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Intrathecal Enzyme Replacement Therapy - ERT Phase I/II Clinical Trial - Phase I/II Results!

At LDN-WORLD (Feb 2017) Shire shared results of the Phase I/II study. They look very promising. See here for a copy of their poster.

Enrollment is completed for this Phase I/II Clinical Trial studying HGT-1110 intrathecal Enzyme Replacement Therapy.

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

Cohorts – The study will be performed over the next couple of years with 15 patients divided into three cohorts of five patients each at increasing dosages of HGT-1110.

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). A placebo is the most efficient way to directly observe the impact of the therapy and should lead to faster and more definite post-trial data analysis and conclusions.

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 will excusable 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 - it only has EMA approval.

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 Enzyme will be made for non-trial participants.

Overall Trial Time Frame – while Shire targets the recruiting and study period to be 2 years ending in December 2013, we anticipate they will have difficulty recruiting patients to this criteria and do not expect trial completion until at least 2014.

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.

What about US 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 MLD Foundation's Medical and Scientific Advisory Board.
Click here for contact information

ClinicalTrials.gov – Trial ID NCT01510028

Detailed Inclusion Criteria:

• Confirmed diagnosis of metachromatic leukodystrophy
• First symptoms of disease at or before 30 months of age
• Ambulatory at the time of screening – defined as the ability to stand up alone and walk forward 10 steps with one hand held.
• Neurological signs of MLD must be present at the screening examination
• Complete criteria at ClinicalTrials link above

February 2010 Update - Shire ERT Program Update

Shire has suspended any further development on their HGT-1111 intravenous ERT therapy after it was shown to not have sufficient effect. They are resuming work on their internally developed HGT-1110 intrathecal ERT product at the preclinical animal testing stage. Work on HGT-1110 was stopped when Shire acquired the HGT-1111 product in April of 2008. (February 2010)

Their statement:

Shire HGT Metachromatic Leukodystrophy (MLD) Program Update 19 February 2010

Shire HGT had planned to initiate a Phase 2/3 study with intravenous (IV) enzyme replacement therapy (ERT) for treatment of MLD in 2009. However, clinical data from the ongoing Phase 1/2 extension study, collected on an ongoing basis over the last few years, demonstrates that the IV route of administration is not succeeding. Therefore, Shire has decided to suspend further development of an IV formulation of arylsulfatase A (ASA) derived from CHO cells, also known as HGT-1111. Shire plans to share these clinical data publicly at an upcoming scientific meeting and is working closely with the clinical investigators caring for participants continuing to receive HGT-1111 to evaluate next steps for these patients.

Going forward Shire believes that direct delivery to the central nervous system (CNS) offers the best chance for development of a successful treatment for MLD. Shire plans to develop HGT-1110, a formulation of ASA derived from human cells and compatible with direct CNS delivery for MLD patients. This human cell line has been used successfully by Shire for the development of other ERTs for Hunter syndrome, Fabry disease, and type 1 Gaucher disease. Shire’s CNS platform was recently advanced with the initiation of a Phase 1/2 trial using direct delivery of idursulfase to the CNS in Hunter patients. Development of the HGT-1110 formulation suitable for direct delivery to the CNS is ongoing, and preclinical studies are planned for 2010. Shire is committed to the MLD community.

We continue to work diligently to bring a much-needed therapy to patients and their families.

Download PDF

Shire statement on HGT-1111 availability outside the clinical trial and the Massart family ... 16-July-2009

July 2009 Update - International Phase II/III ERT Clinical Trial Update

Dr. Marc Patterson from the Mayo Clinic in Rochester Minnesota presented an update on the proposed International Phase II/III HGT-1111 Clinical Trial at the MLD Family Conference™ in Valley Forge Pennsylvania on June 27th, 2009. The information supplied below is only what is publicly available at the time of this update. Please continue to check back periodically for updates.

A video of Dr. Patterson's presentation can be seen on our video page.

PRINCIPAL INVESTIGATOR
Dr. Patterson will be the Principle Investigator (PI) for this trial. The purpose of the trial is to determine efficacy (effectiveness) of HGT-1111, the recombinant biotech enzyme designed to do the work of the missing or low levels of Arylsulfatase A (ARSA). Dr. Patterson has extensive experience with clinical trial management and is very experienced in gathering the proper data to have an efficient trial process.

IRB & FDA APPROVALS
These two applications are in process as of July 2009, but are not yet final. The details below are subject to change if either group so requests.

DOSAGE & INFUSIONS
Infusions are proposed to be weekly. Infusion centers (locations not yet named) will be set up in the US, Europe, and South America to reduce patient travel for their infusions.

ELIGIBILITY & RECRUITING
The 30 participants in this trial will all be late infantile meeting specific eligibility criteria - ages 15-36 months and able to walk 10 steps with only one hand held for assistance. Participant recruiting is expected to start before the end of 2009. Two or three participants are expected to be identified each month.

Until the FDA and IRB approve the proposed trial there is no active participant recruiting and there cannot be any formal enrollments. We expect enrollments to start before the end of 2009.

COMPASSIONATE USE/NAMED ACCESS - AVAILABILITY OF HGT-1111 OUTSIDE OF THE TRIAL
Shire has stated they are unable to produce enough of the HGT-1111 enzyme for this experimental enzyme replacement therapy to provide it to any anyone outside of the clinical trials (* & *). They are working with the sole source of supply, a contract manufacturer put in place before Shire acquired the experimental therapy, as well as investigating all alternatives for increasing production including bringing manufacturing in house*.

EVALUATIONS & DATA COLLECTION
All potential participants will be evaluated in Rochester, MN for consideration as a trial participant. At the start of the trial, and each quarter throughout the 9-month trial, the participants will be evaluated in Rochester. This is to assure consistency of the collected measurement data.

PLACEBO CONTROL
The trial is proposed as a randomized 2:1 placebo design to directly show the differences in progression of those receiving the enzyme and those on the placebo. The placebo participants will have a specific "rescue" criteria where they will be automatically be taken off of the placebo and provided the enzyme if a specific decline is noted. There was much discussion about the specifics of this rescue point. The placebo control was recommended by Shire's independent MLD advisory board of outside experts based on the Phase I/II trial data* and the goals of this Phase II/III trial. Videos of Dr. Dali presenting the Phase I/II trial results in Munich March 2009, and of Dr. Patterson re-presenting the result in June 2009 can be found here.

DATA ANALYSIS & ESTIMATED POST TRIAL REVIEW SCHEDULE
After the completion of the trial the data is compiled, analyzed, and - presuming good results - is presented to the FDA for their review. The best case for this portion of the process is 3 months for the analysis and 6 months for FDA review under their accelerated review process.

MLD Foundation estimates that with 2 participants recruited per month, 30 participants, and a 9 month trial period per participant, the data collection phase could be complete 24 months after the first participant starts (based on 9 months after the last participant starts) -- assuming everything happens as forecasted.

Using this best case 24 months for the trial itself plus the a best case data analysis (3 months) and an expedited FDA review of 6 months results in a best case of 33 months – however, MLD Foundation estimates it is highly likely the recruiting, analysis, trial logistics, and post-trial reviews will likely take 48 to 60 months to complete after the first participant is enrolled*.

MLD Foundation will continue to work closely with Dr. Patterson, Shire HGT, and both the FDA's Orphan Products & Review divisions to expedite all aspects this trial wherever possible.

POST TRIAL ENZYME ACCESS
All participants, including placebo participants not previously rescued, will be provided the enzyme on an open label extension study after the trial ends and while the trial results are compiled and studied.

Please note that this is a summary of the proposed Phase II/III clinical trial for HGT-1111. These details are subject to change during the IRB and FDA approval processes.

As of June 2009, our Shire HGT Global Medical Affairs contact is Lisa Sturk, Senior Medical Science Liaison, [Lisa has since left the company]

* is a link to a reference document. Click on the "*" to view the document.

February 2009 Update - Phase I/II ERT clinical trial summary released

The data from the Phase I/II safety and dosing study of Metazyme (originally developed by Zymenex - now called HGT-1111 by Shire HGT) completed in Europe last fall has been processed and is now being published. This Phase I/II clinical trial was designed to study safety and dosing. Efficacy (effectiveness) was not a formal purpose of the trial.

A quick summary of the conclusions is that sulfatide reductions were noted in the CSF (cerebrospinal fluid) of the children on the highest dose. Shire is very optimistic about the Phase II/III efficacy trials scheduled to start late the first half of this year. Dr. Christine Dali from Copenhagen, the Phase I/II trial principal investigator (and a member of MLD Foundation's Medical and Scientific Advisory Board), will present and discuss this data with the families at our Munich MLD Family Conference™ and then for peer review at the ACMG meeting in Tampa later in March. Dr. Maria Escolar, the principal investigator for the Phase II/III international clinical trial, will present via video and the Shire Medical Director for the enzyme development, Dr. Norman Barton, will also be in attendance in Munich.

A more detailed summary of the trial follows:

CONDITIONS:
* 13 affected late infantile MLD children were studied (average age 34 months).
* Two children withdrew due to travel issues and disease progression.
* There were three different dose levels with no placebo control.
* Infusions were every other week for 52 weeks.
* Families traveled to Copenhagen for the infusions.
* Infusions were well tolerated.
* Seven children had mild to moderate infusion related reactions due to rhASA antibodies present in these children. Reactions are fairly common with ERT. Symptoms were managed with pre-infusion medications.

RESULTS:
* The doses were all tolerated
* No safety issues were discovered
* The cerebrospinal fluid (CSF) of the high dose children showed a reduction in galactocerebroside-3-sulfate (sulfatide) levels.
* No change in motor or cognitive function was noted

CONCLUSIONS:
* The Phase II/III trial is scheduled to start in the US late in the first half of 2009
* The dosage will be studied at higher levels and probably with weekly infusions
* A control placebo group will likely be needed to truly gauge the affect on motor and cognitive skills in the treated group.

A link to the actual abstract for the data can be found here

We remain very actively involved with Shire HGT and the researchers involved. We will continue to keep this information updated.

September 2008 Update - Shire Completes Phase I Safety Trials in Europe

Shire HGT completed the Phase II safety and efficacy clinical trial in Europe of 12 patients. Clinical results are being processed and have not been made public.

Participants in the clinical trial are being continued on HGT-1111 under a compassionate use/named access program.

We are awaiting an announcement of the next steps in EMEU approval as well as updated details on US Phase I/II clinical trials which are anticipated in the next few months.

April 24, 2008 Update - Shire Acquires Metazyme from Zymenex

Shire HGT has acquired Metazyme from Zymenex for $135M. Shire will continue to expedite the testing and market release of Metazyme. Shire can and will likely apply significant corporate resources to these later stage tests and an expedited market release.

Metazyme is a promising enzyme replacement therapy (ERT) for MLD.

This is exciting for MLD affected families. Shire can and will likely apply significant corporate resources to these later stage tests and an expedited market release.  In addition, this external endorsement of Metazyme seems to validate the effectiveness of this ERT in advance of seeing published Phase II European clinical trial results.

Metazyme is nearing completion of Phase II clinical trials in Europe. An IND has been granted by the FDA to prepare for Phase II clinical trials in the US. In addition, Orphan Drug Status has been granted in both Europe and the US for Metazyme. Additional details on the status of Metazyme can be seen on the Zymenex page on this site.

The Shire press release can be seen here.

We will post more details as they come available.

Overview - Shire's Enzyme Replacement Therapy

Shire HGT has shown a proof of concept with mice for an enzyme replacement therapy (ERT). They are in the pre-clinical stage of development.

A natural history study and patient registry are currently in the planning stages, with the goal of beginning patient enrollment by the end of 2007.  These studies will help scientists to better understand disease progression and pathology in MLD, and will be used to inform the design of future clinical trials.

MLD Foundation is under non-disclosure agreement with Shire HGT and agreed at a private meeting in March 2007 to work closely with Shire to help facilitate the registry and their pre-clinical efforts, including surveying and contacting MLD affected families. When clinical trial recruitment starts in 2008 we will assist with that as well.

Shire is investigating several methods of dosing, intrathecal and intravenous, so both the central and peripheral nervous systems receive the proper dosing of the enzyme.

Existing FGE Products

Shire has demonstrated successes with its proprietary technologies, including human cell line, gene activation and Formylglycine Generating Enzyme (FGE). During 2006, Shire's HGT division posted revenue growth of over 30%, mainly as a result of the approval and launch in the US of ELAPRASE, a treatment for Hunter Syndrome, and the continued worldwide roll-out of REPLAGAL, their ERT therapy for the treatment of patients with Fabry disease.

Product Pipeline

Their ERT product pipeline consists of ERT therapies for Gaucher disease, Sanfilippo Syndrome (dog & mouse successes), and Metachromatic Leukodystrophy (mouse proof's of concept). They are adding a new condition every 12 months to the pipeline and expect approximately 18 months for each to be developed. Their GA-GCB enzyme for the treatment of Type 1 Gaucher disease started recruitment for Phase 3 clinical trials commenced in Q1 2007.

HGT ERT for MLD

Shire HGT is developing an investigational ERT to replace the deficient or absent arylsulfatase A (ASA) for the treatment of Metachromatic Leukodystrophy (MLD).  The company is using its proprietary FGE technology to create highly productive human cell lines for the manufacture of sulfatases.  Co-expression of FGE with a sulfatase leads to significantly increased enzymatic activity, in vitro, as compared to sulfatases produced without this technology.   Shire HGT’s MLD program is currently in preclinical development. 

Schedule

Shire is not yet recruiting for clinical trials - they are not scheduled to start until 2008 or later. The natural history and registry project will start recruiting later in 2007. Shire's May 10th 2007 presentation to a UK analyst shows their MLD therapy contributing to Shire's 2014 revenues as a released product . There is a lot of research and numerous trials to be performed in the meantime.

Please be sure to sign up for MLD Foundation's Announcement e-mail list to be kept abreast of progress by Shire and other research.

Contact

The Shire HGT contact is Carol Cannon (Medical Affairs)

Backgrounder ... Shire HGT

Shire Human Genetic Therapies (Shire HGT), is a business unit of Shire PLC, a global specialty pharmaceutical company. Metachromatic leukodystrophy (MLD):

Shire HGT specializes in researching, developing and commercializing therapeutics primarily for the treatment of genetic diseases caused by protein deficiencies. We have a high quality product portfolio and a relatively low risk, well-balanced development pipeline, especially in the area of enzyme replacement therapies. These biologics products generally have significant periods of market exclusivity resulting either from orphan drug designation or patent protection.

Shire HGT is based in Boston, MA, and has 600 employees in 16 countries around the globe.

Media Releases

June 11, 2007 

Shire Human Genetic Therapies (Shire HGT), a business unit of Shire PLC, a global specialty pharmaceutical company, is focused on developing innovative therapies for life-threatening genetic diseases.  Shire HGT applies its proprietary technologies, including human cell line, gene activation and Formylglycine Generating Enzyme (FGE), to the discovery, development and manufacturing of protein therapies to treat genetic diseases.  With over 600 employees in 16 countries around the globe, Shire HGT is dedicated to providing hope for patients and their families, for better, healthier lives. 

Shire HGT is developing an investigational ERT to replace the deficient or absent arylsulfatase A (ASA) for the treatment of Metachromatic Leukodystrophy (MLD).  The company is using its proprietary FGE technology to create highly productive human cell lines for the manufacture of sulfatases.  Co-expression of FGE with a sulfatase leads to significantly increased enzymatic activity, in vitro, as compared to sulfatases produced without this technology.   Shire HGT’s MLD program is currently in preclinical development.  A natural history study and patient registry are currently in the planning stages, with the goal of beginning patient enrollment by the end of 2007.  These studies will help scientists to better understand disease progression and pathology in MLD, and will be used to inform the design of future clinical trials. 

For more information about the program, please contact Carol Cannon at Shire HGT Medical Affair

Shire Links

2006 Shire HGT Financial Report

May 2007 Presentation to Buckingham Financial Group

January 2007 Presentation to Morgan Stanley