This week
brings the publication of the (much-anticipated) EXPEDITION 3 study. This
reports the results of a very large drug trial of a drug that is hoped to
reduce the progression of Alzheimer’s disease. As you might be able to tell by
the name, it has been preceded by two previous similar studies.
What is unique
about this study? Firstly, the people involved all had ‘early’ Alzheimer’s
disease. Secondly, participants had to have ‘evidence’ of Alzheimers pathology –
this is key because in the previous studies although all the participants had
dementia, a significant number ended up having dementia of another cause.
What are the
other notable aspects of the design? The scales they used assessed ‘everyday’
performance (as best as a validated scale can), rather than an abstract
cognitive assessment; the study compared cognitive performace after 18 months
of treatment, which is a reasonable time given the tradeoff of the cost of a
trial such as this, and the rate of progression of the disease.
What are the
results? Unfortunately, there was no significant difference when comparing the
two groups after 18 months.
There are many
lessons for researchers in the Parkinson’s world to learn from this study. A
potential reason for failure is that even at the stage of ‘mild’ dementia,
there may be too much ‘toxic protein’ in the brain for the process to be
reversed, or slowed. To overcome this would require recruiting people with evidence of the disease, but without symptoms. Fortunately, this is exactly whom we hope to identify in PREDICT-PD.
Another potential reason for the failure of this drug in three trials is that with
solenizumab, they’re barking up the wrong tree. The drug has been specifically
designed to reduce the amount of abnormal amyloid protein in the brain.
However, although there is strong evidence for the Amyloid Hypothesis, the lack
of efficacy of anti-amyloid treatments has brought many in the field to
challenge the concept. In Parkinson’s there is less doubt over the Synuclein
Hypothesis, and the challenge remains to find a compound that can reduce it, or
stop it accumulating and causing brain destruction.
Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease
Abstract
BACKGROUND
Alzheimer’s
disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary
tangles. The humanized monoclonal antibody solanezumab was designed to increase
the clearance from the brain of soluble Aβ, peptides that may lead to toxic
effects in the synapses and precede the deposition of fibrillary amyloid.
METHODS
We conducted
a double-blind, placebo-controlled, phase 3 trial involving patients with mild
dementia due to Alzheimer’s disease, defined as a Mini–Mental State Examination
(MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores
indicating better cognition) and with amyloid deposition shown by means of
florbetapir positron-emission tomography or Aβ1-42 measurements in
cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at
a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The
primary outcome was the change from baseline to week 80 in the score on the
14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale
(ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater
cognitive impairment).
RESULTS
A total of
2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab
and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14
score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no
significant between-group difference at week 80 (difference, −0.80; 95%
confidence interval, −1.73 to 0.14; P=0.10). As a result of the failure to
reach significance with regard to the primary outcome in the prespecified
hierarchical analysis, the secondary outcomes were considered to be descriptive
and are reported without significance testing. The change from baseline in the
MMSE score was −3.17 in the solanezumab group and −3.66 in the placebo group.
Adverse cerebral edema or effusion lesions that were observed on magnetic
resonance imaging after randomization occurred in 1 patient in the solanezumab
group and in 2 in the placebo group.
CONCLUSIONS
Solanezumab
at a dose of 400 mg administered every 4 weeks in patients with mild
Alzheimer’s disease did not significantly affect cognitive decline. (Funded by
Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665.)
Has anyone noticed a recent paper on the use of baicalein to reduce amyloid load and stop further formation of it in mice?
ReplyDeleteA case of vascular dementia has almost completely resolved in 10 weeks taking Donepezil and a mix of food additives and supplements including baicalein. This result should be a pointer to similar combinations in Parkinson's.