Greater Insights on Skyhawk’s RNA Splicing Agent SKY-0515 for Huntington Disease

Maura McCarthy

Huntington disease (HD) is an inherited movement disorders that causes cells in parts of the brain to gradually break down and die. Patients living with HD develop chorea and abnormal body postures, as well as problems with behavior, emotion, cognition, and personality. There are currently no approved disease-modifying therapies, so the disease is managed through a combination of physical or occupational therapy, speech therapy, counseling, and other medications to handle chorea and emotional symptoms.

Over the years, there have been several attempts to bring a disease-modifying agent to market, but several trials have stalled in later-stage studies. More recently, in October, the Australian Human Research Ethic Committee (HREC) approved a phase 1 program to assess Skyhawk’s small molecule HD candidate SKY-0515. SKY-0515, designed for brain penetration and distribution in peripheral tissue, is built to modify the RNA expression of huntingtin (HTT), thus reducing the production of the mutated protein that leads to disease progression in HD.

The phase 1 trial is a first-in-human, multi-part, randomized, double-blind, single- and multiple-ascending dose study assessing SKY-0515 in healthy volunteers and, subsequently, patients with HD. To learn more about SKY-0515 and the upcoming trial, NeurologyLive^® sat down with Maura McCarthy, head of corporate development at Skyhawk. She provided context on the benefits behind RNA-splicing treatment approaches, the ways HD trials have changed over the years, and how SKY-0515 has remnants of risdiplam (Evrysdi; Genentech), a previously approved RNA-splicing agent used for spinal muscular atrophy.

Can you provide a comment on the upcoming phase 1 trial of SKY-0515?

We don't have a ton of details that are public, but the available information indicates that it's an Australian phase one trial involving healthy volunteers. We have a SAD and a MAD, and we also have what we call Part C in Phase One, designed as a patient study. We haven't released much information about that yet, but the intention is for it to involve patients on the back end of Phase One.

What makes SKY-0515’s mechanism of action promising as a potential treatment for HD?

There are pros and cons to every drug and mechanism. If I were to go back in history, I would mention that the founders of Skyhawk (therapeutics) worked on risdiplam, the first small molecule splicing modifier. Kathleen McCarthy, the founding chief scientific officer, and Sergey Paushkin, one of the co-inventors of the risdiplam molecule, worked on this. I bring this up because it is the first-in-class small molecule splicing modifier that modifies the disease for spinal muscular atrophy patients. The theory behind that molecule was to change the splicing mechanism, thereby modifying the downstream protein. This is very similar to our approach. We have become one of the world's experts in the chemistry of splicing modification, which is differentiated from traditional protein-targeting chemistry. Not many pharmaceutical companies or chemical libraries have a large portion of chemistry useful for this type of targeting.

We've spent years building up this proprietary library, which was part of our founding strategy as a company and is differentiated from other approaches to this mechanism of action. While we've followed antisense oligonucleotide approaches and the theory behind current Huntington's treatments, we haven't seen them work in the clinic. Our view is that we love the antisense approach as a lead blocker for other approaches. If you look at how spinal muscular atrophy treatments were developed, there was an antisense that focused on the block and tackle approach to knocking things down, and then the small molecule was developed. Our idea is to build small molecules that are available to much larger markets over time. To answer your question in a very long way, it's a very similar mechanism to risdiplam; splicing modification is changing the downstream protein. In this case, we're modifying all Huntington's proteins, both mutant and non-mutant Huntington's, similar to PTC’s (Therapeutics) approach. We believe our molecule has some advantages versus PTC, which we haven't published or spoken about. It all depends on what you see in the clinic. We're grateful to PTC, glad they're in the clinic, and think highly of their science and scientists in this program. Hopefully, it'll work for patients.

How have Huntington disease drug trials changed over the years?

It's a good question, and I'm not the expert on clinical trials; I'm the head of corporate development, not the head scientist. However, I think we've been able to learn from previous trials. At what stage do we enroll patients? Are they later-stage or earlier-stage patients? Do you look at combination opportunities in the initial trial design? These are things on our minds. We're implementing SAD and MAD trials, public in Australia, for healthy volunteers. But looking carefully at historic trials, how they've approached patients at different stages in the disease, is crucial. We're spending a lot of time on that and have respect for CHDI [Foundation] and other leading patient-focused foundations in the industry. We intend to continue speaking with them about different ways of designing trials.

If the study is successful, what would be the next steps? Talk a little bit about the future goals.

For this drug, we've already planned how we imagine the full set of trials through NDA. We're aggressively moving on this schedule, laying out phase 1, phase 2, and the pivotal NDA (trials) and how we would get there. We're learning from our predecessors, and that's a nice thing for us. We're also trying to be innovative on our own, being thoughtful about tactical and strategic trial design to get us there. We also have a pipeline behind this of other neurology and oncology drugs. For NeurologyLive, we have a few other important disease areas that we're focusing on using this RNA splicing mechanism in small molecules to interrogate those other diseases. We have hope that as we progress from risdiplam to Huntington's as a field, this mechanism holds promise for neurology, especially for people in places like Belize and Bogota, not just in Boston. We're glad there are different shots on goal, delighted to see gene therapies having success, glad to see intrathecal injections through antisense working. But those are 2 million or a million-dollar or $750,000-a-year treatments, and they just aren't available now for larger populations. We have hope that this mechanism will provide that.

Transcript was edited for clarity by artificial intelligence.