Phase 2a Trial of PBT2 in AD Sup****ts Further Investigation
Susan Jeffrey
July 30, 2008 (Chicago, Illinois) -- The results of a phase 2 trial of
PBT2 (Prana Biotechnology), a metal-protein-attenuating compound, show
that the drug was safe and well tolerated over the 12 weeks of
administration to patients with Alzheimer's disease (AD).
Treatment with the highest dose tested in the trial was associated
with a reduction in the concentration of amyloid-=E2 (A=E2) in the
cerebrospinal fluid (CSF) but not in the plasma of these patients, and
there was some improvement in 2 measures of executive function in this
small safety study.
The study, led by Lars Lannfelt, MD, from Uppsala University Hospital,
in Sweden, and Craig Ritchie, MBChB, from Imperial College London, in
the United Kingdom, was published online July 29 in Lancet Neurology
to coincide with its presentation here at ICAD 2008: Alzheimer's
Association International Conference on Alzheimer's Disease.
Jeffrey L. ***mings, MD, professor of neurology and of psychiatry and
behavioural sciences at the David Geffen School of Medicine at the
University of California, Los Angeles, who was on the trial advisory
board and is a consultant and stockholder of Prana Biotechnology,
presented the results at a press conference.
"We feel that in this 12-week study, we showed that PBT2 was safe and
well tolerated, [and we have no reservations about] advancing this to
higher doses and more trials in larger patient populations," Dr.
***mings said.
Toxic Interaction
The ac***ulation of A=E2 in the brain is thought to be a central process
in AD. Copper and zinc interact with A=E2, increasing its aggregation
and toxicity. PBT2 is the second generation in a novel class of
agents, called metal-protein-attenuating compounds (MPAC). MPACs are
low-affinity metal-complexing compounds, but not chelators, the
authors note; they prevent the interaction of metal ions with A=E2
without lowering their concentration.
PBT1, also known as clioquinol, was investigated in phase 2 clinical
trials but was found to have a toxicity that discouraged further
development, Dr. ***mings noted.
In this phase 2a study of PBT2, Dr. Lannfelt and colleagues recruited
78 patients with early AD, defined as a Mini Mental State Examination
score between 20 and 26 or an Alzheimer's disease *****sment scale-
cognitive subscale (ADAS-cog) score of between 10 and 25. Patients
were randomized to receive placebo or either 50 mg or 250 mg of PBT2
for 12 weeks; the primary outcome was safety and tolerability.
Over the trial, 54% of patients had at least 1 treatment-emergent
adverse event, but events were not different between groups. There
were no withdrawals because of adverse events, and no serious adverse
events were re****ted in treated patients, the authors note. In
particular, there was no evidence of any features consistent with the
subacute myelo-optic neuropathy that had been a concern with PBT1, the
authors write.
Treatment-Emergent Adverse Events End point 50 mg PBT2 250 mg PBT2
Placebo
Adverse events, n (%) 10 (50) 18 (62) 14 (48)
Secondary outcomes of interest were plasma and CSF biomarkers and
cognition. The investigators re****ted that in patients treated with
the 250 mg dose, there was a significant reduction in A=E2 protein
levels in the CSF(a 13% reduction compared with placebo).
"This, for us, is the most im****tant outcome because it has been
difficult to develop agents that successfully intervene in the A=E2
process in the brain; the measure in CSF is the closest measure we
have to what is happening in the brain," Dr. ***mings said.
There was no effect on A=E2 levels in plasma, which, the authors say,
suggests a central effect of the drug on A=E2 metabolism. These findings
also highlight the ability of PBT2 to selectively affect brain but not
peripheral A=E2, the authors write.
As for the findings on cognition, Dr. ***mings noted, "one does not
expect a robust clinical outcome in a small short clinical trial, and
the ADAS-cog, the primary outcome of most clinical trials of
Alzheimer's disease, showed no difference between the drug and placebo
groups in this trial. It is of interest, however, that 2 executive
function measures -- Trails B and verbal fluency -- showed a drug-
placebo difference in favor of PBT2."
For example, at the end of 12 weeks of treatment, patients in the 250
mg group completed the Trail-Making Test, Part B, an average of 48
seconds faster than they had at baseline, whereas those taking placebo
completed the timed test an average of 5 seconds slower. "That is a
very significant outcome," he said.
Dr. ***mings told Medscape Neurology & Neurosurgery that the next step
is to plan their approach for a phase 2b study. "I think that, having
shown safety data for 250 mg, [we should now] test higher doses to see
if there's greater efficacy."
Hurdles Still Ahead
In a Reflection and Reaction article accompanying the publication of
the trial in Lancet Neurology, Norman R. Relkin, MD, director of the
memory disorders program at Weill Cornell Medical College, in New
York, sees cause for encouragement in these findings, but cautions
that "to go forward as a treatment for AD, PBT2 must still overcome
the high hurdle of additional safety and efficacy testing in large-
scale clinical trials."
The success or failure of the drug is predicated on 2 controversial
hypotheses about the pathogenesis of AD, Dr. Relkin adds. "The first
is the amyloid hypothesis, which still has many advocates despite the
recent failures of the first 2 anti-amyloid drugs (tramiprosate and
tarenflurbil) to complete phase 3 studies," he writes. The second and
arguably more controversial hypothesis relates to the role of metal
ions in AD. Many factors affect the ac***ulation of A=E2, but whether
the attenuation of the interactions between metal ions and A=E2 will be
sufficient to alter the course of AD is unclear.
"If we assume that the amyloid hypothesis holds water, future clinical
studies with PBT2 will not only test the mettle of MPACs, it will also
provide the first real-world test of the im****tance of metal-ion
homeostasis in the pathogenesis of AD," Dr. Relkin concluded.
The study was funded by Prana Biotechnology. Dr. ***mings re****ts he
is a consultant to and stockholder in Prana Biotechnology. Disclosures
for study coauthors appear in the paper. Dr. Relkin has disclosed no
relevant financial relation****ps.
Lancet Neurol. 2008; Published online before print July 29, 2008.
ICAD 2008: Alzheimer's Association International Conference on
Alzheimer's Disease: Press conference. Presented July 29, 2008.
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