SKYHAWK THERAPEUTICS

AN UPSIDE DOWN APPROACH TO CLINICAL TRIALS: LEADING TO SOME EXCITING RESULTS

Skyhawk Therapeutics, a US-based pharmaceutical company, has developed a new medication that aims to slow the progression of Huntington’s Disease. Let’s start from the beginning and go through Skyhawk’s timeline:

SKY-0515 is taken as a once-daily pill by mouth. It is designed to lower the levels of two harmful proteins linked to HD (Mutant huntingtin(mHTT) and PMS1). You can read more in regards to this approach in our article published September 18, 2025.

1) Huntingtin protein. In people with HD, the huntingtin gene carries a fault (mutation) that causes the body to produce an abnormal version of the huntingtin protein, called mutant huntingtin (mHTT). This abnormal protein is what drives the disease. SKY-0515 lowers levels of both the normal and the mutant form of huntingtin.

2) PMS1 protein. PMS1 plays a role in a process called “somatic expansion.” To understand this: everyone with HD is born with a certain length of genetic repeat in their huntingtin gene, but in some cells — especially brain cells — that repeat gradually gets longer over a person’s lifetime. This lengthening is called somatic expansion, and research suggests it may influence when symptoms first appear. By lowering PMS1, SKY-0515 may help slow this process. Somatic expansion is one of the most actively studied areas in HD research today.

Phase 1 trial 

Skyhawk chose to take a different path from other pharmaceutical companies and begin their clinical trials, Down Under, in Australia and New Zealand. 

The Phase 1 trial had three parts. Parts A and B enrolled healthy volunteers who do not carry the HD gene mutation. Part C enrolled people living with HD. The main goal  was to check that the drug is safe and well tolerated by the body.

On 27 January, Skyhawk announced results from a 9-month interim analysis (a planned look at the data while the trial is still ongoing) of Part C participants in the Phase 1 trial.

 

Key findings included:

  • SKY-0515 was safe and well tolerated.
  • Participants taking SKY-0515 showed reductions in mutant huntingtin levels in blood that were “dose-dependent” — meaning the higher dose produced a greater reduction than the lower dose.
  • At the higher dose, average reductions of about 62% in mutant huntingtin were seen
  • Levels of PMS1 were reduced by about 26%, but there is not yet enough data to know whether this reduction is large enough to meaningfully slow somatic expansion.
  • The drug was shown to reach the brain, which is essential for any treatment targeting HD.

 

Phase 2/3 trial — FALCON-HD

Based on the promising interim results from Phase 1 the company then started a Phase 2/3 trial called FALCON-HD. The company yet again began with sites in Australia and New Zealand. Proceeding with 2 sites in the country of Georgia.  A different approach to site selection reflecting a broader global approach to recruitment

As noted by Masoud Mokhtarani, Senior Vice President of Clinical Development, “Based on global feasibility assessments, sites in Georgia were selected due to their strong clinical research infrastructure, access to the target patient population, and limited competition from other ongoing clinical trials.”

The Phase 2/3 trial is designed both to find the best dose and to test whether the drug has a meaningful effect on HD symptoms. 

FALCON-HD is enrolling people at stages 2 and 3 of HD, as defined by the HD Integrated Staging System (HD-ISS).  This is a newer way of classifying how far HD has progressed, currently used only in clinical trials rather than in everyday medical practice. The trial aims to enrol around 520 participants in total. Each participant is randomly assigned to receive either SKY-0515 (at one of three different dose levels) or a placebo, The drug is taken as a once-daily pill for at least 12 months.

As well as continuing to monitor safety, FALCON-HD is designed to measure whether SKY-0515 has a meaningful effect on the signs and symptoms of HD. Researchers are also tracking biological markers to see whether the drug affects levels of huntingtin and PMS1 proteins in the body.

Provisional approval pathway in Australia

On 3 March, Skyhawk announced that Australia’s Therapeutic Goods Administration (TGA) — the Australian equivalent of the EMA or FDA — has determined that SKY-0515 meets the eligibility criteria for its “provisional approval” pathway. This is a regulatory route that can allow earlier access to a promising medicine based on preliminary clinical data, before full Phase 3 trials are completed. Skyhawk has submitted a formal application to the TGA, and that review is now underway. It is important to note that this milestone does not guarantee that the drug will be approved or made available — it simply means the process for an early review has begun.

On June 1st, Skyhawk announced results from a 12-month interim analysis from the Phase 1 trial providing further insights into the potential of SKY-0515 (press release).

  • As with the 9 months results treatment resulted in a dose-dependent reduction in mutant huntingtin(mHTT) protein in blood of up to to 69% – the largest reduction reported so far in any HD clinical trial
  • Reductions on PMS1 mRNA of up to 26%
  • At 3, 6, 9, 12 months, participants demonstrated positive mean changes from baseline Composite Unified Huntington’s Disease Rating Scale(cUHDRS).
  • Favourable trends were also observed across all cUHDRS subcomponents, including Total Motor Score, Total Functional Capacity, Symbol Digit Modalities Test and Stroop Word Reading Test.
  • The Company also announced that the Australia and New Zealand portion of its Phase 2/3 FALCON-HD trial completed enrolment 6 months ahead of schedule with 144 patients enrolled
  • The worldwide Phase 2/3 FALCON-HD trial has expanded to 8 countries

Looking ahead

Although still in development, SKY-0515 and the FALCON-HD trial represent an important step forward in the search for disease-modifying therapies for Huntington’s disease.

This study brings new hope for the HD community as researchers continue to explore treatments that target the underlying biology of the disease.

More details are available at ClinicalTrials.gov NCT06873334 and www.falcon-hd.com. 

Read the full press release here.

– Article written by Dina de Sousa

– Illustrations by EHA Communication Team

 

new FB feed (19)

dictionary:

siRNA

A way of silencing genes using specially designed molecules of RNA – like DNA but made of only a single strand – that target the message molecules in cells and tell them not to make a certain protein

new FB feed (19)

dictionary:

phenoptype

Phenotype refers to an individual’s observable traits, such as height, eye color and blood type. A person’s phenotype is determined by both their genomic makeup (genotype) and environmental factors.

new FB feed (19)

dictionary:

oxidative seres

an imbalance between unstable molecules called “free radicals” and protective “antioxidants” in your body

new FB feed (19)

dictionary:

Metabolism & bioenergetics

describe how your body turns food into fuel and uses that energy to live. 

new FB feed (19)

dictionary:

Small Molecule

a tiny chemical compound, much smaller than big biological structures like proteins, that can easily travel inside our cells to act as medicine (like aspirin or ibuprofen), a building block (like glucose), or a signaling tool in the body, often taken as pills because they’re easy to absorb and distribute

 

new FB feed (19)

dictionary:

Nucleic acid

(DNA and RNA) are the essential information-carrying molecules in all life, acting like blueprints that store and transmit genetic instructions for building and operating cells, directing everything from growth to protein production, and passing traits from parents to offspring.

new FB feed (19)

dictionary:

SNP-single nucleotide polymorphisms

a single-letter spelling difference in a gene. SNPs, pronounced ‘snips’, are common and most don’t change the function of the gene.

 
new FB feed (19)

dictionary:

at risk

You do not know if you carry the genetic mutation for HD gene 

 
new FB feed (19)

dictionary:

TFC-total 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.
Scores range from 0 to 13, with higher scores indicating better functional capacity. 

 
new FB feed (19)

dictionary:

Double-blinded

 means that neither the participant nor the clinical trial doctor can choose or know the group the participant is in until the trial is over. This approach helps to prevent bias.

new FB feed (19)

dictionary:

Open label

A trial in which the patient and doctor know what drug is being used. Open label trials are susceptible to bias through placebo effects.

new FB feed (19)

dictionary:

Gene therapy

a technique that aims to treat or prevent diseases by modifying a person’s genes. It involves introducing, removing, or changing genetic material (DNA or RNA) within a patient’s cells.

new FB feed (19)

dictionary:

UHDRS- Unified Huntington Disease Rating Scale

A standardized neurological examination that aims to provide a uniform assessment of the clinical features of HD

new FB feed (19)

dictionary:

CAG 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

new FB feed (19)

dictionary:

Wild-type

the opposite of ‘mutant’. Wild-type huntingtin, for example, is the ‘normal’, ‘healthy’ protein

new FB feed (19)

dictionary:

Tolerabilty

How well a person can handle a treatment without having serious or uncomfortable side effects.

new FB feed (19)

dictionary:

Striatum

Part of the brain that  coordinates multiple aspects of cognition, including both motor and action planning, decision-making, motivation, reinforcement, and reward system.

new FB feed (19)

dictionary:

Randomized allocation

A type of allocation strategy in which participants are assigned to the arms of a clinical trial by chance.

new FB feed (19)

dictionary:

Radioligand

a radioactive substance that binds to a specific target in the body, allowing visualization of that target’s distribution and activity

new FB feed (19)

dictionary:

Protein

Protein builds, maintains, and replaces the tissues in your body. The building blocks of life.

new FB feed (19)

dictionary:

Premanifest / Prodromal

Prior to onset or diagnosis of movement symptoms.

new FB feed (19)

dictionary:

Placebo

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.

new FB feed (19)

dictionary:

PK - Pharmacokinetics

The movement of drugs through the body

new FB feed (19)

dictionary:

PD - Pharmacodynamics

The body’s biological response to drugs

new FB feed (19)

dictionary:

PET scan

Positron emission tomography which produces detailed 3-dimensional images of the inside of the body.

new FB feed (19)

dictionary:

Neuron

Brain cells that store and transmit information

new FB feed (19)

dictionary:

MRI

Magentic resonance imaging: A technique using powerful magnetic fields to produce detailed images and visualizes the structure of organs, tissues, and bones 

new FB feed (19)

dictionary:

mHTT

Mutant huntingtin protein. The protein produced by the faulty HD gene.

new FB feed (19)

dictionary:

Manifest

after HD diagnosis, or when symptoms are already showing

new FB feed (19)

dictionary:

Longitudinal study

A study where each participant is looked at several times over a time period – unlike a cross-sectional study, where each participant is looked at only once

new FB feed (19)

dictionary:

HTT

one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15

new FB feed (19)

dictionary:

fMRI

functional MRI:As with MRI, a technique using powerful magnetic fields  but focusing on brain function by measuring and mapping changes in blood flow, revealing which areas of the brain are active during specific tasks or cognitive processes

new FB feed (19)

dictionary:

CSF - cerebrospinal fluid

A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord.

new FB feed (19)

dictionary:

Efficacy

A measure of whether a treatment works or not

new FB feed (19)

dictionary:

ASO(Antisense oligonucleotides)

A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene

new FB feed (19)

dictionary:

Biomarker

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

new FB feed (19)

dictionary:

BDNF

Brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD.

new FB feed (19)

dictionary:

Allele

one of the two copies of a gene

new FB feed (19)

dictionary:

Plasma

Liquid component of the blood.

new FB feed (19)

dictionary:

Gene

The basic unit of heredity passed from parent to child. Genes are made up of sequences of DNA and are arranged, one after another, at specific locations on chromosomes in the nucleus of cells.

new FB feed (19)

dictionary:

Phase

Clinical trial phases are different stages of research that assess the safety and effectiveness of a new medical treatment or intervention in humans.

Each phase has a specific goal and involves a different number of participants. Generally, there are 4 phases (I-IV), with Phase I focusing on safety and dosage, Phase II on efficacy and side effects, Phase III on comparing the new treatment with standard treatments, and Phase IV on long-term safety monitoring.