The Huntington's disease (HD) community is experiencing renewed optimism following encouraging results from recent clinical trials, marking a significant shift after previous setbacks in the search for effective treatments. These developments offer hope for disease-modifying therapies that could alter the course of this devastating neurodegenerative disorder.
Setbacks and New Directions
The HD research field faced a challenging period when Roche halted the phase 3 trial of tominersen, an antisense oligonucleotide (ASO), due to worsening HD symptoms. Simultaneously, Wave Life Sciences' ASOs, WVE-120102 and WVE-120101, showed no benefits in a phase 1/2 trial, leading to their discontinuation. These failures were a major blow to the HD community, prompting a re-evaluation of therapeutic strategies.
However, these setbacks have spurred innovation and a deeper understanding of HD. Post-hoc analyses of the tominersen trial suggested potential benefits in younger patients with less disease burden, leading to the ongoing phase 2 dose-finding trial, GENERATION HD2. Furthermore, the HD research landscape has expanded, with approximately 50 companies now engaged in developing novel treatments.
Promising Therapeutic Advances
uniQure's phase 1/2 gene therapy, AMT-130, has shown significant promise, slowing disease progression by 80% on the composite Unified Huntington's Disease Rating Scale (cUHDRS). The FDA has granted AMT-130 Regenerative Medicine Advanced Therapy designation, highlighting its potential to address unmet needs in HD treatment. AMT-130 is administered directly into the basal ganglia.
Wave Life Sciences is also advancing with WVE-003, a different ASO that selectively targets the mutant huntingtin gene. A phase 1b/2a trial demonstrated a statistically significant 46% reduction in mutant huntingtin (HTT) protein compared to placebo. These results have prompted the company to pursue accelerated approval from the FDA. The 28-week study showed that even eight weeks after the last dose, levels of the mutant protein were 44 percent lower than placebo (p=0.0002), suggesting that quarterly or less-frequent dosing could be possible.
Novel Therapeutic Approaches
Beyond ASOs and gene therapy, researchers are exploring diverse strategies to combat HD. PTC Therapeutics is developing PTC-518, an oral drug targeting non-allele specific mutant HTT protein lowering. Interim analyses have shown dose-dependent lowering of the HTT protein in peripheral blood cells, with a mean 30% reduction in mutant HTT levels. A global phase 3 pivotal trial is anticipated to commence soon.
Skyhawk Therapeutics is pursuing an RNA-targeting small molecule, SKY-015, to reduce the number of CAG repeats in the mutant allele. Phase 1 trial results presented at the European Huntington's Disease Network meeting in September showed a 72% reduction in huntingtin mRNA levels. SKY-015 is administered orally as a daily pill.
Other approaches under investigation include CRISPR-based genome editing, led by Dr. Blair Leavitt at Incisive Genetics, and neural progenitor transplantation, based on research from the University of Milan. These innovative strategies aim to correct the genetic defect or counteract the effects of HD at a cellular level.
The Importance of Continued Research
The progress in HD research is encouraging, but it is crucial to acknowledge the challenges that remain. Clinical trials are essential to validate the efficacy and safety of new therapies. As Dr. Ralf Reilmann notes, results seen in small subject numbers need to be confirmed in larger trials. The HD research community remains committed to pursuing a multimodal approach to treating HD, combining different therapeutic strategies to achieve optimal outcomes for patients.
