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Compilenewborn
On September 6, BioMarin Pharmaceuticals announced that the U.
S.
Food and Drug Administration (FDA) has suspended the Phearless Phase 1/2 clinical trial of the gene therapy BMN307
.
BMN307, a phenylalanine hydroxylase (PAH) gene therapy based on adeno-associated virus 5 (AAV5), is being evaluated in the Phearless study for the treatment of adult patients with phenylketonuria (PKU)
PKU, also known as PAH deficiency, is a rare hereditary disease that manifests at birth.
It is characterized by defects in PAH that cannot decompose phenylalanine (Phe)
.
Phe is an amino acid commonly found in many foods
BMN307 aims to obtain defective PAH in PKU patients
.
The FDA clinical suspension is based on temporary safety results from a preclinical, non-GLP pharmacology study
Cancer is a long-term fear faced by gene therapy because of the risk that the virus used to introduce genes into patient cells may inadvertently trigger mutations or destroy the mechanism that prevents cells from becoming cancerous
.
BioMarin conducted this preclinical study to understand the persistence of BMN307 activity in mice carrying two germline mutations, which may make the mice susceptible to malignant tumors
.
One of the mutations eliminated the missing PAH gene in PKU, and the second mutation made the animal immunodeficient
Among the 63 treated mice, 7 received the highest dose of BMN307 (2e14 Vg/kg), and 6 of them found liver tumors during liver autopsy 52 weeks after the administration, and there is evidence that the AAV vector part Integrated into the genome
.
At 24 weeks, no lesions were observed in any mice
So far, BioMarin has only given subjects a lower dose of BMN307 (2e13 vg/kg or 6e13 vg/kg) in the Phase 1/2 clinical study of Phearless, although the trial protocol includes a third higher dose Group
.
Part of the reason is based on the risks found in historical rodent studies, so the subjects of the Phearless study are regularly monitored for liver health
The clinical significance of the results of these preclinical rodent studies has not yet been determined, and cancers caused by AAV integration have not been observed in large animals or humans
.
BioMarin is suspending further patient enrollment in this global Phase 1/2 study until the investigation of these findings is completed
This clinical suspension is another setback faced by the BioMarin gene therapy development project
.
Last summer, the FDA refused to approve the company's lead gene therapy for hemophilia A valrox industry
The FDA's decision on valrox did not stem from safety, but from the lack of data on the durability of valrox's efficacy
.
The therapy aims to provide a functional copy of factor VIII, and factor VIII is lacking or defective coagulation factors in haemophilia A patients
.
Since then, the data reported by BioMarin shows that in patients treated with valrox, the expression levels of functional factor VIII have all declined over time, although they still seem to be able to avoid bleeding
.
Hank Fuchs, head of BioMarin's research and development, pointed out that more than 3,000 patients have received gene therapy, and there has been no report of cancer
.
However, he also pointed out that malignant tumors have also been observed in mice using other AAV vectors
.
For patients who have been treated with low-dose BMN307 in the company's Phearless Phase 1/2 study, they will continue to carefully assess and monitor their health conditions to understand and reduce any risk of cancer
.
It is worth mentioning that, after two cancer cases were found in a clinical trial earlier this year, Bluebird Bio suspended the marketing of the β-thalassemia gene therapy Zynteglo, which uses a lentiviral vector.
.
Reference source: FDA slaps clinical hold on BioMarin's PKU gene therapy
