Editor's Note: This message was posted to the Storage Diseases Discussion Board By Tony Bailey (father of McKenna, who has MPS I-H). The message was replied to by Dr. Peters from The University of Minnesota (see his address below), who is in the major group in the United States who does BMT's. This was posted on this forum at the request of Tony Bailey.
Posted by Tony Bailey on Wednesday, 30 December 1998, at 12:14 a.m.
First off, nice looking site guys! Am I in the discussion portion of this site? It appears that I am but I see no activity. My question to you is; is the ISDCSG involved in any way with Enzyme replacement therapy for MPS 1H, or is the ISDCSG strictly focussed on BMT's? I have attempted to e-mail Dr.Peters directwith this question but have not gotten a response.
Sincerely,
Tony Bailey/ Father of McKenna Bailey MPS 1H
Re: Enzyme replacement therapy
Posted by Dr. Charlie Peters, Fairview-Univ. Medical Ctr., Univ. of Minnesota and The International Storage Disease Collaborative Study Group on Wednesday, 30 December 1998, at 8:53 a.m., in response to Enzyme replacement therapy, posted by Tony Bailey on Wednesday, 30 December 1998, at 12:14 a.m.
I attempted to reply to Mr. Bailey on Dec. 18; however, the message was not delivered. However, this reply may be more effective in reaching a larger audience. Enzyme replacement therapy has been a very beneficial treatment for patients with type 1 Gaucher disease. It has greatly improved the internal organ involvement and some bone problems. Unfortunately,
children with the neurologic forms of Gaucher (i.e., types 2 and 3) have demonstrated progressive neurologic deterioration despite aggressive ERT.
How does this experience over many years in Gaucher disease apply to Hurler syndrome and the potential for ERT with alpha-L-iduronidase? Some of the same principles apply. Namely, ERT (Dr. Emil Kakkis at UCLA) would be expected and has indeed shown promising results in 10 MPS I patients (8 Hurler-Scheie, 1 Hurler, 1 Scheie) with respect to: 1) decreased fatigue,
2) improved indurance, 3) improved appetite, 4) improved range of motion, 5) reduction in liver size by >20% within 6-12 weeks, 6) leukocyte enzyme levels reach approximately 18% of normal, 7) urinary glycosaminoglycans are reduced, 8) side effects/complications have been mild including the production of antibodies and hives, 9) conclusion--ERT appears to be a promising treatment for many somatic features of MPS I disease.
First, Dr. Kakkis is to be commended on this excellent work and the promise which it holds for children and families with MPS I disease. Obviously, for many families, bone marrow or umbilical cord blood transplant may present too many risks for their child for a variety of reasons which include but are not limited to: 1) the severity of the disease (e.g., Scheie or Hurler-Scheie), 2) the absence of a matched brother or sister donor, 3) the morbidity and mortality associated with transplant. ERT can therefore be seen as an alternative with some but not all of the benefits attributed to transplant.
The primary concerns which remain regarding ERT for any disease with a neurologic component include the inability of ERT to achieve significant, beneficial levels in the brain and the possibility that antibodies will ultimately affect the benefit of the ERT. In children with Hurler syndrome, transplant has been shown to favorably alter the neurologic and neuropsychologic function of these children compared to children who have not been transplanted. Clearly, these aspects of the disease are devastating and transplant has had a major impact here.
We all look forward to the development of the safest and most effective therapies for MPS and other diseases (e.g., the leukodystrophies) whether they be ERT (Dr. Emil Kakkis), gene transfer/gene therapy (pioneering work by Dr. Chester B. Whitley), alternative stem cell sources (mesenchymal stem cells), etc. However, in our enthusiasm for these new therapies, we must critically examine their risks, benefits, and limitations. The nearly 2 decade long experience with transplant remains the standard against which all new therapies can and should be measured.
Posted by Tony Bailey on Friday, 5 February 1999, at 10:20 p.m., in response to Re: Enzyme
replacement therapy, posted by Dr. Charlie Peters, Fairview-Univ. Medical Ctr., Univ. of Minnesota and
The International Storage Disease Collaborative Study Group on Wednesday, 30 December 1998, at
8:53 a.m.
To: Dr. Charlie Peters
From: Tony Bailey, Father of McKenna Bailey MPS IH
I would like to apologize about your unsuccessful attempt at responding
to my original e-mail, it appears that my return e-mail address which was
going out in the "from" portion of all my e-mails was incorrectly entered in
my system. This has since been corrected.
First I want to thank you for your timely and most informative response
to my inquiry on this forum. Getting non-published information from the
professionals involved in ERT (Enzyme replacement Therapy) has not been
easy. I can understand their hesitance on commenting on areas that could be
argued as being speculative. However as you well know, when parents with
MPS I children are considering treatments that are "on the cutting edge,"
there is limited printed data available. In addition there is the issue of the
printed data being out-dated. Because of this and because I am a parent who
has gone through the process of assessing my child for a BMT, I have learned
that dealing in the area of speculation is a necessary and critical part of
getting the overall picture when it comes to assessing our child for
treatments such as these.
In your response to my post you concluded by saying; "We all look forward to
the development of the safest and most effective therapies for MPS and other
diseases. However, in our enthusiasm for these new therapies, we must
critically examine their risks, benefits, and limitations. The nearly 2
decade long experience with transplant remains the standard against which
all new therapies can and should be measured." I agree whole-heartedly with
this statement, and I think you are correct in that this forum is an excellent
place for you to post this kind of information. I'm certain that your time here
will be very effective in reaching a good number of MPS families. In fact I
have started a project of my own recently. I am attempting to put together an
information source for MPS I families and patients in an effort to help them
become more educated on the various treatments for MPS I patients such as
BMT, ERT, and Gene Therapy. For now my primary focus is on BMT and ERT
because as you said and I want to encourage parents to, "critically examine
their risks, benefits, and limitations." In addition my aim is to offer
these parents information in a manner that anyone can understand. Dredging
through miles of medical jargon is quite a challenge for a parent who has just
learned that their child is dying. My aim is to provide a neutral source that is
specific to MPS I parents and the treatments that are available for them.
I would therefore like to ask for you to contribute with any new statistical
data you might have to offer on BMT in addition to what I presently have.
I have included the articles that I have acquired so far and put them at the
bottom of this post so as not to clutter up this letter more than need be.
My aim is to help MPS I families make more informed decisions concerning
these treatments.
I would therefore like to ask your permission to use some of the information
you offer here in this effort.
You covered many important issues pertaining to BMT and ERT in a clear and
concise manner, which I think many parents like myself could benefit from.
I would also like to ask you a few questions here that I hope you can shed
some light on. There are many MPS I families trying to get a better grasp
on understanding the comparisons of these two treatments for MPS I so that
when ERT becomes available to them they can be better prepared to make
the decisions that come with this.
In your response you stated that "ERT can therefore be seen as an alternative
with some but not all of the benefits attributed to transplant."
1. Other than the neurologic aspects, can you tell me briefly the other
benefits that a BMT for MPS IH offers that ERT does not appear to offer?
2. Can you give me your input on what you believe to be the potential
for ERT and BMT to work in conjunction with each other? For instance, do
you believe it is possible that ERT could be used as a pre-medication
treatment plan to position them better going into a BMT? Also, do you think
there is a potential for ERT to offer benefits to a Post BMT Hurler child who
is not maintaining a satisfactory level of engraftment?
In conclusion, I very much realize that your input here is not in anyway
a replacement for an individual assessment of a child. This is a statement
that I have displayed prominently with the data I include. I am simply
trying to address the need for myself and many other MPS I parents to get
a better grasp on what the introduction of this new treatment (ERT) means
for their child. With this new information we can know how to begin looking
differently at the option of BMT now that there will be an additional
treatment option for them. Any help you can give me in this effort would be
greatly appreciated.
Sincerely,
Tony Bailey
Editor's Note: Tony Bailey included a list of abstracts to Dr. Peters, which are also listed on our abstract link. Therefore, for the sake of space, they were edited out here.
Re: ERT, reply to Mr. Bailey
Posted by Dr. Charlie Peters on Monday, 8 February 1999, at 4:49 p.m., in response to Re: Enzyme replacement therapy, posted by Tony Bailey on Friday, 5 February 1999, at 10:20 p.m.
I would first like to thank Mr. Tony Bailey for his very thoughtful response and for all of his efforts to help eduacate MPS families about their options for therapy. He posed 2 questions which I have reprinted here:
1. Other than the neurologic aspects, can you tell me briefly the other
benefits that a BMT for MPS IH offers that ERT does not appear to offer?
Response: It is difficult to provide a complete answer to this question because of the still limited
experience with ERT. Issues such as IV access, need for repeated and long-term administration of enzyme arise. The extent to which bone deformities will or will not become amenable to orthopedic surgery would be a question. Other areas such as long-term heart and lung function will need to be addressed.
2. Can you give me your input on what you believe to be the potential
for ERT and BMT to work in conjunction with each other? For instance, do
you believe it is possible that ERT could be used as a pre-medication
treatment plan to position them better going into a BMT? Also, do you think
there is a potential for ERT to offer benefits to a Post BMT Hurler child who
is not maintaining a satisfactory level of engraftment?
Response: it is perhaps too early to say how ERT and BMT could be used in conjunction with each other. I am not sure that ERT for a brief period of time before BMT would be very helpful. On the other hand there are children whose engraftment/enzyme activity level after BMT is not ideal. They might be considered for ERT after BMT. If a child with a less severe form of MPS I is treated with ERT and begins to show changes in intellectual/neurologic function, that child might be considered for BMT. It is my intention to cooperate as completely as possible with the ERT team at UCLA and to advance our ability to collect specific information on the outcomes in children with MPS I, whatever therapy they received (ERT, BMT, both, or neither)
Once again Tony thank you very much for raising these very important questions. All of us in the MPS field look forward to learning more about ERT and its impact.
Sincerely yours,
Charlie Peters, M.D.
Editor's Note: The letter to Dr. Kakkis asking him to participate in this forum was quite lengthy and included the following questions and the post that we posted on the MPS Discussion Forum at the University of Minnesota (which I have edited out for the sake of space). Dr. Kakkis has conducted ERT Trials in California
1. a. As mentioned above, we have found very little information that helps
MPS I families understand the differences in the degree of the benefits of
ERT for MPS IH verses MPS-IS, and MPS-IH/S. We realize that you have an
extremely limited number of cases to extract this kind of information from
and that there is a substantial degree of guess work here, however it is a
very important area of concern for us an therefore any input you can offer
here would be a great help.
b. Someone has recently raised the question to us that in some trial
in England where ERT was performed on MPS I-H children, there were some
adverse reactions with them because of the total absence of any natural
enzyme. Can you tell us more about the trials in England (we have been
unable to gain any information from anyone concerning these trials)? Have
you been able to address the problem they supposedly reported concerning
problems in children with no enzyme activity?
2. Does your approach to ERT for Hurlers patients differ from how ERT is
performed on
Gauchers patients? If so how? And if this approach is in fact different, can
you give us your thoughts on the potential for ERT to effect the
neurological aspects of Hurlers.
3. Can you give us your input on what you believe the potential for ERT to
be a treatment that could offer positive results to Hurlers children who
have had a BMT but aren't maintaining a satisfactory level of engraftment.
Could ERT be an option for the child at that point?
4. On the subject of BMT, is it possible that ERT can work in conjunction
with a BMT in other ways as well, such as a treating patients with ERT as a
pre-medication treatment plan to position them better for a BMT.
5. Is the issue of the side effect of antibodies simply a nuisance side
effect or can this effect/inhibit the uptake of the enzyme. In other words,
can the presents of substantial antibodies during ERT substantially inhibit
the ultimate success of the ERT for the MPS I patient both short and long term?
Response from Dr. Kakkis:
Enzyme replacement therapy for MPS I had long been considered as possible
treatment for the disorder. Years of research clarified how this might
be achieved but the research reached the point of treating dogs with MPS I
but not children. THe Ryan Foundation begain supporting the work with
the goal of reaching a clinical trial. While this effort was in progress,
a new start-up called BioMarin Pharmaceutical took on the project in April
of 1997. By september a new drug application was filed with the FDA (an
IND) and by December 1997 the first of ten patients started on therapy.
By May of 1999 all 10 patients will have received therapy for one year.
The therapy was administered by a weekly iV infusion and monitored through
a large number of clinical and biochemical analyses. The results showed
that all of the patients had a reduction in liver by 6 weeks in and that
by 26 weeks all were in the normal or near normal range. Urinary
excretion of GAG or MPS, decreased by 60-80% in all kids by 6 weeks into
therapy. All but one of the kids are near normal now. THe patients
reported improvements in endurance, joint pain ,range of motion, airway
and snoring, vision in two cases,severe headaches in 3 and other problems
of MPS I. Hives were seen in 5 patients but these occurred only once in 2
patients. No life threatening reactions occurred and all the patients
continue on therapy.
BioMarin is working on a scaled up facility and will filing to get FDA
approval this year. The company hopes to make the enzyme available to all
before the end of this year.