European Commission Approves Palynziq® (pegvaliase injection) for Treatment of Phenylketonuria (PKU) in Patients Aged 16 Years or Older

First Enzyme Substitution Therapy Approved in Europe to Treat the Underlying Cause of PKU in Patients Aged 16 Years or Older at Doses up to 60 mg

Treatment Lowers Phe and Suggestive of Beneficial Effects on Inattention and Mood Symptoms

More than 18,000 Patients Aged 16 and Older Affected by PKU in Europe and the Middle East

SAN RAFAEL, CA, USA I May 6, 2019 I BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) today announced that the European Commission (EC) has granted marketing authorization for Palynziq® (pegvaliase injection) at doses of up to 60 mg once daily, to reduce blood phenylalanine (Phe) concentrations in patients with phenylketonuria (PKU) aged 16 and older, who have inadequate blood Phe control (blood Phe levels greater than 600 micromol/L) despite prior management with available treatment options. Palynziq, a PEGylated recombinant phenylalanine ammonia lyase enzyme, is the first enzyme substitution therapy approved in Europe to target the underlying cause of PKU by helping the body to break down Phe.  In addition, the EC acknowledged that the Phase 3 trial and extension study is suggestive of an improvement in inattention and mood symptoms.

On March 1, 2019 BioMarin announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), adopted a positive opinion for the company's Marketing Authorization Application (MAA) for Palynziq. This is BioMarin's second approved treatment for this rare genetic disease.

PKU is a rare genetic disease that manifests at birth and results in a variety of cumulative toxic effects on the brain and is marked by an inability to break down Phe, an amino acid that is found in most forms of protein. PKU affects approximately 50,000 diagnosed patients in the developed world, and in Europe, approximately 1 in every 10,000 newborn babies are affected by this disease.I Approximately 18,000 patients aged 16 and older are affected by PKU in Europe and the Middle East.  Left untreated, high levels of Phe become toxic to the brain and may lead to serious neurological and neuropsychiatric-related issues, affecting the way a person thinks, feels, and acts. Due to the seriousness of these symptoms, in many countries, infants are screened at birth to ensure early diagnosis and treatment to avoid intellectual disability and other complications. According to EU treatment guidelines, PKU patients should maintain lifelong control of their Phe levels. 

"The approval of Palynziq is the latest milestone after more than 15 years of an ongoing commitment to the PKU community.  BioMarin has brought the only two approved therapies for PKU to patients around the world, and we will continue to draw on our expertise in PKU to advance the standard of care in this serious rare disease," said Jean-Jacques Bienaimé, chairman and chief executive officer of BioMarin. "Today would not be possible without the efforts of our employees, partners in Europe, patients, families and clinicians.  We thank the European Commission for recognizing the vast potential benefits of Palynziq for patients affected by PKU."

"Palynziq is a new and promising treatment for the PKU community," said Dr. Amaya Bélanger-Quintana, Head of the Metabolic Department of the University Hospital Ramon y Cajal, Madrid, Spain.  "Many adult PKU patients struggle daily with their special diet, leading many of them to relax or stop their treatment despite knowing the negative consequences this will have on to their well-being.  Palynziq provides a new opportunity for adult PKU patients to attain the metabolic control their doctors and they want for themselves."

On May 24, 2018, the U.S. Food and Drug Administration (FDA) approved Palynziq® (pegvaliase-pqpz) Injection to reduce blood Phe concentrations in adult patients with PKU, who have uncontrolled blood Phe concentrations greater than 600 µmol/L on existing management.

The Palynziq EC approval was based on the totality of data from the Palynziq clinical development program including a Phase 3 pivotal study, PRISM-2, which showed that a group of patients taking either 20 mg or 40 mg of Palynziq maintained mean blood Phe levels at 553.0 µmol/L and 566.3 µmol/L respectively after eight weeks, compared to their baseline in the randomized discontinuation trial (RDT) of 596.8 µmol/L and 410.9 µmol/L. The corresponding 20 mg and 40 mg placebo treated groups mean blood Phe levels returned to pre-treatment baseline levels of 1509.0 µmol/L and 1164 µmol/L compared to their RDT baselines of 563.9 µmol/L and 508.2 µmol/L respectively, the EU Summary of Product Characteristics (SmPC) allows for daily doses up to 60mg. The 8-week PRISM-2 double-blind, placebo-controlled, randomized drug discontinuation trial (RDT) consisted of 86 patients who were randomized to either remain on Palynziq or receive matching placebo. 

The approval was also based on data from an ongoing open-label extension study at 36 months, where patients being treated with Palynziq showed a sustained reduction in mean blood Phe over time, durability of response and an increase in participants reaching important blood Phe thresholds. Mean blood phenylalanine levels reduced from 1233 micromol/l at baseline to 565 micromol/l at Month 12 (n=164) and 345 micromol/l at Month 24 (n =90), and these reductions in mean blood phenylalanine levels were maintained through Month 36 (341 micromol/l; n =48).  At 36 months, 66% reached Phe levels of ≤360 µmol/L and 72% reached Phe levels of ≤600 µmol/L (the recommended treatment target in the EU).  These results were observed concurrent with a median increase in protein intake from intact food of 25g over baseline after 36 months on treatment. In addition, the data collected in the Phase 3 trial and extension study was suggestive of an improvement in inattention and mood symptoms as measured by the inattention subscale of the investigator-rated Attention Deficient Hyperactivity Disorder Rating Scale (ADHD-RS IV) and the Profile of Mood States (POMS) tool that was modified to be specific to PKU (PKU-POMS). 

Phase 3 Study Design

The Phase 3 program consists of two studies.  PRISM-1 study was a Phase 3 open-label, randomized, multi-center study that enrolled 261 patients, and its primary objective was to characterize the safety and tolerability of Palynziq during induction, titration, and maintenance dosing. The secondary objective of the study was to evaluate blood Phe levels during induction, titration, and maintenance dosing to achieve a target dose of Palynziq 20mg/day or 40mg/day.

215 patients who completed PRISM-1 or PAL-003 (Phase 2 long term extension) enrolled into PRISM-2, which included a randomized, double-blind, placebo-controlled discontinuation study to evaluate the efficacy and safety of subcutaneous injections of Palynziq self-administered by adults with PKU, followed by an open-label extension.  The primary efficacy endpoint is change from the RDT baseline in blood Phe at eight weeks.

Patients who reached a target dose and achieved ≥20% decrease in blood Phe from PRISM-1 baseline were randomized into the RDT portion of the PRISM-2 study to either continue their Palynziq dose or to start matching placebo.  Those participants not reaching a ≥20% reduction in blood Phe from PRISM-1 baseline did not match the inclusion criteria for the RDT and enrolled into the open label extension portion of the study.  In the open-label extension, physicians were allowed to modify dose based on blood Phe response using a range of doses from 5 mg/day to 60 mg/day. Patients were evaluated for safety, changes in Phe levels and neurocognitive assessments focused on inattention and mood symptoms. 

About Phenylketonuria

PKU, or PAH deficiency, is a genetic disorder affecting approximately 50,000 diagnosed patients in the regions of the world where BioMarin operates 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. If the active enzyme is not present in sufficient quantities, Phe accumulates to abnormally high levels in the blood and becomes toxic to the brain, resulting in a variety of complications including severe intellectual disability, seizures, tremors, behavioral problems and psychiatric symptoms. As a result of newborn screening efforts implemented in the 1960s and early 1970s, virtually all individuals with PKU under the age of 40 in countries with newborn screening programs are diagnosed at birth and treatment is implemented soon after. PKU can be managed with a Phe-restricted diet, which is supplemented by low-protein modified foods and Phe-free medical foods; however, it is difficult for most adult patients to adhere to the strict diet to the extent needed for achieving adequate control of blood Phe levels.

To learn more about PKU and PAH deficiency, please visit www.PKU.com. Information on this website is not incorporated by reference into this press release.

About Palynziq

Palynziq substitutes the deficient phenylalanine hydroxylase (PAH) enzyme in PKU with the PEGylated version of the enzyme phenylalanine ammonia lyase to break down Phe. Palynziq is administered using a dosing regimen designed to facilitate tolerability; Palynziq's safety profile consists primarily of immune-mediated responses, including anaphylaxis, for which robust risk management measures effective in clinical trials are in place.

The dosing and administration of Palynziq follows an induction, titration, and maintenance paradigm. Periodic blood Phe monitoring is recommended, and patients should be counseled on how to adjust their dietary intake, as needed, based on blood Phe concentrations. 

U.S.  FDA-Approved Indication

PALYNZIQ® (pegvaliase-pqpz) Injection is a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations in adult patients with phenylketonuria (PKU) who have uncontrolled blood phenylalanine concentrations greater than 600 µmol/L on existing management.

About BioMarin

BioMarin is a global biotechnology company that develops and commercializes innovative therapies for patients with serious and life-threatening rare and ultra-rare genetic diseases. The company's portfolio consists of seven commercialized products and multiple clinical and pre-clinical product candidates. For additional information, please visit www.biomarin.com. Information on such website is not incorporated by reference into this press release.

BioMarin® and Palynziq® are registered trademarks of BioMarin Pharmaceutical Inc.

I van Wegberg AMJ, MacDonald A, Ahring K, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12(1):162. Published 2017 Oct 12. https://doi.org/10.1186/s13023-017-0685-2. Last accessed: May 2019

SOURCE: BioMarin Pharmaceutical

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