Sarconeos: Nature’s solution to age-related muscle degeneration

Highlights:

• Sarconeos is a medication that has been developed to address age-related muscular atrophy
• It works by enhancing protein synthesis and energy production in muscles in addition to reducing fat mass and adipocyte diameter

• The target of Sarconeos is the MAS1 receptor, which plays a role in muscle anabolism and inhibition of myostatin through its activity on the renin-angiotensin system
• Results from clinical studies demonstrate promising outcomes for the use of Sarconeos in sarcopenia

Introduction

Sarcopenia is a term derived from two Greek words, "Sarco," meaning flesh, and "penia," meaning poverty. It describes an age-related progressive loss of muscle mass leading to adverse outcomes like increased risk of falls, functional decline, and frailty. This term was first introduced in the 1980s and received formal recognition as a disease in 2016. The age-related decline in muscle tissue is frequently accompanied by an increase in fat mass, leading to what is known as sarcopenic obesity. In 2012, the journey aiming at screening and discovering drug and nutraceutical candidates for targeting sarcopenic obesity started.

The road to Sarconeos

The SARCOB program, a consortium of 5 French academic laboratories with two companies, was initiated in 2012. The academic partners involved in this program were Université Pierre et Marie Curie, AgroParisTech, and INRA Clermont Ferrand. The two companies were Biophytis and Metabrain Research, with the former being the program lead (1). The goal of the consortium was to find candidate treatments for sarcopenic obesity (a class of obesity in older adults that is characterized by low skeletal mass coupled with high fat levels). The program lasted for two years and managed to identify potential candidate molecules. Several phytoecdysones (secondary plant metabolites) passed the screening process.

The most abundant phytoecdysone is 20-hydroxyecdysone (a steroid hormone). In mammals, this molecule was found to benefit several cardiovascular parameters. It was also found to increase muscle mass and strength, reduce inflammation, act as antidiabetic, and reduce adipose tissue development (1, 2). This made the molecule a strong candidate that could be pursued for further development.

Where does the active ingredient in Sarconeos come from?

The active ingredient in Sarconeos capsules is 20-hydroxyecdysone, a compound extracted from an edible plant, Stemmacantha carthamoides (3, 4). In plants, 20-hydroxyecdysone is believed to act as a deterrent for invertebrate predators (2). The said hormone plays a key role in arthropods development through influencing nuclear ecdysone receptors (a receptor found in arthropods (like spiders, horseshoe crab, and bees) and plays a role in development and reproduction).

In mammals, the receptor mentioned above is lacking, but 20-hydroxyecdysone exerts a role manifested in protein synthesis and energy production in muscles (2, 4). In addition to the previous, the compound was found to stimulate erythrocyte production, reduce cholesterol levels, decrease triglyceride lipase activity, and possess immunomodulatory actions, among others. For example, studies on mice models showed that 20-hydroxyecdysone prevents the increase in the fat mass and adipocyte diameter (2).

Based on its desirable effect on muscle mass and other useful properties, Sarconeos was developed. The molecule was designed to treat/prevent muscle-related pathologies like sarcopenia (3).

About Sarconeos and how it works

Sarconeos (BIO101) is an oral, first-in-class drug that plays a role in muscle metabolism. As mentioned earlier, the active ingredient in Sarconeos is 20-hydroxyecdysone. According to preclinical studies, Sarconeos works by activating the MAS1 receptor in muscle cells, a key player in the renin-angiotensin system (RAS) (3, 5). The RAS system plays a role in controlling fluid balance in the body and influences blood pressure. In addition, RAS is involved in regulating muscle metabolism and plays a role in muscle function and mobility (5). Activation of the MAS receptor has been found to promote muscular anabolism (biosynthesis) and inhibit myostatin (a protein released by muscle cells that acts by inhibiting their growth).

Understanding and characterizing the receptor that 20-hydroxyecdysone works on to perform its action was not an easy task. To elucidate the pathway, mouse myoblast cell line and in vivo mice models were utilized (4). On the cell line, the anabolic activity of 20-hydroxyecdysone was demonstrated, where the bioactive compound resulted in a significant enlargement in myotube (muscle fiber) diameter in a manner similar to insulin-like growth factor-1 (2, 4, 6). The effect of 20-hydroxyecdysone is mediated by the inhibition of myostatin gene expression. Further investigation revealed that downregulation of the MAS receptor gene prevented 20-hydroxyecdysone from inhibiting the activity of the myostatin gene, suggesting MAS as the target receptor (4). Finally, in vivo models revealed that oral supplementation of the aforementioned molecule resulted in increased protein production and decreased myostatin gene expression in the soleus muscle. This was accompanied by an improvement of several myogenesis markers, like MyoD (a protein that plays a major role in myogenesis and regulates muscle differentiation).

About Biophytis (the product owner)

Biophyitis is clinical-stage biotechnology company that develops therapeutic agents aimed at slowing down the degenerative effects resulting from the aging process and improving the functional capacity. Currently, the company has two candidate molecules in its pipeline (7).

The first molecule is Sarconeos (BIO101), which is being investigated in 3 programs. The first program is called the COVA program, where Sarconeos has passed preclinical, phase 1, and phase 2 and is currently in phase 3 trial. This program is investigating the role of Sarconeos in COVID-19 patients. The second program for Sarconeos is the SARA (SARcopenia and sarcopenic obesity in patients Aged ≥ 65 years) program, which has finished preclinical, phase 1, and is currently at the end of phase 2 studies. This program is intended to explore the role of the medication in treating sarcopenia. The third program is the MYODA program, which is investigating the drug as a treatment option for Duchenne muscular dystrophy (DMD) (a rare, severe, progressive, genetic muscular disease that is characterized by muscle weakness causing difficulties in movement, and at later stages breathing troubles and premature death) (7, 8). As part of this program, Sarconeos has received an orphan drug designation (ODD) by the Food and Drug Administration and the European Medicines Agency (7). ODD status is given to certain drugs that show promise in treating, preventing, or diagnosing orphan diseases (rare conditions affecting 200,000 people or less according to US definition) (9). The MYODA program has finished the preclinical stage.

The second molecule developed by the company is Macuneos (BIO201), which is still in the preclinical stage (7). 

Sarconeos in clinical studies

Encouraging preclinical results have paved the road for testing of the medication on humans. The clinical program designed to test the efficacy of Sarconeos entailed three main studies, including SARA-PK (the phase 1 study that allowed selection of doses for SARA-INT and assessed the pharmacokinetic profile), SARA-OBS (an observational study that allows the characterization of population and main parameters of SARA-INT), and SARA-INT (interventional study evaluating safety and efficacy in older individuals (10).  

Results from the SARA-PK program have found that Sarconeos was safe and well tolerated after oral administration to healthy old volunteers (11). Assessment of pharmacokinetic profile revealed that the medication has a short half-life and no plasma accumulation, making it suitable for twice-daily administration. The outcomes of this study determined that the dose can be up to 1400 mg/day in single administration (10).

Before initiating the clinical studies, there was a need to characterize and determine the patient population and inclusion criteria suitable for trialing the medication (12, 13). This was the objective of the SARA-OBS program. This observational study enrolled 300 individuals aged 65 years and older at risk of mobility disability in 8 sites across Europe and the United States (14). This study characterized sarcopenia using NIH foundation criteria, entailing grip strength and lean mass as points to determine weakness (14, 15). In addition, the investigators used the short physical performance battery test (SPPB), which evaluates balance, gait, strength, and endurance using a series of tests (14, 16). Results of the study revealed that the aforementioned recruitment criteria were suitable and could be used to select patients for the study (17, 18). For example, recruited patients demonstrated a high body mass index, which was aligned with other large clinical studies examining sarcopenia. The SPPB score indicated that patients were at risk of mobility and disability as the results were comparable to other trials. Other used parameters like gait speed, among others, validated the selection criteria, making many patients from this study eligible to advance to the SARA-INT (17, 18).

Initial clinical studies on obese individuals highlighted that compared to placebo, 20-hydroxyecdysone had better results in terms of fat mass and adipocyte diameter reduction and improved insulin sensitivity (3, 12). Results from the SARA-INT study revealed that Sarconeos shows promising outcomes in slowing down disease progression and clinical improvement of mobility, disability, and mortality (3). In addition, the medication has a very good safety profile.

Conclusions

Sarconeos resulted from the fruitful collaboration of commercial and laboratory research centers and aimed to address sarcopenia and other conditions. Preclinical study results highlighted beneficial outcomes of its active constituent 20-hydroxyecdysone, prompting the development of clinical studies to test its efficacy. This molecule was developed by Biophyitis, a biotechnology company that has this medication and others in its pipeline. The development of Sarconeos entailed three programs, which tested all aspects, from identifying the properties of the medication to selecting the suitable population to pursue clinical testing. It provides hope for the treatment of age-related muscle degeneration.

References

1.            ICFSR 2014 International Conference on Frailty and Sarcopenia Research March 12-14, 2014 Barcelona, Spain Frailty-sarcopenia.com: International Conference on Frailty and Sarcopenia Research; 2014 [cited 2022 24-03]. Available from: https://frailty-sarcopenia.com/ABSTRACT-ICFSR-2013.pdf.

2.            Dinan L, Dioh W, Veillet S, Lafont R. 20-Hydroxyecdysone, from plant extracts to clinical use: Therapeutic potential for the treatment of neuromuscular, cardio-metabolic and respiratory diseases. Biomedicines. 2021;9(5):492.

3.            Sarconeos - Biophytis adisinsight.springer.com: Springer; 2022 [updated 08-Feb-2022; cited 2022 24-03]. Available from: https://adisinsight.springer.com/drugs/800045685.

4.            Abstracts of the 8th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Paris, France, 4-6 December 2015. Journal of Cachexia, Sarcopenia and Muscle. 2015;6(4):398-509.

5.            Sarconeos (BIO101) Biophytis.com: Biophytis; 2022 [cited 2022 24-03].

6.            Gorelick-Feldman J, MacLean D, Ilic N, Poulev A, Lila MA, Cheng D, et al. Phytoecdysteroids increase protein synthesis in skeletal muscle cells. Journal of agricultural and food chemistry. 2008;56(10):3532-7.

7.            Biophytis: Biophytis; 2022 [cited 2022 25-03]. Available from: https://www.biophytis.com/en/.

8.            Duan D, Goemans N, Takeda Si, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nature Reviews Disease Primers. 2021;7(1):13.

9.            Sharma A, Jacob A, Tandon M, Kumar D. Orphan drug: Development trends and strategies. Journal of pharmacy & bioallied sciences. 2010;2(4):290-9.

10.          Abstracts of the 10th International Conference on Cachexia, Sarcopenia and Muscle Wasting, Rome, Italy, 8–10 December 2017 (Part 1). Journal of Cachexia, Sarcopenia and Muscle. 2017;8(6):999-1080.

11.          Dioh WG, Phillippe. Singore, Susanna Del. Lafont, Rene. SARA-PK: A single and multiple ascending oral doses to assess the safety and evaluate the pharmacokinetics of BIO101 in healthy young and older volunteers.: Biophytis; 2017 [cited 2022 26-03]. Available from: https://www.biophytis.com/wp-content/uploads/2019/02/Biophytis-2017-Oral-and-poster-presentation-at-ICFSR-April-27-29-2017-Dioh-et-al.pdf.

12.          ICFSR-2016-Abstracts. The Journal of Frailty & Aging. 2016;5:1-114.

13.          Dioh WG, Phillippe. Singore Susanna Del. Lafont, Rene. A randomized, placebo-controlled trial to evaluate the efficacy and safety of BIO101 on Sarcopenic Obesity. The Journal of Frailty & Aging2016 [cited 2022 26-03]. Available from: https://www.biophytis.com/wp-content/uploads/2019/02/Biophytis-2016-Poster-presentation-at-ICFSR-April-28-29-2016-Dioh-et-al.pdf.

14.          To CBAHT, Older IMIH. SARA-OBS CLINICAL TRIAL: BASELINE CHARACTERISTICS OF SARCOPENIA/SARCOPENIC OBESITY IN THE ELDERLY. Innovation in Aging. 2017;1(S1):355.

15.          Studenski SA, Peters KW, Alley DE, Cawthon PM, McLean RR, Harris TB, et al. The FNIH sarcopenia project: rationale, study description, conference recommendations, and final estimates. J Gerontol A Biol Sci Med Sci. 2014;69(5):547-58.

16.          Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol. 1994;49(2):M85-94.

17.          Dioh W, Margalef C, Dupont P, Dilda P, Lafont R, Veillet S, et al. SARA Clinical program for evaluating safety and efficacy of Sarconeos in a Phase 2b clinical trial. Age.78:7-86.

18.          Dioh W, Margalef C, Lafont R, Dupont P, Dilda P, Zia G, et al. SARA-INT, A double-blind, placebo controlled, randomized clinical trial to evaluate safety and efficacy of Sarconeos (BIO101).

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