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crossrianbow

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[交流] 紧急求助————提供有价值文献资料的虫友悬赏100金币，上不封顶

亲爱的虫友们：
最近要研究桑酶素这个玩意，有童鞋知道哪个高校或者研究所有研究这个东西的吗？或者企业有大批量生产这个东西的没？

桑酶素CAS号：19130-96-2

具体需要的文献资料是：
1.全球范围内桑酶素的研发情况，产品及市场现状
2.有哪些企业或研究机构在生产这个东西，市场占有情况如何

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1楼2011-04-22 18:03:51

已阅回复此楼关注TA 给TA发消息送TA红花 TA的回帖

nkbeholder

木虫 (正式写手)

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小木虫(金币+0.5):给个红包，谢谢回帖
crossrianbow(金币+66): 2011-04-24 12:48:56
chinarencxp: 谢谢积极参与 2011-04-24 14:17:16

dialog数据库查到的，治疗Glycogen storage disease type II的临床试验都中止了啊！

--------------------------------------------------------------------------------

Drug: Duvoglustat
Synonyms: 1-deoxynojirimycin hydrochloride; AT2220; AT2220-ERT combo therapy; duvoglustat-ERT combo therapy; HGT 3510; HGT-3510
Chemical Name: 3,4,5-Piperidinetriol, 2-(hydroxymethyl)-, (2R-(2alpha,3beta,4alpha,5beta))-, hydrochloride
Molecular Formula: C6H13NO4.HCl
CAS® Registry Number: 73285-50-4
Related CAS Registry Number: 19130-96-2 (1-deoxynojirimycin)
Therapeutic Class:

Other Alimentary Tract and Metabolism Products
Other Alimentary Tract and Metabolism Products
Mechanism of Action:

Alpha-glucosidase stimulants
Enzyme stimulants
Enzyme modulators
Protein folding stimulants
Protein folding modulators
Originator Company: Amicus Therapeutics (USA)
Parent Company: Amicus Therapeutics
Other Company: Mount Sinai School of Medicine

Highest Phase: Preclinical

Development Status:

Preclinical, USA, Glycogen storage disease type II
Discontinued II, Canada, Glycogen storage disease type II
Discontinued II, France, Glycogen storage disease type II
Discontinued II, Germany, Glycogen storage disease type II
Discontinued II, USA, Glycogen storage disease type II
Discontinued I, USA, Glycogen storage disease type II
Introduction:
Amicus Therapeutics is developing duvoglustat, a small molecule orally active compound designed to restore the activity of alglucosidase alfa in patients with Pompe's disease. A multinational, open-label, phase II, clinical study was initiated in North America and Europe. However, Amicus suspended enrolment in this study in February 2009. The IND for duvoglustat was subsequently placed on clinical hold. In September 2009, the US FDA converted the clinical hold to a partial hold in order to allow Amicus to conduct a phase I trial in volunteers. This trial has been completed and the company is now focussing on the development of duvoglustat in combination with enzyme replacement therapy.

Pompe's disease (glycogen storage disease type II) is an autosomal recessive lysosomal storage disease caused by genetic mutations in a key enzyme alglucosidase alfa (acid alpha-glucosidase, GAA).

Amicus' technology is based on the concept of using pharmacological chaperones for the treatment of genetic disorders. The company is pioneering the approach which is based on the discovery that many genetic disorders are caused by a missense mutation that may lead to a misfolded protein with the impaired biochemical function. These mutant proteins are subsequently degraded or form aggregates. Consequently, little or no enzyme can reach the lysosome, where it normally breaks down glycogen. This results in a gradual accumulation of lysosomal glycogen in the liver, muscle, nerve and heart tissue, causing tissue degeneration. Amicus' oral, small molecule pharmacological chaperones are designed to "guide" the mutant protein to fold correctly into its normal 3D conformation, thus recovering the residual native protein activity and restoring its biological function. The technology provides an alternative to enzyme replacement therapy approach for the treatment of human genetic disorders.

Company agreements
Amicus Therapeutics exclusively licensed patents and patent applications pertaining to the technology from the Mount Sinai School of Medicine. The technology covers pharmacological chaperones for the prevention or treatment of human diseases or clinical conditions by increasing the activity of wild-type and mutant enzymes. The terms of the agreement includes royalties on sales only. The agreement expires upon expiration of the last of the licensed patent rights.

In November 2007, Amicus Therapeutics entered into a co-development agreement with Shire Human Genetic Therapies, a subsidiary of Shire plc, for Amicus' three compounds from a family of pharmacological chaperones for the treatment of lysosomal storage disorders. The collaboration included migalastat (Amigal(TM)) for Fabry's disease, isofagomine (Plicera(TM)) for Gaucher's disease and duvoglustat for Pompe's disease (see separate profiles). Under the terms of the agreement, Shire will receive rights to commercialise these product outside the US with Amicus retaining all commercialisation rights for the US. Amicus received a non-refundable licensing fee of US$50 million, and was eligible for development and sales-based milestone payments of up to US$390 million, as well as tiered, double-digit royalties on net sales. Both Amicus and Shire undertook a joint development programme of duvoglustat as HGT 3310, towards marketing approval in the US and Europe with 50:50 shared expenses/1/. However, in October 2009, Amicus reacquired all global development and commercialisation rights from Shire for its lead lysosomal storage programmes, with both companies mutually terminating their collaboration. Shire paid Amicus $US5.2 million in the fourth quarter of 2009; full and final payment for any outstanding amount under the collaboration to complete all future obligations, financial and otherwise/2/.

Key development milestones
Monotherapy: previously, Amicus initiated a phase II clinical trial of duvoglustat for the treatment of Pompe's disease in June 2008. The study was designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of 12 weeks of treatment with duvoglustat in 18 adult patients (NCT00688597). In February 2009, Amicus suspended enrolment following self-reported serious adverse events by the two already enrolled patients who subsequently withdrew from the trial. These events were determined by the site investigator as probably related to treatment with duvoglustat. Following discussion with the FDA, the IND was placed on clinical hold. In September 2009, Amicus announced plans to initiate an open-label single-dose phase I trial investigating the pharmacokinetics of duvoglustat in muscle tissue in healthy subjects. The US FDA agreed to the proposal for the phase I trial and converted the clinical hold into a partial hold in order to allow Amicus to conduct this trial. The trial commenced in October 2009/2/ /3/ /4/ /5/ /6/. Based on results from a phase I open-label study, and previously completed studies, Amicus decided not to advance duvoglustat as a monotherapy for Pompe's disease, to focus on combination therapy/7/ /8/.

A total of 72 healthy volunteers received duvoglustat in three double- blinded, placebo-controlled, dose-ascending phase I studies evaluating the safety, tolerability and pharmacokinetics of duvoglustat. Positive results were reported across all studies/9/ /10/ /11/.

Amicus has also completed the ex-vivo response study (NCT00515398) testing the effect of duvoglustat on various Pompe's disease mutations/9/.

The US FDA granted duvoglustat orphan drug designation for Pompe's disease in the US/1/.

Combination therapy: In March 2011, the US FDA lifted the partial clinical hold on the IND for duvoglustat. The regulatory authority agreed with the company's proposal to resume clinical development for Pompe's disease, starting with a phase II trial of duvoglustat in combination with enzyme relplacement therapy/12/. Amicus plans to initiate the phase II trial in the first half of 2011, with preliminary results expected to be available in the second half of 2011/8/.

Amicus conducted preclinical studies evaluating the safety and efficacy of combination of duvoglustat and ERT for the treatment Pompe's disease. Preclinical animal studies provided encouraging results. Amicus conducted additional preclinical proof-of-principle studies to assess the feasibility of a combination therapy that may benefit patients with Pompe's disease who are not amenable to chaperone monotherapy/2/ /5/. Data from preclinical studies of duvoglustat in combination with ERT were presented in February 2010. These data showed that co-administration of duvoglustat and ERT resulted in prolonged half-life of ERT in the circulation, potentiated enzyme activity in cells and provided greater substrate reduction in target tissues compared with ERT monothrapy/13/.

Patent information
Amicus has an exclusive licence to three US patients covering duvoglustat, two pending US patent applications, as well as corresponding foreign applications. The US patents for duvoglustat expire in 2018. The patents and patent applications cover methods of increasing the activity of and preventing the degradation of GAA, and methods for the treatment of Pompe's disease using duvoglustat.

Pharmacology Overview:
Pharmacodynamics:
  Dose-dependently increases GAA levels in cells from blood and skin samples from patients with various GAA mutations
  Mechanism of action:
  Alpha-glucosidase stimulants
Enzyme stimulants
Enzyme modulators
  Protein folding stimulants
Protein folding modulators
  Activity versus parent drug: unspecified parent

Clinical Overview:
Route(s) of Administration: PO
  Administration Freq.(per day):
  Drug Interactions:
  Unknown.

Adverse Events:
In all three phase phase I trials in healthy volunteers, duvoglustat was well tolerated with no serious adverse events. No adverse events were deemed to be definitely or probably related to the drug. In the multiple ascending dose phase Ib study in 24 volunteers, all possibly- related adverse events were mild in intensity and resolved spontaneously/9/ /10/.
Drug Interactions:

Pharmacokinetics:
In a phase Ia study in 32 healthy volunteers, duvoglustat had good oral bioavailability and a plasma t sub(1/2) value of 4-5h/10/.
Pharmacodynamics (Metabolic Disorders):
In an (ex vivo) response study evaluating the effect of duvoglustat on various Pompe's disease mutations, blood and skin samples were collected from 30 patients with Pompe's disease with a variety of mutations in acid alpha-glucosidase (GAA). Cells derived from these samples were treated with duvoglustat. Interim data available from 26 patients showed that 24 had cells that had a dose-dependent increase in GAA levels, including 22 patients who had at least 1 copy of the common splice site mutation IVS1-13T>G. It is believed that >80% of Caucasian adult patients have at least 1 copy of this common splice site mutation/9/.

References:
1. Shire plc. Shire Expands its Human Genetic Therapies Pipeline Through In-Licensing Agreement With Amicus Therapeutics. Media Release. : 8 Nov 2007. Available from: URL: http://www.shire.com. (English).
2. Amicus Therapeutics. Amicus Therapeutics Announces Third Quarter 2009 Financial Results and Strategic Business Updates. Media Release. : 30 Oct 2009. Available from: URL: www.amicustherapeutics.com. (English).
3. Amicus Therapeutics. Amicus Therapeutics Announces Plan to Initiate Phase 1 Study of AT2220 for Pompe Disease. Media Release. : 30 Sep 2009. Available from: URL: http://www.amicustherapeutics.com. (English).
4. Amicus Therapeutics. Amicus Therapeutics Suspends Enrollment for Phase 2 Clinical Trial of AT2220 for Pompe Disease. Media Release. : 27 Feb 2009. Available from: URL: http://www.amicustherapeutics.com. (English).
5. Amicus Therapeutics Inc. Amicus Therapeutics Announces Positive Progress of Three Lead Clinical Programs and General Outlook for 2009. Media Release. : 12 Jan 2009. Available from: URL: http:// www.amicustherapeutics.com. (English).
6. Amicus Therapeutics. Amicus Therapeutics Begins Phase 2 Clinical Trial of AT2220 in Pompe Disease. Media Release. : 3 Jun 2008. Available from: URL: http://www.amicustherapeutics.com. (English).
7. Amicus Therapeutics Inc. Amicus Therapeutics Announces First Quarter 2010 Financial Results and Product Pipeline Advancements. Media Release. : 6 May 2010. Available from: URL: http:// www.amicustherapeutics.com. (English).
8. Amicus Therapeutics. Amicus Therapeutics Provides 2011 Business Outlook and Expected Key Milestones. Media Release. : 11 Jan 2011. Available from: URL: http://www.amicustherapeutics.com. (English).
9. Amicus Therapeutics. Amicus Therapeutics Presents Data from Clinical Ex Vivo Response Study and Phase 1 Studies of AT2220. Media Release. : 13 Mar 2008. Available from: URL: http:// www.amicustherapeutics.com. (English).
10. Amicus Therapeutics. Amicus Therapeutics Announces Positive Results From Two Phase 1 Clinical Studies of AT2220 for Pompe Disease. Media Release. : 23 Oct 2007. Available from: URL: http:// www.amicustherapeutics.com. (English).
11. Amicus Therapeutics. Amicus Therapeutics Commences Phase 1 Clinical Trials for AT2220 for Pompe Disease. Media Release. : 14 Dec 2006. Available from: URL: http://www.amicustherapeutics.com. (English).
12. Amicus Therapeutics. Amicus Therapeutics Announces FDA Agreement to Commence Phase 2 Study of AT2220 Co-administered with Enzyme Replacement Therapy for Pompe Disease. Media Release. : 8 Mar 2011. Available from: URL: http://www.amicustherapeutics.com. (English).
13. Amicus Therapeutics. Amicus Therapeutics Presents Positive Data Update From Phase 2 Extension Study of Amigal(TM) for Fabry Disease. Media Release. : 11 Feb 2010. Available from: URL: http:// www.amicustherapeutics.com. (English).

Revision Date: March 8, 2011

Adis R&D Insight
© 2011 Adis International Limited. All rights reserved.
Dialog® File Number 107 Accession Number 159768