With the buzz surrounding amyloid-targeting therapies, it is easy to
lose sight of the fact that other treatments are being tested as well.
Presentations at the 11th annual Alzheimer’s Association International
Conference (AAIC, formerly ICAD), held 16-21 July 2011 in Paris, France,
provided snippets of new information on ongoing trials.
One that is being closely watched is the Alzheimer’s Disease
Cooperative Study (ADCS) Phase 3 trial of a plasma-derived human
antibody product called intravenous immunoglobulin (IVIG), or Gammagard,
developed by Baxter Healthcare. In small studies, this treatment has
resulted in both improved cognition and increases in brain volume in AD
patients (see ARF related conference story).
"As far as I know, the only experimental treatment that has shown a
positive correlation between a biomarker and a clinical measure is
IVIG," said Pierre Tariot at the Banner Alzheimer’s Institute in Phoenix, Arizona, who serves as a sub-investigator in the ADCS/Baxter IGIV trial.
It is not yet clear whether IVIG decreases amyloid-β in the
brains of AD patients, but the antibody mixture does contain some
antibodies against Aβ (Dodel et al., 2011 and Szabo et al., 2010).
The drug could have other mechanisms of action, as well, such as immune
system-modulating properties, which could explain its beneficial
effects. This suggestion came from Norman Relkin at Weill Cornell
Medical College in New York City in his AAIC presentation. Relkin
measured plasma cytokine levels in 24 AD patients who had enrolled in a
prior Phase 2 placebo-controlled IVIG clinical trial. Results from that
trial indicated that the cognitive symptoms of patients receiving the
treatment improved (see ARF related conference story and ARF conference story).
In these patients, nine out of 31 blood cytokines tested increased
significantly, and in a dose-dependent manner, following IVIG treatment.
The nine cytokines were IL-1A, IL-4, IL-5, IL-6, IL-8, IL-13, GCSF,
EGF, and VEGF; increases in IL-5 and IL-8 best correlated with six-month
cognitive outcomes. Relkin is currently leading the ADCS Phase 3
multicenter trial of IVIG in 390 AD patients. That study is now fully
enrolled and expected to read out during the first half of 2013.
AAIC featured a handful of presentations on IVIG. A poster by William Shankle,
at the Hoag Neurosciences Institute in Newport Beach, California,
reported a slowing of cognitive and functional decline in a subset of 17
patients with AD or Lewy body disease when these patients were treated
with IVIG for up to five years. This slowing persisted for up to three
years after stopping IVIG in patients who discontinued the treatment.
These are not data from a blinded trial; through his private practice in
Newport Beach, California, Shankle has for some years administered IVIG
to a number of patients, who pay for this treatment out of pocket.
"While this is not a controlled, clinical trial, it has the advantage of
adjusting each outcome to the patient’s own rate of decline before IVIG
treatment," wrote Shankle in an e-mail to ARF.
At AAIC, Anton Porsteinsson of the University of Rochester Medical Center presented some of the data from the Phase 2 trial of ELND005 (aka scyllo-inositol),
a potential oral treatment for AD, being developed by Elan Corporation
and partner Transition Therapeutics. The drug has been shown to inhibit
aggregation of Aβ in transgenic TgCRND8 mice (McLaurin et al., 2006), and based on Phase 2 trial data, the companies announced they would take the compound into Phase 3 (see ARF related news story).
Originally, 353 patients with mild to moderate AD were randomized
to one of three doses of ELND005 (250, 1,000, or 2,000 mg), but Elan
later dropped the two higher doses because of safety concerns. At AAIC,
Elan and academic scientists reported on a poster that there were no
deaths in the placebo group versus one death in the 250 mg group and
five and four deaths in the two higher dose groups, respectively.
Infections also were more common in the high-dose groups. All subsequent
functional and biomarker analyses pertain to the lower 250 mg dose.
With regard to function, Stephen Salloway of Brown
University, Providence, Rhode Island, showed data indicating that the
treatment group and the placebo group did not differ significantly on
the neuropsychological test battery (NTB) or AD Cooperative
Study-Activities of Daily Living Scale (ADCS-ADL). This means the study
missed its co-primary endpoints. The scientists then moved on to
subgroup analyses pre-specified in the protocol, and saw that patients
with mild AD receiving 250 mg of ELND005 had significantly higher NTB
scores at week 78 compared to placebo.
With regard to biomarkers, at week 78, the 84 patients receiving
250 mg of the drug had an increase in their brain ventricular volume
compared to the 82 patients on placebo. Ventricular volume expansion
indicates atrophy of brain matter. This difference was seen in the
subset of patients with moderate AD, not in those with mild AD. Both
mild and moderate patients treated with 250 mg of ELND005 also had a 27
percent decrease in CSF amyloid-β 42 (Aβ42) levels after 78 weeks of
treatment. CSF total-tau (t-tau) and phosphorylated tau (p-tau) did not
change with ELND005 treatment. In toto, then, patients with mild AD
showed a positive trend on the study’s primary cognitive outcome and CSF
Aβ42 reduction, but no significant change in ventricular volume or CSF
t-tau or p-tau, whereas more advanced patients had no cognitive benefit
or brain shrinkage.
One of the new kids on the block is PF-04447943, a selective
phosphodiesterase-9A (PDE9A) inhibitor that elevates the amount of
cyclic GMP in brain and CSF. Pfizer is testing the drug in AD, but as
reported in Paris, results of a multicenter, randomized, double-blind,
placebo-controlled Phase 2 trial were not particularly encouraging.
Although the drug was generally safe, Elias Schwam of Pfizer in
Groton, Connecticut, explained that after 12 weeks of treatment, there
was no significant difference in ADAS-cog scores or in the global
clinical scores between 91 patients with mild to moderate AD who
received 25 mg of the drug and 100 patients who received placebo. "This
suggests that, within mild to moderate, a target like cyclic GMC does
not show efficacy in a short trial," said Schwam. "Maybe the treatment
is effective in earlier stages of disease."
Too Little Too Late
A growing number of researchers are seeing recent failures in AD
clinical trials as a sign that treatment is being given too late in the
disease process. "We have had some spectacular Phase 3 failures in mild
to moderate disease. It is precisely for these failures that we need to
move earlier," said Reisa Sperling of Harvard Medical School. She will be lead investigator for a therapeutic trial of preclinical AD planned by ADCS (see ARF related Webinar).
A proposal for another trial in preclinical AD has also been
submitted for funding by the Alzheimer’s Prevention Initiative (API) of
Banner Alzheimer’s Institute in Phoenix (see ARF conference series), according to a presentation by API’s co-director Pierre Tariot. If approved and funded, that trial should begin by the end of 2012, or, more likely, the beginning of 2013, Tariot told ARF.
In his presentation at AAIC, Tariot reviewed several alternative
approaches for designing clinical trials for preclinical AD. He
suggested that, in the future, when sufficient data become available to
conduct the necessary modeling, Bayesian designs may be well suited to
such studies. These permit use of accumulating data analyzed at frequent
intervals to decide how to modify aspects of the study as it is being
conducted (see ARF related news story).
In the meantime, the first trial proposed by API incorporates a
so-called adaptive frequentist design with a nested cohort study. The
primary outcome of the study would be a change in cognition, but it
would also measure different biomarkers. Changes in the biomarkers would
be used to make decisions during the trial without prespecifying a
hierarchy in response pattern. This information would then serve to
design future trials in a different way, as well as to establish the
predictive, prognostic, and correlateive value of biomarkers. "Multiple
hypotheses can be addressed in this type of trial," said Tariot.
The trial would be carried out in cognitively normal carriers and
non-carriers of mutations causing early onset AD, including a large
kindred from Colombia, in which AD is caused by the E280A presenilin-1
(PS1) mutation. Tariot and colleagues have calculated that the trial
will probably need to enroll 300 participants without clinical symptoms
of AD, including both mutation carriers and non-carriers; carriers would
be randomized to treatment. API has proposed a prototype treatment in
the grant proposal, although all involved agree that the best available
agent will need to be used when such a trial is launched, and the choice
could change. Tariot could not, however, disclose the drug the
investigators have incorporated in the grant proposal. (see ARF related news story).
"I am really impressed with people wanting to go earlier, as it
might be easier to go on to conduct another Phase 3 trial," said Nick Fox
of University College London, U.K., who chaired the session at which
Tariot spoke. However, in discussions following the presentation, some
conference attendees questioned the rationale of going full-steam with a
large trial of preclinical AD before there are officially validated
biomarkers or cognitive tests for the condition. Both API and a sister
effort for preclinal-stage trials, the Dominantly Inherited Alzheimer’s
Network (DIAN), are doing extensive work on biomarkers and cognition in
preparation for clinical trials in their respective populations.
Others question the conclusion that the current failure of AD
drugs to succeed in trials of mild to moderate AD means researchers
should focus on treating preclinical stages of disease. "People make the
argument that, by the time you have AD, you have too much neuronal loss
and it is too late. I do not think there are enough data to say that,"
said Eric Siemers of Eli Lilly and Company. "The other drugs to
date never got into the brain in sufficient quantities to really test
the hypothesis. But if you can make the rate of cognitive decline faster
[as it happened with semagacestat], you might also make it
This is Part 2 of a series on clinical trial news. See also Part 1.
To view commentaries, primary articles and linked stories, go to the original posting on Alzforum.org here.
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