Just before the new year, Wave Life Sciences announced that the drug in their huntingtin lowering trial, PRECISION-HD2, had successfully lowered the concentration of mutant huntingtin protein, while healthy huntingtin was left unchanged.
Why is this so exciting?
To put it simply: if you inherit Huntington’s disease, you have one sick gene and one healthy gene. Both genes code for a protein called huntingtin. This protein is believed to play a crucial role in the progression of Huntington’s disease.
The idea is that if we are able to lower the level of huntingtin, we will be able to slow down, or perhaps even stop, the development of Huntington’s disease. We call this approach Huntingtin lowering.
However, if we look closer, the road to treatment may be a bit more nuanced and complex.
Sick & healthy huntingtin
Both the sick and healthy gene is responsible for producing huntingtin. In a person with Huntington’s disease, the overall level of huntingtin protein will consist of both: 1) sick – or mutant – huntingtin and 2) healthy – or wild-type – huntingtin.
These two groups of huntingtin make up the total level of huntingtin.
Many huntingtin lowering drugs that are currently being tested lower the total level of huntingtin. In other words, both the mutant huntingtin and the healthy huntingtin is being reduced. This is for instance the case with Roche’s huntingtin lowering drug RG6042 – now known as tominersen.
The distinction between sick and healthy huntingtin is what makes Wave’s approach so unique.
Learn more: Unpacking Wave’s PRECISION-HD2 announcement
Instead of lowering the total level, Wave only targets the concentration of mutant huntingtin. Why is this distinction important?
The mysterious huntingtin (?)
Well, we don’t know exactly how huntingtin works. Maybe the protein has an important function that we are not yet aware of?
Keeping the healthy protein intact – the one that is produced by the healthy gene – might therefore be important in the long-term.
And that is why Wave believe it is important to only target the mutant huntingtin while leaving the healthy huntingtin unchanged.
The results of PRECISION HD2 showed that Wave was able to reduce mutant huntingtin and leave healthy huntingtin unchanged.
The reduction of mutant huntingtin was 12 % – a relatively modest reduction. However, Wave expect the lowering to be dose-dependent: a higher dose, a bigger reduction of mutant huntingtin.
That is why Wave doubled the dose – from 16 milligrams per injection to 32 milligrams.
In the end of 2020, the company will have the results of whether this increase in dose had a larger effect on the level of mutant huntingtin.
Huntingtin lowering = treatment?
No drug has yet been shown to slow progression of Huntington’s disease. In other words, we are still not sure how lowering the level of huntingtin will impact Huntington’s disease – or even if it will affect disease progression at all.
With that being said, an exploratory analysis showed that huntingtin lowering correlated with improved symptoms after 3 months of treatment – which is very promising.
The last drug development step is therefore to study whether there is a link between huntingtin lowering and disease progression (known as “clinical effect”).