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Enzyme Replacement Therapy - ERT Phase I/II Clinical Trial - Now Recruiting!

Shire HGT is currently recruiting for a Phase I/II Clinical Trial to study their HGT-1110 intrathecal Enzyme Replacement Therapy. 15 late-infantile patients will be studied for 40 weeks each to determine safety and target dosage.

The following Clinical Trial summary was prepared by the MLD Foundation. This page is continually updated and the content is copyrwritten - please copy the paragraph above and link to this page when sharing this information.

Study Summary – Every other week intrathecal injections for 40 weeks via an intrathecal drug delivery device (IDDD) or port implanted in the patient's abdomen.

Cohorts – The study will be performed with 15 patients divided into three cohorts of five patients each at increasing dosages of HGT-1110; 10, 30 & 100 mg at each infusion.

Enzyme – Recombinant human arylsulfatase A, which is expected to work in the same way as normal human arylsulfatase using a method known as 'recombinant DNA technology': it is made by human cells that have received a gene (DNA) that makes them able to produce arylsulfatase A.

Inclusion criteria – includes being ambulatory at the time of screening for admission into the trial, first symptoms before 30 months of age, and under the age of 8. Exclusion criteria includes participation in any other ongoing Clinical Trial and any sort of prior transplant. See full inclusion criteria below.

Placebo – there will be 5 placebo patients in the trial (2 each in the lower dose cohorts and 1 in the higher dose cohort). While not desirable from a trial participant's perspective, a placebo is the most efficient way to directly observe the impact of the therapy with a control group of patients. It should lead to a faster and more definite post-trial data analysis and conclusion.

Placebo "Rescue" – we are seeking a formal statement from Shire that placebo patients will be "rescued" and provided enzyme at the end of the 40 week study period.

Multi-Site – the trial has been approved by the EMA and will accessible to those living in Europe at several European sites. It will not, to the the best of our knowledge, be accessible in United States as it does not have FDA approval.

Denmark, Copenhagen is one of the sites. We will list others as they are conformed to us.

Continuation of Enzyme Access After the Primary Study Period – We are seeking a Shire confirmation that trial participants will be continued on the ERT until all patients in all three cohorts have completed the primary trial period, and throughout the study of the trial results.

Compassionate Use/Named Access – to the best of our knowledge no Compassionate Use or Named Access to HGT-1110 will be made for non-trial participants.

Phase I/II Trial Time Frame – Shire estimates the recruiting and study period to be 2 years ending in December 2013, we anticipate they will have difficulty recruiting patients to their criteria and do not expect completion of this trial until at least 2014.

Overall HGT-1110 Development Time line – A Phase II/III Clinical Trial will follow the current trial to establish efficacy at the dosage determined optimal by the current trial. It is unlikely product will approved by the regulatory agencies and be generally available, assuming good clinical trial results and best case executions, until 2015 or 2016, or perhaps longer.

Why is the Trial Targeted for Late Infantile MLD? – The current Phase I/II Clinical Trial is targeted at the late-infantile from of the disease because this form of the disease is the most rapidly progressing and hence it is easier and faster to show the efficacy of the enzyme therapy.

Access for Juveniles, Adults, and Those Already Advanced in the Disease – It is Shire's intention, after drug approval, to make the ERT available to patients with all forms and stages of MLD (as medically viable) including late-infantile, juvenile, and adult forms. Please note, your treating doctor (not Shire) may determine that your loved one is too advanced to see any benefit from the therapy.

Participating in the Trial – Please feel free to contact us for up to date information on the trial and assistance contacting the appropriate Shire and investigative staff to be considered for the Clinical Trial. It is likely that all trial inquiries will need to be made by your doctor.

What about US & other Non-European Patients? – The FDA has not approved this clinical trial for trial centers in the United States. The every other week infusions must be performed at a specified trial site. While US patients could potentially participate by moving to Europe at their expense for the duration of the trial and the extension period, please consider the significance of this burden for a therapy that is yet to be proven efficacious (that's why the trial is underway) and remember there is a randomized placebo control group.

Principal Investigator – Christine í Dali, MD of the University Hospital Copenhagen, Rigshospitalet. * Dr. Dali is also a member of the MLD Foundation's Medical and Scientific Advisory Board.

ClinicalTrials.gov – Trial ID NCT01510028

Orphan Designation – HGT-1110 has Orphan designation by both the EMA for Europe (EU/3/10/813) and the FDA for the US*.

Detailed Inclusion Criteria:

• Confirmed diagnosis of metachromatic leukodystrophy (by both blood enzyme & urinary sulfatide levels)
• First symptoms of disease at or before 30 months of age
• At the time of screening:
• Neurological signs of MLD must be present
• Ambulatory at the time of screening – defined as the ability to stand up alone and walk forward 10 steps with one hand held.
• Patient must be able to complete 40 weeks of every other week infusions at a designated clinical trial site
• Complete criteria at ClinicalTrials link above

Detailed Exclusion Criteria:

• History of hematopoietic stem cell transplantation
• Known or suspected hypersensitivity or high risk of anesthesia
• Enrolled in another clinical study that involves clinical investigations or use of any investigational product (drug or device) within 30 days prior to enrollment in this study or at any time during the study.
• Patient is 8 years of age or older.
• Complete criteria at ClinicalTrials link above

Shire HGT - Historical Overview

Shire HGT was originally known as TKT - Transkaryotic Therapies before it was acquired by Shire PLC to form Shire Human Genetic Therapies (Shire HGT). TKT had developed Replagal, a genetically engineered form of -galactosidase A for treatment of Fabry disease when it was acquired. It had three other drugs in various stages of development: DYNEPO for the treatment of kidney disease-related anemia, ELAPRASE/I2S - An enzyme replacement therapy for the treatment of Hunter Syndrome, and GA-GCB -a glucocerebrosidase for the treatment of Gaucher disease. The three ERTs are manufactured through a proprietary process derived from human cell lines, an advanced technology compared to conventional method of using Chinese hamster ovary lines. A Shire overview of TKT from 2005 can be seen here.

Their current (as of Jan 2012) ERT product offering and development road map include:

Type 1 Gaucher ... VPRIV

Fabry Disease ... REPLAGAL (US) ... in Registration

Duchenne Muscular Dystrophy (DMD) ... HGT 4510

Hunter syndrome CNS ... HGT 2310

Metachromatic Leukodystrophy (MLD) ... HGT 1110

Sanfilippo A syndrome ... HGT 1410

Sanfilippo B syndrome

Prior MLD ERT Program - HGT-1111 (Metazyme)

Shire HGT had a prior intravenous ERT in development. They referred to this product as HGT-1111. It was called Metazyme when it was acquired from Zymenex in April of 2008 as therapy already in Phase I/II clinical trial in Europe. This ERT proved to not be efficacious and further development of this product ceased in February of 2010.

More history on the HGT-1111/Metazyme therapy, including clinical trial details and results, can be found here.

Shire Links

* Shire Product Pipeline

* Shire Mission

* 2010 Annual report

* 2006 Shire HGT Financial Report

* May 2007 Presentation to Buckingham Financial Group

* January 2007 Presentation to Morgan Stanley