Meeting in Japan Highlights Research on NeoPhe in the Treatment of PKU
By Reuben Matalon, MD, PhD, University of Texas, Galveston, TX
From the Winter 2007 issue of National PKU News.
The International Congress on Inborn Errors of Metabolism (ICIEM) 2006 in Japan was exciting.
It included presentations on the topics described in the previous article,
as well as on my special area of interest, LNAA (large neutral amino acids),
in particular NeoPhe, which is a new preparation of LNAA.
LNAA in PKU TreatmentThe use of large neutral amino acids (LNAA), in the treatment of PKU had three platform presentations: one from New Zealand, and two presentations from my group at the University of Texas Medical Branch. Numerous research studies have now shown that these large neutral amino acids, given as a supplement by mouth, can effectively compete with the transport of phenylalanine (phe) in the gastrointestinal tract, thus lowering blood phe levels to an extent.
The presentation from New Zealand involved the use of LNAA and its effect on brain and plasma phe levels and neuropsychological performance in early treated patients with PKU. The study of 16 patients compared brain phe level to plasma phe level and found no significant difference. However, some patients showed a decrease in brain phe level while on LNAA. Also, blood phe decreased with LNAA when the patients were not taking other PKU medical foods; additionally, the researchers concluded that LNAA supplementation has a positive impact on “executive function.” The New Zealand study was more ambitious than our study design, which simply examines blood phe, and is very interesting.
The platform presentation from UTMB dealt with an early “open-label” study and with the second phase of a double-blind placebo control study. Results of the open-label study are in press.
Special NeoPhe SymposiumA special Symposium on NeoPhe, the new preparation of LNAA, was held with participants from the United States and a number of other countries. Data were presented by Dr. Laura Fiori from Professor Marcello Giovannini’s group in Italy. She presented two patients from a double-blind placebo control study (the “gold standard” for conducting clinical trials) who had reduction in blood phe level of 20 to 30% when on NeoPhe compared to the group taking a placebo.
Drs. Alberto and Alessandro Burlina from the University of Padova in Italy also shared their experience with NeoPhe. Four patients on NeoPhe showed an excellent response: blood phe levels dropped significantly, and neuropsychological testing results improved while the patients were taking a NeoPhe supplement.
Professor Peter Novikov from the University of Moscow presented data on five patients who participated in another double-blind placebo control study. His experience was similar to the other groups, with blood phe levels in the patients dropping significantly while they were taking NeoPhe. Prof. Elena Grechanina from the University of Kharkiv also presented her results with four patients. Blood phe levels dropped while the patients were taking NeoPhe, similarly to what has been seen in other trials.
I presented data from the United States. Blood phe levels in all patients dropped while they were taking NeoPhe. Again, the range of the drop was similar to what was found in the other groups: on average, a 30% reduction of blood phe.
Dr. Claudia Braga from the University of Porto Alegre, Brazil intended to present data from her recent study, but unfortunately she could not come to the meeting. However, she sent the data to me. Her patients showed the typical drop of 20-30% in blood phe levels while on NeoPhe. The trial of our study with NeoPhe was short: one week on NeoPhe and one week on placebo. Each patient was given one tablet per kg body weight (0.5gm/kg/day) divided with meals, so that a 60 kg person took 20 tablets at breakfast, 20 at lunc, and 20 at dinner. I also indicated that I had better results when the pills were given with meals and not before meals as the protocol originally called for, and I suggest just half a tablet per kg so that a 60 kg person takes 10 tablets with each meal (total of 30 tablets rather than 60 each day).
Future StudiesThere was a discussion of future trials. Obviously we need a longer term trial to evaluate efficacy, safety/toxicity, and compliance. Such trials are in the planning stages. The discussion during the symposium was very lively and participants from different centers expressed willingness to participate in the planned new study. We are currently working with them to establish a uniform protocol to decide on the length of the new study and the end points to be measured.
Dr. Debra Louis from the US Food and Drug Administration (FDA) was present at the symposium and made some important and thoughtful comments for the planned future study. Centers that treat PKU were excited about the simplicity of the approach to lower blood phe levels using NeoPhe, which can be used for all PKU patients, whether or not they respond to BH4.
Another preparation of LNAA, PreKUnil, was discussed. Its use was discouraged because of a deficiency in the amino acid lysine; it should be used only with lysine supplementation.
I am thankful for the generosity of MACPAD (Mid-Atlantic Connection for PKU & Allied Disorders) and STAPAD (South Texas Assoc. for PKU & Allied Disorders). These organizations provided funds from National PKU Awareness Month in May that have allowed me to continue these important studies and to plan for large-scale clinical trials.
Last update: February 2008
National PKU News: www.pkunews.org