Print It's No Secret: Oral Drug Branaplam Reduces Hunting, But Safety Concerns Hinder Development - HDBuzz

Print, not secret: Oral drug branaplam lowers huntingtin protein, but safety concerns hamper development

⏱️10 min. reading time |The results of the VIBRANT-HD study have now been published in a peer-reviewed journal.The study tested the oral drug Branaplam, which lowered HTT but caused serious safety issues, and the study was eventually stopped.

Danger! Automatic translation - possibility of errors

In order to share HD research reports and academic updates with as many people as possible, this article has been automatically translated by AI and has not been edited by a human editor.Although we try to provide accurate and comprehensible information, AI translations may contain grammatical errors, misinterpretations, or unclear words. For the most accurate information, please refer to the original English translation or a later edited version.If you see any serious mistakes, if you are a native of this language and want to improve the correct translation, please contact editors@hdbuzz.net.

Results from a clinical trial called VIBRANT-HD, which examined an oral drug designed to reduce levels of the protein huntintin (HTT), have been published in the journal Nature Medicine.The study showed that the drug could reduce HTT levels in people with Huntington's disease.However, evidence of nerve damage led to early termination of the study.Although the clinical trial ended some time ago and was not successful, the publication of the results in a peer-reviewed journal is an important milestone in the research of this drug.Let's see what we learned from this new episode.

Why is it important to reduce HTT?

Huntington's disease (HD) is caused by genetic mutations that lead to amplification of the HTT gene.This produces a misfolded version of the extended Htt protein.Over time, widespread HTT destroys brain cells and leads to movement, thinking, and mood symptoms called HD.

One of the most promising disease-modifying strategies in HD is lowering HTT.By reducing the amount of extended HTT in the body, researchers hope to slow or stop the progression of the disease.Various methods are being tested, including antisense oligonucleotides (such as Tominersen and Roche's Waves WVE-003), RNA interference (such as uniQure's AMT-130), and small molecules.(such as Novartis' Votoplam and Skyhawk's SKY-0515). The study focused on pranaplam, a small molecule drug that can be taken orally.

What is Branaplam and how does it work?

Branaplam was originally developed to treat spinal muscular atrophy (SMA), a genetic childhood disease that also causes neuronal death.In SMA, branaplam works by changing the way RNA is processed, allowing cells to make more of the protein that people with the disease lack.RNA is the genetic messenger molecule in the cell that carries instructions for making different proteins.

The researchers found that branaplam also affects the processing of HTT-RNA.Instead of delivering the normal HTT-RNA message, the drug promotes the insertion of a "pseudexon," an extra piece of genetic code in HTT-RNA that contains molecular stop signals.This damages the RNA before it produces protein, resulting in low levels of normal and extended HTT protein.

After this discovery, scientists at Novartis believed that pranaplam could be used not only to treat spinal muscular atrophy, but also to treat HD.They began studying it first in animal studies and then in clinical trials.

What is important is that Branaplam can be taken orally and distributed throughout the body.It also reaches the brain and can reduce HTT levels there.It was the first oral hybrid module that was tested in people with HD.Since then, other companies have been working to develop their own oral HTT-lowering drugs, including Skyhawk Therapeutics, PTC Therapeutics and Novartis.

What did the researchers think was necessary to achieve the benefits?

Based on human genetics and animal studies, scientists estimate that reducing HTT levels in the brain by about 30-50% could slow the progression of HD while still maintaining enough normal HTT to maintain healthy cell function.

Low levels of HTT in the brain are reflected in low levels of HTT in the cerebrospinal fluid (CSF), which washes the brain.In clinical trials, HTT levels in CSF can be measured by lumbar puncture to check how well the drug is working.This allowed the researchers to check whether the desired reduction of 30-50% was achieved.

Safety signals from animal studies

Before Branaplum was tested on humans with HD, several animal safety studies were conducted.There were some concerns: dogs and primates (monkeys) showed signs of peripheral nerve damage after treatment with high doses of Branaplum.This nerve damage was measured by increased levels of neurofilament light chain (NFL), a protein released when nerve cells are damaged.

More importantly, the increase in NfL occurs before the nerve damage is seen using other methods and decreases again after the drug is stopped.Therefore, the HK study includes a very careful observation - especially of NfL and the functioning of the nervous system.

VIBRANT-HD Clinical Trial

The VIBRANT-HD study was a Phase 2b study designed to test the safety, tolerability and biological effects of branaplam in people with HD.Participants were given branaplam or a placebo (a sugar pill) and neither the researchers nor the participants knew who was getting what.

The participants took branaplam once a week.The first dose tested was 56 mg once a week, but the plan was to increase this slowly over the course of the study to find the best possible dose.Intensive monitoring for neurotoxicity was performed, and NfL levels were used as an early biomarker of safety.

What happened in the study?

Only 26 participants were enrolled before the study was stopped. When safety concerns arise, dosing is first suspended and then permanently stopped. Officials and independent observers have agreed that the risk ratio is not good.

To ensure that the researchers could learn as much as possible from this clinical trial, the participants who received branaplam were followed up for a full year after treatment was completed to monitor improvement.

Did Branaplam reduce HTT?

Yes.Although it was discontinued early, the study clearly showed that Branaplum reduced HTT levels in the brains of the study participants.CSF levels of extended-release HTT were reduced by approximately 25% compared to placebo after 17 weeks.

This corresponds to predictions from animal studies and models. Blood tests also confirmed the expected changes in HTT RNA processing. This was an important proof of concept and paved the way for subsequent clinical studies: an oral drug can lower HTT in people with HD via the mechanism that the researchers previously described.

What safety issues have occurred?

Increase in neurofilament light chain (NfL)

About three-quarters of people who took branaplam experienced an increase in their NfL levels.After 9 weeks, NfL levels were on average over 70% higher.In the placebo group, however, there was no increase in NfL, suggesting that branaplam caused the increase.The good news: After the participants stopped taking the drug, NfL levels in the branaplam group returned to normal.

Symptoms of peripheral neuropathy

Many people taking branaplam experienced symptoms or signs of peripheral nerve damage - including changes in nerve conduction studies;weak reflexes or sensitivity on neurological examination;or heart palpitations, numbness, or other symptoms related to the nerves.It was encouraging that many participants' symptoms partially or completely returned after stopping treatment.This is also consistent with observations from animal experiments.

Change the brain image

MRI scans showed a temporary increase in the size of the posterior ventricles (the normally fluid-filled spaces in the brain that store and circulate cerebrospinal fluid) in people taking branaplam.This effect occurred early, resolved slowly after discontinuation of the drug, and was not associated with worsening symptoms or loss of brain tissue.Similar changes have been observed with other methods of HTT reduction, and the exact cause is still unclear.

Why didn't they just use a lower dose?

The researchers used computer simulations along with animal and human data to answer an important question: Can a low or constant dose of HTT be safe to help people with HD?

The answer was no.Although lower doses are predicted to be safer, they will not reduce the extension of HTT by approx.30% considered necessary for clinical benefit.This formulation played an important role in the decision to stop the development of Branaplam in HD.

What does this mean for the HD community?

While disappointing, the study offers some important findings:

First: It is possible to lower HTT with oral medications.This was the first clear evidence that a tablet could reduce HTT in HD patients.A great success if the alternatives are spinal injections and brain surgery!

Second, it has paved the way for further development of more potent oral GTT-lowering agents that can be administered at lower doses.These second-generation splicing modulators are now entering the clinic, including through Skyhawk Therapeutics and Novartis.

Third, the safety monitoring approach worked as planned.The study design revealed early warning signs before irreversible damage occurred.

Fourth, NfL is a strong biomarker of safety.This is because levels increase before overt nerve damage is seen.Helps to act quickly

Und schließlich: Off-Target-Effekte von Spleiß-Modulatoren bleiben eine Herausforderung. Die bei Branaplam beobachteten Nervenprobleme werden vermutlich durch unbeabsichtigte Effekte auf das RNA-Spleißen verursacht, nicht durch die HTT-Senkung selbst. Das unterstreicht die Notwendigkeit selektiverer Medikamente.

Branaplam has shown that it is scientifically possible to reduce GTT with an oral drug.However, safety concerns - especially nerve damage, although reversible - meant that further use of this particular drug was not possible.Data from VIBRANT-HD have helped develop GTT-lowering treatments that we hope will be safer and more accurate.Although this result is disappointing, research continues.and every study—successful or not—advances the HD field.

Most importantly, we warmly and sincerely thank the HD patients and their families who participated in the VIBRANT-HD study. Through their participation, they provide valuable knowledge to Hong Kong society. Even if Branaplam cannot be developed further, these discoveries would not exist without their generosity, courage and commitment to advancing research for future generations.

- Branaplam is an oral medication designed to lower HTT by changing the way HTT RNA binds, destroying the message before the protein is made.

- In the VIBRANT-HD clinical trial, weekly branaplam reduced CSF increased HTT levels by ~25% compared to placebo.

- This is the first clear evidence that oral drugs can reduce HTT in people with HD.

- However, safety concerns, particularly signs of peripheral nerve damage, emerged early in many participants who received the drug.

- These protective signals were detected using NfL, a biomarker found in blood and cerebrospinal fluid that increases when nerve cells are damaged.

- Most neurologic-related changes are partially or completely reversible after discontinuation of treatment, but the overall benefit-risk ratio is unfavorable.

- A computer model suggests that lower doses of branaflamm are likely to be safer, but do not decrease HTT enough to achieve clinical benefit.

- Therefore, the study was immediately terminated and the development of Branaplam for HD was terminated.

-Although disappointing, this study shows that reduction in oral HTT is possible and highlights the importance of early and robust safety monitoring in HD trials.

For more information about our disclosure policy, please read our frequently asked questions...