Benefit of uniQure's Huntington's gene therapy will be revealed 'in the fullness of time'

uniQure’s Huntington’s disease data were deemed “noisy and difficult to interpret” in June. While a new slice of interim results from the phase 1/2 trial may not help cut through the noise, the principal investigator says efficacy signals are “on the favorable side.”

The company presented interim data from the ongoing early-stage trial Tuesday providing another peek at the gene therapy AMT-130. The latest cut of data extends follow up to 30 months from 39 patients enrolled in the group.

The interim update was riddled with caveats: the patient population is very small with just 16 people actually receiving the study drug. It’s an open label trial. The control group compares AMT-130 to natural history, rather than a placebo.

But principal investigator Edward Wild, Ph.D., University College London, said one thing is clear: any suggestion of improvement or delay in progression of Huntingon’s is very good news for patients.

“I wouldn't want to personally put a finger on what would be seen as clinically significant simply because everyone with HD has always got worse and anything that we can do to deflect that would be a huge breakthrough—particularly if it's sustained,” Wild said on a Tuesday morning conference call. “The results from a small trial in early manifest HD could potentially translate in the fullness of time into hugely significant differences in the life trajectory of everyone who's at risk of Huntington's disease.”

Huntington’s is a rare inherited disease that causes the progressive degeneration of nerve cells in the brain, leading to impairment of physical abilities, movement, thinking and psychiatric disorders. Treatments are available to manage symptoms but there is currently no disease-altering therapy available.

uniQure reported that patients taking AMT-130 showed evidence of preserved neurological function with dose-dependent clinical effects when compared to a natural history comparison.

“We are observing favorable trends in evaluation of motor skills, functional independence, and composite rating scores as compared to a non-concurrent criteria-matched natural history cohort,” said uniQure’s Chief Medical Officer Walid Abi-Saab, M.D., in a Tuesday morning statement.

The results also show a decline in neurofilament light chain, a biomarker associated with Huntington’s that signals degradation of the neurons and disease progression.

On safety, Wild noted that the gene therapy approach seems to not be causing any major complications. He cautioned, though, that since the therapy is rather invasive, requiring a surgery to administer, the safety profile should not be compared to other, less complex treatments. AMT-130 is surgically administered directly into the striatum region of the brain with three different infusions.

“We entered the gene therapy modality accepting upfront that there's going to be an inevitable short-term cost of the surgical mode of delivery, and perhaps the viral vector as well,” Wild said. “But that upfront cost and risk needs to be balanced against the potential for lifelong relief from mutant huntingtin pathology if the therapeutic is effective.”

He continued: “The main thing I would urge the audience to bear in mind is that this modality can't and shouldn't be judged as we would judge a presentation about a small molecule or an [antisense oligonucleotide] or any other therapeutics that we're a bit more used to hearing about in HD.”

With that said, Wild seemed pleased with the safety profile, noting a few cases of inflammation in the brain that were manageable—well within what neurologists such as himself are used to dealing with.

“Overall, the safety outcomes, I think, have been extremely encouraging given the invasiveness and novelty of what's being attempted here,” Wild said. “If it was an asset that was unsafe or poorly tolerated, I think at this stage things would be looking very different particularly in terms of the clinical outcomes.”

Earlier in the clinical journey for AMT-130, several patients who received a higher dose were hospitalized, including one for “fever, vomiting, mania and involuntary limb movements," uniQure said last year. The patients ultimately recovered and the trial got moving again in November last year with a few protocol amendments to prevent adverse events. 

uniQure is hoping to earn accelerated approval from the FDA for AMT-130, which would allow early access to the medication based on a biomarker that predicts clinical efficacy but don’t necessarily show that a treatment has improved a patients’ condition. The company would need to follow up later with a confirmatory trial to secure full approval.

Abi-Saab said that the company believes the accelerated nod is possible—“particularly in light of the messages from senior leadership” of the FDA’s Center for Biologics Evaluation and Research.

The crucial question of clinical efficacy has not yet been answered in the data so far, but Wild and uniQure’s executives seemed encouraged by the clinical signals so far.

“What I'd be looking for next is … more patients, more data, longer term follow up,” Wild said. But the information so far is “what we would expect at this stage if we are about to see the emergence of a dose dependency.”

The natural history comparison used in the phase 1/2 trial has troubled analysts and key opinion leaders, who dubbed the comparator “more qualitative than quantitative,” in a note based on the earlier June data cut issued by Mizuho Securities Monday ahead of the data release.

Mizuho also flagged an inconsistent trend between the low and high dose groups from the June data cut, which appeared in the latest update as well.

Abi-Saab said discussions with the FDA should occur early next year and “depending on how clear the message is for us,” uniQure will provide guidance on next steps for the program.