The FDA has set a high bar for clinical trials evaluating experimental gene editing tools used inside the body. So far, no companies have been able to clear it.
Shares of Verve Therapeutics (VERV) were clotheslined after the company announced American regulators placed a clinical hold on its lead drug candidate. The stock could be found sinking over 25% for much of the day. The asset has yet to begin a clinical trial in the United States, but the freeze ensures it won't be able to initiate a study on the desired timeline.
The not-so-surprising development weighed on many other gene editing peers. Shares of Beam Therapeutics (BEAM) and Prime Medicine (PRME) fell over 10%, while Intellia Therapeutics (NTLA) dropped over 5% before recovering lost ground.
What does this clinical hold mean for Verve Therapeutics and the gene editing landscape broadly?
Precision, Measurement, and Manufacturing
Gene editing is the ability to alter the genome of a cell to change its function. Scientists can potentially turn on, turn off, insert, and delete genetic code to treat diseases at the DNA level.
These tools can be used ex vivo ("outside the body") or in vivo ("inside the body").
- An ex vivo approach generally means harvesting a patient's own cells, engineering them in the lab with a gene editor, growing the cells to a healthy concentration, then transplanting them back into the same patient. The number of process steps increases the complexity and expenses of the procedure, but scientists generally have more control over the approach.
- An in vivo approach means designing a gene editing tool that can be delivered to a specific organ or tissue inside the body and make the intended edit(s). Once an in vivo tool is administered to a patient, there's no way to reverse the effects.
The FDA has allowed ex vivo gene editing tools to be evaluated in clinical trials. Crispr Therapeutics (CRSP) and Vertex Pharmaceuticals (VRTX) leaned on this approach for their drug candidate aimed at rare blood disorders. The asset is widely expected to become the first Crispr gene editor to earn regulatory approval in the United States.
The FDA has not allowed in vivo gene editing tools to be evaluated in clinical trials. It has good reasons, which it outlined in draft guidance published in March 2022. The guidance could be summarized with three words:
- Precision: The FDA wants drug developers to think carefully about designing the proper tools for the job. Investors often see the word "precision" thrown around when discussing gene editing tools. But it's important to be precise when discussing that all-important word. Crispr tools can precisely target a section of a patient's gene, but the edits made aren't always so precise. Tools can accidentally make random and uncontrolled edits, called indel mutations ("insertion deletion mutations"), that permanently impact gene function. First generation gene editors can also result in sloppy repair of edited genomes, or even the shattering of a genome into many small pieces. Both could increase cancer risks.
- Measurement: The FDA wants drug developers to provide evidence that the gene editor made the desired changes inside the patient. This is performed through the development of diagnostics called potency assays, which are complex when biologic, cell, and gene therapy drug candidates are involved. The inability to design adequate potency assays has delayed drug candidates by multiple years -- even when they crush phase 3 clinical trials and everything in the competitive landscape.
- Manufacturing: The FDA wants drug developers to prove quality manufacturing processes are in place. For in vivo tools, it must be proven that viral vectors and lipid nanoparticles used to encapsulate gene editing tools are generally the same molecular size. Similarly, regulators want drug developers to quantify the number of empty delivery shuttles included in drug lots. Manufacturing isn't trivial. A biologic license application (BLA) requesting FDA approval for a drug that succeeded in clinical trials could be over 40,000 pages long. Over half the pages actually contain manufacturing data, not clinical data.
What Does This Mean for Verve Therapeutics?
Verve Therapeutics doesn't know why the FDA placed a clinical hold on its lead drug candidate, but it should receive a detailed hold letter by early December 2022.
The asset, VERVE-101, is intended to disable a gene that causes high cholesterol levels. The initial focus is on a hereditary disease that leaves individuals unable to control cholesterol levels independent of diet, but the company hopes to explore the potential to treat high cholesterol levels in the general population.
The drug candidate is a Crispr base editor, which is a second-generation gene editing technology. Such tools should be generally safer and lower risk than first-generation tools from Intellia Therapeutics, Crispr Therapeutics, or Editas Medicine (EDIT). They can suffer from their own unique precision challenges, however, including a specific type of off-target edit called a bystander edit.
The FDA's clinical hold is likely to focus heavily on the company's potency assays ("precision" and "measurement") and manufacturing quality control ("manufacturing").
The announcement from Verve Therapeutics could also provide a glimpse of what's to come for peers developing their own in vivo gene editors.
- Intellia Therapeutics is in discussions with the FDA ahead of a planned phase 2 clinical trial for its lead drug candidate, NTLA-2001, in transthyretin amyloidosis (AATR). The phase 1 clinical trial was conducted in sites outside the United States, but the company hopes to include American patients in what could prove to be a pivotal study, meaning it could lead to marketing approval.
- Beam Therapeutics has yet to begin IND-enabling studies for its first in vivo base editing tool. IND-enabling studies are the body of preclinical work submitted to the FDA requesting permission to begin a phase 1 clinical trial. The company will surely be tuned into developments from Verve Therapeutics, which licensed some of its tools from Beam Therapeutics.
The high complexity and high stakes of in vivo gene editing, especially with existing tools, makes its easy to see why the FDA has set such a high bar. Once a gene editor is administered to patients, they cannot simply stop treatment if they begin experiencing side effects.
If the clinical hold on VERVE-101 is related to potency assays or manufacturing, then Verve Therapeutics could be looking at a significant delay to enrolling American patients in clinical trials. There's no reason to expect this development to be a showstopper, but shares were likely a little overvalued before the precipitous drop on Nov. 7. Either way, investors will learn more before the end of the year.
