The past ten days have brought a mix of encouraging movement and disappointing news for the Huntington’s disease community.
Several experimental treatments are moving into larger or more advanced clinical trials, including an oral drug designed to lower harmful proteins, a potential treatment aimed at protecting brain cells, and the first human study involving laboratory-grown neural stem cells. At the same time, Roche has ended two Huntington’s programs after one treatment failed to produce meaningful clinical improvement and another raised safety concerns in animal studies. Together, the developments show both sides of Huntington’s research. Scientists are pursuing several very different ways of attacking the disease, but turning promising laboratory findings and biological changes into treatments that actually help patients remains difficult.
One of the most closely watched developments involves SKY-0515, an experimental oral drug being developed by Skyhawk Therapeutics. On July 14, the company announced that its Phase 2/3 FALCON-HD trial had received clearance to expand into the United States, Canada, and the United Kingdom. The larger study could eventually enroll as many as 400 people. SKY-0515 is designed to lower production of mutant huntingtin, the toxic form of the huntingtin protein that causes Huntington’s disease. It also targets PMS1, a protein involved in the gradual expansion of the repeated DNA sequence responsible for the disease. That repeat expansion is important because the genetic mutation can continue to grow in certain brain cells over time. Researchers believe this process may contribute to the worsening of Huntington’s symptoms. Skyhawk has reported early signs that the drug can lower both mutant huntingtin and PMS1. The company has also described encouraging changes in a broad clinical measurement known as the composite Unified Huntington’s Disease Rating Scale. Those findings are still preliminary. The expanded randomized trial will be needed to determine whether the biological changes lead to a real and lasting difference in movement, thinking, daily function, or disease progression.
Another major trial is beginning for Pridopidine developed by Prileina Therapeutics, an experimental drug that has been studied in Huntington’s disease for several years. On July 7, Ferrer and Prilenia announced that recruitment had begun for the Phase 3 PRECISE-HD study. The trial is expected to enroll approximately 400 people with early-to-middle-stage Huntington’s disease at sites in the United States, Canada, the United Kingdom, and Europe. Participants will receive either pridopidine or a placebo for 52 weeks. They will then have the opportunity to continue in a two-year extension in which everyone receives the experimental treatment. Pridopidine activates a protein called the sigma-1 receptor, which helps cells respond to stress and maintain normal function. Researchers believe activating this receptor may help protect nerve cells and preserve their ability to communicate. Earlier pridopidine trials have produced mixed results. The new study is intended to provide a clearer answer about whether the drug can preserve overall function in people with Huntington’s disease.
Researchers are also moving forward with an entirely different approach: replacing or supporting damaged brain cells with laboratory-grown neural stem cells. An update released July 9 highlighted REGEN4HD, described as the first clinical trial to test a treatment made from pluripotent stem cells in people with Huntington’s disease. The Phase 1b/2a study plans to enroll 21 adults between the ages of 18 and 65 who have early symptoms. Researchers will surgically implant neural stem cells called hNSC-01 into the striatum, a part of the brain heavily affected by Huntington’s disease. The cells are intended to support damaged brain tissue and potentially replace some functions lost as the disease progresses. The first part of the trial will test increasing doses to determine what can be given safely. A later group will receive the highest dose considered tolerable. This is primarily a safety study. It is not yet designed to prove that stem cells can slow or reverse Huntington’s disease. Still, it represents an important step toward learning whether a cell-based treatment can be safely delivered directly into the brains of patients.
On July 9, Roche the Swiss pharmaceutical and diagnostics company announced that it was ending the Phase 2 GENERATION HD2 trial of Tominersen. The study included 301 participants. Tominersen was designed to reduce the production of huntingtin protein. Roche reported that the treatment lowered mutant huntingtin and neurofilament light, a marker associated with nerve-cell damage. No new safety problems were identified. However, lowering those biological markers did not translate into meaningful clinical improvement when participants were compared with those receiving a placebo. The result is another reminder that changing a laboratory measurement is not the same as changing the course of a disease. Biomarkers can show that a drug is reaching its target, but patients ultimately need treatments that help preserve movement, thinking, independence, or quality of life. Roche also stopped a separate trial of RG6496, known as POINT-HD. That decision was based on new animal findings suggesting that long-term, repeated dosing could not be continued safely. Only three people had entered the human trial, and Roche said the concern did not apply to the single doses they had already received. The company continues to develop another Huntington’s gene-therapy candidate known as RG6662.
A newly published imaging study may also help researchers improve how Huntington’s progression is measured. The study examined an advanced MRI method known as SANDI, which is designed to detect microscopic changes in the structure of brain tissue. Researchers found that some of the imaging measurements were connected with movement problems, overall disease burden, and brain shrinkage. The technique may eventually provide researchers with another way to monitor changes in the brain or measure whether an experimental treatment is working. More studies will be needed to determine whether the findings hold up over time and across different hospitals and MRI machines. The recent developments do not mean that a new Huntington’s treatment is about to become available. The stem-cell, SKY-0515, and pridopidine programs are still experimental, and none has yet been shown conclusively to slow the disease.
Researchers are now trying to lower mutant huntingtin, limit further DNA-repeat expansion, strengthen the brain’s response to cellular stress, replace or support damaged nerve cells, and develop more sensitive ways to measure progression. The failure of Tominersen is a serious disappointment, particularly because the treatment successfully changed the biological markers it was designed to target. But it also provides researchers with information that may shape the next generation of Huntington’s trials. The past ten days have shown that Huntington’s research is moving forward, but not in a straight line. Some programs will advance, others will fail, and promising biological results will not always lead to improvements that patients can feel.
For families living with Huntington’s disease, the most important fact is that the pipeline remains active. Multiple treatments are now being tested using very different strategies, giving researchers more than one possible path toward slowing or eventually changing the course of the disease.
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