Data presented at the American Academy of Neurology (AAN) meeting this week on experimental therapeutics for Huntington’s disease gave some cause for optimism. And, as good research does, they identified new questions as they answered current ones.

At the meeting, researchers presented new data on antisense oligonucleotide HTTRx (RG-6042, Ionis Pharmaceuticals Inc./Roche Holding AG) that underpinned the decision to increase the dosing interval in the ongoing pivotal trial GENERATION HD1.

Researchers from University College London had first presented initial results from the phase I trial at the 2018 AAN meeting, and full results were published in the May 6, 2019, issue of The New England Journal of Medicine.

The phase I trial of HTTRx now published in the NEJM was the first trial to demonstrate lowering of mutant huntingtin levels, and based on data from the trial, “we made the choice, in discussions with regulators at both the EMA and FDA, to go straight to a pivotal phase study,” Scott Schobel told BioWorld. HD has “severe unmet needs, he said, and “a phase II would have cost at least three to five more years… We didn’t really feel it was good for the community.”

The phase III GENERATION HD1 trial is currently ongoing.

Schobel is associate group medical director and clinical science leader for the IONIS/Roche HTT Rx program at Roche/Genentech neuroscience, and a co-author on an abstract presented by Edward Wild, principal investigator at University College London’s Institute of Neurology and an investigator in the phase I trial of HTTRx.

Wild described a pharmacokinetic/pharmacodynamic modeling that used rodent, primate and clinical data to arrive at dosing levels and frequency.

So far, the only reliable way to measure huntingtin and neurofilament protein is in the cerebrospinal fluid, though attempts to find a way to measure biomarkers in blood plasma, and even saliva, are ongoing.

Researchers first investigated in mouse models how much mutant huntingtin had to be reduced in the brain to have an effect on clinical motor symptoms. They then extrapolated the doses needed in primates to lower huntingtin to the target level – a reduction of 30% to 50% in brain – and tested what reduction in CSF corresponded to target-level reduction in brain tissues.

The researchers also incorporated data from the phase I open-label extension trial of HTTRx to change the dosing frequency nine months into the GENERATION HD1 trial.

In the open-label extension, the team measured CSF levels of mutant huntingtin and showed that even in the patients receiving HTTRx every eight weeks had at least a 40% reduction of mutant huntingtin CSF levels at trough.

According to the model, those reductions correspond to a reduction of 70% in cortical tissue, and 40% in the caudate nucleus, which is part of the midbrain where neuronal death drives clinical symptoms of HD.

At the same time, patients treated every four weeks, who were receiving both twice as much drug and twice as many lumbar punctures as the eight-week cohort, had a higher rate of adverse events.

As a result, the four-week dosing group was dropped from the pivotal trial, which now compares a dose of 120 mg of HTTRx given either every eight weeks or every 16 weeks to placebo.

Gene therapy approach

The fact that Huntington’s disease is at its root due to changes in a single gene not only gives it an obvious target for antisense oligonucleotides like HTTRx. It also makes it a candidate for gene therapy.

At the AAN meeting, Uniqure Inc.’s vice president of clinical development, Joseph Higgins, shared preclinical data on the company’s AMT-130, a huntingtin microRNA delivered to neurons in the striatum via bilateral brain injection.

Uniqure received FDA fast track designation for AMT-130 in April, and plans to dose its first patient in the second half of 2019.

Such brain injection is yet more invasive than the intrathecal injection used for HTTRx. Higgins showed, however, that primate brains reacted to the cannulae much like they do to the electrodes used for deep brain stimulation, with a minimal innate immune response and inflammation.

And, Higgins pointed out, gene therapy has the potential to be curative.

The huntingtin miRNA ultimately spread widely through the brain, though levels were highest in the striatum. Treatment reduced mutant huntingtin in the cortex by up to 90% in monkeys, and up to 75% in pigs, which, Higgins said, weigh in at around 220 pounds and so make a strongly predictive large animal model.

The miRNA is delivered via an AAV5 vector, which, unlike the AAV9 vectors that have become the standard gene delivery method for neurons, does not induce a T cell-based immune response.