Professor Hugh Rickards talks about the findings from the Generation HD1 trial
Update on the tominersen trials by Professor Hugh Rickards, Chair of the Huntington's Disease Association
Last week, the pharmaceutical company, Roche, gave a series of talks outlining the results of their tests on their drug, tominersen. Tominersen is a drug that is given into the spinal fluid. It gets into the brain and reduces the amount of huntingtin protein. An initial trial published in 2019 showed how this drug could reliably reduce the amount of huntingtin protein in the brain in a 'dose-dependent' way (the more you give, the more the huntingtin protein gets reduced). Because this initial trial was so promising, Roche then started a series of trials to find out if this actually resulted in improvements for people with Huntington's disease.
The most important of these trials was GENERATION HD1. This trial compared giving the drug every two months with giving it every four months or a placebo. A placebo is to have something to compare our treatment to. They also don't want either patients or researchers to know which group they are in so have to find a way of doing nothing but looking exactly the same as giving treatment. That's why we have placebo groups. We still don't know if tominersen is any better than doing nothing (in fact, in most cases it looks like it's worse) so we need to compare those getting tominersen to those getting nothing.
In March 2021, GENERATION HD1 was halted suddenly by an independent monitoring committee as it looked like the people getting tominersen were actually appearing to be deteriorating quicker than those who were taking the placebo. Between then and now, Roche has been collecting and analysing the data to try and understand what happened.
This is what I understood from the talks:
- Tominersen can still lower huntingtin protein The huntingtin protein (Htt) still remained pretty low throughout the GENERATION HD1 trial (and in an associated study, GEN EXTEND). This is encouraging as we now know that we can reduce Htt reliably over a long period of time.
- Most people on the two-monthly dose did worse than those taking placebo In general, those people taking the treatment every two months (rather than every four months) did worse than those taking placebo. Roche tried to look at subgroups of people taking the drug every two months with the idea that some subgroups might do better than others, but this wasn’t the case. We still don’t know why people were not doing well in this group even though we were able to reduce their Htt. There are a couple of ideas about why this might be the case. One possibility is that Htt was reduced too much (it’s possible that Htt does some useful things in the body as well as the things that give you Huntington's). The other possibility is that the treatment is having some toxic effects as well as some good effects. This is a common effect of drugs (think of the toxic effects of some cancer treatments).
- In the four-monthly dosing group, a subgroup of younger, less ill patients might have done better than those on placebo This finding has to be viewed with extreme caution. This was shown as a result of 'post-hoc' analysis. This means that the idea to split up the data into subgroups for analysis came after all the data were collected. There are a number of reasons why this method might show false-positive results (results that look more positive than they actually are and which disappear when you try and replicate them). In the end, the group of people in the 'younger, less ill' group was quite small, and nothing large enough to prove an effect. Nonetheless, this group showed a trend that was better than the older, more ill group. I guess one obvious explanation is that younger, healthier brains might be less prone to suffering the bad effects of the treatment, whilst still benefitting from its good effects. Because this group has shown some sign of doing better, Roche wants to pursue this with another trial with younger, less ill people.
- Some worrying signals were present in all groups. One way of measuring the effect of tominersen is to measure the size of cerebral ventricles using MRI scanning. Cerebral ventricles are fluid-filled spaces in the middle of the brain. In most cases, if the ventricles increase in size, this usually means that the brain is getting smaller and is viewed as a bad thing. It’s clear from the scanning data that ventricle size in all the sub-groups continued to increase over the course of the study (when compared to placebo). At the moment there is no clear explanation for this finding. Given that a drug like tominersen would have to be given over years and decades, we really need to understand what is causing the ventricles to expand.
Where does that leave us?
On the positive side, we can now reliably reduce Htt in the brains of people with Huntington's disease, as well as lots of different animal models. At last count, 24 different pharmaceutical and biotech companies had an interest in this area with at least six products in the pipeline. This is a huge step forward. We had a leader in this race, tominersen, which has now slipped back into the chasing pack of products. It’s still in the race though.
Finally, it’s a good time to recognise the bravery and dedication of those people who have been participants in the trials so far. As we’ve seen, trials are a huge personal risk, and the participants have willingly put their bodies on the line for the overall benefit of the Huntington's community and for future generations. They are the unsung heroes and heroines of the story.
You can find out more about getting involved in research here.
If you are affected by Huntington’s disease and need support or advice, please contact us on 0151 331 5444 or email [email protected].
Update on the tominersen trials by Professor Hugh Rickards, Chair of the Huntington's Disease Association
Last week, the pharmaceutical company, Roche, gave a series of talks outlining the results of their tests on their drug, tominersen. Tominersen is a drug that is given into the spinal fluid. It gets into the brain and reduces the amount of huntingtin protein. An initial trial published in 2019 showed how this drug could reliably reduce the amount of huntingtin protein in the brain in a 'dose-dependent' way (the more you give, the more the huntingtin protein gets reduced). Because this initial trial was so promising, Roche then started a series of trials to find out if this actually resulted in improvements for people with Huntington's disease.
The most important of these trials was GENERATION HD1. This trial compared giving the drug every two months with giving it every four months or a placebo. A placebo is to have something to compare our treatment to. They also don't want either patients or researchers to know which group they are in so have to find a way of doing nothing but looking exactly the same as giving treatment. That's why we have placebo groups. We still don't know if tominersen is any better than doing nothing (in fact, in most cases it looks like it's worse) so we need to compare those getting tominersen to those getting nothing.
In March 2021, GENERATION HD1 was halted suddenly by an independent monitoring committee as it looked like the people getting tominersen were actually appearing to be deteriorating quicker than those who were taking the placebo. Between then and now, Roche has been collecting and analysing the data to try and understand what happened.
This is what I understood from the talks:
- Tominersen can still lower huntingtin protein The huntingtin protein (Htt) still remained pretty low throughout the GENERATION HD1 trial (and in an associated study, GEN EXTEND). This is encouraging as we now know that we can reduce Htt reliably over a long period of time.
- Most people on the two-monthly dose did worse than those taking placebo In general, those people taking the treatment every two months (rather than every four months) did worse than those taking placebo. Roche tried to look at subgroups of people taking the drug every two months with the idea that some subgroups might do better than others, but this wasn’t the case. We still don’t know why people were not doing well in this group even though we were able to reduce their Htt. There are a couple of ideas about why this might be the case. One possibility is that Htt was reduced too much (it’s possible that Htt does some useful things in the body as well as the things that give you Huntington's). The other possibility is that the treatment is having some toxic effects as well as some good effects. This is a common effect of drugs (think of the toxic effects of some cancer treatments).
- In the four-monthly dosing group, a subgroup of younger, less ill patients might have done better than those on placebo This finding has to be viewed with extreme caution. This was shown as a result of 'post-hoc' analysis. This means that the idea to split up the data into subgroups for analysis came after all the data were collected. There are a number of reasons why this method might show false-positive results (results that look more positive than they actually are and which disappear when you try and replicate them). In the end, the group of people in the 'younger, less ill' group was quite small, and nothing large enough to prove an effect. Nonetheless, this group showed a trend that was better than the older, more ill group. I guess one obvious explanation is that younger, healthier brains might be less prone to suffering the bad effects of the treatment, whilst still benefitting from its good effects. Because this group has shown some sign of doing better, Roche wants to pursue this with another trial with younger, less ill people.
- Some worrying signals were present in all groups. One way of measuring the effect of tominersen is to measure the size of cerebral ventricles using MRI scanning. Cerebral ventricles are fluid-filled spaces in the middle of the brain. In most cases, if the ventricles increase in size, this usually means that the brain is getting smaller and is viewed as a bad thing. It’s clear from the scanning data that ventricle size in all the sub-groups continued to increase over the course of the study (when compared to placebo). At the moment there is no clear explanation for this finding. Given that a drug like tominersen would have to be given over years and decades, we really need to understand what is causing the ventricles to expand.
Where does that leave us?
On the positive side, we can now reliably reduce Htt in the brains of people with Huntington's disease, as well as lots of different animal models. At last count, 24 different pharmaceutical and biotech companies had an interest in this area with at least six products in the pipeline. This is a huge step forward. We had a leader in this race, tominersen, which has now slipped back into the chasing pack of products. It’s still in the race though.
Finally, it’s a good time to recognise the bravery and dedication of those people who have been participants in the trials so far. As we’ve seen, trials are a huge personal risk, and the participants have willingly put their bodies on the line for the overall benefit of the Huntington's community and for future generations. They are the unsung heroes and heroines of the story.
You can find out more about getting involved in research here.
If you are affected by Huntington’s disease and need support or advice, please contact us on 0151 331 5444 or email [email protected].