The announcement of the failure of two Huntington’s disease trials run by Roche and Wave Life Sciences earlier this year was a great disappointment to clinicians and patients alike, but what do the results mean for the field?
Researchers have been working to develop more effective treatments or even cures for Huntington’s disease, a rare neurodegenerative disease that is normally inherited from a parent with a dominant mutation in the huntingtin gene, for some time.
So far, tetrabenazine (Xenazine) and deutetrabenazine (Austedo) are the only drugs to be approved for treating Huntington’s and they only target the abnormal movements patients experience known as ‘chorea’ and not the basis of the disease.
Both Roche and Wave were trialling antisense oligonucleotides (ASOs), short, synthetic, single-stranded oligodeoxynucleotides that target specific messenger (m)RNAs to reduce, restore or change protein expression.
ASOs are thought to have great potential for targeting neurological disorders and indeed several such therapies have been approved to treat various conditions including Duchenne muscular dystrophy and spinal muscular atrophy since the late 1990’s.
ASOs are considered a good therapeutic avenue for Huntington’s. Sadly, Roche’s trial, the first to reach Phase III for this condition was not effective and those treated with tominersen (Roche’s ASO) actually had a worse response than placebo. In mid-March the company announced the trial would be discontinued, and shortly after that Wave also announced it would be discontinuing trials of its ASOs for treating Huntington’s.
The ending of Roche’s trial leaves a gap in the late-stage trials space for Huntington’s and only two companies have Phase III trials of Huntington’s medication in progress. One—Neurocrine Biosciences’ valbenazine—is focusing on treating symptoms of chorea, like tetrabenazine and deutetrabenazine.
The other is pridopidine, an oral, selective and potent sigma-1 receptor agonist which is being developed by Prilenia Therapeutics. Prilenia acquired the drug from Teva Pharmaceuticals in 2018, which also developed deutetrabenazine.
Pridopidine had mixed results at Phase II and did not significantly improve symptoms of impaired movement (as measured by the Unified Huntington’s Disease Rating Scale total motor score), but patients treated with this drug did have maintenance of functional capacity versus placebo. It is currently undergoing Phase III testing with a focus on whether the drug improves total functional capacity and should read out next year.
“These patients had more ability to manage their financial affairs, to manage the activities of daily living, to continue employment, and so on, and these are the things that matter most to patients,” Prilenia CEO Michael Hayden, M.D., Ph.D., told Clinical OMICs. Hayden was global head of R&D and chief scientific officer at Teva until 2017.
“It was thought before that pridopidine was having major effect on the dopamine system.
Now it’s recognized that at therapeutic doses it selectively binds the sigma 1 receptor and has profound neuroprotective capabilities.”
The Wave trial failed to reduce mutant huntingtin protein to a significant degree and was stopped for this reason. However, Hayden thinks there are several reasons why the Roche trial, which was aiming to lower both mutant and wildtype huntingtin, may have failed.
“One is that intrathecal injection did not reach the crucial areas of the brain that are crucial in Huntington’s disease… two, the knockdown of wild type huntingtin may have been deleterious, because wild type huntingtin is neuroprotective. The third potential reason is that there was an inflammatory response… And then the fourth reason is that this knockdown did not knockdown an alternative spliced form of huntingtin for exon one,” he explained. In some patients with Huntington’s disease, a pathogenic exon 1 huntingtin protein is produced by incomplete splicing of the huntingtin gene.
Roche and Wave are not the only companies working on ASOs, several other companies have earlier stage ASOs in development including Triplet Therapeutics.
“Personally, I was very surprised by the negative news,” Irina Antonijevic, M.D., Ph.D., Triplet’s CMO told Clinical OMICs. “I did not expect a major therapeutic benefit. But what we have now is an unfavorable benefit risk, so really a deterioration of the disease with treatment compared to placebo.”
However, she is not concerned about her company’s ASO development strategy, which plans to advance to Phase I soon. Triplet have a different method of delivery, injecting into the cerebral ventricles in the brain as opposed to Roche’s intrathecal administration, a different target—a genetic modifier rather than the disease gene itself—and a different trial plan to Roche and Wave.
“Even before we got these data, that I think if anything, we just feel what we have planned is the right plan,” says Antonijevic.
She says she hopes that pridopidine will be successful in Phase III, but has some doubts about its long-term impact on the field. “I don’t necessarily feel that this is something that’s advancing the field to a significant extent. If it works, and there’s some benefit to patients, that’s great. But I just really have a hard time putting this data together and concluding that it is truly disease modifying, unlike some of these other approaches that I think are targeting a known root cause of the disease.”
Gene therapy, such as that being developed by uniQure, currently at phase I/II is another possible option for Huntington’s treatment, which is promising, but also has some disadvantages. “One of the key problems is the distribution here. I mean, particularly when you target huntingtin, it is not a disease of one particular nucleus,” says Antonijevic.
Hayden agrees, “the problem in Huntington’s disease, you’ve got to target the whole brain, and delivery mechanisms for getting distribution throughout the whole brain are still extremely difficult.”
Despite the failures so far, both Antonijevic and Hayden are positive about the future. “I think we do know more in Huntington’s disease than in many other particular rare diseases. And I think this gives us a solid base to actually do good clinical trials if we utilize this data,” says Antonijevic.