ecraprost

Drugs R&D 2004; 5 (1): 31-34ADIS R&D PROFILE 1174-5886/04/0001-0031/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

EcraprostAS 013, Circulase™

Ecraprost [AS 013, Circulase™] is a prodrug of prostaglandin E1 within lipidAbstractmicrospheres that is being developed in Japan by Mitsubishi Pharma Corporationand Asahi Glass. It was originally in development with Welfide Corporation. On1 October 2001, Welfide Corporation (formerly Yoshitomi) merged with Mitsub-ishi-Tokyo Pharmaceuticals to form Mitsubishi Pharma Corporation. The newcompany is a subsidiary of Mitsubishi Chemical.

Taisho and Seikagaku Corporation had been involved in the development ofecraprost but discontinued their licences to do so. The effects of ecraprost onreperfusion injury, in preclinical studies, had been reported by Taisho.

Ecraprost is in phase II in Japan and was in phase II in Europe for the treatmentof peripheral arterial disease. It was also in a phase II study in the treatment ofdiabetic neuropathies. However, this is no longer an active indication.

A phase III trial using a lipid emulsion of ecraprost [Circulase™] is underwaywith Mitsubishi Pharma Corporation in the US, using ecraprost for the treatmentof patients with severe peripheral arterial disease, which, because of decreasedblood flow to the extremities, can lead to painful ulcers on the legs and feet andsubsequent amputation. Alpha Therapeutic Corporation (a former subsidiary ofMitsubishi Pharma) was initially involved in trials of ecraprost in the US, but thisresponsibility has been taken over by the parent company.

1. Profile the intimal/medial area and the stenosis ratio whencompared with controls. Ecraprost inhibited plateletadhesion, macrophage infiltration and proliferating1.1 Pharmacodynamicscell nuclear antigen positive cell expression on theinjured arterial walls.[2]

1.1.1 Diabetes

A single drip infusion of ecraprost in 14 type 2 1.1.3 Thrombosesdiabetes mellitus patients with neuropathy signifi- Preclinical studies: In a rabbit model of ballooncantly decreased vibratory threshold in six patients injury, ecraprost 40 μg/kg significantly reduced(classed as ’responders’) but did not affect nerve the intimal/medial area and the stenosis ratio whenconduction velocity in any of the patients. Respond- compared with controls. Ecraprost inhibited plateleters exhibited a significant improvement in subjec- adhesion, macrophage infiltration and proliferatingtive symptoms and improved retinopathy and ne- cell nuclear antigen positive cell expression on thephropathy, relative to non-responders.[1] injured arterial walls.[2]

1.1.2 Ischaemic Heart Disease 1.1.4 Vascular Disorders

Preclinical studies: In a rabbit model of balloon Preclinical studies: In a rabbit model of ballooninjury, ecraprost 40 μg/kg significantly reduced injury, ecraprost 40 μg/kg significantly reduced

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Table I. Features and properties

Chemical name (11α,13E,15S)-11,15,dihydroxy-9-(1-oxobutoxy)prosta-8,13,dien-1-enoic acidbutyl ester

Molecular formula C28 H48 O6

CAS number 37202-86-1

WHO ATC code C (Cardiovascular System)C04A (Peripheral Vasodilators)B01A (Antithrombotic Agents)A10X (Other Drugs Used in Diabetes)

EphMRA ATC code C6A (Other Cardiovascular Products)A10X (Other Drugs Used in Diabetes)B1D (Fibrinolytics)B1 (Antithrombotic Agents)C4A (Cerebral and Peripheral Vasotherapeutics)

Originator Mitsubishi Pharma Corporation: Japan

Licensee companies Asahi Glass: Japan

Highest development phase Phase Discontinued (Preclinical) [Japan]

Properties

Mechanism of action Prostaglandin E1 agonists

Pharmacodynamics Improves vibratory sensation and subjective symptoms in type 2 diabetesmellitus patients with neuropathy; inhibits intimal hyperplasia

Route Unknown route

the intimal/medial area and the stenosis ratio when cutaneous oxygen pressure versus alprostadil andcompared with controls. Ecraprost inhibited platelet placebo. Ecraprost also increased blood flow butadhesion, macrophage infiltration and proliferating statistical significance was not reached.[4]

cell nuclear antigen positive cell expression on the In four patients with severe Raynaud’s diseaseinjured arterial walls.[2] associated with connective tissue disease, ecraprost,

a lipid microsphere formulation of prostaglandin E1

(10μg given once or twice weekly) increased lesion-1.2 Therapeutic Trialsal skin temperature by a significantly greater amountthan that resulting from treatment with pros-

1.2.1 Thrombosestaglandin E1 clathrated in α-cyclodextrin (given

The prostaglandin ecraprost is an effective treat-12 months previously to the same patients). These

ment for patients with intermittent claudication ac-patients reported more improvement in lesion colour

cording to the results of a randomised, double-blindand pain (3 and 24h after infusions) with ecraprost

study in which 80 patients with peripheral arterialcompared with prostaglandin E1 clathrated in α-

occlusive disease received ecraprost at a dosage ofcyclodextrin.[5]

10 or 25 μg/week, or placebo, for 4 weeks. Theproportion of patients with a 60% change in maxi- 1.2.2 Vascular Disordersmal walking distance was significantly higher in the The prostaglandin ecraprost is an effective treat-three ecraprost treatment groups versus the placebo ment for patients with intermittent claudication ac-group. However, there was no difference between cording to the results of a randomised, double-blindgroups in the proportion of patients with a 60% study in which 80 patients with peripheral arterialchange in pain-free walking distance.[3] occlusive disease received ecraprost at a dosage of

In ten patients with chronic peripheral arterial 10 or 25 μg/week, or placebo, for 4 weeks. Theocclusive disease, ecraprost significantly improved proportion of patients with a 60% change in maxi-blood flow volume versus placebo, and trans- mal walking distance was significantly higher in the

© 2004 Adis Data Information BV. All rights reserved. Drugs R&D 2004; 5 (1)

Ecraprost 33

three ecraprost treatment groups versus the placebo than that resulting from treatment with pros-taglandin E1 clathrated in α-cyclodextrin (givengroup. However, there was no difference between12 months previously to the same patients). Thesegroups in the proportion of patients with a 60%patients reported more improvement in lesion colourchange in pain-free walking distance.[3]

and pain (3 and 24h after infusions) with ecraprostIn ten patients with chronic peripheral arterialcompared with prostaglandin E1 clathrated in α-occlusive disease, ecraprost significantly improvedcyclodextrin.[5]

blood flow volume versus placebo, and trans-cutaneous oxygen pressure versus alprostadil and

Referencesplacebo. Ecraprost also increased blood flow but1. Tawata M, Nitta K, Kurihara A. Effects of a single drip infusionstatistical significance was not reached.[4]

of lipo-prostaglandin E(1) on vibratory threshold in patientswith diabetic neuropathy. Prostaglandins 49: 27-39, Jan 1995In four patients with severe Raynaud’s disease

2. Suga H, Tsuchida K, Hasegawa T. Suppressive effects of Lipoassociated with connective tissue disease, ecraprost, PGE1 on intimal hyperplasia after balloon injury in rabbits.

Japanese Journal of Pharmacology 79 (Suppl. 1): 173, 1999a lipid microsphere formulation of prostaglandin E13. Belch JJF, Bell PRF, Creissen D, et al. Randomized, double-(10μg given once or twice weekly) increased lesion- blind, placebo-controlled study evaluating the efficacy and

al skin temperature by a significantly greater amount safety of AS-013, a prostaglandin E1 prodrug, in patients with

Table II. Drug development history

Oct 1995 Clinical-Phase-Unknown for Peripheral vascular disorders in United Kingdom(Unknown route)

Mar 1996 Clinical-Phase-Unknown for Peripheral arterial occlusive disorders in US(Unknown route)

May 1996 Phase-II for Diabetic neuropathies in Japan (Unknown route)

May 1996 Phase-II for Peripheral vascular disorders in Japan (Unknown route)

May 1996 Phase-II for Peripheral vascular disorders in Europe (Unknown route)

May 1996 Phase-II for Diabetic neuropathies in European Union (Unknown route)

Jun 1997 Clinical-Phase-Unknown for Intermittent claudication in United Kingdom (IV)

Sep 1997 Phase-II for Peripheral arterial occlusive disorders in US (Unknown route)

Sep 1997 Phase-II for Peripheral vascular disorders in European Union (Unknown route)

Dec 1997 Phase-II for Peripheral arterial disorders in Japan (Unknown route)

Dec 1997 Phase-II for Peripheral arterial occlusive disorders in Japan (Unknown route)

Dec 1997 Phase-III for Peripheral arterial disorders in US (Unknown route)

Dec 1997 Phase-II for Peripheral arterial disorders in European Union (Unknown route)

Nov 1999 Preclinical development for Reperfusion injury in Japan (Unknown route)

Apr 2000 Yoshitomi is now called Welfide Corporation

May 2001 Ecraprost is the pINN for AS 013

May 2003 No development reported - Preclinical for Reperfusion injury in Japan(unspecified route)

May 2003 No development reported – Phase-II for Diabetic neuropathies in Japan(unspecified route)

Aug 2003 Ecraprost is no longer licensed to Seikagaku in Japan

Aug 2003 Discontinued – Phase-II for Diabetic neuropathies in Japan (unspecified route)

Aug 2003 Discontinued – Preclinical for Reperfusion injury in Japan (unspecified route)

Aug 2003 Discontinued – Phase-II for Diabetic neuropathies in European Union(unspecified route)

Aug 2003 Discontinued – Phase-II for Peripheral arterial disorders in European Union(unspecified route)

Aug 2003 Discontinued – Clinical-Phase-Unknown for Intermittent claudication in UnitedKingdom (IV)


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intermittent claudication. Circulation 95: 2298-2302, 6 May 5. Katoh K, Kawai T, Narita M. Use of prostaglandin E1 (lipo-1997 PGE1) to treat Raynaud’s phenomenon associated with con-

4. Matsuo H. Preliminary evaluation of AS-013 (prodrug of pros-nective tissue disease: thermographic and subjective assess-

taglandin E1) administration for chronic peripheral arterialment. Journal of Pharmacy and Pharmacology 44: 442-444,occlusive disease. International Journal of Angiology 7: 22-24,

No. 1, 1998 May 1992


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