Ed Wild of University College London is a leading scientist and the international coordinator (with Sarah Tabrizi) in a very promising trial using antisense oligonucleotide technology in Huntington patients. This is the interview he gave me before attending the Huntington’s Days 2018 meeting in Turin, Italy.
You are testing a candidate drug that could be the most significant breakthrough in Huntington’s disease since the discovery of the HD gene. What’s so exciting and unprecedented?
EW: HTTRx (now called RG6042 since Roche took over its development) is the first drug ever given to Huntington’s disease patients that targets the known cause of the disease – the mutant huntingtin protein. Designed by Ionis Pharmaceuticals, the drug is an antisense oligonucleotide (ASO) – a modified DNA molecule that tells cells to make less of the huntingtin protein. In theory, preventing formation of mutant huntingtin protein should treat all aspects of the disease and even delay the onset of the disease if given early enough. The first priority for this trial was safety – to test whether the drug could be given safely and did not produce any untoward side effects. On that crucially important outcome, it performed remarkably well – there were no serious adverse events in people given the drug, and 100% of patients completed the full course of four injections. Where the trial exceeded our expectations was when we measured the level of mutant huntingtin protein in the spinal fluid, which is a reflection of the level in the brain. In patients receiving the highest doses, the level was reduced by as much as 40 to 60%, which is a degree of reduction we would expect to produce clinical benefit, based on work done in HD animal models. This is the first time ever that an ASO drug has successfully reached the central nervous system and lowered the level of a protein known to cause a neurodegenerative disease. I think that’s why there was such excitement about the announcement: for HD, we’ve shown for the first time that we can successfully engage with the harmful protein; for the broader neurodegeneration field, ASO drugs offer a “clean”, targeted way to alter the level of many disease-causing proteins– and to do so, in theory, before the proteins build up and cause damage.
This is an huntingtin-lowering treatment, and I understand it is reversible. Do you think RNA silencing is a better strategy than correcting the gene?
EW: Yes, ASO therapy is reversible. In the trial, we dosed patients monthly, and if any untoward side effects had emerged, we could have stopped dosing and the effects of the drug would be expected to wear off on their own. We can find out the long-term effects by continuing to give doses regularly. There is certainly an appeal to the idea of receiving a single dose of a huntingtin-lowering agent that persists indefinitely – but I would want to be 100% certain what the very long-term effects of huntingtin lowering are before volunteering for an irreversible treatment like that. Several strategies including virally-delivered RNA interference drugs, are being worked on that would behave like that, but the ASO approach is much further ahead and is a really good way to test whether huntingtin lowering is safe and effective.
The trial began in 2015, where are we now?
EW: The first doses were given in September 2015. The results were as above – the drug was admirably safe and well-tolerated, and we saw dose-dependent lowering of mutant huntingtin of up to 40-60% in the highest dose groups. There were no clinical improvements in any group, which is exactly what we expected from a very short 4-month treatment period in a very slowly progressive disease. On several clinical measures, we saw an encouraging relationship between the degree of huntingtin lowering and the clinical change during the trial, but that is not evidence of clinical efficacy – it perhaps gives us optimism that things may move in the right direction clinically, if we continue treatment for long enough. All 46 of the brave volunteers who took part in the phase 1/2 trial have been invited to participate in an open-label extension study which is now well underway. Everyone in that study will receive regular injections, at doses we believe will be therapeutic. This will give us important information about the effects of longer-term treatment.
What about the phase 3 trial? Ionis trial for spinal muscular atrophy (SMA) did so well that regulators asked them to halt the trial early. How long do you think you have to wait before knowing if HTTRx works well enough?
EW: Intensive planning is well underway for the next trial which will test whether the drug slows progression of HD, in a large number of patients. We expect an announcement in the coming months about the details of the trial which have not yet been finalised. I hope that the trial will start enrolling patients in late 2018 or early 2019. We don’t yet have any information about what countries will be involved, or how many patients, but it will certainly be a much larger, longer trial involving multiple countries. The SMA trial halted early because of unexpectedly good efficacy. Huntington’s progresses more slowly, so an outcome like that is perhaps less likely, and Roche and its partners will design the trial to give the best chance of success. There are too many variables at the moment to be sure of when we will know for sure whether the drug works, but I’d advise the community to brace themselves for a wait of at least five years – and to try to take comfort from knowing that things are going very well and moving as quickly as possible.
What do you expect from CRISPR in your field? Would you support HD germline editing?
EW: Genome editing using CRISPR or other technologies offers great promise for treating many diseases and Huntington’s is a prime example since it is caused by the same basic mutation in all cases. It will take a lot of work to establish whether this can be done safely in humans, plus we will have to conquer the huge problem of delivering a protein-based therapeutic to the whole human brain. But the potential is so huge that it is important we work to overcome these challenges. I see no reason why, if we can safely do so, we should not allow people to delete the mutation from every cell in their bodies, including the germline to free future generations from the suffering caused by this terrible disease. This would need to be carefully regulated of course.