Pauline Anderson

July 05, 2017

VANCOUVER — Deutetrabenazine used to treat chorea in patients with Huntington's disease (HD) continues to be safe over the long term, with stabilization of motor symptoms at 1 year, results of a new extension trial show.

"The study showed there is continued suppression of chorea over time," Samuel Frank, MD, associate professor, Department of Neurology, and Movement Disorders Clinic, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

"Over a year, there is continued improvement of the total maximal chorea score, as well as stabilization of the total motor score. So motor issues beyond chorea are also stabilized over a year, which is important in a progressive process."

The findings were presented here at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2017.

54-Week Results

Chorea is the most prominent motor dysfunction of HD. It can increase the risk for injury and interfere with daily functioning.

As well as motor dysfunction, HD is characterized by cognitive impairment and behavioral-emotional symptoms.

Deutetrabenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor that contains deuterium, a nontoxic naturally occurring form of hydrogen.

It was approved earlier this year to treat chorea in HD. The approval was based on a randomized controlled study (FIRST-HD) showing that the agent reduced Unified Huntington’s Disease Rating Scale (UHDRS) total maximal chorea (TMC) by 4.4 units at 12 weeks compared with 1.9 units in placebo recipients, with a mean between-group difference of –2.5 units (95% confidence interval, –3.7 to –1.3; P < .001).

The new open-label, single-arm extension study was conducted at 37 sites in the United States, Canada, and Australia. It enrolled 119 patients in two cohorts: rollover patients from the original study who were initially exposed to placebo or the active drug and patients switched to deutetrabenazine from a stable dose of tetrabenazine.

The two drugs are structurally similar, but the carbon-hydrogen bond in deutetrabenazine is stronger. This makes it "much smoother" in terms of the delivery, said Dr Frank.

"So even though you’re getting the same amount of drug, there are less peaks, fewer ups and downs over a longer period of time."

The US Food and Drug Administration approved tetrabenazine in 2008 based on the TETRA-HD study (a randomized, placebo-controlled, double-blind study in patients with HD). It was the first approved treatment for HD in the United States (although other drugs had been used "off-label").

By week 54, the mean daily dose of deutetrabenazine reached 42.1 mg in the rollover cohort and 44.2 mg in the switch cohort.

"If you look at the total daily dose, it creeps up over time, and part of the reason for that is that the tolerability is good," commented Dr Frank.

He noted that the dose increased over time even in patients who had switched from a stable dose of tetrabenazine.

No Evidence of Parkinsonism

At week 54, TMC was reduced by 4.1 units in the rollover group and by 3.0 units in the switch group. Total motor score (TMS) was reduced by 4.3 in the rollover cohort and increased by 1.2 in the switch cohort.

"The change is well within the range of normal fluctuation and not consistent with a worsening over time," said Dr Frank. 

He emphasized that the mean change in the UHDRS parkinsonism subscore of the TMS was stable over the course of the study. "This is an important point. Often over the course of the illness, patients with HD may develop more slowness and stiffness with less chorea," he said. 

"Medications can sometimes highlight that change or be an independent cause of parkinsonism, and we found no evidence for the development of parkinsonism over the 54 weeks," Dr Frank continued.

The exposure adjusted incidence rate (EAIR) of patients reporting any adverse event (AE), serious AEs, and AEs leading to withdrawal was similar for the rollover and switch groups. The most common AEs were falls, somnolence, and depression.

Rates of EAIRs were similar to those in the original trial.

Study investigator Joseph Jankovic, MD, professor of neurology, distinguished chair in movement disorders, Baylor College of Medicine, Houston, Texas, noted that the TETRA-HD study showed a 3.5-point difference in the chorea score between tetrabenazine and placebo, while the FIRST-HD study showed a difference of only 2.5.

"I believe that this indicates that the deutetrabenazine dose was too low and the true 'equivalency' ratio between deutetrabenazine and tetrabenazine is probably higher than 1:1, perhaps 1.5:1."

Dr Jankovic pointed out that a third drug — valbenazine —   was recently approved for the treatment of tardive dyskinesia. This brings to three the number of drugs available to treat hyperkinetic movement disorders that act as dopamine depleters by blocking VMAT2.

"All three drugs are probably equivalent in efficacy but have different pharmacokinetic and safety profiles," Dr Jankovic, author of a recent expert opinion on this topic, told Medscape Medical News.

Because of differences in pharmacology and pharmacokinetics, both deutetrabenazine and valbenazine promise to be at least as effective as tetrabenazine, but with a lower risk for AEs, such as sedation, insomnia, depression, parkinsonism, and akathisia, said Dr Jankovic.

Dr Frank has disclosed no relevant financial relationships. Dr Jankovic reports he receives research and training grants from Teva and serve as a consultant for Teva.

International Congress of Parkinson's Disease and Movement Disorders (MDS) 2017. Abstract 468. Presented June 6, 2017.

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