BioMarin has announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), has adopted a positive opinion for the company’s Marketing Authorization Application (MAA) for Palynziq® (pegvaliase) Injection 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. In addition, the CHMP noted that the data collected in the Phase 3 trial and extension study was suggestive of an improvement in inattention and mood symptoms.

In May 2018, Palynziq, a PEGylated recombinant phenylalanine ammonia lyase enzyme, received regulatory approval from the U.S. Food and Drug Administration, making it the first approved enzyme substitution therapy to target the underlying cause of PKU by helping the body break down Phe. 

“For more than a decade, BioMarin has been committed to providing meaningful new treatment options for the PKU community.  Palynziq is the latest result of this commitment and represents the very first enzyme therapy for PKU; an important step forward in advancing the standard of care and in broadening available treatment options for PKU patients,” said Hank Fuchs, M.D., President Worldwide Research and Development at BioMarin. “We thank the CHMP for recognizing the potential of Palynziq to make a difference for patients living with PKU and are grateful to the PKU community for their continued support and participation in the clinical program.”

“People living with PKU have limited treatment options to manage their Phe levels. As a treating physician, I welcome the potential addition of a new option that could substantially lower Phe levels for more patients with this rare, genetic disease,” said Professor Francjan van Spronsen, Head of Metabolic Diseases at Beatrix Children’s Hospital, Center of Expertise for PKU and Tyrosinemia in The Netherlands. “This offers the potential to effectively control Phe levels in patients with PKU and allow for more normal nutritional intake.” 

The CHMP is a scientific committee composed of representatives from the 28-member states of the EU, and Iceland, Norway and Liechtenstein. The committee reviews medical product applications on their scientific and clinical merit and provides advice to the European Commission (EC), which has the authority to approve medicines for the EU. The EC, which typically adheres to the recommendation of the CHMP, is expected to make its final decision on Palynziq in Q2 2019. 

The CHMP based its opinion 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, 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 increased to 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 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 CHMP also considered data from an ongoing open-label extension study at 36 months, where patients being treated with Palynziq showed durability and an increase in participants reaching blood Phe thresholds of physiologically normal (≤120 µmol/L), as well as thresholds recommended in the U.S. (≤360 µmol/L) and the European Union (E.U.) (≤600 µmol/L).  At 36 months, 58% of the participants reached Phe levels of ≤120 µmol/L, 66% reached Phe levels of ≤360 µmol/L. and 72% reached Phe levels of ≤600 µmol/L.  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 CHMP noted that 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). 

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 all 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 that they are diagnosed early and treated to avoid intellectual disability and other complications.

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 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 10 mg/day to 60 mg/day.  Patients were evaluated for safety, changes in Phe levels and neurocognitive assessments focused on inattention and mood symptoms. 

Medical Guidelines Support Lifelong Therapy to Manage PKU

Medical guidelines in both the United States and Europe support the need for lifelong management of phenylalanine (Phe) levels in patients with phenylketonuria or PKU.  In Europe in 2017, The Lancet Diabetes & Endocrinology published shortened medical guidelines, and the Orphanet Journal of Rare Diseases published a full version of the Guidelines stating that untreated blood Phe concentrations greater than 600 μmol/l should be treated. Both publications can be accessed on the website of the European Society for Phenylketonuria (ESPKU). 

In the U.S., the American College of Medical Genetics and Genomics (ACMG) issued guidelines in 2014, which state that treatment of PKU should be initiated as early as possible and must be continued throughout adulthood and “lifelong,” with a goal of maintaining blood levels of Phe for all patients between 120-360 umol/L.  According to the guidelines “the primary goal of therapy is to lower blood Phe, and any interventions, including medications, or combination of therapies that help to achieve that goal in an individual, without other negative consequences, should be considered appropriate therapy.”

Source BioMarin

uniQure, a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today announced two recent online publications of preclinical studies showing significant silencing, or knockdown, of the mutated gene most commonly known to lead to onset of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases. The proof-of-concept studies were conducted by uniQure scientists and utilized the Company’s miQURE™ technology, a proprietary, next-generation gene-silencing platform.

Both studies are published in the scientific journal, Molecular Therapy Nucleic Acids. The first manuscript entitled “Artificial microRNAs targeting C9orf72 can reduce accumulation of the intra-nuclear transcripts in ALS and FTD patients” describes the design and in vitro characterization of artificial micro-RNA (miC) that silence the mutated C9orf72 gene. The second manuscript entitled “Targeting RNA-mediated toxicity in C9orf72 ALS/FTD by RNAi based gene therapy” reports that an AAV vector carrying a DNA cassette encoding miC silences the mutated C9orf72 gene in iPSC-neurons derived from an FTD patient and in an ALS mouse model that carries the human gene with the C9orf72 mutation. The studies show significant silencing of C9orf72 in human-derived iPSC neurons, and the mutated C9orf72 was also reduced in the cell nucleus. AAV5-miC injected into the striatum of ALS mice reduced mutated C9orf72 in the transduced areas.

“These findings are potentially significant for the treatment of ALS and FTD patients, and the ability to silence C9orf72 transcripts in the nucleus may prove to be critical for therapeutic efficacy of gene therapies for these diseases,” stated Sander van Deventer, M.D., Ph.D., chief scientific officer of uniQure. “In ALS, mutated C9orf72 transcipts are confined to the cell nucleus causing so-called RNA foci, which are toxic clumps of mutated C9orf72 RNA that sequester critical proteins, resulting in cellular dysfunction and death. Whereas most miRNA constructs exclusively target cytoplasmic mRNA, AAV5-miC significantly reduced formation of RNA foci in the nuclei of neurons from C9orf72 mice.”

“Taken together, these preclinical findings further support the feasibility of advancing this program through research and potentially into development of a promising gene therapy with the potential to alleviate the toxicity caused by the mutated C9orf72 in ALS and FTD,” he added. “These data illustrate the potential of our miQURE platform to degrade disease-causing genes, without off-target toxicity. We are very pleased to have these data published in a highly relevant journal for the field and look forward to further exploring this opportunity.”

Source: uniQure