Huntington’s disease: a therapeutic field on a bumpy ride

Huntington’s disease is a rare genetic condition that causes nerve cells in the brain to decay over time. For years, biotechs have been trying to develop treatments to cure Huntington’s disease but much to no avail. Trial failures and abandoned studies have loomed the Huntington’s community for decades but recent therapeutic milestones suggest that there might be light at the end of the tunnel.

The disease occurs when a genetic mutation in the HTT gene occurs. This gene codes for a protein called huntingtin, which helps nerve cells function. Since the DNA does not have enough information to make huntingtin, these proteins grow abnormally and instead of aiding neuron growth, it destroys them. The nerve cells in the brain are most affected by this mutation. 

People affected by Huntington’s disease experience symptoms such as chorea, which is characterized by uncontrolled movements like jerking and twitching, loss of coordination, difficulty walking and swallowing, and slurred speech, to name a few. Over the past few decades, a number of clinical trials set out to manage these symptoms, let alone cure the disease, but only a handful have seen even mild success.

Takeda jilts Wave Life Sciences, Bayer dumps BV-101

Japanese multinational Takeda deserted its collaborator Wave Life Sciences, having already sunk $260 million into its Huntington’s partnership program in October. Just last week, Bayer binned its gene therapy BV-101 to focus “on the most promising assets,” it said in an article by Fierce Biotech.  

That begs the question: what makes therapeutic attempts for Huntington’s disease not so promising?

One of the major reasons why biotechs pull the plug on clinical trials is because Huntington’s is a rare disease. According to a report published in the National Institutes of Health, how rare diseases progress is poorly understood because there aren’t enough natural history studies that have been conducted. 

“Historically, one of the challenges in Huntington’s disease drug development was the need for large, costly phase 3 outcomes studies to support regulatory approval,” Anne-Marie Li-Kwai-Cheung, chief development officer of Wave Life Sciences, told Labiotech.

Not enough patients are recruited because of how small the patient population is, which leads to trial results lacking significance. Huntington’s disease affects one in 10,000 to 20,000 people in the U.S. The low prevalence of Huntington’s disease makes it harder to figure out whether a treatment is truly successful in the clinic.

Besides this, the efficacy of drug candidates has failed to outweigh the risks in the clinic. For instance, Swiss pharma giant Novartis canned branaplam, a drug that reduced the levels of mutant huntingtin protein by interfering with mRNA splicing – the process by which non-coding regions of RNA are removed and spliced back together with the coding regions called exons. Unfortunately, safety alarms went off when patients who took the drug began experiencing early signs of peripheral neuropathy, a condition that occurs when the peripheral nervous system is damaged. 

Similarly, American biotech NeuBase Therapeutics gave up on its Huntington’s disease candidate in an effort to cut costs. With this, came 60% of its workers being laid off in 2022. And Massachusetts-based Triplet Therapeutics, which was solely focused on research and development (R&D) in Huntington’s disease, closed the curtains after it struggled to find investors to develop its lead candidate as Huntington’s was regarded back then as a misfortune-ridden therapeutic field.

Wave’s WVE-003 and Roche-Ionis’ tominersen: Targeting Huntington with antisense oligonucleotides

Yet, after decades of trial and error, biopharmas are mapping out a way to get their drug candidates into and beyond the clinic. Despite Takeda ditching Wave, the latter plans to sail through with the clinical development of its RNA drug WVE-003. It is a first-in-class antisense oligonucleotide that selectively lowers mutant huntingtin protein by targeting a single nucleotide polymorphism (SNP3) – a kind of variation in the DNA – located on the protein’s messenger RNA (mRNA) that is not present on the wild-type huntingtin (wtHTT) mRNA. This helps block the mutant protein without disrupting normal huntingtin production.

In a phase 1b/2a study, the drug elicited a 46% decline in the levels of mutant huntingtin protein after 24 weeks. This was linked to the slowing of caudate atrophy – a condition in which the caudate nucleus, a part of the brain that controls movement, shrinks.

“Caudate is one of the primary areas where Huntington’s disease manifests in the brain, and there are clear correlations between caudate loss and clinical outcomes, giving it potential to be used to design a clinical development path to accelerated approval,” said Li-Kwai-Cheung.

This is a step up after Wave shelved two of its Huntington’s programs because of disappointing clinical trial results where the drugs did not bring about any change in mutant huntingtin levels.

This isn’t the first time a biopharma is raising hope after being beaten down. Roche called off a phase 3 trial of tominersen in 2021 after the drug was reviewed by the Independent Data Monitoring Committee. Now, Roche and its California-based partner Ionis Pharmaceuticals are testing tominersen in a phase 2 trial for patients with early manifest Huntington’s disease. 

Unlike WVE-003, tominersen is an antisense oligonucleotide designed to reduce the production of all forms of the huntingtin protein. Previously, tominersen was able to reduce the levels of toxic huntingtin proteins. 

uniQure’s AMT-130 gene therapy shows clinical success for Huntington’s disease treatment

Another promising candidate for the Huntington’s community is Netherlands-based uniQure’s AMT-130. This one-time gene therapy is carried by an AAV5 vector and is tailored to silence the huntingtin gene to inhibit the production of mutant protein. A phase 1/2 trial reaped positive results in June. In 80% of patients who received AMT-130, disease progression slowed down. Cerebrospinal fluid (CSF) neurofilament light protein (NfL) levels dropped. CSF and NfL are biomarkers of nerve damage in neurodegenerative diseases like Huntington’s and Alzheimer’s disease.

“We are very pleased with these new data demonstrating a statistically significant, dose-dependent slowing of the progression of Huntington’s disease and lowering of NfL in the CSF at 24 months,” said Walid Abi-Saab, chief medical officer of uniQure, in a press release. “We believe this is the first clinical trial of any investigational medicine for Huntington’s disease to show evidence of a potential long-term clinical benefit and reduction of a key marker of neurodegeneration. Moreover, given the one-time administration of AMT-130, we are in a unique position to continue accumulating longer-term patient outcomes from the phase 1/2 studies to support the emerging therapeutic benefit.”

The candidate has been awarded orphan drug, fast track and Regenerative Medicine Advanced Therapy designations from the U.S. Food and Drug Administration (FDA), which quicken its chances of being approved.

FDA revokes partial clinical hold on PTC drug PTC518

To add to the small pool of Huntington’s drugs to receive fast track status, PTC Therapeutics’ PTC518 bagged this designation in September. PTC518 arose from the biopharma’s splicing platform. It is an oral small molecule that enters deep into the brain to reduce mutant Huntingtin protein levels. It splices an imperfect exon called a pseudoexon when forming RNA that helps halt huntingtin production.

The drug was assigned fast track status after positive phase 2 results were reported in June. PTC518 lowered mutant protein levels by 22% and 43% with 5mg and 10mg respectively. After 12 months, patients experienced notable slowing in progression of motor symptoms. This news prompted the FDA to lift its partial clinical hold that it had slammed in 2022 upon demanding more dosage data. 

Prilenia’s Huntington’s candidate pridopidine accepted for EMA review

Meanwhile, Dutch biotech Prilenia Therapeutics’ Huntington’s candidate is en route to approval. Two weeks ago, it presented clinical data for pridopidine at the Huntington Study Group 2024 Congress in Ohio, U.S. The twice-daily pill is a sigma-1 receptor (S1R) agonist that has also been fast tracked by the FDA. Although pridopidine missed primary and secondary endpoints, according to last year’s top line data, it was later revealed that the drug was efficacious in patients who were either on low doses of chorea and anti-dopaminergic medications or not taking them at all.

Recently, it was accepted by the European Marketing Authorisation for a review, and if approved, it “could be the first treatment for Huntington’s disease with the ability to impact progression.”

“All we have to give patients right now is a small handful of options that may offer some degree of symptom control for HD-related chorea and behavioral complications,” said Ralf Reilmann, neurologist and European Principal Investigator for the pridopidine trial, in a press release. “Patients deserve better than to slowly and inexorably decline from this devastating disease, and this could be the biggest advance in therapy in years. Pridopidine could, for the first time, provide an option that may slow down decline in several functionally relevant disease domains and thus potentially offer patients and their families an extension to the quality time they have together. ”

Furthermore, there is an antibody therapy in the clinic for the treatment of Huntington’s disease. California-based Annexon Biosciences’ ANX005 targets C1q, a molecule in the complement pathway that causes neuroinflammation. The candidate blocks C1q to delay neurodegeneration. A phase 2 trial showed that ANX005 was able to do this. However, five patients dropped out of the study – three of them due to drug-related issues. This saw a plummet in stocks by 30%, in 2022.

Sage Therapeutics backs out but hope for the community remains

The therapeutic field has seen a number of ups and downs. Only yesterday, Massachusetts-based Sage Therapeutics scrapped its Huntington’s program after its allosteric modulator dalzanemdor flunked a phase 2 trial. This comes as a shock as the drug was once thought to hold promise. 

As the therapeutic sector mourns this loss, there remains cautious optimism in the Huntington’s community. With the EMA’s ongoing review of pridopidine and encouraging results for uniQure’s AMT-130, Wave’s WVE-003, and Roche’s tominersen, effective treatments seem to be on their way.

“While there have been many setbacks in the field, we only recently have had the means to target the disease at the genetic level,” said Li-Kwai-Cheung. “There have been quite a few failed studies – but these failures have provided learnings that are still moving the field forward. I truly believe that a breakthrough in Huntington’s disease will come soon – it’s important we keep pushing for the families living with Huntington’s disease.”