Huntington’s Gene Therapy Back on Track to File for FDA Approval

The last year has been a rollercoaster for individuals with Huntington’s and their families. A small trial of a gene therapy called AMT-130 showed signs of slowing disease progression. Its developer, uniQure, intended to file for regulatory approval. 

The trial used external controls, historical data from people with Huntington’s, which the Food and Drug Administration had said was sufficient for regulatory submission. But last November, the agency informed uniQure that external controls were no longer sufficient and that the company would need to conduct a new trial. 

Advocates worried that this would require some participants to undergo invasive surgery without receiving an experimental intervention as a control, which many consider unethical because it subjects participants with an incurable disease to an invasive, multihour surgery without any prospect of benefit 

After a backlash from Huntington’s disease organizations and scientific experts, the FDA has once again changed its mind and now says the data is enough to file for regulatory approval. 

“Following regulatory hurdles late last year, the Huntington’s disease community united like never before,” Amy Gray, president and CEO of the Huntington’s Disease Society of America (HDSA), said in a statement last week. 

The HDSA partnered with organizations and advocates across the U.S. and delivered a community petition with more than 47,000 signatures to the FDA, and participated in dozens of legislative meetings to share the need for approving new treatments. 

The data supporting AMT-130

Huntington’s is an incurable neurodegenerative disease that affects individuals while they’re still in their 30s and 40s. The earliest symptoms affect movement and coordination, which progresses toward cognitive decline and psychiatric symptoms. 

This new genetic treatment may change the course of the disease by targeting its genetic cause: A mutation in the HTT gene, which leads to the production of toxic forms of the huntingtin protein. 

In a three-year, 17-patient, Phase 1/2 trial, the treatment  appeared to slow down disease progression. The therapy uses a small piece of genetic code, called microRNA, designed to prevent brain cells from making the mutated form of the protein. The gene therapy is packed into a virus and delivered to the brain via a one-time 12- to 18-hour brain surgery. 

Some participants developed side effects due to the method of drug administration but these were manageable and resolved on their own. The therapy was successful in reducing the levels of a marker of neuronal damage in the cerebrospinal fluid called NfL.

Since the study didn’t have a placebo group, the researchers compared the progression to historical data that followed patients progressing with the disease. 

On average, historical data showed that people with the disease tend to decline by 1.52 points over three years on an 18-point measure of symptoms and day-to-day function. However, study participants who received the gene therapy declined by just 0.38 points, a difference of 1.14 points (or a slowing of the disease by 75 percent). One of the participants who had to retire due to his symptoms was even able to return to work. 

Next steps for uniQure

Now uniQure is working to file for accelerated approval later this year. This allows people with diseases that have very limited treatments to access a new medication on the basis of promising data that predicts a clinical benefit while the company conducts a definitive Phase 3 trial.

“The consistency and strength of the clinical data generated to date give us great confidence in the product’s potential to make a meaningful difference for patients,” Matt Kapusta, chief executive officer at uniQure said in a press release.