Phase III PRISM-2 study of pegvaliase successful in treatment of PKU (phenylketonuria)- BioMarin

BioMarin announced that the pivotal Phase III PRISM-2 study (formerly referred to as 165-302) of pegvaliase met the primary endpoint of change in blood Phe compared with placebo. This is the first placebo controlled study demonstrating the ability to improve Phe levels in PKU (phenylketonuria) patients who at baseline do not have to follow a Phe-restricted diet. Typically, a Phe-restricted diet does not allow any protein intake outside of medical food. Patients in the trial were estimated to be eating 75% of the daily recommended allowance for protein intake for a healthy adult. In the secondary endpoints of the 8 week RDT, no benefit in inattention or mood scores were observed in patients treated with pegvaliase compared to placebo. In an exploratory sub study of cognitive function in 9 patients, the Cambridge Neuropsychological Test Automated Battery (CANTAB) showed trends of improvement favoring pegvaliase. In contrast to the short term results of the RDT, supportive evidence of the association of reduced blood Phe and improvement in inattentiveness comes from two long term evaluations in the PRISM-1 and PRISM-2 studies. In these studies, ADHD-RS assessments were obtained prior to treatment and at various times thereafter (scale range 0-27 points, higher score indicating greater impairment).

In the open label PRISM-1 study (formerly referred to as 165-301 or feeder study), 49 patients had baseline inattention scores greater than 9 (defining patients with inattentive symptoms at baseline). Of the 35 patients whose Phe was reduced during PRISM-1 by greater than 20%, the mean improvement in inattention was 7.3 points, while the 14 patients whose Phe was reduced by less than 20% only showed an improvement of 3.7.

In the PRISM-2 study, the 72 patients were evaluated regardless of the baseline scores. Among those who completed 41 weeks in the open-label extension, patients were divided into quartiles based on the magnitude of their Phe reduction from baseline. The quartile of patients having the largest Phe reductions (to values lower than ? 1,296 umol/L) had mean improvements in their ADHD-RS inattention score of 7.5 while the patients with the smallest Phe reductions (to values no less than Practice guidelines issued by the American College of Medical Genetics and Genomics (ACMG) support the need for lifelong management of Phe levels in patients with phenylketonuria or PKU.

The guidelines state that the treatment goal for PKU patients should be blood levels of phenylalanine (Phe) for all patients between 120-360 umol/L. The Long Term open label portion of the PRISM-2 study demonstrated sustained and substantial reductions in Phe levels. Of the 90 patients who had been treated for at least 41 weeks in this portion of PRISM-2, 40% had achieved a Phe level of 120 umol/L or less (120 umol/L is considered the upper limit of normal), 60% had achieved a Phe level of 360 umol/L or lower (the target Phe level according to the ACMG guidelines) and 79% had achieved a Phe level reduction of 20% or greater.