International multicenter randomized, placebo-controlled phase III clinical trial of β-d-mannuronic acid in rheumatoid arthritis patients

Rezaieyazdi, Zahra; Farooqi, Abid; Soleymani-Salehabadi, Hossein; Ahmadzadeh, Arman; Aslani, Mona; Omidian, Saiedeh; Sadoughi, Arezoo; Vahidi, Zohreh; Khodashahi, Mandana; Zamurrad, Shazia; Mortazavi-Jahromi, Seyed Shahabeddin; Fallahzadeh, Hossein; Hosseini, Mostafa; Aghazadeh, Zahra; Ekhtiari, Parvin; Matsuo, Hidenori; Rehm, Bernd H. A.; Cuzzocrea, Salvatore; D’Aniello, Antimo; Mirshafiey, Abbas

doi:10.1007/s10787-018-00557-2

Cited by 15 publications

(18 citation statements)

References 34 publications

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“…High efficacy and safety of M2000 have been confirmed in phases I and II clinical trials on patients with RA and AS (Ahmadi et al, ; Fattahi et al, ). In a multinational randomized phase III clinical trial on RA patients, oral administration of M2000 (500 mg/kg twice a day) for 12 weeks was associated with beneficial therapeutic effects and no side effect in these patients (Rezaieyazdi et al, ). Based on the positive effects of M2000 on the expression of miR‐155, SOCS1, SHIP1, and NF‐κB genes in the HEK293‐TLR2 cell line, shown in a previous study (Pourgholi et al, ), we investigated the effects of this drug on the expression of the mentioned genes and the severity of inflammation in RA patients not responding to conventional drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Compared to Diclofenac, Piroxicam, and Dexamethasone, the oral or intraperitoneal administration of M2000 has shown higher tolerance and biocompatibility and significantly reduced paw edema and joint destruction in rat's arthritic model (Mirshafiey, Cuzzocrea, Rehm, & Matsuo, ). The high efficacy and safety of this new drug have been confirmed in clinical trials of phases I/II, and III on patients with RA and also in clinical trials of phases I/II on patients afflicted by ankylosing spondylitis (AS) (Ahmadi et al, ; Fattahi et al, ; Rezaieyazdi et al, ). Furthermore, the results of a clinical trial showed that 12‐week treatment with M2000 (500 mg twice a day) reduced the expression levels of IL‐17 and RORγt in RA patients (Barati, Jamshidi, Ahmadi, Aghazadeh, & Mirshafiey, ).…”

Section: Introductionmentioning

confidence: 90%

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Immunopharmacological effect of β‐d‐mannuronic acid (M2000), as a new immunosuppressive drug, on gene expression of miR‐155 and its target molecules (SOCS1, SHIP1) in a clinical trial on rheumatoid arthritis patients

Mortazavi-Jahromi

Aslani

Omidian

et al. 2019

Drug Development Research

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The positive impacts of β‐d‐mannuronic acid (M2000) on the gene expression of miR‐155, its target molecules (SOCS1 and SHIP1), and NF‐κB transcription factor were demonstrated in a study using the HEK293‐TLR2 cell line. This new drug has been approved as a safe and effective medication by a randomized, multinational, phase III clinical trial on RA patients. The present study aimed to evaluate the oral administration effect of M2000 on the expression levels of the mentioned genes in RA patients. This research was conducted on 12 RA patients and 12 healthy individuals. After extraction of total RNA from PBMCs of patients and synthesis of cDNA, the expression levels of miR‐155, SOCS1, SHIP1, and NF‐κB genes were measured through quantitative Real‐time PCR at baseline and after 12 weeks of M2000 therapy. Our findings showed that the miR‐155 gene expression level significantly decreased in the M2000‐treated patients compared with the baseline (0.76‐fold, with p < .05). The expression levels of SOCS1 and SHIP1 genes significantly increased in the patients treated with M2000 compared with the before treatment (1.46‐, 1.54‐fold, with p < .01, p < .05, respectively). In addition, it was found that the gene expression level of the NF‐κB transcription factor significantly reduced in M2000‐treated patients compared with the baseline (0.81‐fold, with p < .05). This study showed that the oral administration of M2000 was able to reduce the expression of the miR‐155, increase the expression of SOCS1 and SHIP1, and decrease the NF‐κB gene expression (Trial Registration Number: IRCT2017100213739N10).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Immunopharmacological effect of β‐d‐mannuronic acid (M2000), as a new immunosuppressive drug, on gene expression of miR‐155 and its target molecules (SOCS1, SHIP1) in a clinical trial on rheumatoid arthritis patients

Mortazavi-Jahromi

Aslani

Omidian

et al. 2019

Drug Development Research

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“…[21][22][23][24][25] Some previous data about M2000 in ankylosing spondylitis and rheumatoid arthritis clinical trial phase II and III showed great tolerability and biocompatibility with no side effects. [26][27][28] Previous studies showed that M2000 has an anti-angiogenesis and anti-proliferative effect in-vitro and invivo models. Some data suggested that M2000 can induce apoptosis in cultured fibrosarcoma cells.…”

Section: Derived Suppressor Cells (Mdscs) and Regulatory T Cells (Tregs)mentioning

confidence: 99%

“…The β‐D‐Mannuronic acid (M2000) with low molecular weight, (patented DEU: 102016113018.4), is one of the Alginic acid comonomers in which anti‐inflammatory and immunosuppressive properties have been confirmed in the numerous experimental models of multiple sclerosis, nephritic syndrome, immune complex glomerulonephritis (ICG) and adjuvant induced arthritis (AIA) . Some previous data about M2000 in ankylosing spondylitis and rheumatoid arthritis clinical trial phase II and III showed great tolerability and biocompatibility with no side effects . Previous studies showed that M2000 has an anti‐angiogenesis and anti‐proliferative effect in‐vitro and in‐vivo models.…”

Section: Introductionmentioning

confidence: 99%

A randomized, controlled, phase II clinical trial of β‐D‐mannuronic acid (M2000) in pre‐surgical breast cancer patients at early stage (T1‐T2)

Kashefi

Omranipour

Mahmoodzadeh

et al. 2019

Clin Exp Pharma Physio

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Summary Following the potent efficacy of β‐D‐Mannuronic acid in a breast cancer murine model, we evaluated the efficacy of this novel non‐steroidal anti‐inflammatory drug in breast cancer patients in the present clinical trial. The study was an 8‐week randomized, controlled, phase II clinical trial (IRCT: 2017012213739N7 (in 48 pre‐surgical breast cancer patients. Patients who had breast cancer at early stage, with invasive ductal carcinoma, were placed on a waiting‐list for surgery and were allocated to the study. β‐D‐Mannuronic was administrated at a dose of two capsules (1000 mg/d) orally during a period of 8 weeks. The end point of this study was when the patients were admitted for surgery. Moreover, the patients' well‐being status was followed up on for safety. There were no statistically significant differences between treatment and non‐treatment groups at baseline. β‐D‐Mannuronic acid therapy, from 20 patients, showed that in one patient (5%) tumour size was decreased; in five patients (25%) tumour growth was stopped; and in 14 patients (70%) the growth rate in the treatment group did not show significant change, compared to the non‐treatment group. Evaluation of two tumour markers (carcinoembryonic antigen and cancer antigen 15‐3) showed that there was no significant difference between before and after treatment. Although the use of some non‐steroidal anti‐inflammatory drugs in a long time period has shown a prophylactic effect in breast cancer, their therapeutic efficacy in a short time period is unknown, whereas treatment with β‐D‐Mannuronic acid during 8 weeks could show 30% therapeutic effects in pre‐surgical breast cancer patients.

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“…The safety profile of this new drug has been evaluated in a preclinical study based on the assessment of acute and chronic pharmacotoxicology in an experimental model 13 . Moreover, the potent efficacy and safety of this new drug were approved in phase 1/2/3 clinical trials on rheumatoid arthritis, as well as in a phase 1/2 clinical trial on ankylosing spondylitis 14‐16 …”

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confidence: 99%

Mannuronic Acid in Low‐Risk and Intermediate‐1‐Risk Myelodysplastic Syndromes

Ghaderi

Nodehi

Bakhtiari

et al. 2020

The Journal of Clinical Pharma

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The discovery of hematologic improvement and bone marrow modification by the drug β‐D mannuronic acid (M2000) during treatment of rheumatoid arthritis in phase 1/2/3 clinical trials prompted us to design a new trial to target hematologic deficits in myelodysplastic syndromes (MDS). In this open‐label, randomized phase 2 clinical trial, the potential effect and tolerability of drug M2000 was assessed in patients with low‐ and intermediate‐1‐risk MDS. The primary efficacy end point was hematologic improvement after 12 weeks of β‐D‐mannuronic acid therapy. Among 34 enrolled patients, half received their conventional therapy plus β‐D‐mannuronic acid, and the other half received only conventional drugs. In the conventional + β‐D mannuronic acid treatment group, hematologic improvement and development of transfusion independence and/or reduction in transfusion requirements were seen in 12 patients (92.3%) and 1 patient (7.7%), respectively. Moreover, 5 patients (38.5%), 2 patients (15.4%), and 1 patient (7.7%) in the β‐D‐mannuronic acid‐treated group showed hematologic improvement of the major parameters of erythroid, neutrophil, and platelet responses, respectively, based on the International Working Group criteria), whereas in the conventional treatment group as control, no hematologic improvements including erythroid, neutrophil, and platelet response was seen. In this trial, the addition of β‐D mannuronic acid to conventional treatment showed promising results in MDS patients with low and intermediate‐1 risk with effects on hematologic improvements without significant adverse effect.

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International multicenter randomized, placebo-controlled phase III clinical trial of β-d-mannuronic acid in rheumatoid arthritis patients

Cited by 15 publications

References 34 publications

Immunopharmacological effect of β‐d‐mannuronic acid (M2000), as a new immunosuppressive drug, on gene expression of miR‐155 and its target molecules (SOCS1, SHIP1) in a clinical trial on rheumatoid arthritis patients

Immunopharmacological effect of β‐d‐mannuronic acid (M2000), as a new immunosuppressive drug, on gene expression of miR‐155 and its target molecules (SOCS1, SHIP1) in a clinical trial on rheumatoid arthritis patients

A randomized, controlled, phase II clinical trial of β‐D‐mannuronic acid (M2000) in pre‐surgical breast cancer patients at early stage (T1‐T2)

Mannuronic Acid in Low‐Risk and Intermediate‐1‐Risk Myelodysplastic Syndromes

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