Authors: Perry D. Cohen, Wilson H. DeCamp, Linda Herman, Arnold M.
Kuzmack, Stan Planton, Carolyn Stephenson, Peggy Willocks and Paula
Parkinson Pipeline Project, Washington, DC
poster examines three failed clinical trials for promising new
Parkinson’s therapies. All have similar designs that require surgical
intervention to deliver the treatment and utilize sham brain surgery as
a placebo control. It relates common reasons for their failure and gives
close scrutiny to evidence on the benefits vs. risks of placebo brain
Phase II of all three trials were multicenter, randomized, double blind,
sham surgery controlled studies All three showed favorable results in
the open label Phase I trials, but did not meet their endpoints in Phase
All three trials were conducted using the dopamine replacement theory as
treatment by either viability of available dopamine (GDNF), production
of dopamine from transplanted cells (Spheramine), or genetic alteration
for the production of dopamine (CERE 120).
GDNF (Neurotrophic factor) – recombinant GDNf delivered by pump
sponsored two open label phase I safety trials of GDNF in 15 patients.
The studies were initially for six months, with some patients treated
for up to 3 1/2 years. Based on the clinical endpoint of reduction in
the UPDRS motor "off" score, the efficacy ranged from 39 to 57%.
Randomized, double blind, placebo controlled, parallel group phase II
trials were initiated in 34 patients. The clinical endpoint was the
Change in UPDRS motor score in the practically defined off condition at
The sponsor (Amgen, Inc.) terminated the phase II trials in September
2004. The rationale given was that, “Six months of treatment with GDNF
delivered to the putamen failed to improve UPDRS scores compared to
placebo." There was “evidence of alteration of brain function,” a likely
reference to changes on neuroimaging, but improvement on UPDRS scores
did not meet the primary endpoint of the trial. However, a participant
from the Bristol (UK) study died of an unrelated cause, and, upon
examination of his brain via autopsy, neural sprouting was noted (the
first report of its kind).
Open label extension studies were begun to resolve differing trial
results. But in Sept. 2004, Amgen sent letters to clinical investigators
halting further clinical studies, due to safety concerns – development
of lesions in the cerebellum of 4 test monkeys and "anti r metHuGDNF
neutralizing antibodies found in two of the study participants to date.”
Spheramine [Retinal Pigmented Epithelial (RPE) Cells]
In 2000, Titan Pharmaceuticals in a Phase I open label trial consisting
of six participants with advanced disease (3 3.5 or greater on the Hoehn
& Yahr scale) received unilateral treatment (for their “worst” side)
transplanting RPE cells (without the use of immunosuppression), using a
donor eye from a cadaver. (One eye can be used to treat hundreds or
patients.) At 12 months, an average improvement of 48% in the UPDRS M
(off) outcome measure was realized, along with improvements seen in
other measures of motor function and quality of life. One participant
dropped out because of a later diagnosis of Parkinson’s Plus.
Participants continued to be followed through 48 months, maintaining a
44% average improvement and continue to be followed. It was reported,
"The data also demonstrate a very good preliminary safety profile for
Spheramine. There has been no evidence to date of any significant side
effects in any of the patients . . . a reduction in dyskinesias for most
patients and . . . no ‘off state’ dyskinesias . . . observed."
(Titan handout, April 2002)
In 2003, a phase II study was initiated with a randomized, double blind,
placebo controlled (sham surgery) trial of 71 patients (78 were actually
recruited) receiving treatment bilaterally, and received fast track
approval by the FDA. Titan was joined with the U.S. Berlex sponsor,
which is also Schering AG (Germany), and was later acquired by Bayer
(Bayer Schering/Titan). In July 2008, Titan announced that Phase II did
not meet its primary or secondary endpoints and Bayer Schering AG
withdrew as a sponsor. The sponsors (Bayer Schering / Titan) announced
that they had discontinued development of Spheramine in July 2008.
Titan stated that its "potential cell based treatment for Parkinson's
Disease failed to meet its primary and secondary endpoints in a Phase
IIb study, and likely won't be continued by partner Bayer Schering
Pharma... Initial analysis of results from the 71 patient study of
Spheramine designed to test the safety, tolerability and efficacy of the
treatment found that it had no significant differences from sham surgery
arms after 12 months of follow up." (Company press release dated 7/2/08)
CERE 120 (neurturin) – Gene therapy
CERE 120, a gene therapy product in development for the treatment of
Parkinson’s disease, was administered to the putamen with adeno
associated virus carrying the gene for neurturin, a growth factor
related to GDNF and shown in experimental models to protect dopaminergic
neurons from degeneration. Six patients received a low dose and six a
high dose (1.4 x 10^11 vs. 5.7 vector genomes). Neurturin was well
tolerated and appeared to reduce symptoms by approximately 40%
(p<0.001), as measured by the Unified Parkinson’s Disease Rating Scale
(UPDRS) motor “off” score, in an open label Phase 1 study in 12 patients
with advanced disease. (Company press release dated 10/10/2006)
The sponsor (Ceregene) announced the
phase II trial failure in Nov. 2008.
Analysis of the phase II trial data did
not demonstrate an appreciable
difference between patients treated with
CERE 120 versus those in the control
group. Both groups showed an approximate
7 point improvement in the protocol
defined primary endpoint (Unified
Parkinson’s Disease Rating Scale motor
off score at 12 months), relative to a
mean at baseline of approximately 39
points. Both groups had a substantial
number of patients who demonstrated a
meaningful clinical improvement from
baseline. CERE 120 appeared to be safe
and well tolerated."
spokesman stated "...we are stunned by
the results of this trial and will
continue to analyze the data in order to
gain greater insight into the factors
that may have contributed to this
negative outcome, not only to build upon
this insight for our Parkinson’s
program, but also to help assure
continued successful development of our
product candidates for other diseases.”
(Company press release dated 11/28/08)
In an in depth interview with the
Michael J. Fox Foundation, Raymond T.
Bartus, PhD, executive vice president
and chief scientific officer of
Ceregene, reported that they are
attempting to redesign the Cere 120
trial to expand the delivery target area
and increase dosage. Two trial
participants died from unrelated causes,
providing the opportunity to view the
progress of the neurturin through
autopsies. Discoveries were made that
may enable research to continue in the
Based on the design of the three studies
described above, we suggest two possible
reasons for the unanticipated failures
in phase II.
• Selection bias
resulted in different types of PD
patients being enrolled.
of such bias are:
Be valued for the knowledge and skills we bring to the table.
Examples of such bias are:
tremor dominant vs. rigidity dominant symptoms
responders vs. non responders to standard therapy
responders vs. non responders to placebo
optimized on medications vs. non optimized
Sham brain surgery as placebo may be so powerful that it overwhelms
treatment effects for a time (maybe up to 2 or more years, but
usually not more than 1 year).
an effect could force type 2 errors when the interim study results are
analyzed after a short time.
Dr. Stanley Fahn of the Columbia
University Medical Center has stated:
“A negative trial result does not necessarily mean that the compound
in question is of no therapeutic value – especially when that
compound has demonstrated promise in animal studies and earlier,
smaller, human trials. There could have been a problem with the
study design or lack of optimum dosage of the experimental compound.
A variation in the study design (e.g., different duration, different
dosage, different patient selection criteria, a change in method of
drug delivery) may yield different results, and should be explored
before any particular approach is abandoned."
terminated in late phases
NA = not approvable
requiring dopaminergic therapy
phase 2/3 trial
brain uptake of
phase 3 trials
terminated, 10/2007 and 4/2008
tapping of keys
NA, 3/2006 &
3 in North America, 6/2008
analysis of the three recent failed trials points to questions that need
to be addressed in order to justify what many consider to be unjustified
risk to ask patients to take, given expectations that even if they do
not benefit personally science will advance.
What adjustments in the design of statistical controls are necessary
to account for the impact of the context of an experimental protocol
that alters expectations of participants by randomization into
treatment and control groups?
What scientific criteria are used to determine efficacy or the lack
of efficacy of a treatment?
What assumptions are made about the interaction effects between a
treatment response and a placebo response?
What factors should be considered when selecting samples from a
heterogeneous populations as the evidence grows that some endpoints
may be achievable only for patients (responders) with certain
genetic variants or clinical sub types of the disease or are
influenced by other factors including the method of delivery?
presentation adds urgency to the need for these discussions, because
trials are failing, and promising therapies are being shelved in what
has been called the “tyranny of the type 2 error". (M. Hutchinson, S.
Gurney and R. Newson. GDNF in Parkinson disease: An object lesson in the
tyranny of type II. Journal of Neuroscience Methods. 163, 2, July 2007,
The above failed phase II studies were for therapies that were known to
work for some people over extended periods. The members of the Parkinson
Pipeline Project have analyzed possible explanations for this poor
record of accomplishment. We have come up with hypotheses that fit the
pattern of results seen in these studies. Our goal is to present a clear
and convincing argument that these are plausible hypotheses that merit
further study and such a study is a very high priority.
There is considerable research on pain, depression and the mechanism of
the placebo effect. These studies suggest that an experimental protocol
that views placebo surgery as a "bias" to be minimized may in fact
undermine the validity of the study. Key questions are raised that
researchers and regulators need to answer in order to prevent type 2
(false negative) errors. Based on the research literature and the
experience from DBS (a surgical intervention and the most important new
therapy for PD in the 40 years since Levodopa was introduced 40 years
ago), alternative design features and methods are needed.
Given the number of new, promising, surgically delivered, treatments in
the PD pipeline, policy discussions among FDA officials, scientists and
knowledgeable patient advocates (including patients that volunteer for
experimental treatments) on both the scientific and ethical issues about
what constitutes adequate control in the study design must be a high
priority to provide guidance to sponsors. The topic needs to be
addressed fully before other promising therapies are shelved based on
faulty assumptions about human behavior and the response to medicines.
The authors wish to acknowledge the support of the Parkinson's Disease
Foundation to the work of the Parkinson Pipeline Project.