BOSTON -- Late-breaker presentations at the American
Academy of Neurology's annual meeting included promising results with several
very different approaches to the problem of reducing "off" time in
Parkinson's disease without compromising "on" time offered by
- A gene therapy to provide replacement
of aromatic amino acid decarboxylase (AADC), the enzyme that converts levodopa
into active dopamine
- An ultra-extended release form of carbidopa-levodopa
Investigators reported results from early studies of the
first two of these treatments; the apomorphine trial was a phase III study,
with details released prior to the meeting and the subject of a previous MedPage Today
The three studies were included in the AAN's
"Emerging Science" program during which investigators gave 3-minute
platform talks with more information available in posters.
- Subcutaneous apomorphine infusion
One of the problems with current Parkinson's disease
therapies is that dopaminergic neurons gradually become unresponsive to
levodopa, which is a prodrug for dopamine. Lab studies have traced the
phenomenon to loss of AADC activity within the target neurons -- suggesting
that if AADC activity could be restored, so too could levodopa's effectiveness.
Chadwick Christine, MD, of the University of California
San Francisco, presented results of a small trial involving packaging an AADC
gene into an adeno-associated virus vector (a standard gene therapy tool),
using real-time MRI to guide delivery into the putamen. This was a phase Ib
trial testing three dosing regimens of the agent, dubbed VY-AADC01.
The study is still ongoing and Christine presented data only for the two of the
regimens, delivering 450 and 900 μL per putamen in five patients each. (A third
cohort is also receiving 900 μL but in a larger bolus.)
PET scans showed that the cohort receiving 900 μL had 50%
increase in dopaminergic activity 6 months after treatment, indicating that the
AADC gene had been delivered successfully and was working as intended.
Moreover, that group has shown a clear and positive clinical response, with a
35% reduction in the level of dopamine-boosting medication needed to control
symptoms at 6 months.
At 12 months, Christine said, patients in that group
showed a whopping 4-hour increase in mean "on" time (i.e., daily time
with symptoms controlled) and a nearly 2-hour reduction in mean "off"
time, as reported in patient-kept diaries.
The treatment was well tolerated with no serious adverse
effects related to the AAV vector, he said.
Another issue with conventional dopaminergic therapy is
the "off" time just mentioned -- the fact that, as the disease
progresses, the desired clinical effects of current dopamine-enhancing drugs do
not last an entire day, and simply increasing the dosing frequency may not be a
Several formulations of carbidopa-levodopa aimed at
attacking the problem are on the market or in development. One such product, an
extended-release version sold as Rytary, was approved in 2015, but manufacturer
Impax Laboratories hopes to improve on it with a new carbidopa-levodopa
formulation called IPX203.
At the late-breaker session, Mark Stacy, MD, of Duke
University in Durham, N.C., presented results from a single-dose phase II study
involving 75 patients randomized to Rytary, an immediate-release
carbidopa-levodopa, and IPX203. Outcome measures included total "off"
time, good "on" time, "on" time without dyskinesia,
"on" time with slight dyskinesia, and "on" time with
For most of these -- including "off" time, good
"on" time, and "on" time without troublesome dyskinesia --
IPX203 significantly outperformed the other two treatments. The differences
from the immediate-release agent were very marked; the new formulation was
incrementally better than Rytary but still achieving statistical significance.
IPX203 was not worse than the other drugs in any measure.
In addition, said Stacy, IPX203 was superior for the
overall duration of effect, need for rescue medications, and in responder rates
according to standard criteria involving Unified Parkinson's Disease Rating
Scale score improvements.
Stacy also said there were no serious or severe adverse
events in the trial. Impax is now recruiting study sites for a phase IIb
multiple-dose trial, the firm said.
AADC gene therapy study was funded by Voyager Therapeutics and the Michael J.
Fox Foundation. The IPX203 study was funded by Impax Laboratories.
Primary Source American Academy of Neurology
Source Reference: Christine C, et al "Intraputaminal AADC gene therapy for advanced Parkinson's disease: Interim Results of a Phase 1b Trial" AAN 2017; Emerging Science Abstract 004.
Secondary Source American Academy of Neurology
Source Reference: Stacy M, et al "Motor effects and safety of IPX203, an investigational extended-release formulation of carbidopa-levodopa, in advanced Parkinson's disease: A single-dose Phase 2 study" AAN 2017; Emerging Science Abstract 005.