Regulatory Breakthrough in Gene Editing: First In Vivo Base Editing Therapy VERVE-101 Cleared for U.S. Clinical Trials

On October 23, gene-editing company Verve Therapeutics announced that the FDA had lifted its clinical hold on its core product, VERVE-101. Verve plans to begin enrolling U.S. patients in its Phase Ib trial of the gene-editing therapy VERVE-101.

In November 2022, the FDA placed a clinical hold on the IND application for VERVE-101. Nearly a year later, Verve has finally been able to initiate relevant clinical trials in the United States. Andrew Bellinger, Chief Scientific Officer at Verve, stated in a press release: “This authorization marks the first time an in vivo base editing candidate product has been permitted to undergo clinical development in the United States.”

Verve Therapeutics is a pioneer in base editing. Its product, VERVE-101, is the first in vivo base editing therapy to enter clinical trials. Designed for the treatment of heterozygous familial hypercholesterolemia (HeFH), this therapy converts an “A” to a “G” in the PCSK9 gene sequence, thereby inactivating the gene and effectively lowering LDL cholesterol. According to the company, the drug can “prevent heart disease with a single injection.”

In vivo gene editing is one of the future directions of gene therapy and has become a consensus within the industry. However, the cutting-edge nature of the technology also determines the cautious attitude of regulatory agencies toward in vivo gene editing, particularly in vivo base editing technologies.

In October 2022, Verve submitted an Investigational New Drug (IND) application for VERVE-101 to the U.S. Food and Drug Administration (FDA). However, in November 2022, the company received a notice from the FDA placing a clinical hold on the trial.

The FDA outlined the reasons for suspending the VERVE-101 clinical trial. They expressed concerns about whether the edited genes could be passed on to future generations and therefore requested additional data to mitigate potential safety concerns associated with this therapy.

In light of these concerns, the FDA has requested that Verve provide additional preclinical data on potency differences between human and non-human cells, risks of germline editing, and off-target analysis in non-hepatic cell types. Meanwhile, the FDA also hopes that Verve can share data from the HEART-1 trial, which was concurrently enrolling patients in New Zealand and the United Kingdom.

In fact, the clinical hold on VERVE-101 was not an isolated incident; the FDA’s cautious regulatory stance has triggered a chilling effect on gene-editing technology in the United States.

Following the suspension of VERVE-101, Intellia Therapeutics, a leader in in vivo gene editing, was impacted. In August 2023, after the FDA requested new preclinical trials, Intellia was required to conduct Phase II clinical trials of its product NTLA-2002 outside the United States first.

Prior to the suspension of VERVE-101, leading gene-editing companies such as Editas Medicine, Beam Therapeutics, and Bluebird Bio had also experienced clinical trial suspensions. In November 2022, Editas announced the suspension of clinical research on EDIT-101, the world’s first in vivo gene-editing therapy. In July 2022, the clinical trial for BEAM-201, Beam’s base-edited cell therapy, was paused. In February 2021, Bluebird Bio announced the halt of two Phase I/II studies of its gene therapy candidate for sickle cell disease, LentiGlobin.

Earlier, Sangamo’s in vivo gene-editing therapy SB-913 entered clinical trials in November 2017 but had its clinical development terminated in February 2019 due to insufficient therapeutic benefit; additionally, some projects have faced clinical holds due to serious adverse events, such as LogicBio Therapeutics’ LB-001 for the treatment of a rare pediatric disease.

Regulatory Dilemmas Force Many Gene-Editing Companies to Obtain Preliminary Clinical Data Outside the U.S. Before Filing IND Applications with the FDA

During the nearly one-year period when clinical trials were suspended, Verve actively communicated with the FDA and submitted additional data to alleviate the agency’s concerns regarding VERVE-101.

Data show that sequencing of sperm samples from six sexually mature male non-human primates before and after treatment with VERVE-101 revealed no evidence of PCSK9 gene editing. Similarly, genotyping of 436 female offspring from mice treated with the murine surrogate of VERVE-101 indicated that PCSK9 gene editing was not transmitted to the offspring.

In the heart-1 clinical trial data, Verve completed dosing of VERVE-101 in the first cohort of three patients during dose escalation. No patients experienced treatment-related adverse events, and all adverse events reported to date have been Grade 1.

Prior to 2022, the FDA rarely approved clinical trials in humans for in vivo gene editing therapies. The progress of approved projects could also be described as “arduous”:

EDIT-101, an in vivo gene-editing therapy developed by Editas and Excision for the treatment of Leber congenital amaurosis type 10, demonstrated a favorable safety profile and significant biomarker improvements in data analyses, but showed suboptimal clinical efficacy in humans. LB-001, an in vivo gene-editing therapy developed by LogicBio for methylmalonic acidemia, is currently listed as “not recruiting” following the company’s acquisition by AstraZeneca. SB-FIX, Sangamo’s in vivo gene-editing approach for hemophilia B, enrolled only one patient before the study was terminated in 2021.

The FDA has always been cautious in its approach to gene editing, with even greater concerns regarding base editing. Base editing employs chemical processes to alter specific letters within a target gene; however, unless the base editing is precisely targeted, random deamination by deaminases may introduce biases in base editing enzymes.

Verve’s technology originates from Beam Therapeutics, whose ex vivo gene editing product was previously placed on clinical hold by the FDA during the same period. The FDA required the company to provide additional control data from genomic rearrangement assessments, further analysis of certain off-target editing experiments, and other relevant data. Although Beam’s program was resumed after submitting the requested information, VERVE-101’s dual nature as both an in vivo editing and base editing therapy has led the FDA to demand more extensive safety data from Verve and to exercise greater caution.

Gene editing companies have expressed understanding of the FDA’s cautious stance. Sekar Kathiresan, CEO of Verve Therapeutics, expressed optimism about collaborating with the agency: “Verve is the first company to use in vivo base editing technology. Being first has its advantages in some respects, but at times you must work with regulators to establish technical standards and define what is needed to move forward, which makes it easier to gain a firm foothold.”

Editas CEO Gilmore O’Neill has also stated, “The caution exercised by regulatory agencies is warranted; it is their job. As for us, we have a responsibility to ensure rigorous risk management while advancing new technologies such as in vivo gene editing.”

When the first human trials of CRISPR gene-editing therapies were initiated in the United States, the FDA adopted a similar stance. Perhaps as more positive results emerge from clinical trials of in vivo gene editing, the FDA’s attitude will gradually become more permissive.

In fact, regulatory agencies have been striving to advance the regulatory and approval frameworks for gene therapies. Recently, senior FDA officials stated that the agency needs to consider accelerated approval pathways for gene therapies. Dr. Peter Marks, head of the FDA’s Center for Biologics Evaluation and Research (CBER), said that the FDA will support the use of measurable biomarkers as surrogate endpoints in gene therapy clinical trials to help drug developers obtain accelerated approval.

The FDA’s gradual relaxation of its regulatory policies on gene editing is well-documented.

One week before the clinical hold on VERVE-101 was lifted, Intellia Therapeutics announced that the U.S. Food and Drug Administration (FDA) had approved its Investigational New Drug (IND) application for NTLA-2001, a therapy for transthyretin (ATTR) amyloidosis with cardiomyopathy. NTLA-2001 is a CRISPR-based in vivo gene-editing candidate, and its global Phase 3 study is expected to launch by the end of 2023, paving the way for the first pivotal trial of in vivo gene-editing therapy in the United States.

Moreover, the lifting of the clinical hold on Verve Therapeutics will also provide valuable insights for the clinical advancement of in vivo base editing technologies.

Kathiresan noted that while some peer companies choose to address regulatory hurdles in the later stages of drug development, it is crucial for Verve to engage with the FDA early in the process, enabling the company to gain a clearer understanding of regulatory requirements. “We have now established a template for the rest of our pipeline, both in preclinical studies and clinical trial design. We know what conditions such products must meet to secure FDA approval,” Kathiresan said.

Next, Verve’s focus will be on obtaining first-in-human data for VERVE-101 to demonstrate the feasibility of base editing technology, followed by dose expansion. Meanwhile, the company will work toward initiating a second human trial of another product, VERVE-102, for the treatment of HeFH, expected to launch in the first half of 2024.

The FDA’s relaxation of regulatory policies on gene editing will also provide valuable experience for clinical trials conducted by domestic gene editing companies.

However, regulatory policy is only one aspect. Currently, only a very small number of companies in China are engaged in the research and development of in vivo gene editing products. Foundational scientific discoveries, patents, technology, and manufacturing processes constitute three major barriers. The industry has witnessed numerous cases where laboratory technologies failed to achieve industrial translation and commercialization. For in vivo gene editing to reach the market, it must also overcome the hurdle of scalability.