Skyhawk reports encouraging 12-month results for oral Huntington’s disease drug SKY-0515

Skyhawk Therapeutics has announced by press release new 12-month data from their Phase 1/2 trial of SKY-0515, an experimental oral treatment for Huntington’s disease (HD). The latest results largely extend the positive trends previously reported at earlier time points, providing additional reassurance that the drug continues to work as designed while remaining generally safe and well tolerated. 

While these findings are encouraging, they come from a relatively small early-stage study. The larger Phase 2/3 FALCON-HD trial is now underway and will be key for determining whether SKY-0515 can truly slow disease progression in people with HD. Let’s get into what this latest update tells us and what’s next for this drug.

A different approach to huntingtin lowering

SKY-0515 is a huntingtin lowering drug that can be taken as a daily pill. This is exciting for the HD community as it is a much less demanding approach for participants in the trial compared to many other huntingtin lowering drugs that need to be delivered by brain surgery or injections into the spinal fluid. 

SKY-0515 works by modifying how genetic message molecules, called RNA, are processed inside cells. Essentially, they work by telling the cell to stop making the protein by adding in a molecular stop sign. This process is called splicing because it “splices” this stop sign in, so drugs that work like this are called “splice modulators.” This is the same type of drug as votoplam, the therapy being tested by Novartis in the Phase 3 INVEST-HD clinical trial. 

Both SKY-0515 and votoplam aim to reduce levels of the expanded form of huntingtin, the harmful version of the protein produced by the HD gene. However, they do in fact lower both the regular and expanded forms of huntingtin so are referred to as “total” huntingtin lowering drugs. 

SKY-0515 is also reported to lower a second target called PMS1, which is involved in the process of somatic expansion. This is the phenomenon causing the gradual growth of CAG repeats in some vulnerable cell types over the lifetime of someone with HD. This possible two-for-one approach is an exciting new angle in the busy field of huntingtin-lowering drugs currently in the clinic – more on that later. 

A Phase1/2 trial to test SKY-0515

The Phase 1/2 study of SKY-0515 was designed to evaluate the drug’s safety, tolerability, and biological effects in both healthy volunteers and people with Huntington’s disease. The latest results come from Part C, the portion of the study involving people with early-stage HD.

In the initial 84-day placebo-controlled phase, participants were randomly assigned to receive either SKY-0515 or placebo. Following this period, participants entered a blinded extension study in which all participants received active treatment at either a lower or higher dose. The new data reflect up to 12 months of treatment and include additional participants who initially received placebo before switching to SKY-0515. Importantly, these data are compared to a natural history study that follows people with HD as they naturally progress and age, not folks on a placebo pill.

This possible two-for-one approach is an exciting new angle in the busy field of huntingtin-lowering drugs currently in the clinic

Researchers have been tracking a range of measures throughout the study, including levels of expanded huntingtin protein, PMS1 (that protein linked to somatic CAG repeat expansion), and clinical measures such as the Composite Unified Huntington’s Disease Rating Scale (cUHDRS). While safety remains an important objective of early-stage clinical trials, these longer-term data can provide valuable insights into whether a drug may be working as designed and whether encouraging clinical trends are sustained over time.

So what does this latest update with 12 month data tell us? 

Huntingtin lowering remains strong

The most recent press release suggests the 12-month data show that SKY-0515 continues to reduce expanded huntingtin protein levels in blood. Participants receiving the higher dose had reductions of ~69% of expanded huntingtin after a year of treatment. This is essentially unchanged from the reductions previously reported at earlier timepoints, suggesting that the effect is durable over time.

The company also reported reductions in the PMS1 messenger RNA of up to 26%. Taken together, these results indicate that the drug is continuing to work as designed, by lowering both of these intended targets throughout the first year of treatment.

Clinical scores remain encouraging

Perhaps the most closely watched data concern cUHDRS, a clinical score that combines readouts from lots of different movement, thinking and functional assessments into a single metric commonly used in HD clinical research.

According to Skyhawk’s latest press release, participants receiving SKY-0515 showed small improvements from their baseline cUHDRS scores throughout the study, with average changes ranging from +0.31 to +0.38 points between three and twelve months.

The company compared these results with an external comparator dataset based on participants from the Enroll-HD and TRACK-HD observational studies. This lets them compare how much they would expect folks with HD to progress on the cUHDRS scale in the same period of time. Those data suggested similar people would be expected to decline by approximately 0.92 points over twelve months.

Importantly, the overall picture at twelve months looks very similar to what was seen at nine months. Rather than fading over time, the signal appears broadly consistent, with treated participants maintaining separation from expected natural-history decline.

The company also reported favourable trends across all four components that contribute to cUHDRS: motor function, daily functioning, processing speed, and cognitive performance.

Encouraging, but not yet definitive

As positive as these findings appear, there are important limitations. The study remains relatively small, involving only a few dozen participants. The clinical comparisons are being made against external natural-history datasets rather than against a large concurrent placebo group followed for a full year. This means the results cannot yet tell us definitively whether SKY-0515 slows HD progression.

Rather than fading over time, the signal appears broadly consistent, with treated participants maintaining separation from expected natural-history decline

However, the findings do add to a growing pattern emerging across several huntingtin-lowering programmes. Recent updates from both Novartis’s votoplam programme and uniQure’s AMT-130 gene therapy have also reported encouraging cUHDRS trends. While each programme uses a different technology and each dataset has important caveats, seeing similar signals emerge across multiple huntingtin-lowering approaches is encouraging for the field and suggests we might be on the right track.

The consistency does not prove that huntingtin lowering is responsible for the reported effects. But it does increase confidence that these signals deserve to be followed up with rigorous testing in larger studies. Ultimately, only well-powered Phase 3 trials with larger numbers of participants followed over longer periods will be able to determine whether these apparent benefits translate into a genuine slowing of disease progression. Critically, we now have evidence across multiple trials that huntingtin-lowering seems to be largely safe with the doses tested in these latest trials. 

The PMS1 question

An intriguing aspect of SKY-0515 is its effect on PMS1. Over the last several years, growing evidence has suggested that somatic expansion might be playing a key role in driving HD. PMS1 is one of several DNA repair proteins involved in this process. By lowering PMS1 levels, SKY-0515 may potentially influence a second disease mechanism beyond huntingtin production itself.

However, an important caveat remains: we currently have no direct evidence that the reductions in PMS1 reported by SKY-0515 are actually slowing somatic expansion in the brains of people with HD where we would hope to see this happen to potentially meaningfully impact pathology driven by this process. 

Critically, we now have evidence across multiple trials that huntingtin-lowering seems to be largely safe with the doses tested in these latest trials

But not having this data isn’t surprising. Measuring somatic expansion in living people is extremely challenging, particularly in the brain, where the process is thought to be most relevant. As a result, PMS1 lowering by SKY-0515 currently should probably be viewed as an interesting and potentially important biological effect rather than a proven disease-modifying mechanism.

One of the key questions for the field will be how researchers attempt to measure and validate this aspect of the drug’s activity in future studies. New biomarkers capable of tracking somatic expansion may eventually help answer whether targeting PMS1 contributes meaningfully to clinical benefit.

Looking ahead

Alongside the Phase 1/2 update, Skyhawk announced that the Australian and New Zealand portion of its pivotal FALCON-HD programme completed enrollment six months ahead of schedule, recruiting 144 participants. Amazing!! The global FALCON-HD study has also expanded to eight countries and aims to enroll approximately 400 participants. Altogether, Skyhawk’s studies have now enrolled more than 175 people with HD.

For now, the press release relaying the new 12-month data largely reinforce the story that emerged at earlier analyses: SKY-0515 continues to lower huntingtin, continues to lower PMS1, and continues to show encouraging clinical trends that have remained stable through one year of treatment. Great news for the HD community. 

Whether those trends represent true slowing of HD progression through huntingtin lowering and/or impacting somatic expansion remains the critical question that the ongoing FALCON-HD trial is designed to answer.

Summary

• New 12-month data from Skyhawk’s Phase 1/2 trial show SKY-0515 continues to lower expanded huntingtin levels by ~69%, with effects remaining stable over a year of treatment and no new major safety concerns reported.
• SKY-0515 is an oral “splice modulator” that lowers both huntingtin and PMS1, a DNA repair protein linked to somatic CAG repeat expansion, offering a potential two-pronged approach to slowing HD.
• Participants treated with SKY-0515 showed encouraging trends on the cUHDRS clinical scale, maintaining small improvements from baseline and outperforming the expected natural-history decline over 12 months.
• While promising, these results come from a small early-stage study and rely on comparisons with external natural-history datasets rather than a large long-term placebo group, so they cannot yet prove definitively that the drug slows HD progression.
• The findings add to a growing body of evidence from multiple huntingtin-lowering programs suggesting that huntingtin reduction can be achieved safely and may be associated with favourable clinical trends.
• The ongoing Phase 2/3 FALCON-HD trial, now enrolling globally, will be critical for determining whether SKY-0515’s treatment translates into meaningful slowing of disease progression in people with HD.