Update from Skyhawk Therapeutics on the Phase 1 clinical trial with SKY-0515.
SKY-0515 is the name of an experimental molecule designed to lower huntingtin (HTT), the protein that, if mutated, causes Huntington's disease.
Since we know that the exact genetic cause of the disease is in the HTT gene, Skyhawk, together with many other companies, has focused on developing drugs that directly target the cause of the disease, namely the toxic protein, which is toxic when it is longer than the normal (i.e., the 'healthy' copy).
It turns out that the longest stretch in the HTT gene can become even longer in some cells as people with Huntington's disease age. This can cause abnormalities in biological functions, leading to toxicity in some cells and ultimately cell death. This continued increase of that extra bit of genetic code within the HTT gene is called somatic expansion.
Some scientists believe that if we could control somatic expansion, we could slow, or perhaps even stop, the progression of the disease.
Interestingly, SKY-0515 also targets a molecule called PMS1, which helps control somatic expansion. So not only could SKY-0515 lower HTT, but it could also help prevent somatic expansion.
On July 10, 2024, Skyhawk Therapeutics announced preliminary results from the ongoing Phase 1 study with SKY-0515.
Phase 1 studies represent the first time a potential new drug has been administered to humans, so the primary objective is to verify safety, not yet therapeutic efficacy.
This was a small trial conducted in Australia on healthy volunteers, on whom SKY-0515 has so far proven to be safe and well tolerated at all tested doses .
Study participants received the drug in increasing doses, so they could investigate which dose is best to test in later phases. A dose-dependent reduction in HTT was found, which means that the higher the dose of the drug administered, the lower the HTT level.
Many companies have designed drugs to target HTT, but these drugs are not all the same and are not administered in the same ways. The interesting thing is that SKY-0515 is a small molecule, which means it can be taken orally. This is obviously a much less invasive way of taking a drug than those that would require a spinal tap (like Wave Life Sciences' SELECT-HD study) or brain surgery (like uniQure's study).
SKY-0515 not only targets HTT, but also somatic expansion. Although there are suggestions that other drugs that reduce HTT may also have this effect, this was not specifically stated in the design of the studies testing such drugs. We also don't yet have data for the somatic expansion component in people. Hopefully this will happen with the next Skyhawk data release.
An important aspect in drug design is potency, or the ability to have an effect at a specific concentration. The more potent a drug is, the less you need to take to get the same effect. And, very often, taking less of the drug can mean there are fewer potential negative side effects. SKY-0515 appears to be very powerful: with just 9 mg (the highest dose tested in phase 1), the drug is able to reduce HTT by approximately 70%. While we can't say for sure that the potency of SKY-0515 means there will be fewer side effects, this will be explored throughout the study.
The 70% reduction is slightly higher than the current target of approximately 50% in other HTT reduction studies. Currently, most companies have targeted a range of 30 to 50 percent for drugs that reduce HTT. If the company finds safety issues with the higher doses, it may choose to reduce the dose and lower the HTT less.
Now Skyhawk will begin the next part of the Phase 1 trial: testing SKY-0515 in patients.
A low dose and a high dose will be tested in patients in the early stages of the disease (corresponding to stages 1, 2 and 3 of the HD-ISS scale). These are people in very early stages, in some cases, even without the absence of clinical manifestations.
If all goes well, Skyhawk plans to launch a Phase 2 study in early 2025.
While the current Phase 1 is being conducted in Australia, we do not yet have details on where the potential Phase 2 study will take place.