The Huntington's disease therapeutic landscape is experiencing a mix of promising advancements and disappointing setbacks, as companies strive to address this rare and devastating genetic condition. Recent clinical data and regulatory milestones offer hope, while trial failures underscore the challenges inherent in developing effective treatments.
Huntington's disease, characterized by the progressive degeneration of nerve cells in the brain, results from a mutation in the HTT gene. This mutation leads to the production of a faulty huntingtin protein, causing a range of motor, cognitive, and psychiatric symptoms. With a prevalence of approximately 1 in 10,000 to 20,000 individuals in the U.S., Huntington's disease presents a significant unmet medical need.
Antisense Oligonucleotide Approaches
Wave Life Sciences is progressing with the clinical development of WVE-003, an antisense oligonucleotide designed to selectively lower mutant huntingtin protein levels. In a Phase 1b/2a study, WVE-003 demonstrated a 46% reduction in mutant huntingtin protein levels after 24 weeks, correlating with a slowing of caudate atrophy. "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," said Anne-Marie Li-Kwai-Cheung, chief development officer of Wave Life Sciences.
Roche, in partnership with Ionis Pharmaceuticals, is also testing tominersen, another antisense oligonucleotide, in a Phase 2 trial for early manifest Huntington's disease. Tominersen aims to reduce the production of all forms of the huntingtin protein.
Gene Therapy Advancements
uniQure's AMT-130, a one-time gene therapy utilizing an AAV5 vector, has shown positive results in a Phase 1/2 trial. The therapy is designed to silence the huntingtin gene, inhibiting the production of the mutant protein. Interim data revealed that AMT-130 slowed disease progression in 80% of patients, accompanied by a reduction in cerebrospinal fluid neurofilament light protein (NfL) levels, a biomarker of nerve damage. "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," stated Walid Abi-Saab, chief medical officer of uniQure.
AMT-130 has received orphan drug, fast track, and Regenerative Medicine Advanced Therapy designations from the FDA.
Small Molecule Intervention
PTC Therapeutics' PTC518, an oral small molecule, has also garnered attention, receiving FDA fast track designation. PTC518 works by modulating RNA splicing to reduce mutant huntingtin protein levels. Phase 2 results demonstrated reductions of 22% and 43% in mutant protein levels with 5mg and 10mg doses, respectively, along with a slowing of motor symptom progression after 12 months. These findings led the FDA to lift a partial clinical hold on the drug.
Regulatory Progress for Pridopidine
Prilenia Therapeutics' pridopidine, a sigma-1 receptor (S1R) agonist, is under review by the European Marketing Authorisation. While pridopidine missed its primary and secondary endpoints in initial data, subsequent analysis indicated efficacy in patients not taking chorea and anti-dopaminergic medications. If approved, pridopidine "could be the first treatment for Huntington’s disease with the ability to impact progression," according to a press release from the company.
Antibody Therapy and Other Approaches
Annexon Biosciences is developing ANX005, an antibody therapy targeting C1q, a molecule involved in neuroinflammation. A Phase 2 trial showed that ANX005 could delay neurodegeneration, although patient dropouts impacted the study.
Recent Setbacks
Despite these advancements, the field has also experienced recent setbacks. Sage Therapeutics recently discontinued its Huntington's program after its allosteric modulator, dalzanemdor, failed in a Phase 2 trial.
Despite the challenges, the Huntington's disease therapeutic field remains cautiously optimistic. "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."
