SKY-0515 Lowers Huntingtin In People With Huntington’s Disease In Trial Update

On September 17, 2025, we received an encouraging update from Skyhawk Therapeutics’ Phase 1 study, taking place in Australia. The recent update suggests that SKY-0515 can lower the huntingtin protein as well as PMS1, another protein which is thought might also drive Huntington’s disease (HD). Importantly, the drug also appears to be safe and well tolerated. A larger Phase 2/3 trial called FALCON-HD is already underway. Let’s get into what we learned from this latest update. 

What is SKY-0515 and how does it work?

SKY-0515 is a pill, taken by mouth, designed to change which proteins are made in the body. The drug works by targeting message molecules, or RNA, which are copied from the DNA code and have the instructions to make different types of proteins. SKY-0515 changes how cells process RNA messages. 

SKY-0515, like PTC Therapeutics’ votoplam, isn’t specific for huntingtin. The pill targets many different messages throughout the body, but huntingtin happens to be one that it targets quite strongly. Because it’s not specific, it also influences the levels of other proteins in the body. Two of the proteins whose levels are changed by the SKY-0515 drug are huntingtin and, perhaps serendipitously, PMS1. 

Lowering huntingtin levels is one of the main approaches companies are testing in the clinic to try and treat HD. The idea is that by reducing the levels of the toxic, expanded form of the protein made in people who have the gene for HD, we can target the root cause of the disease. SKY-0515 is actually a “total” huntingtin lowering drug, meaning it lowers both the expanded and regular forms of the huntingtin protein. 

With multiple huntingtin-lowering approaches now in clinical trials, the HD community is closer than ever to finding therapies that go beyond symptom management.

PMS1 also seems to be targeted by this drug. PMS1 is a DNA repair protein that, when reduced, is thought to slow the “somatic expansion” of CAG repeats. This is the molecular process that makes CAG repeats longer in some cells in the body over time. By reducing the toxic huntingtin protein and also potentially slowing down another one of the disease drivers, the scientists at Skyhawk think they might get a 2 for 1 effect with this drug. 

Testing the waters with SKY-0515

This Phase 1 trial is actually divided into three parts (A, B, and C) and the results we are learning about yesterday come from part C of the trial, which is testing the drug in people with HD. Parts A and B looked at the drug in healthy people without the gene for HD and we already learned about how the drug was working in a previous update from Skyhawk. That update showed the drug appeared safe and working as expected to lower huntingtin in the people in which it was tested. 

Part C of this trial tested 2 different doses of the drug, a low (3 mg) and high (9 mg) dose, and also included people who received a placebo sugar pill. Folks in the trial are then monitored and all sorts of measurements are made from samples, like blood, to see how well the drug might be working. Safety is the top priority in Phase 1 trials, but other data is collected too to give insights into designing the next round of trials and see if the drug appears to work as expected. 

So what’s new?

In this latest update, we got some interim data about Part C of the trial – where they test this drug in people with HD. Skyhawk reported that the drug appears to be generally safe at the doses tested – great news! SKY-0515 was also reported in this update to get into the brain very effectively, a critical challenge for HD therapies.

We also learned that the drug seems to do a good job of lowering the levels of the huntingtin protein, with data shared up to day 84 (12 weeks) into the study. In fact, the more drug participants got, the more lowering Skyhawk could measure in the blood. This “dose-dependent” lowering is a favourable hallmark researchers look out for when testing a new drug and fine-tuning what dose might work best. 

Why is this important?

The results so far suggest that SKY-0515 can lower huntingtin protein in people with HD to a greater extent than has been reported before with a pill. That’s exciting, because until now most huntingtin-lowering approaches have required injections or infusions into the spinal fluid, which are far less convenient and come with additional safety challenges. Having an oral drug that can reach the brain effectively and reduce huntingtin to this degree is a very encouraging step forward.

Another promising feature of SKY-0515 is that it does more than just lower huntingtin. It may also reduce levels of PMS1, a protein involved in the process that makes CAG repeats longer in some cells over time. By targeting both huntingtin and PMS1 at once, SKY-0515 could potentially tackle HD through two different disease mechanisms.

Professor Ed Wild, HDBuzz Editor Emeritus, who is involved in the study, summed it up by saying:

“This is what success looks like at the 3-month timepoint, setting the stage for meaningful impact for people living with HD across the world – for whom an orally administered huntingtin-lowering treatment such as SKY-0515 would be truly transformative.”

What we still don’t know

It’s worth pointing out that this update from Skyhawk is still quite limited in details. While the company shared a graph showing reductions in huntingtin protein levels by dose, they didn’t provide all the details behind some of the claims. 

The most recent press release suggests that SKY-0515 lowers PMS1, but we’ve not yet seen this data. This would be fantastic if it lowered PMS1 to a meaningful level! But without the data, we don’t know if the levels to which PMS1 are lowered would be considered significant. So the questions remain: How much is PMS1 being lowered by SKY-0515? Is PMS1 being lowered to a level that would be meaningful? Is the lowering of PMS1 significant enough to influence somatic expansion of the CAG repeat within the huntingtin gene?

This kind of early communication is sometimes called “science by press release.” The full picture, including the more complete results from this trial, won’t be available until mid-2026. So, while these first signs are encouraging, it’s important to keep expectations realistic and remember that there’s still a lot we don’t yet know.

So what happens next?

After the first 3 months, people in the study will keep taking SKY-0515 in a longer follow-up, where everyone stays on treatment at a low or a high dose for up to a year. We should hear the main results from this part of the trial in mid-2026.

At the same time, a bigger Phase 2/3 study called FALCON-HD is already underway across 10 sites in Australia and New Zealand. This trial will involve about 120 people with stage 2 or early stage 3 HD, as per the HD Integrated Staging System or HD-ISS, and will test different doses of SKY-0515 to be compared with placebo. Importantly, this study will not just look at effects beyond safety and levels of huntingtin and PMS1. It will also see if the drug can help with symptoms like movement, thinking, and daily life, and whether it influences how the brain structure changes with HD.

What does this mean for the HD community?

For people affected by HD, these results are both hopeful and cautious news. On the hopeful side, SKY-0515 is the first oral therapy to achieve such strong huntingtin lowering in people with HD that can be fine-tuned by changing the dose of the drug. SKY-0515 also seems to target PMS1, potentially tackling an additional potential driver of HD. Most importantly, the drug appears to be generally safe. 

By reducing the toxic huntingtin protein and also potentially slowing down another one of the disease drivers, the scientists at Skyhawk think they might get a 2 for 1 effect with this drug. 

That said this is very early data in a small group of people with HD. The trial is also focused on safety and whether the drug is working as expected, but not whether it can slow, halt, or reverse symptoms of HD. It will take larger, longer trials to know if SKY-0515 actually slows or improves the course of HD.

Still, this is a big step forward for the field. With multiple huntingtin-lowering approaches now in clinical trials, the HD community is closer than ever to finding therapies that go beyond symptom management.

Summary

• SKY-0515 is an oral drug that alters RNA processing, lowering levels of huntingtin and potentially PMS1, a DNA repair protein linked to CAG repeat expansion in Huntington’s disease (HD).
• Phase 1 results show safety and brain penetration, with dose-dependent reductions in huntingtin protein—greater than previously achieved with an oral therapy.
• Dual targeting of huntingtin and PMS1 could provide a “two-for-one” therapeutic effect, addressing both toxic protein buildup and CAG repeat expansion, though PMS1 data remain limited.
• Next steps: Full Phase 1 results are expected in mid-2026, while the larger Phase 2/3 FALCON-HD trial is already underway to test effects on symptoms, brain changes, and overall disease progression.

Learn More

Skyhawk’s September 17, 2025 press release.