International multicenter randomized, placebo-controlled phase III clinical trial of β-d-mannuronic acid in rheumatoid arthritis patients
The oral administration of drug β-d-mannuronic acid (M2000) showed a potent therapeutic effect in phase I/II study in rheumatoid arthritis (RA) patients. Here, our aim is to assess the efficacy and safety of this new drug in RA patients under a multinational, randomized placebo-controlled phase III clinical trial.
Patients (n = 288) with active disease at baseline and inadequate response to conventional drugs were randomly allocated to three groups; (1) receiving mannuronic acid at a dose of two capsules (500 mg) per day orally for 12 weeks, (2) placebo-controlled, and (3) conventional. The primary endpoints were the America College of Rheumatology 20 response (ACR20), 28-joint disease activity score (DAS28) and Modified Health Assessment Questionnaire-Disability Index (M-HAQ-DI). In addition, the participants were followed-up for safety assessment.
In this phase III trial, after 12 weeks of treatment, there was a significant reduction in ACR20 between mannuronic-treated patients compared to placebo and conventional groups. Moreover, there was a similar significant improvement for DAS28 following mannuronic therapy. The statistical analysis showed a significant reduction in the swollen and tender joint count in mannuronic-treated patients compared with the placebo group. On the other side, mannuronic acid showed no-to-very low adverse events in comparison to placebo.
The results of this multinational, phase III clinical trial provided a potent evidence base for the use of β-d-mannuronic acid as a new highly safe and efficient drug in the treatment of RA.
KeywordsMannuronic acid M2000 Rheumatoid arthritis DMARDs NSAIDs Clinical III trial
We should appreciate from the medical personnel and provided facilities by the Ghaem Hospital in Mashhad, Loghman Hakim Hospital, Imam Khomeini Hospital, Imam Hossein Hospital in Tehran, Shahid Sadoughi Hospital in Yazd and Department of Rheumatology at Pakistan Institute of Medical Sciences in Islamabad, Pakistan.
Compliance with ethical standards
Conflicts of interest
The authors declare no conflict of interest.
- Ahmadi H, Jamshidi AR, Mahmoudi M et al (2017) Hematological improvement of patients with active rheumatoid arthritis by β-d-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property. Iran J Allergy Asthma Immunol 16:433–442Google Scholar
- Barati A, Jamshidi AR, Ahmadi H et al (2017) Effects of β-d-mannuronic acid, as a novel non-steroidal anti-inflammatory medication within immunosuppressive properties, on IL17, RORγt, IL4 and GATA3 gene expressions in rheumatoid arthritis patients. Drug Des Devel Ther 11:1027–1033. https://doi.org/10.2147/DDDT.S129419 CrossRefGoogle Scholar
- Calabresi E, Petrelli F, Bonifacio A et al (2018) One year in review 2018: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 36:175–184Google Scholar
- Farahani MM, Motevaseli E, Maghsood F et al (2017) Anti-inflammatory property of β-d-mannuronic acid (M2000) on expression and activity of matrix metalloproteinase-2 and-9 through CD147 molecule in phorbol myristate acetate-differentiated THP-1 cells. Iran J Allergy Asthma Immunol 16:443–451Google Scholar
- Fattahi MJ, Jamshidi AR, Mahmoudi M et al (2018b) Evaluation of the efficacy and safety of β-d-mannuronic acid in patients with ankylosing spondylitis: a 12-week randomized, placebo-controlled, phase I/II clinical trial. Int Immunopharmacol 54:112–117. https://doi.org/10.1016/j.intimp.2017.11.003 CrossRefGoogle Scholar
- Hartman L, Rasch LA, Klausch T et al (2018) Harm, benefit and costs associated with low-dose glucocorticoids added to the treatment strategies for rheumatoid arthritis in elderly patients (GLORIA trial): study protocol for a randomised controlled trial. Trials 19:67. https://doi.org/10.1186/s13063-017-2396-3 CrossRefGoogle Scholar
- Hosseini S, Abdollahi M, Azizi G et al (2017) Anti-aging effects of M2000 (β-d-mannuronic acid) as a novel immunosuppressive drug on the enzymatic and non-enzymatic oxidative stress parameters in an experimental model. J Basic Clin Physiol Pharmacol 28:249–255. https://doi.org/10.1515/jbcpp-2016-0092 CrossRefGoogle Scholar
- Jahanbakhshi M, Babaloo Z, Mortazavi-Jahromi SS et al (2018) Modification of sexual hormones in rheumatoid arthritis patients by M2000 (β-d-mannuronic acid) as a Novel NSAID with immunosuppressive property. Endocr Metab Immune Disord Drug Targets 18:530–536. https://doi.org/10.2174/1871530318666180418111354 CrossRefGoogle Scholar
- Mirshafiey A, Khorramizadeh MR, Saadat F et al (2004) Chemopreventive effect of M2000, a new anti-inflammatory agent. Med Sci Monit 10:105–109Google Scholar
- Mirshafiey A, Cuzzocrea S, Rehm B et al (2005a) M2000: a revolution in pharmacology. Med Sci Monit 11:Pl53–Pl63Google Scholar
- Mortazavi-Jahromi SS, Jamshidi MM, Farazmand A et al (2017) Pharmacological effects of β-d-mannuronic acid (M2000) on miR-146a, IRAK1, TRAF6 and NF-κB gene expression, as target molecules in inflammatory reactions. Pharmacol Rep 69:479–484. https://doi.org/10.1016/j.pharep.2017.01.021 CrossRefGoogle Scholar
- Mortazavi-Jahromi SS, Alizadeh S, Javanbakht MH et al (2018a) Anti-diabetic effect of β-d-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property on insulin production, blood glucose, and inflammatory markers in the experimental diabetes model. Arch Physiol Biochem. https://doi.org/10.1080/13813455.2018.1481094 Google Scholar
- Mortazavi-Jahromi SS, Alizadeh S, Javanbakht MH et al (2018b) Cardioprotective effect of β-d-mannuronic acid (M2000) as a novel NSAID on gene expression of oxLDL scavenger receptors in the experimental diabetic model. Immunopharmacol Immunotoxicol 40:284–289. https://doi.org/10.1080/08923973.2018.1455209 CrossRefGoogle Scholar
- Pourgholi F, Hajivalili M, Razavi R et al (2017) The role of M2000 as an anti-inflammatory agent in toll-like receptor 2/microRNA-155 pathway. Avicenna J Med Biotechnol 9:8–12Google Scholar
- Taeb M, Jafarzadeh A, Mortazavi-Jahromi SS et al (2018) Effect of β-d-mannuronic acid (M2000) on oxidative stress enzymes’ gene using healthy donor peripheral blood mononuclear cells for evaluating the anti-aging property. Curr Drug Discov Technol. https://doi.org/10.2174/1570163815666180515122834 Google Scholar
- Wilsdon TD, Hill CL (2017) Managing the drug treatment of rheumatoid arthritis. Aust Prescr 40:51–58. https://doi.org/10.18773/austprescr.2017.012.40:51 CrossRefGoogle Scholar