Alnylam Pharmaceuticals has dosed the first participant in a Phase 1 clinical trial of ALN-HTT02, a novel RNA interference (RNAi) therapeutic for Huntington's disease (HD). The trial, which began in December 2024, represents a significant step forward in the development of disease-modifying treatments for this devastating neurodegenerative disorder.
The Phase 1 trial (NCT06585449) is designed to evaluate the safety, tolerability, and pharmacokinetics of a single dose of ALN-HTT02 administered via spinal injection. The study aims to enroll up to 54 individuals with Stage 2 or early Stage 3 HD, aged 25 to 70. Recruitment is currently underway at sites in the UK, with plans to expand to Canada and additional countries. A portion of participants will receive a placebo, with those initially receiving the placebo having the option to receive ALN-HTT02 after 12 months.
Targeting the Root Cause of Huntington's Disease
Huntington's disease is a genetic disorder caused by a mutation in the huntingtin (HTT) gene, leading to the production of a toxic huntingtin protein that accumulates in the brain. This accumulation results in progressive motor, cognitive, and psychiatric symptoms. Current treatments for HD are primarily symptomatic, addressing the various manifestations of the disease but not its underlying cause. ALN-HTT02 aims to directly address the genetic malfunction causing the disease.
ALN-HTT02 is designed to target exon 1 of the HTT gene, the region believed to be central to the toxic effects observed in Huntington's disease. By using RNA interference (RNAi), ALN-HTT02 leverages the cell's natural machinery to degrade the HTT messenger RNA (mRNA), thus reducing the production of the harmful huntingtin protein. This approach differs from other HTT-lowering strategies, such as antisense oligonucleotides (ASOs) and splice modulators, which employ different mechanisms to reduce HTT levels.
RNAi Mechanism
RNAi works by introducing a synthetic piece of genetic material that contains part of the code for HTT. Once introduced to a cell, the cell’s own molecular machines are used to process the synthetic genetic material. This creates a fragment of the synthetic genetic material that binds to the HTT message to lower it.
Trial Design and Endpoints
The primary endpoint of the Phase 1 trial is safety and tolerability. Researchers will also assess the drug's ability to lower HTT levels in the cerebrospinal fluid (CSF), the fluid that bathes the brain and spinal cord. While clinical tests to measure symptoms will be conducted, a larger trial with different measures would be needed to understand if ALN-HTT02 works to change clinical features of HD.
The Broader Landscape of HD Therapeutics
Alnylam is not alone in the pursuit of HTT-lowering therapies. Other companies, such as Wave Life Sciences, Vico Therapeutics, Roche, PTC Therapeutics, Skyhawk Therapeutics and uniQure, are also developing drugs that target HTT using various approaches. These include ASOs, splice modulators, and viral-delivered RNAi. Each approach has its own advantages and challenges in terms of delivery, specificity, and potential side effects.
Professor Sarah Tabrizi, Director of the Huntington's Disease Centre, expressed enthusiasm for the trial, highlighting the significance of targeting exon 1 of the HTT gene. The trial involves approximately 54 individuals, who will be divided to receive either the drug or placebo, enabling researchers to analyze its safety and efficacy comprehensively. Notably, participants who initially receive the placebo will have the option to receive the actual treatment at a later stage.
With approximately 7,000 individuals living with Huntington's disease in the UK alone, the stakes are high. This condition is inherited, with each child of an affected parent having a 50% chance of inheriting the gene mutation. Currently, patients experience symptoms like depression, difficulty moving, and significant cognitive decline. With no curative treatments available, the testing of ALN-HTT02 is particularly significant for affected families.
Hope for the Future
The initiation of the ALN-HTT02 Phase 1 trial represents a significant milestone in the fight against Huntington's disease. While the trial is primarily focused on safety and tolerability, it also provides an opportunity to assess the drug's ability to lower HTT levels in humans. If successful, ALN-HTT02 could potentially slow or halt the progression of HD, offering hope for a better future for individuals and families affected by this devastating disease.
