Patients receiving protein-based biopharmaceuticals may eventually benefit from a technology to improve their immune tolerance to such treatments, according to early stage research to be published this week in the Proceedings of the National Academy of Sciences (PNAS). The study, led by scientists at BioMarin Pharmaceutical Inc. demonstrated a substantial reduction in the long-term immune response to specific enzyme replacement therapies in an animal model, without the continued use of immunosuppressive drugs. The immune response induced by certain protein-based drugs can reduce the efficacy and safety of treatment and is an increasingly common medical problem caused by the emergence of protein-based drugs used to treat chronic diseases.

"The work presented in PNAS is indicative of our innovative approach to developing and commercializing therapeutics for patients who suffer from enzyme deficiency and other genetic diseases," said Fredric D Price, chairman and CEO of BioMarin. "We are excited by these findings and the potential of this technology to enhance our pipeline of enzyme-based therapies as well as therapies for other, more prevalent diseases."

Repeated administration of protein-based drugs can cause patients to develop neutralizing antibodies that bind to the drugs, remove them from circulation, and ultimately reduce their efficacy and cause adverse side effects. This medical problem is becoming more common as an increasing number of new drugs to treat chronic conditions are protein-based and induce strong immune responses. For example, patients with the inherited genetic disease hemophilia A receive chronic infusions of factor VIII, a recombinant protein that restores normal clotting function and prevents internal bleeding that can lead to injury and death. As many as 20 per cent of hemophilia A patients develop high levels of neutralizing antibodies (called 'inhibitors') that can make factor VIII therapy ineffective. Using the immune tolerance technology developed at BioMarin, it may be possible to reduce or prevent the formation of factor VIII inhibitors. BioMarin plans to evaluate its immune tolerance technology for hemophilia A as well as other enzyme or protein replacement therapies in which neutralizing antibodies interfere with biopharmaceutical treatment.

The data published in PNAS demonstrate a substantial reduction in antibody response to recombinant human alpha-L-iduronidase (rhIDU), an enzyme that normally elicits a strong antibody response in the animal model used for these studies. When the animals were pretreated with a specific regimen of immunosuppressive agents in combination with low dose infusions of the 'high-uptake' form of rhIDU, the antibody response to therapeutic doses of rhIDU was reduced by approximately 37 fold compared to control animals and was maintained at a low level despite continuing weekly exposure to the enzyme. Antibody levels in the tolerized animals remained low for as long as six months while receiving weekly infusions of rhIDU. The toleragenic form of the iduronidase enzyme is the high-uptake form (containing mannose 6-phosphate markers) that increases uptake through the mannose 6-phospate receptors found on the surface of most cell types.

BioMarin develops and commercializes enzyme-related therapies to treat serious, life-threatening diseases and conditions.