Phase 1 results announced for Skyhawk’s drug SKY-0515

Skyhawk Therapeutics has announced results from a Phase 1 clinical study of its experimental huntingtin-lowering drug, SKY-0515. As with all Phase 1 studies, the main goal was to understand safety and tolerability. The announcement is encouraging in that it suggests SKY-0515 can be given safely to people with Huntington’s disease (HD) in the short term. Let’s get into what the company has reported. 

But first, what is SKY-0515?

SKY-0515 is a small-molecule drug designed to alter RNA splicing, the process cells use to edit RNA messages before making proteins. RNA acts as the messenger that carries instructions from genes to make proteins, including the huntingtin protein that is altered in people with HD. 

If splicing is disrupted, the RNA molecule is not edited properly, so the RNA gets sent to the cell’s trash can. In turn, this means there are less available instructions to make certain types of proteins. SKY-0515 is a type of drug called a splice modulator which does exactly what it says on the tin – it messes up splicing.

It turns out SKY-0515 lowers the levels of huntingtin, the protein made from the gene which is altered in people with HD. It also affects other proteins, including PMS1, which was identified as a modifier of HD. Small letter changes in the PMS1 gene can impact when symptoms of HD begin and this protein is linked to somatic expansion – a hot topic in possible mechanisms that might drive HD. 

The scientists at Skyhawk see this as a possible two-for-one effect with their drug. By lowering both huntingtin AND PMS1, SKY-0515 may reduce some of the harmful effects of making the expanded huntingtin protein, AND improve somatic expansion. 

Other huntingtin-lowering therapies in the HD landscape

Skyhawk’s SKY-0515 enters a growing field of strategies aimed at lowering levels of huntingtin, the toxic protein produced by the expanded HTT gene that drives HD. 

Unlike earlier approaches such as antisense oligonucleotides (ASOs) given by spinal tap, or virus-based gene therapies delivered by brain surgery, SKY-0515 is a small-molecule compound which can be taken by mouth and can spread throughout the body. This is very similar to votoplam, another splice modulator in development for HD by Novartis and PTC Therapeutics. 

SKY-0515 is a total huntingtin lowering drug. This means it lowers the regular form of huntingtin, as well as the expanded form of this protein, made due to the HD mutation.  

What was tested in the Phase 1 study?

The Phase 1 study of SKY-0515 was structured in three parts, known as Parts A, B, and C. Parts A and B were conducted in healthy volunteers who do not carry the HD gene. Part C was the portion of the study testing the drug in people with HD. 

Skyhawk previously shared some results from all parts of this trial, reporting that the drug appeared to be safe and behaved as expected, including showing signs of lowering huntingtin in the participants studied.

Part C of the trial tested two different doses of SKY-0515, a lower dose of 3 mg and a higher dose of 9 mg, alongside a placebo, sometimes called a sugar pill. Trial participants don’t know if they are taking a placebo or drug. Participants were closely monitored, with researchers collecting a wide range of measurements from samples such as blood to understand how the drug moves through the body and whether it appears to be having its intended biological effects. 

While safety remains the primary focus of all Phase 1 trials, these additional data can help guide the design of future studies and provide early clues about whether the drug is behaving as scientists hoped. 

What did Skyhawk report in this latest update?

According to Skyhawk’s announcement, SKY-0515 appeared to be generally well tolerated in the Phase 1 study, with no major safety concerns highlighted. This is an important and necessary first step for any drug hoping to move forward in development. Previously, another splice modulator called branaplam, developed by Novartis, had significant side effects in people with HD causing the trial to halt early so we are very grateful for this good news!

This data further supports the idea that huntingtin protein lowering appears to be fairly safe in people over the timeframe of the trial, which aligns with other clinical trial findings for different huntingtin lowering therapies. Again, good news for the whole community!

At the highest dose of SKY-0515 tested, Skyhawk reports that levels of the expanded huntingtin protein were reduced by around 60%. The drug also reduced levels of the messenger RNA molecule encoding PMS1 by about 25%. Although both of these measurements were based off of samples taken from blood, SKY-0515 was reported to be able to reach the brain, which is essential for an HD treatment. 

Importantly, SKY-0515 doses the entire body. Although a lot of HD research focusses mainly on the brain, we know there are effects elsewhere in the body. This may be critical for treating HD because every single cell in the body expresses the toxic huntingtin in HD. 

In a small group of participants who were followed for up to 9 months, Skyhawk reports that people taking SKY-0515 showed average improvements on the composite Unified Huntington’s Disease Rating Scale (cUHDRS), a measure that combines motor, thinking, and daily function. When these results were compared with data from large observational studies, people receiving SKY-0515 appeared to do better than would typically be expected over the same period if they were not taking the drug. 

Astute HDBuzz readers will have noticed that this is a similar type of comparison that was made for the AMT-130 clinical trial data which was contentious among some HD researchers. That said, the direction of apparent change in cUHDRS is encouraging but larger and longer studies are needed to find out whether these changes reflect a significant measurable effect. Going forward, comparisons will likely be made between dosed and placebo groups in the same trial. 

Important caveats to keep in mind

It’s important to note that the information in the release is pretty limited. All that has been shared so far is a press release with partial data, and the results have not yet appeared in a peer-reviewed scientific forum. This means the wider research community cannot independently assess the findings.

There are several reasons to interpret these results cautiously:

• Small numbers: This report is scant on details and the cUHDRS analysis includes data from just 17 participants who received the drug over 9 months. This makes it hard to figure out possible uncommon or long-term side effects.
• Focus on safety, not benefit: These results do not tell us whether SKY-0515 affects HD biology or symptoms in any way, only that it appears to be safe.
• Science by press release: Without access to underlying data, the conclusions we make rely on the company’s summary alone.

None of these points are necessarily unusual, they are simply part of how early drug development works. But they are important context for interpreting the announcement.

What happens next?

Skyhawk already has a Phase 2/3 trial underway, called FALCON-HD. Although this study began with 12 sites across Australia and New Zealand, Skyhawk plans to continue opening trial sites in other countries. More than 90 participants have already received at least one dose of SKY-0515.

FALCON-HD is enrolling people with Stage 2 and early Stage 3 HD and aims to include around 520 participants in total. People taking part are randomly assigned to receive either SKY-0515 or a placebo, and neither the participants nor the researchers know who is receiving which treatment. SKY-0515 is taken as a once-daily pill, at one of three different dose levels, for at least 12 months.

As well as monitoring safety, the study is designed to see how SKY-0515 behaves in the body and whether it has measurable effects on signs and symptoms of HD. Researchers are also looking at biological markers to find out whether the drug affects levels of huntingtin and PMS1 proteins.

The bottom line

It is encouraging to see new therapeutic ideas for HD reaching human testing, and Phase 1 safety data are a necessary foundation for all future progress. 

SKY-0515 adds to the diversity and competition in the huntingtin-lowering clinical landscape, that includes drugs from more than 8 different companies, a huge number for a rare disease! It complements other efforts that target huntingtin in different ways, all towards our goals of finding approaches that can safely and effectively benefit people living with HD.

This not only provides more options in the future, as not all people respond to drugs in the same way, but more lowering drugs on the market will (hopefully) lead to competitive drug pricing.

HDBuzz will continue to follow developments closely and report back when more detailed data becomes available.

Summary

• Encouraging early safety data: Skyhawk Therapeutics reports that its oral splice-modulating drug SKY-0515 was generally well tolerated in a Phase 1 study, including in people with HD.
• Huntingtin lowering observed: At the highest dose tested, SKY-0515 reduced levels of expanded huntingtin protein by ~60% in blood, and also lowered the messenger RNA of PMS1, a gene linked to somatic expansion and HD onset.
• Different from past approaches: Unlike ASOs or gene therapies, SKY-0515 is a once-daily pill that reaches the brain and doses the whole body, adding diversity to the huntingtin-lowering landscape.
• Cautious optimism: Limited participant numbers and press-release–only data mean it’s too early to draw conclusions about benefit, but results support moving forward into larger, longer trials.

Learn more

The original press release and community letter can be found below and on the Skyhawk website.