Advances in Huntington’s Disease 
Research Set the Stage for New Trials

Reducing Adverse Effects

Currently available dopamine blockers for Huntington’s disease—such as haloperidol, riserdal, and thorazine—are used to control hyperkinetic movements. These treatments also are known to have safety and tolerability problems, including adverse effects such as extrapyramidal symptoms, cognitive clouding, and endocrine dysfunction. An alternative drug, tetrabenazine, is a vesicular monoamine transporter 2 inhibitor that controls the release of dopamine. It, too, has adverse effects.

“Depression is probably the more commonly encountered adverse effect of tetrabenazine, which usually manifests in a dose-dependent manner. Somnolence is another big one, as well as worsening exptrapyramidal symptoms,” Dr. Claassen noted. Tetrabenazine is typically taken three times a day. “However, when we look at our clinical population, we find that the average duration of efficacy for this drug is about five and a half hours. As a result, a lot of our patients end up taking it four times a day, and that presents a bit of a burden for them.”

Teva Pharmaceuticals has filed a New Drug Application with the FDA for deuterated tetrabenazine (deutetrabenazine), which demonstrated promising results in phase III clinical trials. Deuterium, or heavy hydrogen, is a nonradioactive, nontoxic isotope of hydrogen, Dr. Claassen explained.

In one double-blind study for which Vanderbilt’s Huntington’s Disease Society of America Center of Excellence was one of the highest enrollers, 90 patients with Huntington’s disease with chorea were randomized one-to-one to receive deutetrabenazine or placebo. The drug, taken twice a day, was titrated to adequate chorea control over eight weeks and maintained for four weeks. The adverse effects were vastly reduced in the treated arm, compared with previous studies of tetrabenazine, Dr. Claassen noted. “In fact, in our experience, somnolence was dose-dependent and seemed to decrease with increased doses of deutetrabenazine.”

Vanderbilt’s center also is involved in an ongoing open-label trial that includes patients who switch from tetrabenazine to deutetrabenazine. Preliminary results confirm that chorea improvement is sustainable with deutetrabenazine. Patients require less deutetrabenazine than tetrabenazine to achieve the same the effect. “Basically, a person on 75 mg of tetrabenazine a day may need only 37.5 mg of deutetrabenazine to achieve the same therapeutic effect,” said Dr. Claassen. Researchers also are exploring deutetrabenazine as a possible treatment for Tourette’s syndrome and tardive dyskinesia.

New Trials

A new phase I trial of antisense oligonucleotides is under way in Canada and Europe. Delivery by lumbar puncture and intrathecal injection to the spinal fluid are being investigated, and researchers will evaluate whether the treatment slows disease progression and reduces the severity of symptoms over time. In addition, two trials that involve the participation of Vanderbilt’s center will investigate new drugs that target neuroinflammation and neurodegeneration in Huntington’s disease, Dr. Claassen said.

—Adriene Marshall