First participants dosed in new POINT-HD huntingtin-lowering trial

A new Huntington’s disease (HD) clinical trial has reached an important milestone: the first participants have now been dosed in POINT-HD, a Phase 1 study testing a new, selective huntingtin-lowering drug. RG6496 is designed to only lower levels of the expanded form of huntingtin (HTT), preserving levels of regular HTT. This exciting new milestone is only possible because of the courage and generosity of participants and their families, who are helping to move HD research forward for everyone. Let’s get into this new trial and what drug they are testing. 

HD Biology 101 

Before we dive into the details of this clinical trial, a quick recap on some HD biology fundamentals. Every person has two copies of the HTT gene, one from their mum and one from their dad. 

In people with HD, one of these copies contains an expanded stretch of DNA that leads to production of a faulty, “expanded” HTT protein, while the other copy makes the healthy, or regular unexpanded, HTT protein. Both copies of the gene are active, so people with HD typically produce both regular and expanded HTT throughout their lives. 

Because HD is inherited in a dominant way, having just one expanded copy is enough to cause the disease, and each child of an affected parent has a 50% chance of inheriting the expanded gene.

What is POINT-HD?

POINT-HD is a Phase 1 clinical trial sponsored by the company Roche. The study is testing an investigational drug called RG6496, which they developed in partnership with Ionis Pharmaceuticals. This drug is designed to only lower levels of the faulty, expanded HTT protein that causes HD, while leaving the regular protein intact.

Phase 1 trials are primarily focussed on safety. This is the first time RG6496 is being tested in people, so the main goals are to understand how safe it is, how it behaves in the body, and how people tolerate it. Researchers will also measure levels of expanded HTT protein in spinal fluid, which can help guide future studies.

POINT-HD is separate from Roche’s other HD trials, including the ongoing Phase 2 GENERATION-HD2 study of tominersen and a Phase 1 gene therapy study they are working on with Spark Therapeutics. Both of these other trials seek to lower total HTT levels – both the regular and expanded proteins. 

A selective approach to lowering HTT

RG6496 belongs to a class of drugs called antisense oligonucleotides, or ASOs. This ASO targets the HTT message molecules, which are the copies made of the HTT gene by the cells’ machinery that encode the instructions to make the HTT protein. Like other ASOs in HD research, it is given by lumbar puncture, also known as spinal tap, into the fluid that bathes the brain and spinal cord.

What makes RG6496 different from tominersen, the other ASO the company has developed, is that it is designed to be selective. Rather than lowering HTT protein levels from both copies of the gene, sometimes referred to as total HTT, it aims to reduce only the expanded version, while sparing the healthy HTT protein.

The drug does this by targeting a tiny genetic difference, called a single nucleotide polymorphism (known as a SNP, pronounced “snip”), that sits on the expanded HTT gene in some people with HD. This “genetic signpost” allows the drug to distinguish between the faulty and healthy gene copies.

Based on large genetic datasets, including Roche’s global HD epidemiology work, around 40% of people with HD are thought to carry this particular SNP on their expanded HTT gene. Only people who carry this genetic marker are eligible to potentially receive RG6496.

While having a limiter on this clinical trial might seem discouraging, this study aims to test the proof-of-concept for this approach. If it works, Roche could then work to identify other SNPs that can be targeted for the remaining 60% of the population with HD. If successful, the end goal will be to treat as many people with HD as possible!

Who can take part in this trial?

POINT-HD plans to enroll 40 adults aged 25 to 65 who have early or mild HD symptoms and meet additional study criteria. Before becoming enrolled participants, volunteers are screened to see whether they carry the target SNP required for the drug to work.

The study has two parts and will last around two years in total:

Part 1 will last about seven months and is placebo-controlled. Participants are randomly assigned to receive either a single dose of RG6496 or a placebo, with three out of four participants receiving the study drug.

Part 2 is an open-label extension lasting about 13 months, in which all participants receive RG6496.

Participants will attend regular clinic visits and complete some digital tasks on a study-provided smartphone. 

Where is the study running?

POINT-HD has kicked off with study sites in New Zealand and Australia, where the first participants have now been dosed. These countries are attractive places for many companies to start early-stage clinical trials as they have fast regulatory and ethics approvals, as well as strong clinical infrastructure with lots of tax incentives for companies to work there. Together with high participant engagement and efficient trial systems, this allows studies to start quickly, and hopefully generate high-quality data, all to help accelerate drug development.

The study is also expected to open soon in Argentina, with additional countries and sites to follow once regulatory and ethics approvals are in place. Details about participating sites will be posted on public trial registries such as ClinicalTrials.gov and on Roche’s ForPatients website as the study expands.

A thank you to participants

Every clinical trial begins with people who are willing to be first. Phase 1 participants, in particular, step into the unknown so that researchers can learn whether a new idea is safe enough to pursue further.

The start of dosing in POINT-HD is a moment to recognise those individuals and families, as well as the HD patient organisations and advisors who helped shape the study. Their involvement ensures that trials are not only scientifically sound, but also as respectful and practical as possible for the people taking part.

POINT-HD is still at a very early stage, and much more research will be needed before anyone knows whether RG6496 could one day become a treatment. But each new study adds another piece to the puzzle, and another reason for cautious optimism as HD research continues to move forward.

Summary

• A new Phase 1 Huntington’s disease trial has begun dosing, testing RG6496, a first-in-human, selective HTT-lowering drug.
• RG6496 is designed to lower only the disease-causing, expanded HTT protein, while preserving the regular protein that is important for healthy cells.
• The drug targets a specific genetic marker found in about 40% of people with HD.
• POINT-HD is primarily focused on safety, tolerability, and how the drug behaves in the body, while also measuring levels of expanded HTT in spinal fluid to guide future research.

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