lasting therapeutic effects and no side effects nor toxicity based on Evidence-Based Medicine (EBM). * Based on the Korean Medicine leading technology development project (Ministry of Health and Welfare) led by Professor Sungchul Kim.

 

 The team has collected and analyzed references on herbal raw materials and composites reported to reduce neuroinflammation, promote neuroprotection and the growth of nerve stem cells, and improve symptoms such as muscle stiffness, muscle pain, and muscle cramps. As a result, they have selected nine Herbal Medicines—peony, licorice, pulvis aconiti tuberis purificaum, turmeric, gastrodia elata, red sage, mokgwa, atractylodes root, and polygala tenuifolia—and developed Mecasin (KCHO-1) composite using clinical data and repeating nonclinical efficacy tests on patients at the ALS ward of the Rare Incurable Neurodegenarative Disease Center at Wonkwang University, Gwangju Medical Center.

Figure 2.  Manufacturing process of Mecasin(KCHO-1)

 Mecasin is a drug that affects nerves from the peripheral to the central nervous system, and is a complementary medicine developed for the first time in Korea to supplement the modern drugs. It was named KCHO-1 because of its protein production of Heme Oxigenase-1 (HO-1) and it has a mechanism protecting the brain nerves.

  In Korean Medicine, degenerative motor neuron disease (ALS) is a disease belonging to numbness which occurs in a state where the body is weakened with qi-stagnancy during Yin and Yang deficiency. It is characterized by fasciculation, and in Korean Medicine, it is referred to as a muscle twitch caused by Yang deficiency. Therefore, in Gamidaebotang**, which is known to treat Yin and Yang deficiency in Bangyak Hapyeon*, four Herbal Medicines—peony, mokgwa, pulvis aconiti tuberis purificaum, and licorice—were used as a basis, and five other safe herbal medicines, which are widely used for treating numbness, were selected. The original prescription was developed based on the Jakyakgamchotang of Shang Han Lun and Junggyeong Jakyakgamchobujatang of Gyeongyakjeonseo***, which is one of Korean & China traditional medicine books6-7).

  Among the degenerative diseases, the most frequent diseases include Alzheimer's and Parkinson's disease, and rare and incurable diseases include ALS and cerebellar degeneration. In the progress, combined diseases of two or more may occur, resulting in a combination of Parkinson's disease and ALS , or ALS accompanied by Frontotemporal dementia (FTD). Therefore, it can be assumed that ALS is not caused by a single cause, but by a combination of various causes.

*Bangyak Hapyeon: A medical book published by Hwang Pil-soo in 1884 (the 21st year of King Gojong) in accordance with the will of medical scientist Hwang Do-yeon.

Source: Encyclopedia of Korean Culture

**Gamidaebotang: One of the prescriptions of Korean Medicine. Gamidaebotang controls weakened qi and blood, and the right and left limbs which are paralyzed by a stroke. Source: Doopedia

***Gyeongyakjeonseo: This book was created by getting the main contents from the medical book Gyeongakjeonseo (景岳全書), which was written by Gyeongak, a medical doctor at the end of the Ming Dynasty.

 

The drug developed with a single component and a single mechanism for degenerative diseases with various causes and symptoms are bound to have treatment limits.

In order to solve this problem, the research team tried to find a clue to the solution from the Korean Medicine, a millennium medicine. As a result, the patients’ quality of life was enhanced by improving various symptoms and prolonging their life. Also, because Riluzole, a medication for ALS, cannot fundamentally protect motor neuron cells, the disease continues to progress. Therefore, it was hypothesized that if the co-administration of standard drugs for ALS, Riluzole, and Mecasin, showed a synergistic effect, it would be possible to suppress the disease progression by reducing the side effects of western medicines and improving various symptoms, while maintaining the minimum dose of western medicines. In addition, Mecasin was developed as the optimized solution to solve various symptoms of degenerative brain diseases (see Figure 2) at once—weakened immune system, memory loss, reduced motor skills, muscle weakness, sleep disorders, digestive disorders (including constipation), pain, depression and anxiety, and poor circulatory and lymphatic system.

Figure 3. Various symptoms in patients with degenerative brain diseases

 Mecasin, a candidate substance treatment for ALS in Korean medicine, was developed through this process. It obtained domestic and international patent approval (PCT) as a composition for the prevention or treatment of degenerative neurological diseases and was patented in the United States in 2019 as a composition for treating degenerative neurological diseases (see Figures 3 and 4).

Figure 4. US Patent of Mecasin (2019)

 According to the studies on Mecasin published in 11 international journals, it was proved that Mecasin increased the expression of antioxidant genes to protect neurons and to have anti-inflammatory effects in the ALS animal model, therefore showing effects on life extension and pain reduction.

 Cell experiments with Mecasin showed the same anti-inflammatory effect by increasing the expression of heme-oxygenase (HO-1) in brain immune cells (BV2 cells) which was conducted in a concentration-dependent manner in an intervention study by Mecasin concentration and antioxidant activity that protects memory cells from oxidative damages.8,9

 

8. Dong-Sung Lee, Sungchul Kim etc. KCHO-1, a Novel Antineuroinflammatory Agent, Inhibits Lipopolysaccharide-Induced Neuroinflammatory responses through Nrf2-Mediated Heme Oxygenase-1 expression in Mouse BV2 Microglia Cells. Evidence-Based Complementary and Alternative Medicine. 2014 : 1-5.

9. Dong-Sung Lee, Wonmin Ko, Youn-chul Kim, Sungchul Kim etc., The herbal extract KCHO-1 exerts a neuroprotective effect by ameliorating oxidative stress via heme oxygenase-1 upregulation. Molecular Medicine Reports. 2016;13: 4911-4919.

In the various studies on its safety (see Table1), Mecasin was evaluated safe, as it did not show any toxicity in the single oral administration, and repeated oral administration tests for 4 weeks, 13 weeks, and 26 weeks, and, at the same time, in the animal toxicity test in the form of pharmacopuncture.

 

Table1. Results of safety assessment of Mecasin

 According to the clinical trial design16) based on the above evidence, the results of Phase 2a clinical trial showed that the degree of inhibition of disease progression—which was analyzed statistically—was significantly higher in the co-administration group (Mecasin and Riluzole) than in the placebo group (Riluzole administration group). This means that there was a delay in disease progression and an improvement in symptoms, and also secured its safety according to drug administration of the co-administration group of Riluzole and western medicines (see Figure 5.) Therefore Mecasin can slows progression of ALS and extends lifespan.

 

16. Sungha Kim, Jae Kyoun Kim, Mi Ju So, Dongwoung Kim, Bongkeun Song, Ilhong Son, Hyung Won Kang, Jongdeok Lee, Sungchul Kim, Mecasin treatment in patients with amyotrophic lateral sclerosis: study protocol for a randomized controlled trial. Trials. 2018;19:225.

 

Figure 5. Comparison of the effects of co-administration group (Mecasin and Riluzole) and placebo group (Riluzole administration group)

 

Before We End

 During the COVID-19 crisis, what our society absolutely needed was “a medical system that works quickly under thorough preparation.” With how Korea stay alerted and how the country established a medical system that quickly responds to unexpected outbreak of diseases, such as viral diseases, could be the factors of how the so-called “K-quarantine” was proved. We must as quickly as possible create a Korean medical system with “a business cluster of rare and incurable diseases,” in which the local governments actively take the lead and the Korean government gets fully prepared by operating such medical system for rare and incurable diseases even there may be a small number of patients.

<Source>

 NIKOM Report of Korean Medicine Policy (No. 1, Volume 5. 2020), Professor Kim Sung-cheol, President of the Korean Medicine Society of Rare Incurable and Severe Disease and Professor at Wonkwang University Professional Graduate School of Korean Medicine.

< References >

1. Gordon PH etc. Progression in ALS is not linear but is curvilinear. J Neurol, 2010;257(10):1713-7.

2. Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 ;4(3):191-206.

3. Drug manufacturing (import) item authorization change order classification No. 119. Riluzole single drug (oral). Drug Administration Division, Ministry of Food and Drug Safety 2009.

4. Kim HY, Kim H, Oh KW, Oh SI, Koh SH, Baik W, Noh MY, Kim KS, Kim SH. Biological markers of mesenchymal stromal cells as predictors of response to autologous stem cell transplantation in patients with amyotrophic lateral sclerosis: an investigator-initiated trial and in vivo study. Stem Cells. 2014;32(10):2724-31.

5. Hwang Do-yeon. Dialectical logic pharmacopoeia. Seoul, Namsandang. 2005:429.

6. Chae In-sik. Translated edition of Shang Han Lun. Seoul, Komoonsa. 1987 : 64.

7. Jang Gae-bin, Gyeongakjeonseo (Volume two). Seoul, Daeseong Publisher. 2010 : 645.

8. Dong-Sung Lee, Sungchul Kim etc. KCHO-1, a Novel Antineuroinflammatory Agent, Inhibits Lipopolysaccharide-Induced Neuroinflammatory responses through Nrf2-Mediated Heme Oxygenase-1 expression in Mouse BV2 Microglia Cells. Evidence-Based Complementary and Alternative Medicine. 2014 : 1-5.

9. Dong-Sung Lee, Wonmin Ko, Youn-chul Kim, Sungchul Kim etc., The herbal extract KCHO-1 exerts a neuroprotective effect by ameliorating oxidative stress via heme oxygenase-1 upregulation. Molecular Medicine Reports. 2016;13: 4911-4919.

10. Kook MG, Choi SW, Seo Y, Kim DW, Song BK, Son I, Kim SC, Kang KS. KCHO-1, a novel herbal anti-inflammatory compound, attenuates oxidative stress in an animal model of amyotrophic lateral sclerosis. J Vet Sci. 2017;18(4):487–497.

11. HohyunJeong, Jongchul Lee, Eunhye Cha, Manyong Park, Ilhong Son, Bongkeun Song, Sungchul Kim. A Study on the Oral Toxicity of Mecasin in Rats. Journal of Pharmacopuncture. 2014;17(4):61-65.

12. Eunhye Cha, Jongchul Lee, Seongjin Lee, Manyong Park, Inja Song

,Ilhong Son, Bong-Keun Song, Dongwoung Kim, Jongdeok Lee, Sungchul Kim. A 4-week Repeated dose Oral Toxicity Study of Mecasin in Sprague-Dawley Rats to Determine the Appropriate Doses for a 13-week, Repeated Toxicity Test. Journal of Pharmacopuncture. 2015;18(4):45-50.

13. Yang M, Lee S, Wang T, Cha E, Jang J, Kim D, Song BK, Son I, Kim J, Kang HW, Kim S. 26-Week Repeated Dose Oral Toxicity Study of KCHO-1 in Sprague-Dawley Rats. J Pharmacopuncture. 2019;22(3):192-199.

14. Cha EH, Jeong HH, Lee JC, Lee SJ, Park MY, Kim SC. A study on single dose toxicity of Mecasinpharmacopuncture injection in muscle. J Korean Med. 2015; 36(2): 36-42.

15. Lee SJ, Jeong HH, Lee JC, Cha EH, Park MY, Song BG, Son H, Kim SC. A study on single dose toxicity of intravenous injection of mecasin herbal acupuncture. J Korean Acupunct Moxibustion Med. 2016;33(1):1–7.

16. Sungha Kim, Jae Kyoun Kim, Mi Ju Son,, Dongwoung Kim, Bongkeun Song, Ilhong Son, Hyung Won Kang, Jongdeok Lee, Sungchul Kim, Mecasin treatment in patients with amyotrophic lateral sclerosis: study protocol for a randomized controlled trial. Trials. 2018;19:225.

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