New Medicines

PalynziqPhenylketonuria in adults


New molecular entity

Development and Regulatory status

Jun 21BioMarin has opted out of converting the EU licence to a GB MA. Palynziq is therefore not licensed for use in the UK at present [18].
Dec 19Biomarin has just started the launch of Palynziq in Germany. No UK price has been set yet nor a date for UK availability [17].
Dec 19Publication of NICE guidance is delayed as the company is awaiting the outcome of the OPTIC study which is critical to providing necessary health economic evidence to support the NICE appraisal. Expect this will also delay UK launch [16].
Jul 19Launched in US [13].
May 19Approved in EU [12].
Feb 19Recommended for EU approval by CHMP - the full indication is "treatment of patients with phenylketonuria (PKU) aged 16 years and older who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 micromol/l) despite prior management with available treatment options”. It is proposed that the drug be prescribed by physicians experienced in the the management of PKU [11].
Nov 18Company is awaiting the outcome of an ongoing European trial (OPTIC Study), which is critical to provide the necessary health economic evidence for a NICE appraisal [14].
May 18Pegvaliase (Palynziq) approved in the US to reduce blood phenylalanine (Phe) concentrations in adult patients with phenylketonuria (PKU), who have uncontrolled blood Phe concentrations >600 micromol/L on existing management [10].
Mar 18Filed in EU using the centralised procedure for treatment of adults with PKU who have inadequate blood phenylalanine control (blood phenylalanine levels greater than 600 micromol/l) despite prior management with available treatment options including sapropterin [9].
Jul 17Biologics License Application (BLA) submitted to FDA for Pegvaliase for treatment of PKU in adult patients who have uncontrolled blood Phe levels on existing management. BioMarin plan to submit an application in the EU Q4 2017 [8].
Feb 17BioMarin intends to file in the US in Q2 17 [7].
Mar 15PEG-PAL has been assigned the Orphan Drug designation in the US and EU [4] .


Substitutes the PAH enzyme in PKU by breaking down Phe.
Phenylketonuria (PKU) or phenylalanine hydroxylase (PAH) deficiency is a genetic disorder affecting approximately 50,000 diagnosed patients in the developed world and is caused by a deficiency of the enzyme PAH. This enzyme is required for the metabolism of Phe, an essential amino acid found in most protein-containing foods [6]. UK prevalence ranges from 1 in 4,500 (Scotland & Ireland) to 1 in 10,000.
Phenylketonuria in adults

Further information


Trial or other data

Oct 19PIII OPTIC study (2018-000648-25) has completed [15].
May 18 A PKU diet is highly effective if followed strictly and current opinion is that it should be life-long; however it is onerous and can be socially isolating. In trials, pegvaliase treatment maintained Phe levels at the upper end of the recommended adult range (120-600 micromol/L); it offers a potential alternative to those who struggle with the diet, but has the disadvantages of increased adverse effects and high cost (estimated average $192,000 in the US [10]).
Mar 16BioMarin note that, 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 [5].
Mar 16BioMarin announce that the pivotal PIII PRISM-2 study (formerly referred to as 165-302) of pegvaliase met the primary endpoint of change in blood Phe compared with placebo (p<0.0001) in preliminary results. During the 8 week PRISM-2 double-blind, placebo-controlled, randomized drug discontinuation trial (RDT), 86 patients were randomized to either remain on pegvaliase or receive matching placebo. The pegvaliase treated group maintained mean blood Phe levels at 527.2 umol/L compared to their RDT baseline of 503.9 umol/L, whereas the placebo treated group mean blood Phe levels increased to 1385.7 umol/L compared to their RDT baseline of 536.0 umol/L. The treatment effect demonstrated in this study represents an approximately 62% improvement in blood Phe compared to placebo. This is the first placebo controlled study demonstrating the ability to improve Phe levels in PKU 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 [5].
Jul 13NCT01889862 ((Prism302) is a three-part, PIII randomized, study of self-administered subcutaneous injection of BMN 165 in 120 adults with phenylketonuria. Part 1 is an open-label run-in period to stabilize the dose in subjects who enroll from a previous BMN 165 study; Part 2 is a double-blind, placebo-controlled, four-arm, discontinuation study to compare the blood Phe concentrations of subjects who continue administration with BMN 165 vs subjects who temporarily receive placebo; and Part 3 is a long-term, open-label extension to evaluate the long-term efficacy and safety of BMN 165 and to provide long-term access to BMN 165 (no placebo). The primary outcome is incidence of adverse effects. The study starts Jul 13 and is due to complete Nov 16 [3].
Jun 13The PIII programme for PEG-PAL (PEGylated recombinant Phenylalanine Ammonia Lyase) for the treatment of phenylketonuria has started. 165-301 is an open-label, multi-center PIII study of an induction, titration and maintenance dose regimen of PEG-PAL self-administered by ~ 90 naive adult PKU subjects. The primary objective is to characterize the safety and tolerability of PEG-PAL. A secondary objective is to evaluate blood Phe levels during induction, titration, and maintenance dosing. After completion of the 165-301 study, subjects are expected to enroll in 165-302, a PIII double-blind, placebo-controlled, randomized discontinuation study, which will also enroll ~ 60 subjects from the PII program who are currently being treated with PEG-PAL. The primary objective of the 165-302 study is to evaluate blood Phe levels. The secondary objective of this study is to evaluate changes in neuropsychiatric assessments as measured by the Inattentive portion of the Attention Deficit and Hyperactivity Disorder Rating Scale (ADHD-RS) and the Profile of Mood States (POMS). These will be administered at baseline, 4 and 8 weeks [2].
Sep 1256 patients >16 years of age with mean baseline phenylanaline (Phe) levels of 1,360 umol/L have been enrolled into four main studies in the PII programme. Patients have not been required to adhere to restricted dietary intake of Phe and have received phenylalanine ammonia lyase, PEGylated recombinant between once and 5 times a week. Of the 25 patients treated with PEG-PAL for at least 1 year, mean blood Phe was 68% lower than pre-treatment baseline levels and all were below 600 umol/L. 20 patients self-administered, some for over 200 days, and had a similar safety profile to other patients in the program. The principal AEs related to PEG-PAL were hypersensitivity-type reactions occurring during initial dosing and consisted of injection-site and disseminated skin reactions or joint pain. The company expects to start a PIII programme in 2H 2013. The preliminary PIII study design includes (1) an open-label study to evaluate safety and blood Phe levels in naive patients and (2) a randomized controlled study in the PII extension study patients to evaluate blood Phe levels and psychiatric and executive function endpoints. All patients in the PIII trial will be offered the opportunity to remain on drug as part of an extension trial. Based on discussions with the FDA, reduction in Phe levels is expected to be the primary endpoint [1].

Evidence based evaluations