BioMarin Pharmaceutical Inc. has announced positive results from the pivotal phase III extension study of Phenoptin (sapropterin hydrochloride), an investigational oral small molecule for the treatment of patients with phenylketonuria (PKU), who have elevated phenylalanine (Phe) levels.

Results confirm that all pre-specified safety and efficacy endpoints of the open-label extension study were met. Data demonstrated the long-term safety and tolerability of Phenoptin as a treatment to control blood Phe levels across a range of doses in PKU patients.

The 22-week multi-centre open-label dose titration phase III extension study enrolled 80 patients who had previously completed the pivotal phase III clinical trial. Patients in the extension study received Phenoptin doses of 5 mg/kg/day, 10 mg/kg/day, and 20 mg/kg/day for two-week intervals each, followed by four weeks at 10 mg/kg/day. Patients completing this first phase of treatment were then treated for an additional 12 weeks with one of the three doses, depending upon their Phe levels at weeks two and six. A total of 79 patients completed both stages of treatment.

Phenoptin demonstrated an excellent safety and tolerability profile for all three doses over the 22 weeks of treatment, which was the primary endpoint of the extension study. There were no withdrawals due to adverse events related to the study drug during the extension study.

Phenoptin provided a dose-dependent reduction in blood Phe levels relative to baseline, with average Phe level decreases of 100 umol/L (1.7 mg/dl), 204 umol/L (3.4 mg/dl), and 263 umol/L (4.4 mg/dl) for patients receiving doses of Phenoptin of 5 mg/kg/day, 10 mg/kg/day, and 20 mg/kg/day, respectively (secondary endpoint).

A once daily dose regimen of Phenoptin was sufficient to maintain the reduction of blood Phe levels throughout a 24 hour period.

The incidence and type of adverse events were comparable to that of the placebo group during the double-blind study and nearly all were mild or moderate in severity. The four most frequently reported events were headache, nasopharyngytis, vomiting, and diarrhoea.

The ongoing phase III diet study is designed to assess the increase in Phe tolerance levels in patients taking Phenoptin, and BioMarin remains on track to announce results from the phase III diet study in the first quarter of 2007.

BioMarin and Serono expect to file the NDA and MAA in the second and third quarters of 2007, respectively. In May 2005, BioMarin entered into a strategic partnership with Serono for the development and commercialisation of Phenoptin for the treatment of PKU.

Phenoptin is an investigational oral small molecule therapeutic for the treatment of PKU. The active ingredient in Phenoptin, sapropterin dihydrochloride, is the synthetic form of 6R-BH4 (tetrahydrobiopterin), a naturally occurring enzyme cofactor that works in conjunction with phenylalanine hydroxylase (PAH) to metabolize Phe. Preliminary clinical data have suggested that Phenoptin has a potential to produce significant reductions in blood Phe levels in the subset of patients who are BH4- responsive.

BioMarin and Serono estimate that Phenoptin could be a potential treatment option for approximately 30 per cent to 50 per cent of the estimated 50,000 individuals in the developed world who have been diagnosed with PKU.

Phenoptin received orphan drug designation to treat PKU from both the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA). If Phenoptin becomes the first drug therapy approved for the treatment of PKU, Phenoptin would receive seven years of market exclusivity in the United States and 10 years in the European Union for this indication.

Additionally, the FDA has granted Phenoptin Fast Track designation, which is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

PKU, a genetic disorder affecting approximately 50,000 diagnosed patients in the developed world, is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH).