Wave Life Sciences: setback for Huntington’s disease trials

30. March 2021. Yesterday, Wave Life Sciences gave an update on PRECISION-HD1 and PRECISION-HD2. Due to disappointing results, the biotechnology company has decided to stop the two Huntington’s disease trials. However, they will continue the development of a third drug candidate. 

The decision to stop the PRECISION-HD trials is not related to the stopped dosing of Tominersen in Roche’s Huntington’s disease trial announced last week.

Stopping Trials

For the last years, Wave has been developing two drug candidates: WVE-120101 and WVE-120102. They have been studied since 2017 and now the final trial results have been analysed: there were no significant change in mutant huntingtin protein in adults with Huntington’s disease. 

This was both the case for WVE-120101 and WVE-120102.

Wave Life Sciences has therefore decided to stop the development of the two drug candidates. In a recently issued press release to the Huntington community, the company states that: 

– After reviewing data from the PRECISION-HD2 trial, we have made the difficult decision to discontinue development of WVE-120102. Complete data from the PRECISION-HD1 trial are not yet available, but the data we have reviewed to date are similar to those in the PRECISION-HD2 trial, and we will also discontinue development of WVE-120101.  

Background

In order to only lower the level of mutant huntingtin, Wave’s two drug candidates were targeting different SNPs (single-nucleotide polymorphism) in the gene. In the PRECISION-HD trials, WVE-120101 and WVE-120102 were targeting SNP1 and SNP2 respectively. These SNPs were used to steer the drug to the mutant huntingtin.

In the beginning, the drug candidates seemed promising with early results indicating that the drugs had lowered mutant huntingtin. However, the final results show that this lowering was not significant – in other words it did not differ from people who received a placebo drug. 

WVE-003: New Drug Candidate

Despite the setbacks in the PRECISION-HD trials, Wave Life Sciences will continue to develop a third drug candidate: WVE-003.

By incorporating novel chemical modifications, WVE-003 is designed differently from the other two drug candidates, WVE-120102 and WVE-120101. 

Wave announces that: – The promising preclinical data we have seen thus far with WVE-003 give us confidence in this novel program.

The company is expecting to start in-human trials with WVE-003 in 2021.

Disappointing 

– I have to say that I’m really disappointed with the trial results, says Astri Arnesen, president of the European Huntington Association. 

Astri Arnesen is disappointed: – I have to say that I’m really disappointed with the trial results.

Arnesen also thinks that the timing makes the news even harder to digest: – Last Monday we were told that Roche’s GENERATION HD would stop dosing participants with Tominersen and now there are two more trials stopping. 

– Have you lost all hope?

– No, I have not.  Despite these two big setbacks I have high hopes for the future.  We learn from everything that has been done so far and there are still a lot of questions that needs to find answers. Fortunately, there are also many other drugs with other methodologies and targets in the pipeline. 

Learn more about ongoing drug development in Huntington’s disease here.

What’s Next?

Important questions to answer in regard to treatment in Huntington’s disease are many. One of them are for instance when treatment should start. Should we be trying to treat those of us with Huntington’s disease earlier? Perhaps even before we can see visible symptoms? 

Despite the recent setbacks in both Roche’s and Wave’s trials, the trials might provide key information that will enable researchers to develop drug candidates in the future. For instance, we know from the Roche trial that we are actually able to lower huntingtin, at least in the spinal fluid where we can measure it.

Several efforts are ongoing that ultimately will enable us to measure levels of mutant Huntingtin in the brain. This is a key to understand whether the drug gets to the brain areas where its most needed and whether the levels are reduced in the different parts of the brain.   

Moreover, huntingtin lowering is not the only avenue in targeting Huntington’s disease. Another approach – which is currently a hot topic in the Huntington community – is DNA damage repair. 

Here, the CAG repeat expansion in the huntingtin gene is targeted. Learn more here.