A month ago, the FDA placed a hold on Verve Therapeutics’ IND application for its single-course, in vivo liver gene editing treatment for patients with heterozygous familial hypercholesterolemia (HeFH), VERVE-101. Now, Verve finally knows why.
In the clinical hold letter sent last week, the agency requested that Verve provide additional information to resolve the clinical hold, specifically more data about the possible risks of accidental germline editing, reported Verve in an SEC filing. Additionally, the FDA requested more data concerning potency differences between human and non-human cells as well as off-target analyses in non-hepatocyte cell types.
HeFH is a relatively common genetic disorder characterized by dangerously elevated levels of low-density lipoprotein cholesterol. It’s an autosomal dominant disorder, and only one parent needs to have an LDLR gene mutation for it to be expressed in offspring. Verve's treatment uses a lipid nanoparticle-mediated delivery to make a single base change at the site of the affected gene.
While VERVE-101 seeks to only make changes in somatic cells, scientists have become increasingly aware of the risk of off-target mutations of base-pair editing therapies. Technology exists to implement germline gene editing, but genetics specialists worldwide have expressed their concerns and the need for an international framework in which ethical limitations are agreed upon before changing heritable DNA for clinical use.
But recent trial data reveals that Verve has been testing for the potential for germline editing in studies of non-human primates and a murine F1 progeny study. The biotech reported last October that sperm samples collected after VERVE-101 dosing showed no evidence of PCSK9 editing and that among 436 offspring of female mice treated with a saturating dose of VERVE-101mu, the PCSK9 edit was transmitted in 0 of 436 animals.
In order to lift the hold, the FDA is also requesting that Verve modifies its trial protocol in the United States to incorporate additional contraceptive measures and to increase the length of the staggering interval between dosing of participants.
