Commentary on PreKUnil Tablet Use

By Dr. Richard Koch, M.D.

From the Winter 2002 issue of National PKU News

As I see it, there are three problems with the use of PreKUnil tablets at the present time:

• I am afraid that women may use them and not realize they cannot be used for pregnancy. Strict diet is still needed to protect the fetus from high blood phe.

• We do not know the long-term effects of greatly elevated blood phe levels upon other body tissues such as the peripheral nervous system, hormonal tissues (such as the adrenal and thyroid glands), and others. For example, the blood-brain barrier for transporting LNAAs into the brain is different from that in peripheral nerves.

• We have not yet documented the dose needed to achieve satisfactory brain levels of phe based on scientifically controlled studies. In fact, we do not know whether we can achieve satisfactory brain phe levels with this treatment over the long term.

We have just completed a very small preliminary study (end of November) to look at the effect of PreKUnil tablets on brain phenylalanine concentration using Magnetic Resonance Spectroscopy. We selected three patients who were out of control, with blood levels over 20 mg/dl (>1200 µmol/L). I wanted to see what the tablets would do for patients on an unrestricted diet. While the brain levels were lowered approximately 10%-25% by the PreKUnil tablets, at least in these three patients we did not see phe levels in the brain that I would be happy with for treatment. This makes me very uneasy about the long-term use of the tablets in patients who have classical PKU. At least for patients with blood phe levels of 20 mg/dl and over, with the dosage we used, our very early data suggest that PreKUnil tablets do not normalize brain phe levels. We will continue to evaluate these patients and three others for 6 months, however.

At present, the U.S. Food and Drug Administration (FDA) is in the process of reviewing the PreKUnil tablets. This will be time-consuming. The agency is very careful at this time to be certain of the quality of products they are approving. Their wariness is understandable, when the agency gets criticized severely for approving products that end up causing major difficulties for patients. I think it will take perhaps a year before a decision is made on whether the tablets can be sold in the U.S.

In conclusion, preliminary research confirms that the transporter for LNAAs into the brain is adversely affected by levels of phe that are consistently over 20 mg/dl (1200 µmol/l), as we see in off-diet or poorly controlled classical PKU. But excess LNAAs, in the form of PreKUnil tablets, improves transport of essential amino acids into the brain (they are reduced in untreated cases and this is associated with the pathology of PKU). The tablets also reduce brain phe levels to some extent. But to be most effective I think that blood phe has to be in a range that permits proper transport of the LNAAs. What this range is we do not currently know; it is probably in the range of 10-15 mg/dl (600-900µmol/l), based on unpublished preliminary research we have done recently. Such blood levels can only be achieved with traditional diet and formula.

While the use of LNAAs may eventually make a significant contribution to PKU therapy, more research is needed to establish the safety and usefulness of this approach, as well as dosage for optimal benefit. In the coming year, we will continue our research in this promising area.