International Meeting Highlights Potential Breakthrough Treatments for PKU

By Sandra Shpilberg, Associate Director Marketing, BioMarin Pharmaceutical Inc., Novato, CA

From the Winter 2007 issue of National PKU News.

On September 10 and 11, 2006, world experts convened in Sendai, Japan, for an international congress to discuss “Tetrahydrobiopterin (BH4) and Alternative Treatments in Phenylketonuria (PKU), Cardiovascular and Other Diseases.”

This satellite meeting to the International Congress on Inborn Errors of Metabolism (ICIEM–www.iciem2006.org), which was sponsored by BioMarin Pharmaceutical Inc. along with Serono, Daiichi Asubio, and Maruho, provided a unique opportunity to focus exclusively on BH4 and alternative treatments in PKU, as well as BH4 in other diseases. Over 130 participants from all over the world attended the congress and took part in 36 oral presentations and two poster presentations.

The congress kicked off with an introduction by Dr. Nenad Blau (Switzerland) and Dr. Yoichi Matsubara (Japan), the chairmen for the meeting. Dr. Blau described PKU as a deficiency in the enzyme phenylalanine hydroxylase (PAH), which is essential for breaking down phenylalanine (phe) in the body. Following this introduction, the congress discussed three key treatment alternatives in various stages of investigation: 1) Cofactor therapy with BH4, 2) Enzyme substitution therapy with phenylalanine ammonia lyase, and 3) gene therapy.

Cofactor Therapy with BH4

  • What it is: BH4 is the natural cofactor that fuels the activity of the PAH enzyme. All humans (excluding those with primary BH4 deficiency) naturally produce BH4. Clinical research on BH4 has proven that when BH4 is given orally to some people with PKU, the activity of the mutated PAH enzyme improves, resulting in a breakdown of phe and lowering of blood phe levels. This is referred to as BH4-responsive PKU.


  • Progress: Dr. Fritz Trefz (Germany) presented results from BioMarin’s “Phase 3” trial of sapropterin dihydrochloride (sapropterin), the generic name for BioMarin’s BH4 product. Patients of all phenotypes participated in the trial (including mild/variants and classic PKU). These patients were off the PKU diet. The age ranged from 8 to 49 years of age. At baseline, mean blood phe was 843 µmol/l (14 mg/dl) and 888 µmol/l (14.8 mg/dl) in the sapropterin and placebo groups, respectively.

    In this trial the blood phe levels of patients on sapropterin versus those of patients on placebo (an inactive tablet) were compared to assess whether sapropterin plays a role in lowering phe levels. Dr. Trefz presentation showed that sapropterin significantly decreased blood phe levels, with an average decrease of 236 µmol/l (3.9 mg/dl), versus no decrease in the placebo group. Dr. Trefz also showed that side effects of BH4 were generally mild and transient. The type and frequency of side effects observed throughout the study were similar in the BH4 and placebo groups. The most frequent side effects occurred in the Infections and Infestations, and Gastrointestinal System Organ classes.
    No serious side effects were reported as a consequence of BH4 treatment.

    In addition, Dr. Raymond Stevens’ (United States) presentation focused on answering the question of whether responsiveness to BH4 is determined by phenotype (your baseline phe level) or genotype (your genetic mutation). Dr. Stevens showed that these relationships are not simple and that responsiveness to BH4 has been shown in patients with both classic and non-classic PKU.

    • Enzyme Substitution Therapy with Phenylalanine Ammonia Lyase (PAL)

  • What it is: In enzyme substitution therapy, the concept is to provide people with PKU with a substitute enzyme to carry out the role of the mutated PAH enzyme, and to breakdown phe.


  • Progress: Drs. Lin Wang (United States), Alejandra Gamez (United States), and Christineh Nevart Sarkissian (Canada) reported significant progress in preclinical studies. The team, in conjunction with BioMarin scientists, has completed studies in PKU mice and demonstrated successful blood phe reduction with the PAL enzyme. Their research demonstrates that when PAL was administered once weekly via subcutaneous injection in PKU mice, the result was a sustained decrease in blood phe levels for a 12-week period. Baseline blood phe levels ranging from 1500 µmol/l (25 mg/dl) to 2000 µmol/l (33.3 mg/dl) decreased to less than 100 µmol /l (1.7 mg/dl) after treatment with PAL. Researchers observed restoration of pigmentation and increase in weight in the PAL treatment groups compared to placebo groups. Antibodies did not appear to impact efficacy in either group, nor were there signs of allergic reactions or local injection site reactions.

    • Gene Therapy

  • What it is: In gene therapy, the concept is to find a mechanism to deliver a normal copy of the PAH enzyme to fix the broken or mutated enzyme in the cells of people with PKU.


  • Progress: Dr. Beat Thony (Switzerland), Akihiro Kume (Japan), and Cary Harding (United States) presented new developments in gene therapy. In their research, they use adeno-associated viruses (AAV), a new approach, to insert a normal copy of the enzyme into the cells of mice. Two variations were discussed: a) subcutaneous (under the skin) injection, and b) injection into the liver. Both variations showed a temporary, but not sustained, decrease in blood phe levels in mice.

    • Conclusion

    To conclude, researchers at the congress show that great hope exists for people with PKU. Many pre-clinical and clinical studies are still necessary to demonstrate safety and efficacy of the treatments, but there is a lot of hope that in just a few years we may have at least one if not multiple breakthrough treatments for PKU.

     

    Last update: February 2008
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