Encouraging news from Skyhawk, as SKY-0515 Phase 1/2 data continues to hold promise

Skyhawk Therapeuticstherapeutics treatments has shared the 15-month results from its Phase 1/2 study of SKY-0515, an experimental once-daily pill designed to lower both expanded huntingtin and PMS1, a protein linked to CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD expansion. The update is a step in the right direction – it seems the drug remains safe, it hits its targets, and it has positive effects on HD symptoms based on tests of movement and thinking. Let’s get into the details of this update, the outstanding questions and what’s next for SKY-0515.

SKY-0515: A potential two-for-one approach to treat HD

Two of the biggest buckets of research into HD therapeuticstherapeutics treatments today are huntingtin-lowering and somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. HD is caused by a long stretch of CAG repeats in the huntingtin gene, which leads to an expanded huntingtin proteinhuntingtin protein The protein produced by the HD gene. that is thought to wreak havoc in cells. Huntingtin-lowering strategies aim to decrease the amount of this harmful protein. 

At the same time, CAG repeats can expand over time in certain cells, due to mistakes made by the DNA repair machinery. Genetic studies suggest that this process, known as somatic expansionsomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain., can influence when HD symptoms begin and how the disease progresses. For this reason, DNA repair genes are another major target of drug design for HD.  

The experimental drug SKY-0515, developed by Skyhawk Therapeuticstherapeutics treatments, targets both huntingtin and somatic instabilitysomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. making it a possible “two-for-one” drug in the way it aims to treat HD. It alters the processing of the huntingtin (HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15) message so that less huntingtin proteinhuntingtin protein The protein produced by the HD gene. is ultimately produced – both the regular and expanded forms. It also reduces levels of PMS-1, a DNA repair protein implicated in somaticsomatic relating to the body CAG expansion.

Whether this dual effect on both extra-long huntingtin and CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD expansion translates into meaningful benefit for people with HD is one of the big questions that clinical trials will need to answer.

The journey of SKY-0515 so far

HDBuzz has been following SKY-0515 since the first results from its Phase 1 study were announced in 2024. Early testing in volunteers without HD suggested that the drug could safely reach the brain and lower huntingtin in a dose-dependent manner. In other words, more SKY-0515 led to more huntingtin lowering. 

The study then moved into people with HD – just 24 participants. For the first 3 months, they received either placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work., a low dose (4 mg), or a high dose (9 mg) of drug. Then everyone in the study was switched to SKY-0515 (the majority on the high dose) and they could continue to take it for an additional 12 months. In September 2025, Skyhawk reported that SKY-0515 continued to appear generally safe and well tolerated and led to substantial huntingtin lowering. We also began to learn more about the other trick up its sleeve – effects on PMS1, strengthening the idea that the drug might act on two processes implicated in HD. 

More data arrived in January 2026, when Skyhawk shared results from people who had received SKY-0515 for up to nine months, and then in June 2026 came consistent 12-month data. Most importantly, there were no dangerous safety signals, which is what this small safety study is mainly designed to test. At the highest dose, the company reported around 69% lowering of expanded huntingtin, alongside 25% reductions in PMS1. Skyhawk also reported encouraging trends on the composite Unified Huntington’s Disease Rating Scale, or cUHDRS, which combines measures of thinking, movement and day-to-day function.

SKY-0515 at 15 months

The most recent update to this data arrived on September 15th, 2026. There are now 15 people who have received SKY-0515 for a total of 15 months. The good news is that the data is positive and consistent with what was previously reported. On average, the high dose of SKY-0515 lowers the amount of expanded huntingtin proteinhuntingtin protein The protein produced by the HD gene. by 60%, while PMS1 RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. message levels are down about 25%. This means that the drug is hitting its known targets – one of the main goals of this study.

After 15 months of SKY-0515 treatment, participants performed better on each individual test, and on the combined cUHDRS, than a comparable group of people with HD drawn from existing natural-history datasets.

Another main goal is to establish that the drug is safe and tolerable. Happily, there are no major new concerns reported in this update. Skyhawk says SKY-0515 has been generally well tolerated across all doses through 15 months of treatment, with no serious adverse events related to the drug. This is reassuring for an early-stage trial.

What’s particularly exciting – and perhaps unanticipated in such a small study – is that SKY-0515 continues to show positive changes in tests of movement and thinking after 15 months, with some results now reaching statistical significance. Researchers measured day-to-day function (total functional capacityTotal Functional Capacity A standardized rating scale for function in HD, used to assess capacity to work, handle finances, perform domestic chores and self-care tasks, TFC), movement skills (total motor score, TMS), and attention and thinking speed  (Symbol Digit Modalities Test and Stroop Word Reading Test). Together, these tests make up an overall measure called  the cUHDRS. After 15 months of SKY-0515 treatment, participants performed better on each individual test, and on the combined cUHDRS, than a comparable group of people with HD drawn from existing natural-history datasets.

At 15 months, the SKY-0515 group had improved by an average of 0.94 points on the cUHDRS compared with where they started. The external comparison group, meanwhile, had declined by 0.65 points, giving a difference of 1.59 points between the two groups. This difference was statistically significantstatistically significant Unlikely to have arisen by chance, according to a statistical test. The same positive effects held when researchers looked at the separate components of day-to-day function, movement, processing speed and reading speed.

It’s also helpful to look at the pattern over time rather than focusing on a single snapshot. Differences between the SKY-0515 and external comparison groups favoured the drug at every measured timepoint and the cUHDRS differences reached statistical significance from 9 months onwards. On average, cUHDRS scores in people receiving SKY-0515 stayed at or above where they started throughout the study, while scores in the external comparison group declined from 6 months onwards.

Some caveats to keep in mind

These encouraging results certainly display a pattern worth paying attention to. But before we interpret it as evidence that SKY-0515 is slowing HD, there are some important t reasons to be cautious about what we can conclude from them. First and foremost, only 15 participants contributed cUHDRS data to the 15-month analysis. 

The fine print of the press release explains why it wasn’t all 24 who began the study. Participants who initially received 3 months of placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work. had only been taking SKY-0515 for 12 months at this point, so they were not included in the 15-month analysis. Some data were also excluded because it did not meet the study’s predefined standards – for example, because part of a test was missing or an unrelated medical issue or new medication could have affected the results.

With numbers this small, results can be influenced by the experiences of just a few participants, and we can’t yet know whether the same pattern will hold up in a much larger group – or with a placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work. control. And that comparison group is another caveat. By this stage of the study, everyone was receiving SKY-0515, so there was no placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work. group alongside them. Instead, Skyhawk compared participants with carefully selected people from large existing HD datasets, including Enroll-HD, 2CARE and CREST-E. 

Statistical methods were used to make these groups as comparable as possible, but an external control can never perfectly recreate a randomised placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work. group. Differences between the groups that researchers haven’t measured or accounted for could contribute to the apparent treatment effect.

Finally, there are some details we know our keen bean HDBuzz readers would like to see fleshed out. Although Skyhawk mentions that SKY-0515 reaches the central nervous system, the release does not provide measurements showing how much huntingtin or PMS1 is lowered specifically in the cerebrospinal fluidCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord.. The press release reports more than 60% lowering of expanded huntingtin and more than 25% lowering of PMS1 RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. at the 9 mg dose, but it is not clear in which biofluid this is and the release does not specify how many of the 15 participants included in this analysis received the high versus low dose. There is also no information about NfLNfL biomarker of brain health levels, the biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable. of brain health used in many clinical trials for HD. We look forward to a more detailed presentation of this dataset to better understand exactly how these biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable. and clinical findings were generated and analysed.

It’s also worth remembering that statistically significantstatistically significant Unlikely to have arisen by chance, according to a statistical test does not automatically mean that SKY-0515 has been shown to slow HD. The cUHDRS difference at 15 months is promising, particularly because differences favouring SKY-0515 were also seen at 9 and 12 months. But this small Phase 1/2 study was primarily designed to learn about things like safety, drug exposure and whether SKY-0515 hits its biological targets, not to provide definitive evidence of clinical benefit. That question needs a larger, properly randomised placebo-controlled study. Fortunately, that study is already underway!

From Phase 1 to FALCON-HD – what’s next for SKY-0515

The much bigger test of SKY-0515 is FALCON-HD, Skyhawk’s ongoing Phase 2/3 study. Unlike the early Phase 1 analyses, FALCON-HD is a randomised, placebo-controlled trial designed to test SKY-0515 in a much larger group of people with HD. Participants receive different doses of SKY-0515 or placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work., allowing researchers to examine safety, huntingtin and PMS1 lowering, and whether treatment makes a measurable difference to the signs and symptoms of HD over time.

Skyhawk also appears to have expanded the worldwide FALCON-HD study. Earlier announcements said that the study would enroll 400 participants, but the latest release now gives a target of 600. 

Statistically significant does not automatically mean that SKY-0515 has been shown to slow HD

SKY-0515 has also begun moving through the regulatory process. In March 2026, Australia’s Therapeutic Goods Administration determined that the drug was eligible for its provisional approval pathway, and Skyhawk submitted an application for that provisional approval. Eligibility for an accelerated regulatory pathway is not the same thing as approval, and SKY-0515 remains an experimental drug.

The Phase 1/2 results give us hope for SKY-0515: the drug appears to be doing what it was designed to do, its safety profile remains reassuring so far, and the clinical measures are moving in an encouraging direction. But FALCON-HD is where we will begin to learn whether those signals translate into a real benefit for people with HD. We hope the promising pattern seen in this small study holds up when SKY-0515 is tested against placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work. in hundreds of participants. As always, HDBuzz will be following the data as they emerge.

Summary: 

• SKY-0515 is a once-daily pill that takes a “two-for-one” approach to HD, lowering both huntingtin and PMS1, a DNA repair protein linked to somaticsomatic relating to the body CAG expansion.
• At 15 months, SKY-0515 continues to do what it was designed to do: the high dose lowered expanded huntingtin by around 60% and PMS1 RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. by around 25%, with no major new safety concerns reported.
• There are encouraging signals on measures of HD symptoms. The SKY-0515 group improved by 0.94 points on the cUHDRS, compared with a 0.65-point decline in an external comparison group, a difference of 1.59 points.
• We don’t yet know whether SKY-0515 slows HD. Only 15 people contributed to the 15-month analysis, and they were compared with people from existing HD datasets rather than a concurrent placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work. group.
• FALCON-HD is the larger, randomised, placebo-controlled Phase 2/3 study that should tell us whether the encouraging signals from this early study hold up.