| December
18, 2003 A
small phase II clinical trial published this week in the Archives
of Neurology supports further investigation of
metal-protein–attenuating compounds (MPACs) for the
treatment of Alzheimer disease (AD). However, Prana’s
(NASDAQ: PRAN) PBT-1 (clioquinol, iodochlorhydroxyquin), the
MPAC used in this investigation, is unlikely to generate an
appropriate risk-benefit ratio for use in the management of
AD. Developmental data sets to date, including those from this
program, suggest that PBT-1’s efficacy, safety, and
pharmacological profiles are all suboptimal.
PBT-1
is a MPAC that inhibits zinc and copper ions from binding to
amyloid constituents, thereby promoting amyloid dissolution
and diminishing the formation of amyloid plaque associated
with AD. Oral and topical clioquinol formulations were
initially developed as antifungal and antibacterial
medications, but were withdrawn from the market in 1970
because of an association with recipients developing a
devastating condition known as
subacute-myelo-optico-neuropathy (SMON), in turn associated
with vitamin B12 deficiency.
Many
over-the-counter and prescription formulations contain
iodoquinol, a related compound, but they are not recommended
for individuals over two years of age and not at risk for
diaper dermatitis. Reports of both clioquinol and iodoquinol-related
adverse effects still crop up: irreversible optic atrophy
(wasting away of the optic nerve, which is primarily
responsible for vision), peripheral neuropathy (non-brain or
spinal cord nerve problems of various sorts), and other
neurological insults.
Companies
including Prana and the Gerolymatos Group in Greece are
reformulating clioquinol to develop it as an AD treatment and
minimize its adverse effects. Given to young mice engineered
to develop Alzheimer-like deposits, clioquinol appeared to
inhibit plaques from forming. In another study, clioquinol
appeared to clear up plaques in mice old enough to have
developed substantial deposits of amyloid.
The
article published this week by Ritchie, et al describes a
36-week, randomized, double-blind, placebo-controlled study of
36 patients and their caregivers. Oral PBT-1 125mg twice daily
was evaluated from weeks 0 to 12, 250mg twice daily from weeks
13 to 24, and 375mg twice daily from weeks 25 to 36. 32
patients generated per protocol data.
One
PBT-1 recipient developed impaired visual acuity and color
vision during weeks 31 to 36 of the trial, while she was
receiving PBT-1 375mg twice daily. The subject’s symptoms
resolved when PBT-1 was discontinued. Although only one other
serious adversity was observed in the PBT-1 group, even the
possibility that this represents SMON or a variant is of great
concern, especially given its relationship with the highest
dose of a dose range generating a poor efficacy profile.
PBT-1’s
efficacy profile, in terms of cognitive ability preservation,
was suboptimal, significant only for a modest magnitude of
therapeutic effect for more severely affected participants. A
statistically significant difference between the cognitive
preservation capacity of PBT-1 and placebo was not observed at
any week. Trends toward statistical significance were noted at
weeks 4 and 24. A statistically significant difference between
the cognitive preservation capacity of PBT-1 and placebo was
not observed for less severely affected participants. A
statistically significant difference favoring PBT-1 receipt
was observed for more severely affected patients at weeks 4
and 24. But at week 36, this difference was relegated to a
mere trend. It remains unclear whether the differences in mean
change from baseline ADAS-cog score (the primary test of
cognitive function) in the PBT-1 arm compared with the placebo
arm at weeks 24 and 36 (7.37 [95% confidence interval,
1.51-13.24] and 6.36 [95% confidence interval, -0.50 to
13.23], respectively) bears clinical significance. As far as
testing cognitive function with The Mini-Mental State
Examination, similarly insignificant statistical differences,
but favorable trends, were observed. Moreover, the
non-cognitive ADAS and Clinician Interview-Based Impression of
Change scores were neither significantly different between
groups nor associated with favorable trends. Pharmacogenetic
correlates of apolipoprotein E genotyping were also not
observed, and are thus unavailable for study subject selection
refinement.
Disappointing
clinical results were associated with biochemical effects that
support further development of MPAC compounds. Significant
compound and/or protocol refinements will be required. For
instance, plasma Aß42 (an amyloid fragment) levels declined
significantly from baseline in the PBT-1-treated group from
week 20 onward. During the same time, plasma Aß42 levels in
the placebo group increased. Ironically, plasma Aß42 changes
were evident only in the less severely affected group.
Data
relevant to copper- and zinc-related parameters were sketchy,
and certain assays were deemed invalid based upon technical
issues during the conduct of the investigation. The
zinc-related biochemical profile appears reassuring, though.
Certain data also suggest that measurements of extracellular
brain PBT-1 levels will be required, together with more
refined plasma pharmacokinetics, before a more optimal dosing
approach can be found and assessed. Vitamin B12 and folate
metabolism also requires further assessment. The potential
PBT-1-associated optic neuropathy suspected in the one study
subject mentioned above is of considerable concern, although a
direct causal link to PBT-1 remains uncertain. 27 subjects are
participating in an open-label extension study. 10 subjects
have received PBT-1 500 to 750mg/d for more than 18 months,
and definite PBT-1-attributable adverse events have yet to be
observed. |
