Huntington’s disease
patients in a recently concluded clinical trial for a potential new drug to
control the disease’s characteristic involuntary movements reported that they
“felt better” overall.
The trial showed that
the compound reduced chorea substantially and with fewer and milder side
effects than a predecessor drug, a significant step, although it does not address the cognitive and psychiatric
symptoms of HD nor attempts to be a “cure.”
Auspex Pharmaceuticals, a San Diego biotech firm focusing on hyperkinetic movement disorders and other rare diseases, announced the highly favorable results for the Phase
III clinical trial for its substance SD-809 on December 16, 2014.
Like Xenazine, the
first ever drug approved by the federal Food and Drug Administration (FDA) for
Huntington’s, SD-809 attacks chorea, the involuntary, sometimes dance-like
movements caused by HD’s devastation of the brain.
As one of its
“endpoints” (research targets), Auspex used the Patients’ Global Impression of
Change scale to measure whether patients actually felt better. The patients’
responses showed convincingly that they did, in part as a result of controlling
chorea.
“I don’t think that there’s ever been a therapy
with patients with HD that has actually demonstrated that patients actually
feel better on this type of patient assessment,” Pratik Shah, Ph.D., the Auspex
president and CEO, said in an interview at Auspex headquarters on December 23.
“This is something
that in the past not everyone has been able to appreciate: the impact of chorea
on the life of a patient. We wanted to put in an instrument that really asked
the question: ‘Does this matter to the patient? Do you feel better?’ Given the
fact that perhaps not everyone outside the HD community really understands the adverse
impact of chorea on the life of a patient and their family, this was an
important question to assess.”
The trial doctors
were asked a similar set of questions about the trial participants. “The
clinicians as well saw a favorable result here,” Dr. Shah said.
As a carrier of the
HD gene mutation who lost his mother to HD nine years ago this month, I was
thrilled to hear the news about SD-809 and to visit Auspex for the second time
in recent months. You can watch my reaction in the video below.
Reducing chorea and
side effects
Significantly, the
clinical trial demonstrated that SD-809 reduced chorea substantially.
“We saw a 37
percentage-point improvement in the SD-809 arm and 16-percent improvement in
the placebo arm, so it’s 21 percentage points above placebo,” Dr. Shah said.
“This is very robust, when you look at all the historical data [from the
Xenazine trial].”
Dr. Shah pointed out that the data are the sum of all the observations made on and by the participants.
“One person can have a two- or three-point reduction and experience great benefit, while a different individual may have the need for a greater numerical reduction,” he said.
Dr. Shah pointed out that the data are the sum of all the observations made on and by the participants.
“One person can have a two- or three-point reduction and experience great benefit, while a different individual may have the need for a greater numerical reduction,” he said.
According to one analyst who compared the two compounds, the reduction in chorea is about the
same seen in the Xenazine trial.
However, SD-809 had
fewer and far milder side effects than Xenazine. Both are taken as a pill.
Neither attacks the root causes of HD, nor the psychiatric and cognitive
symptoms that devastate most HD patients. So such drugs are not a “cure.”
Referring to the
study data, cited in a press release on the Auspex website, Dr. Shah
affirmed that SD-809 caused low levels of side effects such as depression, restlessness,
anxiety, insomnia, sleepiness, irritability, and fatigue. SD-809 caused no problems with swallowing in any of
the patients – 2.2% of those trial
participants on placebo did
experience difficulty with swallowing.
The minimal level of
those side effects is important in HD, because the disease itself often causes
such symptoms, in particular depression, which appeared to be lower in the
SD-809 arm compared to placebo, Dr. Shah noted.
Pratik Shah, Ph.D. (photo by Gene Veritas)
In an assessment of
the total motor (movement) score of the standard HD disease rating scale,
SD-809 led to improvement
– an outcome lacking in the Xenazine trial, Dr. Shah pointed out.
The improvement in
this score suggests that movement problems other than chorea could be
improving, he added.
Yet another trial
measurement showed that participants’ “physical functioning” improved with SD-809, that is, movement required
to do daily tasks such as walking and climbing stairs.
SD-809 as seen by HD
experts
Ninety individuals
took part in the Phase III trial, called First-HD, at 34 sites across the U.S.
and Canada. Half received SD-809, half a placebo. All participants had at least moderate chorea. The study was double-blinded:
neither doctors nor participants knew who was receiving the drug. This is the
most rigorous form of clinical trial. Auspex ran the trial in conjunction with
the Huntington Study Group (HSG).
None of the First-HD
participants was taking Xenazine at the time of the trial. Auspex and the HSG also
conducted a trial known as ARC-HD to study another group of participants
already taking Xenazine but who switched the next day to SD-809 for the trial.
ARC-HD demonstrated that the switch between drugs did not affect the reduction
in chorea and occurred with no serious side effects. In fact, patients shifting
to SD-809 had somewhat less chorea, and at smaller dosages, Dr. Shah noted.
“New, safe and
tolerable therapies for chorea treatment are clearly needed to make this
disease an increasingly treatable condition,” said Samuel A. Frank, M.D., an
HSG researcher and principal investigator for First-HD, in the Auspex press
release. “The primary and secondary efficacy results from this study were
confirmed by the Huntington Study Group independent analysis. These clear and
unequivocal results are clinically meaningful and suggest that SD-809 may play
an important role in the treatment of Huntington's disease symptoms.”
Dr. LaVonne Goodman,
the founder of the Huntington’s Disease Drug Works program and a
clinician who has attended to scores of HD patients, echoed the optimistic
conclusions about SD-809’s efficacy.
“This drug treats
chorea with many fewer side effects associated with tetrabenazine [Xenazine],”
she wrote. “And
most important it improved quality of life.[…] If this drug lives up to the
press release, it could/should replace antipsychotic drugs as primary treatment
of chorea in Huntington's disease.”
Although not yet
convinced that SD-809 is better than Xenazine overall, the researcher-written
website HDBuzz.net affirmed in a generally positive article that the “very
well-run” Auspex trials “prove
that SD-809 could be a useful new tool to help fight excessive movements in
Huntington’s disease.”
How it works
Xenazine’s scientific
name is tetrabenazine, a drug discovered in the 1950s. HD-affected individuals
used tetrabenazine for decades in Europe and Canada, where U.S. families
purchased the drug on an individual basis in person or through mail order. Only
in 2008 did it receive FDA approval.
Chemically SD-809 is
an improvement on Xenazine. It is deutetrabenazine:
a molecule with atoms of deuterium (heavy hydrogen) attached.
“We used in select
places deuterium as a building block,” Dr. Shah explained, pointing to a model
of SD-809 made by an Auspex scientist.
Dr. Shah explains the structure of SD-809 using a
model built by an Auspex scientist. The colors represent the compound’s five
atoms: carbon (black), hydrogen (white), oxygen (red), nitrogen (blue), and
deuterium (green). In scientific terms, SD-809 (deutetrabenazine) is a VMAT2
inhibitor. (photo by Gene Veritas)
Very much like
Xenazine, SD-809 inhibits certain chemical actions in the brain in order to
avoid such symptoms as excess dopamine, which can lead to the involuntary
movements of HD, Dr. Shah explained.
He added that the
addition of deuterium “enabled this molecule to be broken down in the body more
slowly and so it sticks around longer.” As a result, the levels of the drug in
the bloodstream become “smoother.”
For patients, this
means smaller, less frequent dosages and potentially a more optimal performance
of the drug, he said.
Applying to the FDA
After the conclusion
of First-HD and ARC-HD, over 90 percent of the trial participants (excluding a few who dropped out) entered a follow-up
study so that Auspex can further analyze the effectiveness of SD-809 and the
compound’s side effects. This ongoing study gives participants access to the
compound, including those who were receiving the placebo during the trial.
On January 12, Auspex
released additional good news resulting from its ongoing analysis of SD-809:
whereas Xenazine’s instructions warn about the possibility of an abnormal,
prolonged heartbeat, SD-809 does not cause such a symptom to the point of
medical concern.
Dr. Shah stated that
Auspex hopes to complete a New Drug Application for HD and SD-809 during the
first half of this year. Review of such applications typically takes from six
to twelve months, depending on the circumstances.
“We have a huge sense
of urgency, especially given these [clinical trial] results, to do everything
we can to put the application together as soon as we possibly can,” Dr. Shah
emphasized.
Auspex has also
submitted for FDA approval a list of possibilities for SD-809’s eventual
commercial name.
On January 14, Auspex
received orphan drug designation from the FDA for use of SD-809 in Tourette
syndrome, another rare movement disorder.
The company is currently conducting a Tourette clinical trial.
Last year, Auspex
received the same designation for HD. Orphan drug status – for conditions
affecting fewer than 200,000 people in the U.S. – provides special incentives
for companies to produce drugs for these maladies.
Awaiting a price and
revenues
Dr. Shah said that
the company has not yet researched the price of the drug.
The exorbitant cost
of some orphan drugs has caused deep concern among affected families and
patient advocates. Lundbeck, which markets Xenazine, has a program to
assist HD families with the high cost of its drug, which can reach $50,000 at
the wholesale level for an annual supply (click here to read my previous article on the cost of orphan drugs).
“We remain committed
as a company to making SD-809 available to those who need it as much as we
can,” Dr. Shah commented.
As a young company
that only sold stock publicly for the first time in 2014, Auspex has yet to
generate revenues. Investors continue to support the company as it moves
forward with clinical trials and new research, Dr. Shah explained.
Xenazine will lose
its market exclusivity in August 2015 and become subject to generic
competition. This development could put additional pressure on Auspex to market
its drug affordably, but, at the same time, furnish the opportunity to stress
its compound’s greater safety.
New hope and a
platform for future research
“We haven’t had a positive study in HD in many,
many years, so it’s really an opportunity to celebrate a success that we’ve
seen here and to recognize that this is an important step forward for the field
and to kind of spread some good cheer and to have renewed hope for the field,”
Dr. Shah concluded about the SD-809 trial. “It is also important for the
community to remind the people who don’t know treating chorea does matter. It
can affect and does affect people’s quality of life.”
Auspex hopes to use
the SD-809 project as a platform for researching possible treatments that
attack the causes of HD, Dr. Shah said.
“We’re always on the
lookout for what makes sense to invest in there,” he added.
The success of the
drug and its acceptance by HD families and clinicians could help provide the
revenues needed to fund the new research into better remedies, he said.
Dr. Shah (left) with Gene Veritas (photo by Rachel Kenny,
Auspex)
