First Phase 2 Success for Gene Therapy in Parkinson’s

Injecting millions of viral particles deep into the brain may sound
nefarious, but when the particles are relatively benign and carry the
gene for the enzyme glutamic acid decarboxylase (GAD), then the
strategy may have the makings of a therapy for Parkinson’s disease
(PD). As reported in the March 17 Lancet Neurology online, PD patients
who received the viruses in a small Phase 2 clinical trial (see
had better motor control six months later than patients who received
surgery without the viral construct. “This is the first successful
Phase 2 trial for a Parkinson’s disease gene therapy, in the sense that
we met our primary endpoint,” said senior author Andrew Feigin from the
Feinstein Institute for Medical Research, Manhasset, New York. Robert
Hauser, University of South Florida, Tampa, told ARF that "the primary
outcome was positive and the safety profile looked good, indicating
there should be further trials of this approach. If it can be proven to
be effective, it would be a real scientific advance, and it would prove
that we can change the function of neurons with gene therapy," he

Hauser was not involved in the study but is one of the lead
investigators for ADVANCE-PD, a Phase 3 trial of IPX066. This is an
extended-release form of carbidopa-levodopa, a stalwart therapy for
Parkinson’s. Last Monday, top-line data released by Impax Laboratories, Inc.,
which sponsors the drug, suggested that patients on the extended
release formulation have less "off" time, which is when the drug wears
off and motor symptoms return (see company press release).

Though the two trials use very different approaches, both
outcomes are promising. The gene therapy aims to correct an imbalance
deep in the brain in the subthalamic nucleus (STN). In Parkinson’s
disease, neurons in the STN are overactive (“disinhibited” is the
technically correct term) because the dopaminergic neurons in the
substantia nigra that die as the disease progresses normally help drive
inhibitory neurons that calm the STN. That inhibition can be restored
in PD patients by using dopaminergic agents, such as levodopa, or
stimulating inhibitory neurons with electrodes planted deep into the
brain (see ARF related news series).
The gene therapy approach uses viruses to deliver the gene for glutamic
acid decarboxylase. This enzyme catalyzes one of the rate-limiting
steps in the production of γ-aminobutyric acid (GABA), the major
inhibitor neurotransmitter in the STN.

A small pilot trial suggested that GAD gene therapy was safe and potentially effective (see ARF related news story on Kaplitt et al., 2007).
For the Phase 2 trial, Feigin and colleagues randomized 22 PD patients
to the therapy and 23 to serve as controls. Surgeons stereotactically
implanted microelectrodes (as would be done for deep-brain stimulation)
into the STN of all patients. After withdrawal of the electrodes, 34.5
μL containing about 34 billion viral particles were slowly pumped into
the STN through a catheter inserted into the same bore hole. The
control group were injected with a similar volume of saline.

“One caveat is that we limited our analysis to people who
received only the full treatment,” Feigin told ARF. They excluded
people from the analysis if the infusion pumps didn’t work properly, or
the catheter was not correctly targeted to the STN. This is unusual for
clinical trials, which are mostly done on an “intent-to-treat” basis,
meaning that people randomly assigned to a treatment are included in
the final analysis even if they drop out at some point along the way.
This is to ensure that the treatment is generalizable to the population
as a whole. “Our view is that this is not what a Phase 2 trial is all
about. You need a large Phase 3 trial to assess general effects, but
because this was a small Phase 2 trial, we felt we needed to optimize
our chances of seeing benefit,” said Feigin. Some PD researchers
contacted by ARF wondered if the omission of certain patients in the
analysis compromised the validity of the study. But Michael Hutchinson,
New York University School of Medicine, called it a “prudent strategy,”
in an accompanying Lancet Neurology commentary. He noted that in a
previous gene therapy trial of glial-derived neurotrophic factor, “at
least two of 17 patients in the treatment group had catheters in the
wrong place, yet were included in the analysis.”

The patients in the GAD trial were followed for six months
with the primary endpoint being motor function as assessed by the
unified Parkinson’s disease rating scale (UPDRS) motor score.
Parkinson’s disease is notoriously sensitive to placebo effects,
especially for surgical treatments, but in this trial, treatment and
control groups did have significantly different outcomes. Motor scores
improved in the control group by about four points (or 12.7 percent)
over six months, whereas the treatment group improved by eight points
(23.1 percent) over the same period.

Questions still abound. Some researchers wondered if the small
improvement was worth the risks associated with the surgery and a
potential adverse immune reaction to the virus. Hutchinson noted that
improvements after DBS are twice as large as seen in this GAD trial,
and wondered if long-term effects might arise after introducing viruses
into the brain. Hauser also noted that secondary outcomes, such as
global ratings, activities of daily living, or other motor functions
such as the number of finger taps per minute, did not confirm efficacy,
though some trended in the right direction. This could be because the
study was too small, he suggested, though he added that in DBS studies
of the same size, he would expect to see improvements in some of the
secondary measures as well.

One of the secondary measures that showed no difference between
treatment and placebo groups in this Phase 2 study is hours in the off
state. In contrast, the extended-release carbidopa-levodopa formulation
reduced it by 1.2 hours in the Phase 3 ADVANCE-PD trial. “We believe
anything greater than an hour is clinically relevant,” said Hauser.
But, in addition, he believes one of the important benefits of the
extended-release formulation is that patients only need to take it
three times a day, as opposed to four, five, or more times a day for
the current form. Patients’ compliance tends to go down when they have
to take a drug that many times a day, partly because they find it
difficult to reliably schedule the drug before or after meals or
snacks. Then it becomes difficult for the physician to anticipate the
patient’s response to the drug, Hauser told ARF. He believes that not
only reducing off time, but also reducing the frequency of dosing, is
an important advance for patients. Other measures that improved in
patients taking IPX066 included the Clinician Global Impression of
Change and Quality of Life Measures.

The GAD gene therapy may advance Phase 3 as well. Marc Panoff, Chief Financial Officer of Neurologix, Inc.,
which sponsors the therapy, told ARF the company had met with the Food
and Drug Administration and hopes to file for a Phase 3 trial this
year. Matthew During, Ohio State University, and Michael Kaplitt, Weill
Cornell Medical College, New York, are coauthors on the Lancet
Neurology paper and co-founders of Neurologix.

In other Parkinson’s developments, Ceregene,
which is developing gene therapy for neurturin, a form of nerve growth
factor, recently announced that it was moving forward with a Phase 2b
trial in PD as well (see company news release). That therapy had failed to reach its endpoint in an earlier Phase 2 trial (see ARF related news story).

LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskander EN,
Kostyk SK, Thomas K, Sarkar A, Siddiqui MS, Tatter SB, Schwalb JM,
Poston KL, Henderson JM, Kurlan RM, Richard IH, Van Meter L, Sapan CV,
During MJ, Kaplitt MG, Feigin A. AAV2-GAD gene therapy for advanced
Parkinson’s disease: a double-blind, sham-surgery controlled,
randomised trial. Lancet Neurology, March 17 2011. Abstract

Hutchinson M. At last, a gene therapy for Parkinson’s disease? Lancet Neurology, March 17 2011. Abstract


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