Huntington’s community grieves not just one therapeutic setback, but two

For the community of people affected by Huntington’s disease — a group that is no stranger to disappointment — the back-to-back announcements last month still hit like a double whammy.

First, Roche announced it was cutting off the dosing of its experimental therapy tominersen, in a closely watched, much-hyped Phase 3 clinical trial. Then, a week later, Wave Life Sciences said it was abandoning two Huntington’s therapies in earlier stage trials.

“It was like a sucker punch twice within one week,” said Heather Thurgood Wilmoth, whose husband Nathan has Huntington’s and had been a participant in the Roche trial.

The Roche news came as a particular shock — and as a devastation. No other treatment that’s designed to target the roots of the neurodegenerative illness had ever made it that far in the development gantlet, so there was a ton of hope and excitement imbued in the study. Adding insult: Families don’t know why the trial was upended. Roche said only that it was halting treatments based on the recommendation of independent data experts monitoring the trial. It’s still not clear what in the data led to that recommendation. 

People in the Huntington’s community described their reactions as if they were grieving a loss. There are no treatments that slow the course of the universally fatal disease itself, only that work to alleviate symptoms. 

But researchers, patients, and families also vowed to use the information gleaned from the studies to make progress moving forward. During a webinar put together after the Roche news, George Yohrling, the chief scientific officer of the Huntington’s Disease Society of America, described the pipeline for other potential treatments as “deep and diverse.” 

“This in no way alters our resolve to defeat HD,” he said. “If anything it makes it stronger. We know what causes HD, we know that we can lower the protein that we think causes HD. We just now need to figure out a safe and efficacious way, the best way to lower it. That’s where we are. We will do that, we will meet that goal.”

Huntington’s is a genetic disease, but not one caused by a misspelling in the “letters” that make up DNA, like many inherited conditions. Rather, it occurs when someone has too many repeats of the letters CAG in a gene that encodes a protein called huntingtin. People who have 40 or more CAG repeats will develop the disease, often showing symptoms first in their 30s or 40s, while 35 CAG repeats or fewer is considered healthy. (People with a number of CAG repeats in the middle may show symptoms, but not until later in life.)

With more repeats, the longer the huntingtin protein stretches, and it becomes toxic to neurons. The result is a cruel mix of symptoms reminiscent of ALS, Alzheimer’s, and Parkinson’s all together: mood changes and impulsive behavior; trouble walking and talking and eventually swallowing; cognitive declines.

One of the reasons the Roche trial had generated so much excitement was because in an earlier study, researchers had found that the therapy — delivered via an injection into the fluid that bathes the spine — succeeded in lowering levels of the mutant huntingtin protein. The hope was that that reduction could lead to clinical improvements, which was what the placebo-controlled Phase 3 trial was designed to test. 

But then, on March 22, Roche said it was stopping the dosing of both tominersen and placebo. A group called an independent data monitoring committee, which regularly reviewed the trial’s data as it was being generated, had recommended the company halt dosing “based on the investigational therapy’s potential benefit/risk profile for study participants.” 

“It felt like someone punched me in the stomach, and I started hysterical crying,” MaryAnn Emerick, who has HD in her family, said on the webinar about learning the Roche news. She added: “It felt like something was torn from me.”

The data monitoring committee had not identified any new safety issues, Roche said, which led to speculation that perhaps the data were so clear that the therapy wasn’t having a benefit that there was no reason for the trial to continue. But at the time of the announcement, Roche hadn’t even seen the data from the study, and it’s still unknown what led the committee to make the recommendation to cut off dosing. Roche said it will share some preliminary data from the trial at a conference later this month, and is also asking participants to continue seeing their doctors so more data can be collected.

Then, on March 29, Wave announced that it was shelving two experimental therapies that had failed to sufficiently lower mutant huntingtin levels in early-stage trials. 

“This is not the update we were hoping to provide, and we recognize this has already been an extremely challenging month for the HD community,” Wave wrote in a letter. 

As they wait for more details from the Roche trial, researchers still believe that reducing the mutant protein is a smart strategy. They just need to figure out how — perhaps a different dosage or starting treatment earlier in the course of the illness — to make a clinical impact.

“I feel so committed to this huntingtin lowering therapy,” Vicki Wheelock, a neurologist at UC Davis Health, said about tominersen during the webinar. “This is engaging the target. This is the best thing that we’ve had so far.” 

The HD Society’s Yohrling told STAT there were other experimental therapies in trials or in preclinical studies that the community was keeping a close eye on. Many of them also are geared to lower mutant huntingtin levels, though in different ways. 

Among the companies developing HD treatments is uniQure, which is testing a gene therapy that’s designed to block production of the mutant protein. The company announced this month it had enrolled the first group of patients in its early-stage clinical trial. 

Novartis, meanwhile, plans to start a trial this year for its oral drug branaplam, which was originally developed for the condition spinal muscular atrophy but in preclinical studies reduced mutant huntingtin. 

And while Wave abandoned two of its therapies, it is still moving forward with another, refined version of the same kind of compound, an antisense oligonucleotide. It plans to start a clinical trial this year. 

Beyond trying to decrease the mutant protein, another approach Yohrling outlined is halting CAG expansion. Blood tests may show that someone who carries the disease-causing mutation has, say, 42 CAG repeats in their gene. But as people get older, those repeats multiply in neurons and other cells, like a record skipping for longer and longer. The hypothesis, Yohrling said, is that “if we could stop the expansion, we could stop the disease.” 

A company called Triplet Therapeutics, which is focused on these so-called repeat expansion disorders, is pursuing an HD treatment based on this strategy.

For now, though, patients and their families are trying to adjust to the trial news. 

Nathan Wilmoth, 43, of Brandon, Miss., was receiving injections in the Roche trial through last February, when a separate medical issue forced him to pause. He and his family were hoping that they could find a way to restart the therapy when Roche’s announcement came last month.

They’re not sure if Nathan was receiving the placebo or tominersen, but they felt there were some improvements in his walking and cognition. But there’s also been disease progression in the past year. Nathan has more anxiety issues, and Heather holds his hand when he walks to keep him steady. His speech is slurring.

Right now, they’re trying to come up with plans to build a house that can accommodate Nathan as his disease advances, one with a shower that can fit a wheelchair so Heather can eventually wash him and one with a bedroom big enough for a regular bed and hospital bed. They’re having to anticipate when Nathan’s condition gets to that point.

People participate in clinical trials in hopes not just that the drug in question might help them, but that the study might lead to better treatments for others. With Huntington’s, that desire can be personal. There’s a 50-50 chance that people who have the disease pass it on to their children, and Nathan has a 15-year-old and 6-year-old. (When people turn 18, they can choose to get a genetic test to find out whether they have the mutant gene or not.)

“From a selfish standpoint, I’d like to have my husband for longer than just a few years,” Heather said. But she added: “There was a lot of hope that even if it didn’t help Nathan, it would help our kids.”