Join our call for OPEN Natural History Studies

A new Natural History Study (NHS) for MLD was launched a few weeks ago. We have taken the bold step of recommending that families NOT participate in this study … for now:

It is our belief that all natural history studies be OPEN access, meaning the study data be maximized by being made available to other researchers from other academic institutions and companies, and be as collaborative as possible. Properly designed studies will protect your privacy while maximizing the use of your data to facilitate longevity in MLD research. 
In our opinion this new NHS does not adequately meet this criteria. We are (February 2014) in discussions with the study sponsors to address these concerns.
from http://mldfoundation.org/research-natural-history.html (see the detailed explanation near the bottom of this page)
This study is the fourth NHS that we are aware of for MLD and was launched by a long-standing pharmaceutical partner and MLD collaborator, Shire. We want to be clear that our don’t participate for now recommendation is not a Shire specific issue nor is Shire resisting discussing our concerns. Further, this “not participate”  stance is not because there are any fundamental scientific problems with the study, rather it’s that we want to optimize the value, usefulness, and knowledge gained from this rare disease Natural History Study for the researchers and for the patients.
We are actively working to bring the MLD community of Shire, GSK, Biomarin, several academic institutions, several other advocacy groups, and even some local treating clinicians together in the next month or two to collaboratively work on the following concerns and requests so we can get back to helping recruit for this study.
We are asking for two things before we encourage families to participate in this, or any other Natural History Study …
  1. OPEN collaborative Natural History Studies … meaning that the study is designed collaboratively and all of the the collected RAW data is made available openly to all future researchers.
    • MLD natural history studies are invasive and painful for the child who participates (nerve conduction and Lumbar Puncture/Spinal Taps). They also require a commitment that significant time and energy be put forth by families to make the repeat their visits to the study center knowing that they will not be receiving any therapy clinical trial access, i.e. they are giving to hopefully help the next generation of patients, not their own children.
    • Today, the current practice is one company designs their own NHS, collects and silos the raw data, uses the data for their application with the FDA, and then publishes the highlights.  Since only the summary data is published, the next company has to start from scratch with their own new study, engaging & testing more patients, etc.  That requires twice as many patients, twice as much patient sacrifice, twice as much cost, and perhaps twice as much time.  We don’t have a large enough community or enough time to double and triple dip – in fact, yesterday we lost another MLD patient, the 9th we know of this year.
    • The results from natural history studies are necessary for a new FDA/EMA therapy approval applications,however, these patients are untreated so their data is independent of any particular therapy.  Hence a NHS, just like developing a newborn screen, is a matter of common concern, not competitive advantage.
    • We are asking that Natural History Studies be collaboratively designed, collaboratively implemented, and all RAW data (not just the published summaries) be available for any researcher to access for any future study.  This collaborative approach will likely involve cost sharing as well so it’s complicated to set up but this approach allows us to gather the data as efficiently and as quickly as possible – while optimizing the “use” of the patient community.

  2. Give back to the patients/families with each NHS study visit … give the families information to take home after each visit to help them improve quality of life for their loved ones.
    • The NHS study centers have experts in gathering the NHS data, however, while they may understand lysosomal disease or leukodystrophies in general, they are generally not currently providing any direct MLD clinical feedback to the patients.
    • We already have a model for this in our community, the NDRD in Pittsburgh. In fact, families visit and re-visit the NDRD from literally across the country for the clinical expertise  and are then recruited into the natural history studies.  The NDRD has become a source of expertise and clinical support for many similar rare diseases.  They give clinical recommendations to the family to improve day to day quality of life and also become a medical resource for the local treating care team in the family’s home town.
    • We are asking that each study center be equipped to be a Center of Excellence for MLD where they can, and do, provide clinical expertise with each visit in addition to gathering the specific NHS data. This approach, as has been demonstrated by the NDRD, is a model that works for research and the families.
    • We are working to develop a Standard of Care for MLD to further support these clinical Center of Excellence goals and the local treating physicians when they go back home.
To our knowledge, no patients have been recruited for this specific Natural History Study.  We hope to impact the collaborative and clinical nature of how the study proceeds before any patients are enrolled, and frankly do not think these requests will impact the core study design in any significant ways.  As we all know, once patients are enrolled and data gathering momentum is established, change becomes more difficult.
We have excellent contact and influence with the MLD families worldwide. We are using this position and those relationships to try to affect a fundamental change in how Natural History Studies are implemented for MLD and for all rare diseases.
It is very bold to take this sort of position publicly – but it’s our moral responsibility to stand up for the patients.  We firmly believe this “patient-first” while “optimizing research” stance is optimal for patients and researchers.
If your organization supports this philosophy for OPEN Natural History Studies please comment here and then email us to let us know.  Advocacy groups can be the catalyst for these changes.
Dean Suhr, President  co-founder
MLD Foundation  http://MLDfoundation.org     
We C.A.R.E.™ for MLD families around the globe … for over 13 years!

Are normal enzyme levels enough to stabilize MLD?

A very interesting question came up today on the MLD Family Discussion List™ (a private list we run for MLD primary caregivers).  I thought it might inspire some thinking so I am sharing my answer here as well:

I have a question and I don’t know if anyone has an answer but I am wondering if anyone knows what truly stops this disease? Is it a normal enzyme level? Will the kids stop declining if the enzyme level stays normal? Are there other things that contribute to the stabilization of MLD?? 

Your first guess is actually correct – we really don’t know.  It will take lots of years of careful study looking at extended clinical trial/Phase III data, combined with more basic science bench work, natural history, and lots of patient & clinic reported progression/outcome data to really understand this disease.  And on top of a basic understanding we have hundreds of mutations to study.  We’re not planning on shutting down the MLD Foundation anytime soon!

From a practical perspective, the generally accepted consensus is that if the enzyme level in the blood is high enough (remember that “normal” levels vary all over the map and carriers with low blood enzyme levels appear to be metabolically “normal” people) then MLD’s progression will be dramatically slowed or halted. There is truth in this first order basic assumption – but it’s just the start of our understanding.
However (and not to scare you), there are three things to consider as we peel the MLD onion one layer (and there will be more subtleties as we further peel the MLD onion again in the future):
1) The first is that enzyme in the blood is of no value – it needs to be in the nerve cells that need it. Today’s therapies are primarily focused at crossing the CNS (central nervous system) into the brain. We measure enzyme levels in the blood and the CNS because it’s possible – brain biopsies on living people are not good! The state of our ability to get enzyme’s  large molecules reliably across the blood brain barrier (BBB) is in its infancy and the results are inconsistent at best.  The Milano gene therapy acknowledges this challenge by trying to make sure that whatever gets across the BBB produces 5-10x more enzyme than is typical hoping that the overproducing cells will share enzyme with their neighbors. Think of a gas tank in a car – a full tank shows “F” on the dial, but the engine won’t run if the fuel filter (BBB) is blocking the gas from getting to the engine (the brain).
2) The second thing to consider is once enzyme gets past the BBB will it get to all of the cells that need it?  Are some/many of those cells already compromised or unreceptive, does the enzyme (actually it’s a protein) get distributed to all regions of the brain, are the cells fixed so they keep on producing the enzyme or are they waiting for anther infusion like Enzyme Replacement Therapy (ERT) is designed to provide?  To continue the car analogy – the car may run if only 3 cylinders (brain regions) get fuel (enzyme) but you really need fuel to get to all of the cylinders (regions of the brain) to have the optimal/desired performance.
3) As mentioned, today’s therapies are primarily targeted at the brain/CNS, but our nervous system has a second component, the Peripheral Nervous System (PNS) that needs to be “fixed” as well.  The PNS makes sure the messages from the brain/CNS get to the muscles and systems elsewhere in the body.  We have historically seen a lot of transplants where the brain progression is slowed (stopped?) but the motor skills continue to decline (witness the many post-transplant children in wheelchairs).  The PNS is slightly different in its makeup than the CNS.  It also has a barrier, sometimes called the Blood Nerve Barrier (BNB), which is different from the BBB.  The common response when we ask why current research is focused on the CNS and not the PNS is that it makes sense to prioritize the CNS.  The challenge is that, to our knowledge, very little work has been done on the PNS barrier aspects of MLD. The car analogy is when the engine is running but the car is in neutral – lots of power under the hood but it is not getting to the wheels (limbs & organs) so the car is not going anywhere.
Also remember that some of these therapies require time to take hold.  The transplants need to engraft and the “good” cells take over/replace the bad cells before they can be effective. With ERT the thinking is they need to maintain somewhat consistent levels in the CNS which drives dosages and frequency of infusion.  Different issues, progressions and concerns will be at different priorities during the various early and long-term phases of each therapy.
And there are other therapies being developed as well … what if we reduced the amount of sulfatides produced so the little bit of enzyme that many MLD patients have doesn’t have to go as far?  This is called substrate reduction therapy (SRT) and hopefully will require a small molecule which, like alcohol, can more easily cross the BBB.  In the car analogy we still only get a little bit of gas through the clogged fuel filter – but what if the car was lighter and didn’t require as big an engine – their might be enough fuel getting by to be able to get from point A to point B?
We don’t have to completely understand all of this to make progress and see results in therapies.  As I mentioned above, the studies will go on for many more years and hopefully, today’s therapies will be good, tomorrows will be better, and in 5 or 10 years they will be even better as we better understand MLD, the body systems and the therapies of today and the future.  But for tomorrows therapies to be optimal, we do have to take the time to learn from every patient, every success, every valiant effort, every failure, and to explore every creative idea – many of which will lead us to increased knowledge even thought they are a practical dead-end.
At our upcoming Board meeting we are going to talk about investing in an independent formal MLD Registry to start to capture this scientific and medical history data in a more accessible scientifically managed database – we want the data to be there for future researchers to study when they have a creative idea.  And by investing, I don’t just mean a few dollars,  I mean that all of us, all of the MLD patients and their families, will be asked to contribute data as we begin to crowdsource MLD research in ways bigger than just one isolated project after another.

Say it’s not true … New Zealand proposes NO access to an “effective therapy” for a rare disease

Has my Sunday morning coffee not kicked in?  Am I reading this wrong? Tell me it’s not true …

  • Alexion has an “effective therapy” for paroxysmal nocturnal haemoglobinuria
  • New Zealand is proposing to decline access to therapy for its citizens  … not because it does not work – they acknowledge it is an “effective therapy” – rather, they think it’s too expensive.
  • Less than 5% of the over 7,000 rare diseases have therapies and they want to hold one of the few back !!!!!!????

Until this morning, I didn’t even know what paroxysmal nocturnal haemoglobinuria (Marchiafava-Micheli syndrome or PNH) was – all I need to know was they are fellow brothers and sisters with rare disease.  We must come to their support.

Enough already!  Well over 95% of the rare diseases are struggling to understand their disease and develop therapies … yet here we have a disease with a therapy that some bean counting bureaucrat says $$ x number of patients = too much.  What they conveniently ignore in their public stance is that Alexion, like all rare disease drug companies, will work with countries that need help to offset the list price because they care about the patient.  PHARMAC (New Zealand’s purchasing agency) you should care too!

We must not allow any more piecemeal incursions on the progress we are making towards therapies for all rare diseases.  If your disease is lucky enough to have a therapy in the future – the PNH struggle could be yours.  We must education and inform now!

So what can or should you do?  read on – it won’t take much time… Continue reading

DACHDNC recommends Pompe Disease for Newborn Screening Recommended Panel

The Secretary’s Discretionary Advisory Committee for Heritable Disorders in Newborns and Children (DACHDNC/SACHDNC), in a vote of 11 – 2, recommended the addition of Pompe Disease to the recommended uniform newborn screening panel (RUSP). This recommendation will be sent to the Secretary of Health and Human Services to approve adding Pompe to the RUSP.

After the HHS Secretary, Kathleen Sebelius, approves the committee’s recommendation, it is expected to be 3-5 years before the majority of states will be screening for Pompe.  Several states are running pilot and test programs already.

Pompe and MLD are both lysosomal diseases.  The Pompe NBS test uses a Tandem Mass Spectrometer, likely the same instrument that MLD will require when its screen is optimized.

Much like MLD, Pompe has several ages of onset, the early onset is the primary target of the NBS, but the screen will also detect a later onset form.  Early onset Pompe, if undetected, has an average age of death before 9 months. An enzyme replacement therapy developed by Genzyme, Myozyme, was  approved by the FDA in 2006.

The development of Myozyme was the focus of the 2010 film about the Crowley familyExtraordinary Measures, starring  Brendan FraserHarrison Ford, and Keri Russell.  While the film “Hollywood-izes” the story, compresses the actual time the development took, and shows an optimized ending, it is a good overview of what it takes sometimes to get new therapies developed for rare diseases.

A link to the press release can be seen here.

 

Newborn Screening – Should a Viable Therapy be a Requirement for a NBS?

The requirements for adding a Newborn Screen (NBS) to the RUSP (Recommended Uniform Screening Panel by the SACHDNC/DACHDNC (Secretary’s Discretionary Advisory Committee on Heritable Disorders in Newborns and Children) consists of four primary criteria:

  1. An acceptable treatment protocol in place that changes the outcome for patients diagnosed early with the disease
  2. An understanding of the condition’s natural history
  3. An understanding about who will be treated as a patient
  4. A NBS screening test that is reliable for both affected and unaffected patients and is acceptable to the public.

We are slowly becoming better at identifying and diagnosing Rare Diseases, unfortunately diagnosis occurs most often after symptoms are presenting. The great majority of the 7,000+ rare diseases do not have efficacious therapies. More than half of all rare diseases affect children and 30% of those children will not live to see their 5th birthday (1).

“There is always a therapy – it may not be a cure or a disease specific treatment, but we can always do something to optimize quality of life.“ Paraphrase of Dr. Marc Patterson from the Mayo Clinic, Rochester MN.

With MLD and many other rare diseases, the diagnostic odyssey can last years and usually there are multiple misdiagnoses along the way.  If we don’t know what disease we are dealing with we can’t be sure we are providing the best care. A NBS for MLD, even without a treatment, would avoid the diagnostic odyssey and allow parents to know up front what to anticipate for the best care of their child – resulting in an optimized quality of life for their child and for the family.

There are good arguments for requiring a viable treatment before formalizing a NBS as well. Test and treat – don’t create a sense of helplessness and panic where there is no therapy. Don’t cause parents to take desperate actions to “do anything” for their child.

In the absence of a viable treatment a whole slew of questions come to mind … who is going to follow up with and provide social and medical care for the family, is there a financial impact on society for increased earlier care, would the role of the family support organizations change, what about the ethics of detecting a disease with a later onset, or parents that want to opt out except for disease with viable therapies, etc. …

Parents and families are starting to clamor for more medical knowledge sooner so they can better care for their children and industry is also awakening to the advantages of a pre-viable-therapy NBS – the potential negative this would have on the ability to capture natural histories that are necessary to get therapies approved being traded off for the identification of patients for potential study and real disease prevalence information.

I am calling for a NBS Therapy Summit or series of summits in the near future, perhaps starting next fall or winter, to encourage all interested and affected parties to share their concerns, views, issues, and thoughts.  An open discussion will give us all indications as to if the viable therapy requirement should be reconsidered.  If you are a public health official,  researcher, policy/regulatory person, SACHDNC committee member, parent, advocacy group member, an industry representative, clinician, or just interested in this topic I encourage your participation.

Follow this blog and I will keep you posted on any progress towards a summit..

Rare Disease Advocacy – Behind the Scenes

I ran across this article a few minutes ago. It’s a great insight into the challenges those of us working in rare disease advocacy working encounter.

Every person and agency mentioned in this article is someone we at the MLD Foundation regularly come into contact with as we work on behalf of those with MLD.
http://cen.acs.org/content/dam/cen/91/19/09119-cover.pdf

Changing a G-Tube (Gastric Feeding Tube)

Changing a gastric feeding tube also known as a g-tube (sometimes gastrostomy tube), is an area of uncertainty that always seems to generate questions among the MLD Family.  Since there is nothing unique about MLD with regard to g-tubes so I though I would share a series of photos to help anyone who want to know what a g-tube is, what a MIC-KEY™ button looks like, and how easy it is to change (or in an emergency replace) a g-tube.

Continue reading

Intracerebral Gene Therapy Phase I/II Clinical Trial for MLD

We are pleased to share that a Phase I/II Intracerebral Gene Therapy clinical trial for MLD is now recruiting late infantile MLD patients. Dr. Patrick Aubourg and Dr. Caroline Sevin are the co-Principal Investigators.

We have posted complete details of the trial, including inclusion criteria, here.

This trial is based on many years of work in the lab, and on some parallel work with ALD that showed good results.

MLD Newborn Screening – We need your blood & urine!

The MLD Foundation is collaborating with researchers at the University of Washington who are working on developing a newborn screen for MLD that would hopefully address the problems encountered with traditional screening approaches caused by the MLD pseudo-deficiency.

For their work they need samples of blood and urine from 15 affected MLD individuals. All samples would be anonymous/de-identified to the researchers.

Criteria for participating is:

  • A confirmed diagnosis of MLD (No age restriction)
  • No treatment (no transplant)
  • Living within the US (due to need for quick return once samples are drawn)
  • Willingness to prick the skin to obtain blood
  • Willingness to follow instructions to obtain samples
  • Agree to mail samples within 24 hours of obtaining them
  • Agree to release the MLD Foundation and the University of Washington from any liability

If you would like to participate, please send an email to research@MLDfoundation.org

We will respond with the release and send you the packet to obtain the samples.

We hope to have the sample collections completed in the next two weeks.

Thank you for considering to help develop a Newborn screen for MLD.

US Announces BRAIN initiative with $100m of 2014 funding

President Obama today announced the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative and an anticipated $100M of US government funding in the next fiscal year. That is part of several hundred million more committed by private partners and foundations to this project to better understand how the brain works.
http://www.nih.gov/science/brain/

NIH Director Francis Collins discussing the BRAIN initiative

NIH Director Francis Collins – “It aims to bring together nanoscience, engineering, and neurology to make sense of how the brain works—how those circuits in the brain allow us to do all the complicated things that we currently don’t understand.”

There is a lot to understand and while we love the focus on the basic science of the brain – we anxiously await, and hope to contribute to, the goals of this project. And we can’t forget the European Commission’s €1bn award to their Human Brain Project.
http://www.publicserviceeurope.com/article/3011/graphene-and-brain-projects-win-1bn-eu-competition

What do you think? How would you like to see all of this support work together?

Not everyone is pleased: http://www.guardian.co.uk/commentisfree/2013/apr/02/president-obama-brain-mapping-project-not-ideal