BioMarin Pharmaceutical Inc. BMRN announced that the FDA has placed its phase I/II study — PHEARLESS — evaluating its AAV5-phenylalanine hydroxylase gene therapy candidate, BMN 307, under clinical hold. The study was evaluating ascending doses of the candidate in adult patients with phenylketonuria (“PKU”).
The FDA’s decision to place the study under clinical hold was based on interim safety findings from a pre-clinical, non-GLP pharmacology study. In the pre-clinical study, the company evaluated the highest dose of the candidate at the 2e14 Vg/kg level in seven mice out of 63 animals. Data from the pre-clinical study showed that six mice that were administered the highest dose had tumors on liver necropsy after 52 weeks of dosing. These tumors showed evidence for integration of portions of AAV vector into the genome, a key component of the gene therapy candidate. Among these six mice with tumors, five had adenomas (type of non-cancerous tumor that may affect various organs) and one was found with hepatocellular carcinoma. However, the company stated that there were no lesions at 24 weeks following the dosing in mice.
The risk of tumors or malignancy probably led the FDA to place a clinical hold. However, the clinical significance of these pre-clinical findings is yet to be established. Previous studies on other AAV-based gene therapies under development demonstrated integrational mutagenesis and resultant cancer formation in mice. However, cancers due to AAV integration in large animals or humans have never been observed in the past and translatability of the risk of tumors in humans is uncertain.
The company initiated dosing in the PHEARLESS study in September last year and has dosed patients with only lower doses — 2e13 vg/kg or 6e13 vg/kg — of the candidate so far. The company is yet to dose any patient with the highest dose of the candidate
BioMarin has temporarily halted enrollment in the study until the investigation is completed. The company is currently working with the FDA and other health authorities to decide a future path for the development of BMN 307 in PKU patients. Meanwhile, the company plans to investigate the preclinical data, and continues to carefully evaluate and monitor the already dosed patients in the PHEARLESS study for any malignancy risks.
BioMarin’s shares are down 7.2% in pre-market trading today in response to the news. Shares have declined 5.2% in the past year compared with the industry’s decrease of 1.2%.
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PKU is a rare genetic enzyme deficiency disorder that manifests at birth and if left untreated causes high levels of Phe, which leads to a variety of cumulative toxic effects on the brain. According to information provided by the company, approximately 70,000 individuals in the regions of the world where BioMarin operates are diagnosed with PKU.
BMN 307 is the third potential treatment and first gene therapy for treating PKU being developed by BioMarin. The company has two approved PKU therapies — Kuvan and Playnziq in its portfolio. However, we note that Kuvan has lost exclusivity in the United States and Europe. Moreover, Playnziq is distributed under a Risk Evaluation and Mitigation Strategy (“REMS”) program, which restricts its availability to certain certified specialty pharmacies. Although years away, the successful development of BMN 307 will likely drive long-term growth at BioMarin.
Kuvan generated sales of almost $150 million in the first half of 2021, reflecting a decline of 38.9% year over year due to generic competition. Dr Reddy’s RDY and Par Pharmaceuticals, a subsidiary of Endo International ENDP, markets Kuvan generics in the U.S. market. Playnziq generated sales of more than $110 million in the first six months of 2021. Sales are expected to be in the range of $220-$260 million in 2021. BioMarin believes Playnziq has a peak commercial opportunity of roughly $1 billion as it demonstrated dramatic Phe reductions in PKU patients in pivotal studies.
A few other companies are also developing treatments for PKU in early-stage studies, which include Synlogic’s SYBX small molecule candidate, SYNB1618; and Homology Medicines’ gene therapy, HMI-102.
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BioMarin currently carries a Zacks Rank #3 (Hold). You can see the complete list of today’s Zacks #1 Rank (Strong Buy) stocks here.
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