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New Inclusion/Study Group added to Trial

A fifth study Group E has been added to the inclusion matrix. Group E is for <18 month-olds with a GMFC-MLD score ranging from 1 to 4. The current Group D has a tighter inclusion criteria including being early symptomatic and a younger sibling of a trial participant.

You can learn more about the details of the trial including the now five study groups here. Or jump right to the detailed inclusion criteria here.

Recruiting is Open

Phase II ERT Trial Recruiting Status and Sites

Takeda, who acquired Shire in early 2019, has opened recruiting for a Phase II Clinical Trial for SHP611, an ERT therapy for MLD. Their marketing name for the study is the EMBOLDEN Study. You can learn more about the details of the trial including the four study groups here. Or jump right to the detailed inclusion criteria here.

The trial will include pre-symptomatic, and for the first time, symptomatic late infantiles (and their younger pre-symptomatic siblings). For participation with symptomatic children, please see the discussion below.

They have announced 24 sites, including for the first time,10 sites in the US. The sites will open one by one throughout 2019.

OPEN SITES
• Chicago, Illinois, USA ... started recruiting April 201
• Pittsburgh, Pennsylvania, USA ... in review for August 2019 opening

Please check back here for updated details and a list of open sites ... Follow us on Facebook and subscribe to our Announcement Email list to keep up to date.

Overview ... Phase II ERT Clinical Trial ... The "Embolden" Study

updated 19-April-2019

Takeda (formerly Shire) has announced their Phase II Clinical Trial to expand their evaluation of the efficacy of their SHP611 Enzyme Replacement Therapy (ERT) for MLD. They call this study the "Embolden" study.

Compared to the Phase I/II trial they have increased the dose, increased the frequency, will be opening sites around the world including for the first time in the US, and will be including symptomatic late-infantile patients.

THERAPEUTIC APPROACH

The therapy is an Enzyme Replacement Therapy (ERT).  Much like a diabetic receives regular insulin injections for diabetes, this is a weekly infusion (injection) of an enzyme designed to substitute for the body’s missing ARSA enzyme.  ERT has been successfully used for other lysosomal diseases for over a decade.

INFUSION

The drug delivery will be weekly through a small port (soft rubber-like button) that is placed under the skin, usually on the front/side of the patient.  

From the port, a catheter (tube) is connected to the spinal column which is a pathway for the enzyme infusions to flow freely into brain. The cerebral spinal fluid (CSF) is on the other side of the blood brain barrier and freely circulates through the spine to the brain. This permanent port eliminates the need for a lumbar puncture with each weekly infusion.   

The infusions only take a few minutes, involve a quick needle prick into the port, and a bit of time post-injection to monitor for any reactions. The dose is 150mg (per kg), a higher and more frequent dose than the prior trial. The trial lasts 105 weeks (2 years) with an expectation that benefiting participants will be able to continue on the therapy after the formal trial ends as has been the case with the past studies. 

RECRUITING

35 patients will be recruited in 4 four study groups, see table below.

PARTICIPATING IN THE TRIAL

Please feel free to contact us for up to date information on the trial, to do a pre-assessment of your loved-ones eligibility, to discuss expectations, and for assistance contacting the appropriate Takeda and investigative staff to be considered for the Clinical Trial. It is likely that all formal trial inquiries will need to be made by your doctor directly to the Principal Investigator – we can help with that process. MLD Foundation has been working with Shire (now Takeda) since 2007 on this therapy and can quickly guide you.

COST

The drug and all study related testing will be paid for by the trial sponsor. Families should discuss the need for additional travel support, if any, at the time of assessment and enrollment.

STUDY GROUPS & INCLUSION

The 35 participants being recruited for this trial will all be late infantiles, however, unlike previous phases, they will be recruiting children with varying degrees of disease progression, see table below.

The key inclusion criteria are:
   • confirmed MLD diagnosis
   • no prior/current therapy
   • late infantile form of the disease<
   • must present with gait disorder as first MLD sign (motor disorder, not cognitive)
   • gait disorder must be documented in medical records as occurring in the first 30 months
click to jump to the detailed inclusion criteria

* Please contact us to discuss how your child may or may not fit this inclusion and exclusion criteria.

There are five groups of participants that are segmented by their GMFC-MLD scores.

Comments
• ERT does not require myelin and nerve damage already done, rather, its goal is to dramatically slow or potentially stop further progression/damage.
• Pre- and very early symptomatic children will have the best long term outcomes. (group A – GMFCS-MLD levels 1 & 2)
• It is not clear to us whether those showing advanced symptoms (groups B & C) when they start ERT will see much slowing of progression ... see Discussion & Thoughts, below 
• Group D is for younger affected siblings of participants enrolled in the trial.

WHAT IS GMFC-MLD?

Gross Motor Function Classification System or GMFCS is a 5 level clinical classification system that describes the gross motor function of people on the basis of self-initiated movement abilities. Particular emphasis in creating and maintaining the GMFCS scale rests on evaluating sitting, walking, and wheeled mobility. Distinctions between levels are based on functional abilities; the need for walkers, crutches, wheelchairs, or canes / walking sticks; and to a much lesser extent, the actual quality of movement.

The original version of the GMFCS was developed in 1997 cerebral palsy. The current GMFC-88 has been adapted to the unique characteristics of MLD and is refereed to as GMFC-MLD.

The following three graphics may help you to preliminarily self-determine what GMFCS-MLD level your loved one might be. The 3rd graphic provides more detailed descriptions broken out by age group from birth to 18 years old.

Click for more details by age group from birth through age 18:

EXCLUSION

Those who have had other therapies including HSCT (transplant) or gene therapy, those with MSD (multiple sulfatase deficiency), and patients initially presenting with cognitive or behavioral symptoms (usually indicative of a later onset form of MLD).

SUMMARY & ADDITIONAL DETAILS

Study Summary – Every week intrathecal injections for 105 weeks via an intrathecal drug delivery device (IDDD) or port implanted in the patient's abdomen.

What is Clinical trial? – Clinical trials are research studies performed in people that are aimed at evaluating a medical, surgical, or behavioral intervention. They are the primary way that researchers find out if a new treatment, like a new drug or medical device (for example, a pacemaker) is safe and effective in people. Efficacy, while desired and measured, cannot be guaranteed.

Infusion Time – The weekly infusion is expect to take just a few minutes, but it is likely patients will be monitored for an hour or two after each infusion to watch for any allergic reactions – which are not likely but is part of understanding the drug.

Cohorts – The study will be performed with 35 patients divided into four cohorts at varying degrees of disease progression.

Matched Historical Controls – these are untreated patients that will be identified through a separate CHOP natural history study and matched to treated patients based on medical history and progression. This enables Takeda to compare the efficacy of therapy to the natural history of untreated disease.

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.

Intrathecal Port– The spinal fluid naturally circulates between the spinal column and the brain 3.7 times per day and it is on the "other side" of the blood brain barrier that is a typical barrier to intravenously delivered enzyme.* This intrathecal therapy delivers the enzyme directly into the spinal fluid. In order to minimize the chances of infection or injury due to repeated spinal puncture, a small port (a little larger than a US dime in diameter) will be implanted in the abdomen just under the skin - usually on the patient's side or front which is connected via a very small catheter to spine and into the CSF.* The Enzyme is injected through the skin into the port and transfers via the catheter (tubing ) to the spinal fluid.* This port is being studied as an integral part of the Clinical Trial. Please note - this is a static bolus device, not a pump. Image above is the new (December 2013) Sophysa mini Soph-A-Port®.

Placing the port and catheter is minor surgery and will require sedation. Please ask us about how to best sedate MLD patients.

24 International & US Sites – United States (California, Florida, Illinois, Iowa, Minnesota, New York, Ohio, Pennsylvania, Utah) Belgium, Brazil, Canada, Denmark, France, Germany, Israel, Japan, Mexico, Netherlands, Spain, United Kingdom.

You may enroll and start therapy at one site and then transfer to another site closer to home as it opens.

==> Details for each site, including contact information, can be found here.

Local Infusion Sites – Enrollment and periodic assessments must be at a primary study site (see above), however, it is Takeda's desire to enable the weekly infusions to occur locally, if appropriate local resources are available. These local resources will have to be evaluated, authorized, and trained on a case by case basis.

Continuation of Enzyme Access After the Primary Study Period – Takeda has indicated they will continue to supply of enzyme after the study period.

Primary End Points – Decline or lack of decline in GMFC-MLD. Group A is expected to decline no more than 2 levels. Additional observations and tests will be for Expressive Language Function Classification in Metachromatic Leukodystrophy (ELFC-MLD), change from baseline in Cerebrospinal Fluid (CSF) sulfatides levels, etc.

Compassionate Use/Named Access – to the best of our knowledge no Compassionate Use or Named Access to SHP611 will be made for non-trial participants.

Phase II Trial Time Frame – Takeda estimates the recruiting and study period to be 2 years ending in Late 2022.

Development Time line – This ERT has been in various stages of Clincal Trial since 2012.

Why is the Trial Targeted for Late Infantile MLD? – Most MLD Clinical Trials target the late-infantile form 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 and Adults – It is Takeda's desire, after drug approval, to make the ERT available to patients with all forms and stages of MLD where efficacy can be expected. Studying the ERT in late-infantiles is the fasted path to therapy approval by regulatory agencies (FDA, EMA, etc.) Please note, your treating doctor (not Takeda) may determine that your loved one is too advanced to see any benefit from the therapy.

ClinicalTrials.gov – Trial ID NCT03771898

Takeda Embolden Study Overview – Trial Overview provided by Takeda

Orphan Designation – SHP611 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)
• Gait disorder due to spastic ataxia or weakness attributed to MLD by 30 months for Groups A-C.
• Participant's age at time of informed consent – see table above
• Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) – see table above
• Patient must be able to complete 106 weeks of every week infusions at a designated clinical trial site
• Informed consent by parents

Detailed Exclusion Criteria:

• Multiple Sulfatase Disorder
• History of hematopoietic stem cell transplantation or gene therapy before or during the trial
• Initial presentation of behavioral or cognitive symptoms of MLD
• 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.
• Complete criteria at Clinical Trials link above

DISCUSSION & THOUGHTS ...

Pre-symptomatic and very early symptomatic late infantiles (Groups A & D) – The primary outcome measures for this trail focus specifically on Group A, those with very little progression. Halting or dramatically slowing progression when there has been minimal damage will give the best long term outcomes. Group D is younger siblings of trial participants, most of which will likely be pre- or very early symptomatic.

Symptomatic Late Infantiles (Groups B & C) – MLD Foundation believes the primary purpose of these two groups is three-fold ... to identify when a patient is too advanced for ERT to be effective, as a study arm to compare with Group A, and to provide some matched natural history control.

This is a clinical trial ... and specifically with Groups B & C, it is a study to determine how and if ERT works when your child is progressed. Note that there might still be progression in Groups B & C even if group A seems to hold more steady. As such, we think expectations for parents considering Group B & C enrollment should be well informed and appropriately tempered.

Over the past 20 years we have met hundreds of families and their MLD loved ones in person, we've followed your journeys, and we have a good sense of how MLD progresses. We've also been working with institutional and biotech R&D, development and clinical trials for over a decade. We have a lot of experience to share with you. These are tough decisions.

We know every family's situation and considerations are different. Our hope is that you will be well informed before you make whatever decision you make. There is no right or wrong decision and we will support you regardless.

Feel free to call, email or text us to discuss this in more detail in your personal situation. We are happy to help.