A scientific paper declared a while ago positive results for a trial of the drug deutetrabenazine in Huntington’s disease. The trial studied a new way of treating uncontrollable movements in HD. Now the drug is approved for treatment in the US and is launched as Austedo. Confusing stuff!

Read more: New HD drug approved

What’s chorea?

One of the most common symptoms in Huntington’s disease is unwanted movements, ranging from fidgeting to uncontrollable movements of the legs, body and head. These can interfere with daily activities like drinking a cup of tea or tying shoelaces. Doctors call this symptom chorea. Fun fact: the word ‘choreography’ comes from the same Greek root, meaning ‘a dance’.

The rollercoaster of side-effects and wearing off is one reason why a slower-acting form of tetrabenazine might be useful.
The rollercoaster of side-effects and wearing off is one reason why a slower-acting form of tetrabenazine might be useful.

Let’s stay focused. Is treatment for chorea completely new?

For quite a while, a drug called tetrabenazine has been used to treat chorea. It’s quite widely used – in fact, in the USA and Europe, tetrabenazine is the only drug that’s specially licensed for use in Huntington’s disease. In the USA it also goes by the brand name Xenazine. However, as with many drugs, tetrabenazine is not perfect. Once it’s in the body, it gets removed quite quickly. That means some people need to take the drug up to three times a day. This can be tricky or inconvenient, especially if someone has problems with swallowing or thinking, which are common in Huntington’s disease.

Tetrabenazine can also have side-effects. These range from sleepiness and nausea to anxiety and depression. In some people, these side-effects occur shortly after taking a dose, when the drug is at its highest level in the body. Later, when the drug wears off, the chorea symptoms can come back. All these ups and downs can mean people taking the drug can feel like they’re on a rollercoaster.

So what’s changing with Austedo (deutetrabenazine)?

The drug designers at Auspex Pharmaceuticals developed a clever way of tackling this problem. They made slight changes to the chemical makeup of Tetrabenazine by making some of its hydrogen atoms a little bit heavier. By subtly altering the way the drug interacts with the body, they hoped this meant it could still have the good effects of improving chorea, but only two doses would be required each day and there would be fewer negative side-effects. In other words: fewer ups and downs.

They named this new and improved version Deutetrabenazine. Recently, Auspex was taken over by the drug giant Teva Pharmaceuticals, who took on the challenge of testing this new drug in Huntington’s disease patients. Teva is now launching the drug as Austedo.

Austedos’ evolution looks like this: Tetrabenazine → Deutetrabenazine → Austedo

Putting it to the test

In order to see whether the Deutetrabenazine solved some of the problems associated with Tetrabenazine, Teva conducted a placebo-controlled double-blind randomized controlled trial. That’s a huge mouthful, but it’s the best way to test if a drug works. Placebo-controlled means some people get the active drug while others get a sugar pill, in other words a ‘dummy’ pill. That helps distinguish between effects of the actual drug and the effects that comes from being in the trial itself. Double-blind means neither the patient volunteers nor the trial staff know who’s on what pill. Randomized means the choice of drug or placebo is made at random.

A placebo or dummy pill helps distinguish between effects of the drug and the warm glow that comes from being in a trial.

The trial, called First-HD, was carried out in 34 hospitals in America and Canada. Each volunteer was involved for 13 weeks in total. For the first 8 weeks, the dose of the drug was increased slowly to the maximum. Patients then stayed on the maximum dose for 4 weeks and were assessed at different times. The last assessment was completed one week after stopping the drug. In total 45 patients were given the ‘dummy’ pill and 45 given the real drug. Patients took the drug twice a day, once in the morning and once at night.

As well as measuring chorea, the trial looked for other effects like swallowing and balance. Patients were asked whether they felt better on the drug, and their doctors were asked if they thought their patients had improved.

So does it work?

The trial result was positive – deutetrabenazine reduced people’s chorea significantly more then placebo. That’s good news, though perhaps not hugely surprising, given the high similarity with tetrabenazine, which we already know works.

If any of this sounds familiar, it’s because we’ve known about these results for a while – they were first announced in late 2014 and we reported on that announcement at the time.

So what’s actually new?!

First-HD is the trial that's finished, testing deutetrabenazine against placebo. ARC-HD is still in progress, testing the effects of switching from tetra to deutetrabenazine.
First-HD is the trial that’s finished, testing deutetrabenazine against placebo. ARC-HD is still in progress, testing the effects of switching from tetra to deutetrabenazine. Image credit: Huntington Study Group

There are a few interesting points in there. First, beyond simply reducing chorea severity, patients reported that on average they felt a little better overall when they were taking the drug rather than placebo – and their doctors agreed that they appeared better overall, too. That’s important, because there’s no point treating symptoms if doing so doesn’t make people feel better.

Second, there was an improvement in swallowing, which was assessed using a questionnaire. The study team suggest that this apparent effect on swallowing might explain another finding, that drug-treated patients gained a little weight, while those on the placebo lost a little. In Huntington’s disease, patients tend to lose weight, and swallowing difficulties are one thing that can contribute to that. Weight gain were therefore also assessed during the trial.

Deutetrabenazine or Tetrabenazine?

You’ll note that the First-HD trial tested the new drug against placebo – literally testing whether deutetrabenazine is better than nothing. That can’t tell us whether the new drug is better than the one it’s intended to replace – tetrabenazine.

Another ongoing trial, ARC-HD is directly comparing what happens when patients switch over from tetrabenazine to deutetrabenazine.

Ultimately a lot will depend on the experience of individual patients prescribed deutetrabenazine, either as a first-line treatment for chorea or to replace tetrabenazine. Inevitably, cost will play a factor, too.

 


This article by Dr Peter McColgan first appeared in HDBuzz.net on August 17, 2016. It is edited by Dr Ed Wild and further edited by Maiken Arnesen