Putting it in print: oral drug branaplam lowered huntingtin, but safety concerns halted development

The results of a clinical trial, called VIBRANT-HD, investigating an oral drug designed to lower huntingtin (HTT) protein have now been published in Nature Medicine. This study found that the drug could reduce HTT levels in people with Huntington’s disease. However, signs of nerve damage meant the study was stopped early. Although the clinical trial ended a long time ago now and was not successful, the publication of the results of this study in a peer reviewed journal is an important milestone in the research of this drug. Let’s get into what we learned from this new publication. 

Why lowering HTT matters

Huntington’s disease (HD) is caused by a genetic change that leads to an expansion in the HTT gene. This in turn leads to the production of a faulty version of the HTT protein which is also expanded. Over time, expanded HTT damages brain cells, leading to the movement, thinking, and mood symptoms that characterise HD.

One of the most promising disease-modifying strategies for HD is HTT lowering. By reducing the amount of expanded HTT in the body, scientists hope to slow or even stop disease progression. Several approaches are being tested, including antisense oligonucleotides (like Roche’s tominersen and Wave’s WVE-003), RNA interference (like uniQure’s AMT-130), and small molecules (like Novartis’ votoplam and Skyhawk’s SKY-0515). This study focused on branaplam, a small-molecule drug that can be taken by mouth.

What is branaplam and how does it work?

Branaplam was originally developed to treat spinal muscular atrophy (SMA), a childhood genetic disease that also causes nerve cell breakdown. In SMA, branaplam works by changing how RNA is processed, allowing cells to make more of a protein that is missing in people with this disease. RNAs are the genetic message molecules in the cell that carry the instructions for making different proteins. 

Researchers discovered that branaplam also affects the processing of HTT RNA. Instead of producing a normal HTT RNA message molecule, the drug encourages the inclusion of a “pseudoexon” – an extra piece of genetic code in the HTT RNA molecule that contains molecular stop signals. This causes the RNA to be destroyed before it can make protein, resulting in lower levels of both the regular and expanded HTT proteins. 

Following this discovery, the scientists at Novartis thought that branaplam could be used to treat HD, as well as SMA. They set out to begin investigating this, first with animal studies and then with a clinical trial. 

Importantly, branaplam can be taken orally, and is able to spread throughout the body, as well as reaching the brain to lower HTT levels. It was the first oral splicing modulator tested in people with HD. Since then, other companies have been working to advance their oral HTT lowering drugs, like Skyhawk Therapeutics, PTC Therapeutics, and Novartis.

What did researchers think was needed for benefit?

Based on human genetics and animal studies, scientists estimate that reducing HTT levels in the brain by about 30–50% might slow HD progression while still preserving enough regular HTT for healthy cell function.

Lower HTT levels in the brain are reflected by lower HTT levels in the cerebrospinal fluid (CSF), the liquid which bathes the brain. HTT levels can be measured in CSF during clinical trials using a spinal tap to check how well the drug is working. This is how researchers could check if they reached the 30-50% lowering they were aiming for. 

Safety signals seen in animal studies

Before testing branaplam in people with HD, many safety studies were done in animals. These did raise some concerns, and they found that dogs and non-human primates (monkeys) showed signs of peripheral nerve damage after being treated with higher doses of branaplam. This nerve damage was measured by rising levels of neurofilament light chain (NfL), a protein released when nerve cells are injured. 

Importantly, NfL increases happened before nerve damage could be seen by other methods but went back down after the drug was stopped. Because of this, the HD trial included very close safety monitoring, especially of NfL and nerve function.

The VIBRANT-HD clinical trial

The VIBRANT-HD study was a phase 2b trial designed to test the safety, tolerability, and biological effects of branaplam in people with HD. Folks in the trial were given either branaplam or a placebo sugar pill but neither the researchers or participants knew who got what. 

Branaplam was taken once weekly by participants in the trial. The first dose tested was 56 mg once per week but the plan was to slowly increase as the trial progressed to find the best dose possible. There was intensive monitoring for nerve toxicity and NfL levels were used as an early warning safety biomarker. 

What happened in the trial?

Only 26 participants were enrolled before the trial was halted. After safety concerns emerged, dosing was first paused and then permanently stopped. Regulators and independent monitoring committees agreed that the benefit–risk balance was not favourable.

To ensure that the researchers learned as much as possible from this clinical trial, participants who had received branaplam were followed for a full year after stopping treatment to track recovery.

Did branaplam lower HTT?

Yes. Despite the early stop, the study clearly showed that branaplam lowered levels of HTT in the trial participant’s brains. CSF levels of expanded HTT fell by about 25% compared with placebo after 17 weeks. 

This matched predictions from animal studies and modelling. Blood tests also confirmed the expected changes in HTT RNA processing. This was an important proof-of-concept that has paved the way for subsequent clinical trials: an oral drug can lower HTT in people with HD by the mechanism scientists had mapped out.

What were the safety problems?

Rising neurofilament light chain (NfL)

Around three-quarters of people taking branaplam showed increases in NfL. At 9 weeks, NfL levels had increased by over 70% on average. Conversely, no NfL increases were seen in the placebo group, suggesting branaplam was causing the rise. The good news is that after trial participants stopped taking the drug, NfL levels returned toward normal in the non-placebo group. 

Signs of peripheral neuropathy

Most people taking branaplam showed signs or symptoms suggesting peripheral nerve damage, including changes on nerve conduction tests; reduced reflexes or sensation on neurological exam; or tingling, numbness, or other nerve-related symptoms. Encouragingly, symptoms were partially or fully reversible in many participants after stopping treatment. This also matched what was seen in animal studies.

Brain imaging changes

MRI scans showed a temporary increase in lateral ventricle size (normal fluid-filled spaces in the brain used to store and circulate CSF) in people taking branaplam. This effect appeared early, was partially reversed after stopping the drug, and was not associated with worsening symptoms or brain tissue loss. Similar changes have been seen with other HTT-lowering approaches, and the exact cause remains unclear.

Why not just use a lower dose?

Researchers used detailed computer models combining animal and human data to ask an important question: could a lower or less frequent dose be safer and still lower HTT enough to help people with HD? 

The answer was no. Lower doses were predicted to be safer but they would not reduce expanded HTT by the ~30% thought necessary for clinical benefit. This modelling played a key role in the decision to end development of branaplam for HD.

What does this mean for the HD community?

Although disappointing, this study provides several important lessons: 

First, that HTT lowering with oral drugs is possible. This was the first clear demonstration that a pill can lower HTT in people with HD. A significant win when the alternatives are spinal injections and brain surgery! 

Second, it set the stage for iterations of more potent HTT-lowering oral drugs that can be given at lower doses. These 2nd generation splice modulators are working their way through the clinic now, being advanced by Skyhawk Therapeutics and Novartis. 

Third, that the safety monitoring approach worked as intended. The trial design successfully detected early warning signs before irreversible harm occurred.

Fourth, that NfL is a powerful safety biomarker, as the levels rose before clear nerve damage, helping researchers act quickly.

Finally, that off-target effects of splice modulators remain a challenge. The nerve problems seen with branaplam are thought to be due to unintended effects on RNA splicing, not HTT lowering itself. This highlights the need for more selective drugs.

The bottom line

Branaplam showed that lowering HTT with an or%Ral drug is scientifically feasible, but safety concerns, particularly nerve damage, albeit reversible, meant that this specific drug could not be continued. The knowledge gained from VIBRANT-HD has helped guide the design of HTT-lowering therapies that we hope are proven to be safer and more precise. Although this was a disappointing result, research continues, and each study, successful or not, moves the HD field forward.

Above all, we recognise and sincerely thank the people with HD and their families who took part in the VIBRANT-HD trial. By volunteering for this study, participants contributed invaluable knowledge to the HD community. Even though branaplam could not move forward, the insights gained would not exist without their generosity, courage, and commitment to advancing research for future generations.

Summary: 

• Branaplam is an oral drug designed to lower HTT by changing how HTT RNA is spliced, causing the message to be destroyed before protein is made.
• In the VIBRANT-HD clinical trial, weekly branaplam lowered expanded HTT levels in CSF by ~25% compared with placebo.
• This is the first clear demonstration that an oral drug can lower HTT in people with HD. 
• However, safety concerns emerged early, particularly signs of peripheral nerve damage in many participants receiving the drug.
• These safety signals were detected using NfL, a blood and CSF biomarker that rises when nerve cells are injured.
• Most nerve-related changes were partially or fully reversible after stopping treatment, but the overall benefit–risk balance was not favourable.
• Computer modelling showed that lower doses of branaplam would likely be safer but would not lower HTT enough to provide clinical benefit.
• As a result, the trial was stopped early and development of branaplam for HD has been discontinued.
• Although disappointing, the study shows that oral HTT lowering is possible and highlights the importance of early, robust safety monitoring in HD trials.