Readouts approach for biggest Huntington’s hopes

Upcoming data from Roche/Ionis and Wave Life Sciences will be an important test of potentially disease-modifying candidates.

The prospects for patients with the inherited neurodegenerative condition Huntington’s disease are poor. There is no cure and sufferers typically die within a couple of decades of developing symptoms.

So it is no wonder that the progress of potentially disease-modifying antisense projects is being watched with excitement. Data this year should give a better idea of whether Roche/Ionis’s RG6042 and Wave Life Sciences’ WVE-120101 and WVE-120102 could stop or slow the progression of Huntington’s.


In Huntington’s disease, a mutation in the gene coding for the huntingtin (HTT) protein leads to the production of a toxic version of HTT which clumps together and accumulates in neurons, eventually killing them. All three of the above candidates, which are administered intrathecally, are designed to bind to HTT mRNA and suppress production of the protein.

RG6042, also known as IONIS-HTTrx, takes aim at all HTT mRNA. WVE-120101 and WVE-120102, by contrast, selectively target the mutant form, but not the wild type, the theory being that by knocking out only the mutant HTT protein they could combat the cause of Huntington’s while leaving healthy HTT protein intact.

Wild-type HTT protein is thought to have several important roles in the brain, so this feature could give WVE-120101 and WVE-120102 a safety advantage over RG6042, Wave believes.

But RG6042 is further ahead, having entered a phase III trial earlier this year. Data from the pivotal study, Generation-HD1, are not due for a couple of years, and could be even further away after Roche recently changed the protocol to include dosing every four months, necessitating a three-month pause in enrolment.

However, Roche plans to file the project with regulators by early 2020, likely basing the submission on results from an open-label extension study due this year, as well as on interim biomarker data from Generation-HD1 and results from a natural history study, Leerink analysts believe. RG6042 could therefore be approved by the end of next year if all goes well.

The open-label extension study will be crucial to confirm results seen in an earlier phase I/II trial; all 46 patients rolled over into the extension phase, which is measuring certain functional endpoints, as well as collecting safety data and biomarker information. A definitive link between reduction in mutant HTT protein and symptoms has yet to be proven, although Ionis presented a post-hoc analysis of the phase I/II trial that suggested a correlation.

That study detected a significant reduction in mHTT of 40-60% in the cerebrospinal fluid; this, according to Ionis, corresponds to a 55-85% reduction in the brain. A maximum reduction of mHTT was predicted to occur at approximately six months after the first dose, something the extension study could also help confirm.

On a Wave?

The first half of the year will also see data from placebo-controlled phase I/II trials of Wave Life Sciences’ stereopure antisense Huntington’s candidates WVE-120101 and WVE-120102. These assets target different single nucleotide polymorphisms (SNPs) on the mutant huntingtin gene: rs362307 (SNP1) and rs362331 (SNP2) respectively. Around 70% of Huntington’s patients carry SNP1, SNP2 or both, according to Wave.

The two studies, which are taking place in Canada, Poland and the UK, have enrolled around 50 patients with early or intermediate-stage Huntington’s who have screened positively for the target SNP.

The Precision-HD trials are primarily measuring safety, but Wave is also expected to release data on levels of both mutant and normal HTT protein. The studies are also looking at clinical endpoints including change in the Unified Huntington’s disease rating scale.

Success in the Precision-HD trials would help validate Wave’s overall approach, and could also spur interest from Takeda. The Japanese group has an option to co-develop and co-commercialise WVE-120101 and WVE-120102 – as well as several other Wave candidates – once they have shown proof of mechanism.

If all goes to plan Wave could get US approval for WVE-120101 and WVE-120102 in 2021, Leerink analysts estimate. With around 60,000 Huntington’s patients in the US and Europe, and few other therapeutic options, the market should be big enough to accommodate both products.   

But Wave is still at a disadvantage, being smaller and a year or so behind. And it still needs to show that its more selective approach holds water.

Antisense Huntington's projects 
Project Company/ies Study Trial ID 2024e sales ($m)
RG6042/IONIS -HTTrx Roche/Ionis Generation-HD NCT03761849 372
RG6042/IONIS -HTTrx Roche/Ionis Phase I/II  NCT02519036  
RG6042/IONIS -HTTrx Roche/Ionis Open-label extension NCT03342053  
WVE-120101 Wave Life Sciences Precision-HD1 NCT03225833  288
WVE-120102  Wave Life Sciences Precision-HD2 NCT03225846 216
Source: EvaluatePharma,

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