Phase 1/2 Trial of Potential Gene Therapy for PKU Doses First Patient

Phase 1/2 Trial of Potential Gene Therapy for PKU Doses First Patient
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A Phase 1/2 clinical trial evaluating BioMarin Pharmaceutical’s investigational gene therapy BMN 307 for people with phenylketonuria (PKU) has dosed its first patient.

Enrollment is ongoing at the University Hospital Birmingham NHS Foundation Trust (UHB), in the U.K. BioMarin is actively working to open additional sites in other countries. More information is available here.

“More than 70 years ago, the first child was treated for PKU in the United Kingdom at Birmingham Women’s and Children’s Hospital. Today, we continue to make strides in PKU treatment through the clinical study of a gene therapy for PKU,” Tarekegn G. Hiwot, MD, PhD, the trial’s principal investigator at the UHB, said in a press release.

“Building upon our experience of delivering two approved PKU therapies to the PKU community, BMN 307 gene therapy combines BioMarin’s leadership in the development of PKU therapies with our expertise in gene therapy development and manufacturing,” said Hank Fuchs, MD, president of Worldwide Research and Development at BioMarin.

BioMarin’s gene therapy recently received fast track designation in the U.S. for the treatment of PKU, adding to the orphan drug designations granted previously in both the U.S. and Europe.

These designations are meant to speed up BMN 307’s development and review by providing regulatory support and financial benefits, and ensure marketing exclusivity for a period of time upon approval (seven years in the U.S. and 10 years in Europe).

In a separate press release announcing the recent fast track designation, Fuchs noted the new designation, “combined with our ability to conduct our clinical studies incorporating material manufactured using a commercial-ready process will further facilitate rapid clinical development of BMN 307 gene therapy.”

PKU is caused by mutations in the PAH gene, resulting in lower levels of phenylalanine hydroxylase (PAH), an enzyme responsible for the breakdown of phenylalanine — an amino acid obtained through diet. (Amino acids are the building blocks of proteins.)

Low PAH levels lead to the toxic buildup of phenylalanine, which can cause severe neurologic damage and intellectual disabilities.

Currently, BioMarin’s Kuvan (sapropterin dihydrochloride) and Palynziq (pegvaliase-pqpz) are the only approved treatments for PKU. They control phenylalanine levels by boosting PAH activity or by a PAH-independent phenylalanine breakdown pathway.

In contrast, the company’s new investigational therapy, BMN 307, is designed to target the genetic cause of the disease by delivering a functional copy of the PAH gene to the patient’s liver cells using a modified and harmless version of an adeno-associated virus (AAV), called AAV5.

By delivering a functional PAH gene to cells, BMN 307 is expected to promote PAH production, normalize phenylalanine levels, and prevent further damage. In a mouse model of the disease, the therapy was shown to lead to a lifetime normalization of phenylalanine levels.

The Phase 1/2 trial, called PHEARLESS (NCT04480567), will evaluate the safety, tolerability, and effectiveness of a single into-the-vein administration of BMN 307 in about 100 people, 15 and older, with PKU.

The six-year study comprises a dose-escalation phase, in which several doses of BMN 307 will be tested, followed by a dose expansion phase once the ideal dose has been selected. In terms of effectiveness goals, the trial will assess whether the gene therapy can normalize phenylalanine blood levels and allow patients to follow a non-restrictive diet.

BMN 307 will be produced using a commercial-ready process at BioMarin’s award-winning gene therapy manufacturing facility, in Novato, California. This will facilitate the therapy’s clinical development and potentially support its approval.

“BioMarin has been committed to the PKU community for more than 15 years and remains dedicated to the research and development of innovative therapies to advance the standard of care for people with PKU,” Fuchs said.

“We applaud [BioMarin’s] unwavering commitment to drive research to bring a third treatment to the PKU community and for their substantial contributions to the overall body of scientific knowledge in PKU that they continue to make,” Christine S. Brown, MS, executive director of the National PKU Alliance, said.

BioMarin also is sponsoring an international, observational study, called PHENOM (NCT03505125), in 63 adults with PKU to identify the most relevant and meaningful disease markers and clinical outcomes to use in future clinical trials.

BMN 307 represents the company’s second investigational gene therapy program, the first being Roctavian (previously known as BMN 270 and Valrox) for severe hemophilia A. Approval decisions by regulatory agencies in the U.S. and in Europe were delayed to late next year or 2022 following requests of longer-term data from a Phase 3 clinical trial (NCT03370913).

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
Total Posts: 4
Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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