Besides news on the most closely watched anti-amyloid drugs, the 8th Clinical Trials on Alzheimer’s Disease (CTAD) conference, held in Barcelona, Spain, November 5-7, featured a parade of lesser-known investigational therapies. Spanning Phases 1 to 3, they are a motley mix of new approaches and repurposed wares. True to the history of Alzheimer’s drug development thus far, many fizzled out when it came to showing efficacy. Others are being advanced to the next phase, some with and some without having met primary endpoints in the previous trial. Parts 3 to 5 of this CTAD series summarize clinical trial results presented there, organized by Phase 3 on downward.
In the last session of CTAD, Michela Gallagher of Johns Hopkins University, Baltimore, fired up a tired audience with news that a proprietary low-dose formulation of the atypical antiepileptic drug levetiracetam, called AGB101, was set to start a Phase 3 efficacy study in amnestic MCI in early 2016. Using an atypical anticonvulsant drug, this approach grew out of basic cognitive neuroscience advances, developed in Gallagher’s and other labs over the past decade, about how information is encoded in the medial temporal lobe memory system of the brain. This treatment strategy targets an age-related hyperactivity of the hippocampus, which in people at the MCI stage of AD occurs opposite hypoactivity of the entorhinal cortex. Both functional MRI and high-resolution MRI have localized the hyperactivity to the CA3/dentate gyrus part of the hippocampus, tied it to decline toward dementia, and shown that amyloid-positive MCI patients are most prone to further hippocampal hyperactivity and faster decline (e.g., Celone et al., 2006; Hämäläininen et al., 2007; Yassa et al., 2010; Huijbers et al., 2015).
After a pilot study showed promise for levetiracetam, Gallagher and colleagues evaluated three doses of the drug in a Phase 2 study (May 2012 news; Mar 2015 news). In that trial, a low-dose range brought down hippocampal hyperactivity, restored entorhinal activity, and boosted performance on a memory task, though Gallagher cautioned that these comparisons were within-subject and the group showed large variability. Levetiracetam is FDA-approved at up to 3,000 mg daily for the treatment of epilepsy. This aMCI program will use 220 mg daily, which has been safe thus far, Gallagher said at CTAD.
Sites in the United States, Canada, and Europe will evaluate a low-dose, extended-release formulation of levetiracetam in a Phase 3 registration trial, Gallagher told the audience. People with MCI due to AD and a positive florbetapir scan will be randomized to take drug or placebo for 18 months. As currently designed, the trial’s success will hinge on the CDR-sb as a single primary outcome, following FDA guidance for trials at that stage of the AD continuum (Kozauer and Katz, 2013). The CDR-sb’s ability to capture small treatment effects in early AD was questioned at CTAD (see Q&A with Steven Ferris).
As a secondary outcome, Gallagher chose atrophy of the entorhinal cortex. Whole-brain and hippocampal atrophy have more commonly been used as outcome measures in trials; however, analysis of longitudinal cohorts such as ADNI and BIOCARD suggested to Gallagher that shrinkage in the entorhinal cortex precedes, and indeed predicts, shrinkage of the hippocampus in Alzheimer’s disease (Desikan et al., 2010; Eskildsen et al., 2013; Miller et al., 2013).
In the past, other members of the racetam class of drugs have been tried unsuccessfully in Alzheimer’s disease, though they are different molecules and were used at higher doses (e.g., Growdon et al., 1986; Croisile et al., 1993; Flicker and Grimley Evans, 2001).
Another entrant into Phase 3 is the serotonin receptor 6 antagonist RVT-101. This drug was developed and taken through Phase 2 by GSK under the name SB-742457, and sold in 2014 to the startup company Axovant. At CTAD, Axovant’s Lawrence Friedhoff presented no new data, but announced plans to evaluate this drug in dementia with Lewy bodies, as well. A Phase 3 study for AD has started enrolling.
Deep Brain Stimulation
Meanwhile, Constantine Lyketsos, also at Johns Hopkins, told the audience that deep brain stimulation of the fornix is poised to move into Phase 3 based on partial success in Phase 2. The fornix is a bundle of fiber tracts that carry signals from the hippocampus to other brain areas. This approach views Alzheimer’s disease as a circuit problem, and tries a circuit-based solution, Lyketsos said. Thought to strengthen connectivity, or perhaps even neurogenesis (Mirzadeh et al., 2015), deep brain stimulation requires surgery to embed a lead electrode into the brain and a stimulator pack under the skin. DBS has accrued ample safety and procedural experience, as some 100,000 people worldwide, most of them Parkinson’s patients, have been exposed to it. DBS of the fornix is the most advanced among several attempts to try stimulation in Alzheimer’s; another stimulates the nucleus basalis of Meynert (Sep 2013 news; May 2014 news). Following a promising pilot study in six patients (Laxton et al., 2010; Smith et al., 2012), in 2012 a seven-center Phase 2 trial began in the United States and Canada. At CTAD, Lyketsos presented its one-year results.
This trial enrolled 42 people with mild AD between the ages of 45 to 85, who had to have evidence of functional decline in the previous year to ensure they were progressing. Everyone had electrodes implanted in the area immediately anterior to the fornix, but subsequently participants were randomized to either have them activated (the “on” group) or not (the “off” group) for the following year. After that everyone had their stimulator turned on for an open-label, second year of study. Study staff was blinded such that the technicians who adjusted the stimulators were separate from the people who assessed the study participants, Lyketsos said. The whole two-year trial requires participants to come for 13 visits after the surgery and follow-up is nearly complete, Lyketsos said. “We do not have the problem of how to deal with missing data.”
On the primary objective—to learn whether AD patients tolerate neurosurgery and subsequent stimulation—the study succeeded. “This appears to be safer than we had been concerned about. The cognitive testing before and four weeks after surgery was practically identical. The surgery itself was not harmful, and adverse effects during the first year were very comparable between the groups,” Lyketsos told the audience.
The secondary objective—to learn whether DBS of the fornix worked—was more elusive. Both the “on” and the “off” groups declined significantly at one year after surgery, and neither the CDR-sb or the ADAScog13 showed a clear difference between the groups. Curiously, however, a biomarker outcome, brain glucose metabolism measured by FDG-PET, did show a “robust, widely distributed increase” in the “on” group, Lyketsos said.
Next, the researchers analyzed subgroups to see if some of the patients might have responded. They uncovered an age effect, whereby people with early onset AD appeared to have fared poorly on treatment, but people with late-onset AD LOAD looked as if they possibly had benefitted on the ADAS-cog and CDR-sb. Participants under 65 turned out to have had worse brain metabolic deficits than older participants already at baseline, and from there the younger patients declined faster on treatment than did the “off” group. Blood-flow imaging and FDG PET indicated that the younger patients had come into the study with more advanced brain disease than the older ones, even though they appeared equally impaired on the clinical measures on which they were being recruited. “The younger people were beyond the very mild disease we are targeting,” Lyketsos said. In the older patients, “there is a hint of a possibility that fornix DBS might work,” he added.
This was enough for the sponsor, the company Functional Neuromodulation Ltd., to go on, and the researchers are now designing a Phase 3 pivotal study. It will recruit people older than 65 who have early AD confirmed by amyloid PET. Lyketsos said the trial might include a composite outcome and follow people longer. Gil Rabinovici of UCSF noted that the sequence by which specific circuits come under attack can differ between early and late-onset AD. For example, some early onset AD cases are marked by more pronounced degradation of posterior cortical areas than the hippocampus. That, too, could explain why stimulation of the fornix works only in particular subsets of AD.
ELND005 in Limbo
This compound—aka scyllo-inositol or AZD-103—has a circuitous history, with clinical trials going on in Alzheimer’s disease since 2005. It started as a proposed anti-Aβ oligomer agent but, after it failed to improve cognition in Phase 2, it was recast as a signal transduction modulator that might be able to soothe agitation and aggression in advanced AD (see Apr 2008 conference news). It received fast-track designation from the FDA and was undergoing a Phase 2/3 trial when its company, Transition Therapeutics, announced last summer that that trial, too, had missed its primary endpoint. The company then terminated the trial’s 36-week safety extension.
At CTAD, Anton Porsteinsson of the University of Rochester School of Medicine and Dentistry, New York, talked the audience through the data. “This was a negative study,” Porsteinsson said. From a randomized population of 175 patients with probable AD in both the treatment and placebo groups, the researchers analyzed a modified intent-to-treat population of 167 patients in each group. Eighteen patients in each arm dropped out of this 12-week trial. Diarrhea, cough, lethargy, and falls were more common in the drug than the placebo group, but clinicians generally feel that the suffering of agitated patients at this stage of AD, and the burden on their caregivers, is so great that this safety profile would be acceptable. The problem was that the groups were no different on the primary outcome, a modified version of the neuropsychiatric inventory (NPI), or on either secondary endpoint, an agitation/aggression excerpt of the NPI and a modified clinical global impression of change.
“What else can we learn from this? Is there a signal buried under main findings?” Porsteinsson asked in his CTAD talk. He then presented a post hoc subgroup analysis. It suggested a trend shy of statistical significance that the most severely affected patients might have benefitted. They are people whose NPI scores were not only high but also marked by acting out aggressive behaviors such as shoving, slamming, or intruding. The patients who did not respond had more of the milder behaviors this version of the NPI records, such as fidgeting and stubbornness. “The most severe patients seem to have responded,” Porsteinsson said. The company hopes to continue developing this compound, but has to secure funding, Porsteinsson wrote to Alzforum. Transition Therapeutics posted slides from Porsteinsson’s presentation on its website. For Phase 2 results, see Part 4 of this series.—Gabrielle Strobel
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