Should I Try the New Drug? Weighing Risks versus Benefits
By Virginia Schuett, MS, RD, editor
From the Fall 2007 issue of National PKU News.
It is my role to share new information about PKU research through the newsletter.
As your editor, there are times when I also feel an obligation to ask probing
questions about that research. So I want to outline some questions and concerns
I have about the new drug, sapropterin. I realize that my views may be different
from those of others in the PKU community, so I invite anyone to write to me
(by October 22) and I will gladly consider printing some of the comments
in the next newsletter.
The phe-restricted diet has been the only PKU treatment available since the 1960’s,
when newborn screening finally meant that PKU could be identified and treated from birth.
The treatment has been remarkably successful on the whole; in fact, over the years,
PKU has been widely viewed as a “model for the prevention of mental retardation.” We have
only to look at the “success stories” of so many young people with PKU to see how the diet
works at its best. Still, we know that the diet is not a perfect treatment. It is a challenge
to maintain, and not everyone manages it as successfully as we might like. There also are
unanswered questions about some nutritional aspects of the diet as well as about various
neurocognitive effects in some children.
So when a promising drug like sapropterin is finally within reach, I can see how it is tempting
to rush to embrace it. The possibility of lowering blood phe levels and/or liberalizing the diet
is definitely enticing. However, be aware that research has shown that the vast majority
of people with “classical” PKU will not benefit from the drug; those with at least one genetic
mutation conferring some residual enzyme activity (where treatment likely is already more liberal)
have a much better chance of responding.
Also, be aware that sapropterin is a drug and no drug is free of side effects for everyone using it.
If you are going to be taking a drug or you are going to be giving your child a drug for many years,
you need to think about a number of issues.
Whatever your unique circumstance, at this very early stage in our understanding of sapropterin
in PKU treatment, I think that everyone who considers trying the drug should do so with eyes wide open.
While I believe that BioMarin has worked very hard to bring us this drug and has the best interests of
the PKU community in mind, I think it is only prudent to carefully weigh the potential risks and benefits.
In cases where the diet is not well controlled, the benefits may easily outweigh the potential risks;
however, I am less certain at this point whether the potential risks are worth the expected benefits for
children and others who are well-controlled on the diet. Everyone will have to make this judgement for
themselves, in discussion with their PKU clinic staff. Here are some things that I would consider:
Starting and Stopping the Drug
If you begin using the drug for the purpose of liberalizing the diet, remember that unlike for most drugs where you can easily stop the treatment if it doesn’t work out (for one reason or another), once you start sapropterin and change an established dietary regimen, it will not be easy to reinstate a more strict diet should the need arise. To me, this is an important issue.
Long Term Safety
The longest study that BioMarin has done is reported to be 26 weeks. Is this really long enough to understand and fully evaluate potential safety issues, when you are considering using the drug for many years, if not for a lifetime? I know that many clinicians and researchers believe the drug is entirely safe. And true, the drug has been used in some European countries for many years and reported to be “safe.” But the number of PKU patients using it there, especially for any length of time, is small.Of course it is very good that to-date no obvious “serious adverse effects” have been reported. However, I worry about less obvious effects of the drug, ones that would take time to develop and might be very difficult to identify.
Also, the “many years of experience” with using BH4 in Japan and Europe that is widely quoted has been mainly for a completely different disease caused by a deficiency of BH4 (and typically at a dose less than the 20 mg/kg given as a starting dose by BioMarin). In PKU, the BH4 cofactor is present in normal amounts. Could there be a difference in long term safety and how the body reacts to large amounts of BH4 when it is added on top of normal amounts already present in the body?
Because we are not just making up for a BH4 deficiency by giving the extra BH4, it is likely that this extra BH4 will affect biological systems other than just the single one (the phenylalanine to tyrosine conversion) that we are targeting. These effects may be positive or negative, mild or serious; we may not even begin to fathom what they will be, perhaps for many years. For example, do we know what the long term effects of the extra BH4 will be on the two neurotransmitters, dopamine and serotonin, whose synthesis is controlled by enzymes that also use BH4 as a cofactor (tyrosine hydroxylase and tryptophan hydroxylase)? Or do we know the long term effects on nitric oxide synthase (an enzyme that also uses BH4 as a cofactor and is important for vascular function) and possible negative effects on the vascular system at a cellular level? Some people think that the effects on these enzymes and their metabolites will be positive, but there is absolutely no way to know this without specific research looking at these biological systems and how they are affected.
Clinical/Practical Aspects
Establishing responsiveness and dose. Protocols are now being developed by several groups of experienced physicians and nutritionists for determining how to best establish responsiveness and optimal dosage (which will not always be easy and will require frequent blood monitoring), as well as to provide guidelines on diet changes. But because everyone is different in their response to the drug, there are no absolute guidelines for dosage, or for increasing phe intake after starting the drug (if that is being considered); a “trial and error” process will be necessary, with its own demands and challenges both for patients/parents and for clinic staff.Blood phe control. Will using the drug result in better blood phe level control—or possibly worse control? While some people may use the drug only for the purpose of lowering blood phe levels, others will use it for liberalizing the diet. In my view, there is an inherent danger in liberalizing the diet, when it will be easy to go “overboard” with formerly restricted items (such as regular bread, cereal, pasta, etc.) once the diet is liberalized, resulting in worse, not better blood phe levels. There are no data on compliance issues using sapropterin over the long term.
Clinic staff time. Does your clinic staff have the time to give you the attention you will need? A substantial increase in staff time will be needed to work with families using the drug, especially initially. Remember also that the staff will be inexperienced in using this drug, unless they have participated in earlier Biomarin trials, so they will have lots to learn.
Cost/Insurance Coverage
The estimated cost of the drug is high. Although the exact price has not yet been set, it could cost much more than PKU formula, depending on how much of the drug is needed (up to $30,000 or more per year according to BioMarin’s chief medical officer, as quoted in a Wall Street Journal article on 5/15/07). BioMarin will have a Patient Assistance Program set up through the National Organization for Rare Disorders (NORD), which will help many people get access to insurance coverage on a case by case basis, or even provide the drug without charge in some instances. However, there are still unknowns about individual situations. For example, self-insured plans could simply exclude the drug. If you are considering using the drug, you should thoroughly understand the long term implications for insurance coverage.
Overall Concerns
My biggest concerns are long term safety, which remains unproven, and the difficulty that people will have returning to a more restricted diet should any of the practical aspects of taking the new drug prove to be unsatisfactory. Each person considering using the drug must weigh the risks against the potential gains for their own unique situation.
Last update: February 2008
National PKU News: www.pkunews.org
E-mail: schuett@pkunews.org