Clostridium butyricum M588- Miyarisan Pharmaceutical

At a glance

Originator Miyarisan Pharmaceutical
Class Antidiarrhoeals; Probiotics
Mechanism of Action Gastrointestinal microbiome modulators

Orphan Drug Status

Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

No
New Molecular Entity No

Highest Development Phases

Marketed Diarrhoea

Most Recent Events

16 Jun 2015 Phase II development is ongoing in the USA
04 Nov 2009 Clinical development is ongoing in USA
02 Nov 2005 Phase-II/III clinical trials in Diarrhoea in USA (PO)

Development Overview

Introduction

Miyarisan Pharmaceutical has developed a proprietary strain of Clostridium butyricum M588 [C. butyricum Miyairi 588 strain, CM588, Miya-BM^®, Cdactin-O, CBM588] for the prophylaxis and treatment of C. difficile-associated disease (CDAD) and antibacterial-associated diarrhoea (AAD). The oral therapy will be administered concomitantly with antibacterial therapy. C. butyricum M588, a butyric acid-producing, spore-forming obligate anaerobe, was discovered by Dr Miyairi in 1933 at Chiba Medical College. C. butyricum M588 has been shown to antagonise the growth of several enteric pathogens, including C. difficile, Candida albicans, Escherichia coli, Klebsiella spp., Salmonella spp. and Vibrio spp. C. butyricum M588 also exhibits a proliferative effect on intestinal mucosal cells, promoting normal function and colonisation of microflora.

The product has been launched in Japan, where it has been used for over 30 years as a non-antibacterial treatment for AAD. The US-based company Osel Inc. in-licensed the product and has exclusive rights to commercialise it in North America and Europe, where it is currently in clinical development. The product will be manufactured in the same facility that supplies Japan, under the same validated process. Osel is investigating the use of C. butyricum M588 for the prevention and/or treatment of C. difficile infections.

Company Agreements

Osel signed a definitive in-licensing agreement with Miyarisan Pharmaceutical Company in March 2005 for the rights to Miyarisan's C. butyricum M588 product in North America and Europe. Osel had planned to conduct pivotal clinical trials in the US first, followed by trials in Europe^[1].

Key Development Milestones

Miyarisan Pharmaceutical Company's proprietary C. difficile M588 product (Miya-BM^®) was approved by the Japanese Ministry of Health, Labor and Welfare, and has been launched for the treatment of CDAD and AAD in that country^[1].

Osel has completed a randomised, double-blind, placebo-controlled phase II study of Clostridium butyricum M588 in healthy outpatient adults receiving oral antibiotics. Results showed that the drug was safe and suggested a trend for efficacy. Another phase II trial was planned to evaluate the efficacy of the drug in hospitalised patients with antibiotic-associated diarrhoea and CDAD, and also its effect in the prevention of CDAD (NCT01077245). However, this trial was withdrawn prior to enrolment in February 2010 due to lack of recruitment. Osel planned to pursue a phase III efficacy trial and advance the drug through fast track licensure with the US FDA. However, as at June 2015, the product had not advanced to phase III trials. Osel's pipeline continued to list C. difficile M588 as in phase II clinical trials.

Osel enrolled the first patients into its phase II/III clinical trial of the C. difficile M588 product (Cdactin-O) for the prevention of AAD and CDAD in October 2005. The phase II portion of the study was conducted at 12 centres in the US, enrolling 600 patients with infections necessitating antibacterial treatment with β-lactams or cephalosporins. Two parallel phase III studies were subsequently planned; one each for β-lactam and cephalosporin recipients^[2].

Osel is also planning to explore the therapeutic potential of the drug in irritable bowel syndrome.

Drug Properties & Chemical Synopsis

Route of administration PO
Formulation unspecified
Class Antidiarrhoeals, Probiotics
Target Gastrointestinal microbiome
Mechanism of Action Gastrointestinal microbiome modulators
WHO ATC code
A07F (Antidiarrheal Microorganisms)
EPhMRA code
A7F (Antidiarrhoeal Micro-Organisms)

Indication	Biomarker Function	Biomarker Name	Number of Trials
Clostridium infections	Detailed Description	L-Tryptophan Kynurenine D-Tryptophan 1 more biomarker names Show less	1 1 1
Clostridium infections	Outcome Measure	Tumor necrosis factor alpha (TNF-alpha) Transforming growth factor-beta (TGF-beta) TNFRSF1A syndecan binding protein 2 L-Tryptophan Kynurenine Interleukin-8 (IL-8) IL1RL1 D-Tryptophan 7 more biomarker names Show less	1 1 1 1 1 1 1 1 1
diarrhoea	Detailed Description	L-Tryptophan Kynurenine D-Tryptophan 1 more biomarker names Show less	1 1 1
diarrhoea	Outcome Measure	Tumor necrosis factor alpha (TNF-alpha) Transforming growth factor-beta (TGF-beta) TNFRSF1A syndecan binding protein 2 L-Tryptophan Kynurenine Interleukin-8 (IL-8) Interleukin-6 (IL-6) IL1RL1 D-Tryptophan 8 more biomarker names Show less	1 1 1 1 1 1 2 1 1 1
gastrointestinal disorders	Detailed Description	L-Tryptophan Kynurenine D-Tryptophan 1 more biomarker names Show less	1 1 1
gastrointestinal disorders	Outcome Measure	Tumor necrosis factor alpha (TNF-alpha) Transforming growth factor-beta (TGF-beta) TNFRSF1A syndecan binding protein 2 L-Tryptophan Kynurenine Interleukin-8 (IL-8) IL1RL1 D-Tryptophan 7 more biomarker names Show less	1 1 1 1 1 1 1 1 1
infections	Detailed Description	L-Tryptophan Kynurenine D-Tryptophan 1 more biomarker names Show less	1 1 1
infections	Outcome Measure	Tumor necrosis factor alpha (TNF-alpha) Transforming growth factor-beta (TGF-beta) TNFRSF1A syndecan binding protein 2 L-Tryptophan Kynurenine Interleukin-8 (IL-8) IL1RL1 D-Tryptophan 7 more biomarker names Show less	1 1 1 1 1 1 1 1 1
renal cell carcinoma	Outcome Measure	Interleukin-8 (IL-8) Interleukin-6 (IL-6) Human Microbiome 1 more biomarker names Show less	1 1 1

Drug Name	Biomarker Function
Clostridium butyricum M588- Miyarisan Pharmaceutical	D-Tryptophan	Detailed Description, Outcome Measure
	Human Microbiome	Outcome Measure
	IL1RL1	Outcome Measure
	Interleukin-6 (IL-6)	Outcome Measure
	Interleukin-8 (IL-8)	Outcome Measure
	Kynurenine	Detailed Description, Outcome Measure
	L-Tryptophan	Detailed Description, Outcome Measure
	syndecan binding protein 2	Outcome Measure
	TNFRSF1A	Outcome Measure
	Transforming growth factor-beta (TGF-beta)	Outcome Measure
	Tumor necrosis factor alpha (TNF-alpha)	Outcome Measure

Indication	Phase 0	Phase I	Phase II	Phase III	Phase IV
Constipation	-	-	1	-	1
Infections	-	1	-	-	1
Major depressive disorder	-	-	-	-	1
Renal cell carcinoma	-	1	-	-	1
Adenocarcinoma	-	1	1	-	1
Gastrointestinal disorders	1	2	2	-	1
Clostridium difficile infections	-	-	-	-	1
Diarrhoea	1	2	-	-	-
Clostridium infections	-	1	-	-	1
Colon cancer	-	-	1	-	-

Indication	Qualifier	Patient Segment	Phase	Countries	Route / Formulation	Developers	Event Date
Diarrhoea	-	-	Marketed	Japan	PO / unspecified		02 Nov 2005
Diarrhoea	-	-	Phase II/III	USA	PO / unspecified		02 Nov 2005

Adverse drug reaction	Total safety reports	Serious reports	First reports
Cardiovascular disorders	1	1	-
Digestive system disorders	2	2	-
Drug response related complications	2	2	-
Infections	1	1	-
Pathological conditions signs and symptoms	2	2	-

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