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Full Throttle Ahead: will a small pill be one of the first?

Claudia Azañedo — Fri, 25 Sep 2026 17:20:15 +0000

FULL THROTTLE AHEAD

WILL A SMALL PILL BE ONE OF THE FIRST?

The international Huntington’s disease (HD) community has been waiting a very long time for its first disease-modifying treatment — a treatment that could slow, stop, or potentially reverse the progression of HD.

As a rare disease community, we are fortunate to have several players at the table. The frustrating part is that developing these treatments takes time.
But one of the most interesting stories began with something very small: a pill.

Where it all began

Let’s start at the beginning.

In February 2019, a group of HD advocates heard Dr. Anu Bhattacharyya present what PTC Therapeutics was developing. She described a small molecule, PTC518, that could potentially reduce the production of huntingtin protein(HTT) and, ultimately, slow the progression of HD.
At the time, it sounded almost too good to be true.

Fast-forward seven years, and that same medicine — now known as votoplam — has progressed from an early idea to a global Phase 3 clinical trial.
That is quite a journey.

PTC stands for Post-Transcriptional Control, referring to the way the company’s technology can influence how RNA is processed inside cells.

Where did the idea come from?

The story actually started with another neurological disease: SMA.

PTC Therapeutics was developing medicines for SMA and had learned how to influence the way cells process RNA.
At around the same time, Novartis was developing a drug called branaplam, also for SMA. Scientists discovered that branaplam unexpectedly affected the processing of HTT RNA, the RNA molecule that provides instructions for making huntingtin protein. This was an important discovery.

It showed that it was possible, using a small molecule, to alter the way the cell processes HTT RNA — and therefore potentially reduce the amount of HTT being produced.

Branaplam was subsequently investigated in an HD clinical trial. Unfortunately it was discontinued after concerns about nerve damage emerged. But the underlying scientific idea remained.

PTC Therapeutics essentially asked:
If a small molecule can alter HTT RNA, could we develop our own molecule specifically designed to do this in HD?
And that is what they set out to do.
Many molecules were tested. The most promising candidates were repeatedly refined and improved. Eventually, one emerged: PTC518.

So, how does PTC518 work?

Imagine the Huntington’s disease gene (HTT) is a recipe for making a harmful protein.

Normally: HTT → recipe → huntingtin protein.

Scientists found a hidden piece in the HTT recipe.
PTC518 makes the cell put that hidden piece into the recipe.
That hidden piece contains a STOP sign.

So: HTT → recipe + STOP sign → cell throws the recipe away → less huntingtin (this happens in both copies of the gene)

The journey from an idea to Phase 3

The development of PTC518 has moved through several important stages.

2020 — Phase 1 begins
PTC Therapeutics began the Phase 1 clinical trial of PTC518 in healthy volunteers.
Assess its safety and biological effects.

2021 — Early evidence
Phase 1 results provided evidence that PTC518 could reduce HTT levels. This supported taking the programme forward into people living with HD.

June 2022 — PIVOT-HD begins
The PIVOT-HD Phase 2a trial began in people with HD.
This was an important step: the drug was no longer simply an interesting laboratory concept. It was now being tested in the people it was ultimately intended to help.

2024 — Encouraging results
Results from PIVOT-HD showed sustained, dose-dependent reductions in huntingtin protein.
There were also encouraging trends in several clinical measures.

However, it is important to remember that these were early-stage results. A reduction in HTT is encouraging, but the critical question is whether that biological effect = a meaningful slowing of HD progression.
And that is exactly what a Phase 3 trial is designed to determine.

December 2024 / January 2025 — Novartis enters the picture

Then came another major development.
Novartis and PTC Therapeutics entered into a global licensing and collaboration agreement for PTC518.

The programme moved under Novartis, and PTC518 was given a new name: votoplam. Novartis took responsibility for the continued development, manufacturing and, ultimately, commercialization of the medicine.

In many ways, it felt like the story had come full circle.

Remember branaplam?

Novartis had originally been involved in discovering that a small molecule could influence HTT RNA.
Now, years later, Novartis was taking forward a different molecule — one developed specifically from that scientific insight and refined for HD.

May 2025 — PIVOT-HD results

The PIVOT-HD study produced another important milestone.

The trial met its primary endpoint, demonstrating a significant reduction in blood huntingtin protein.

Again, these results were encouraging — but they did not yet prove that votoplam slows the progression of Huntington’s disease.
That question requires a much larger and longer study.

And that brings us to today.

2026

In March 2026, the INVEST-HD Phase 3 trial began enrolling participants.

The purpose of INVEST-HD is to determine whether votoplam can actually slow the progression of HD. And the scale of this trial is impressive: at the six-month mark, Novartis had opened 117 trial sites across 27 countries, with the aim of reaching 210 sites in 32 countries and enrolling approximately 770 participants.

To put that into perspective, the Roche GENERATION HD1 trial ultimately involved 96 sites.

The speed and geographical reach of INVEST-HD are remarkable.
The trial is opening in countries and regions that have rarely, if ever, had the opportunity to participate in an HD clinical trial — including countries such as Bulgaria, Romania, Slovakia, Japan, Taiwan, Argentina, Colombia and Mexico.

For the global HD community, that matters.
It means more families have the opportunity to participate in research, and it demonstrates the scale at which this programme is now being developed.

Hence the title:

FULL THROTTLE AHEAD

But let's keep our feet on the ground

There is an understandable sense of excitement around votoplam, science is compelling, reduction in huntingtin protein is encouraging, speed and scale of the Phase3 are impressive.
And, perhaps most importantly, there is now a serious global effort to answer the question: Can we actually slow Huntington’s disease?

But we still have to wait.
The INVEST-HD study itself is expected to run for approximately three years, followed by analysis of the results.
So we are still some distance away from knowing whether votoplam will become a disease-modifying treatment for HD.
And that distinction is important: Promising is not the same as proven.

At the same time, there are many other approaches being developed across the HD field — from gene silencing and gene therapy to other ways of targeting huntingtin, inflammation, cellular pathways and the underlying biology of the disease.
That is something we should celebrate.
Because the future of HD treatment does not necessarily depend on one single drug.
As we have seen in other diseases, different treatments may work better for different people, at different stages of disease, or through different mechanisms.

For now, the HD community can allow itself a little optimism.

A small pill that began as an intriguing scientific idea has travelled a very long way.
From PTC518…
to votoplam…
from an idea presented to advocates in 2019…
to a global Phase 3 trial in 2026.
We don’t know yet whether this will be the breakthrough we have been waiting for.
But for the first time, the question is no longer simply:
“Could this work?”
We are now much closer to finding out.
And that, in itself, is something worth watching.
Full throttle ahead.

– Article written by Dina de Sousa

A Rollercoaster Ride to Hope

Claudia Azañedo — Tue, 07 Jul 2026 16:22:48 +0000

A Rollercoaster Ride to Hope

The AMT-130 Story, and What the FDA's June 2026 Announcement Means for Our Community

Our community’s first meeting with the pharmaceutical company uniQure took place in September 2018. At the time, the idea that a gene therapy could actually slow HD felt like pie in the sky. Nearly eight years later, on June 17, 2026, that hope took a major step toward becoming real.

This update walks through that journey — the excitement, the setbacks, and the advocacy that helped get us here — and what it means going forward.

What is AMT-130?

Gene therapy aims to treat disease by changing the genetic instructions inside our cells. Imagine your DNA is a cookbook. If one recipe contains a mistake, gene therapy works like an editor, correcting or blocking the faulty recipe.

AMT-130 is designed to reduce production of the harmful huntingtin protein that causes HD. It uses a harmless virus to deliver a small genetic molecule into the brain that “switches down” the faulty huntingtin gene. The treatment is given once through MRI-guided brain surgery and has been tested at both a low and a high dose.

So far, AMT-130 has been studied in two Phase I/II clinical trials:

United States: Began in June 2020. Participants were randomly assigned to receive either AMT-130 or a sham (imitation) brain surgery.
Europe: Began in February 2022 in Warsaw, Poland, and later expanded to sites in the UK. Everyone in this study received AMT-130.

The Journey So Far

September 24, 2025 – Landmark results
Three years after treatment, people who received the high dose of AMT-130 showed a 75% slowing in disease progression compared with matched external controls alongside favourable biomarker changes. You can read more here.
November 3, 2025 – A difficult reversal
Following an October 29 pre-submission meeting, the FDA told uniQure it no longer agreed that the trial data — compared against that matched “external control” group rather than an internal placebo group — were sufficient, on their own, to support a Biologics License Application (BLA), the formal request to market AMT-130 in the US.
This was a major disappointment. A new trial would require more volunteers to undergo brain surgery without receiving the treatment, raising serious ethical concerns for this fatal, progressive disease where every year of delay matters.
Late 2025 to January 2026 – The community responds
As they say, “you can’t keep a good man down”: patient advocacy groups in the US quickly mobilised and started 2 petitions which were signed worldwide. On January 22, 2026, with the petitions having gathered more than 48,000 signatures, representatives hand-delivered them to FDA alongside more than 11,000 messages sent to Congress.The petitions called on the FDA to honour its prior guidance and expedite review by allowing uniQure to file a BLA for accelerated approval consideration for its investigational gene therapy, AMT-130
Community representatives also secured a place in discussions with the FDA, helping ensure patients’ voices were heard.
March 2, 2026 – The setback confirmed
The FDA confirmed its position, saying the existing data were still not enough for approval and again recommending a new randomized, sham-controlled trial.
April 30, 2026 – Progress in the UK
While discussions continued in the US, uniQure announced a positive meeting with the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). The company confirmed plans to apply for UK approval in the third quarter of 2026.
June 17, 2026 – A turning point
In a major reversal, the FDA and uniQure reached a breakthrough alignment. The FDA agreed to allow uniQure to submit an application for accelerated approval based on the totality of their existing Phase I/II data and three-year follow-up, bypassing the need for a highly controversial sham-surgery study. Read the press release here.

What Happens Next?

It’s important to understand what this does—and doesn’t—mean.

AMT-130 is still experimental. It has not yet been approved and is only available through clinical trials.
The FDA application has not yet been submitted. uniQure expects to file it in Q3 2026, after which the FDA review process will begin.
Accelerated approval is conditional. If granted, it would allow earlier patient access while requiring a follow-up study to confirm the treatment’s long-term benefit.
The UK review is happening separately. uniQure also plans to submit its application to the MHRA during Q3 2026.

Even with these important steps still ahead, June 17, 2026 represents a genuine milestone. The achievements are thanks to the trial participants who volunteered for brain surgery, the researchers who continued pushing forward, and a community that refused to give up when the path became more difficult.

For the first time, a treatment has shown in people that it may be possible to slow the progression of Huntington’s disease.

– Article written by Dina de Sousa

AN UPSIDE DOWN APPROACH TO CLINICAL TRIALS

Claudia Azañedo — Fri, 19 Jun 2026 12:06:03 +0000

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 is in the process of submitting a formal application to the TGA. 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 Clinical Trial NCT07378644 and www.falcon-hd.com.

Read the full press release here.

– Article written by Dina de Sousa

– Illustrations by EHA Communication Team