15 June 2012. Are AD therapeutics about to go viral? NeuroPhage Pharmaceuticals, a small startup company, is banking that viral capsids will break up aggregates of Aβ and other amyloidogenic proteins. Company researchers outlined their strategy at the 12th International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy, which took place in the Swedish capital from 9-12 May 2012. While novel immunotherapies also made a splash at the meeting (see also ARF related news story), interest in some older treatments for Alzheimer’s disease resurfaced as well. Researchers debated the virtues of combining acetylcholinesterase blockers with monoamine oxidase inhibitors; new evidence emerged on vitamin B’s punch to slow neurodegeneration in people with high homocysteine levels; and a hypertension drug found new life as a potential AD treatment. Finally, scyllo-inositol, a compound that missed its primary endpoint in a recent trial, hung on tenaciously as a potential treatment for neuropsychiatric symptoms.
Richard Fisher from NeuroPhage based in Cambridge, Massachusetts, said that his company’s strategy is to capitalize on the interaction of the filamentous M13 phase with Aβ. M13 may be better known to researchers for its versatility in cloning genes, but researchers previously found that it binds to and disrupts amyloid fibrils. Fisher detailed preclinical data to show that NPT001 and NPT002, proprietary derivatives of M13, do the same and also prevent Aβ toxicity in cell culture assays. In vivo, these capsids colocalized with and reduced plaques in mouse models of AD. A bilateral injection of phage into the hippocampus kept plaques at bay for six weeks, and the mice performed better in novel object recognition and spontaneous alternation tasks. Curiously, while the phage reduced plaque burden by half, suggesting Aβ was solubilized, interstitial Aβ did not change. Fisher said he is unsure why, but thinks that the phage and Aβ become tightly complexed.
Fisher acknowledged challenges in translating this approach into humans, not least being how to get sufficient numbers of phage particles into the brain. Intrathecal administration may be the answer. Fifty percent of a bolus of viral particles injected intrathecally into monkeys made it into the brain, he said. Assuming the company can overcome the creep factor of having phage infused directly into brain, NeuroPhage plans a Phase 1 trial in AD patients for 2013. The company will use amyloid PET imaging to test if NPT002 can break down plaques. Other scientists frequently mix the words "intrigued" and "out there" when discussing NeuroPhage’s research. It grew out of Beka Solomon’s early work on filamentous phages in AD (see ARF related conference story); indeed, Solomon’s son Jonathan is president and CEO of the company.
Another plaque buster, scyllo-inositol (aka ELND005), was developed by Elan Pharmaceuticals in collaboration with partner Transition Pharmaceuticals (see ARF related news story). In a Phase 2 clinical trial, the drug failed to significantly improve cognition or function in patients with mild to moderate AD (see ARF related news story). The compound did reduce Aβ in cerebrospinal fluid, and the companies claimed that exploratory analyses suggested improved clinical endpoints in some patients. With these results, they moved the compound into a Phase 3 trial where the two highest doses (1 g and 2 g twice daily) caused such serious adverse events that they were dropped (see ARF related news story). At a mini-symposium in Stockholm, an entirely new story emerged. Apparently, low doses of scyllo-inositol may benefit AD patients not by blocking Aβ aggregation, but by reducing myoinositol in the brain.
Elan’s Gene Kinney recounted how falling myoinositol levels were discovered when company researchers used NMR to confirm scyllo-inositol had made its way into the brain. The researchers noticed that, as brain scyllo-inositol rose, its myo-isoform fell. Going back to animal models, they found that the myo isoform dropped by as much as 70 percent when the animals imbibed drinking water laced with scyllo-inositol. Why is this important? Previously, researchers had reported elevated brain myoinositol in patients with AD, Down's syndrome, and bipolar disorder, said Kinney (see Miller et al., 1993). More recently, a group in Japan correlated elevated brain myoinositol with behavioral and psychological problems in AD patients. Lithium, which has been used for many years to treat neuropsychiatric disorders, may work in part by reducing myoinositol. In fact, a 30 percent reduction of myoinositol is predictive of lithium efficacy, said Kinney. By reducing myoinositol, could scyllo-inositol treat neuropsychiatric symptoms in AD patients?
Susan Abushakra, also from Elan, reported that the 250 mg dose of scyllo-inositol drove down brain myoinositol by about 40 percent. She also said that post-hoc analysis of the Phase 2 trial indicated that fewer neuropsychiatric symptoms emerged in patients on drug compared to those on placebo. Pierre Tariot, Banner Health, Phoenix, Arizona, dove into that analysis in depth. While patients on 250 mg scyllo-inositol declined at the same rate on the neuropsychiatric inventory (NPI) over the 78 weeks of the trial as those on placebo, Tariot considered it worthwhile to specifically investigate the emergence of new symptoms during the course of the treatment. He looked for an increase from a score of zero on two or more of the test items in the NPI; these include aberrant motor activity, agitation/aggression, anxiety, apathy, appetite change, delusions, disinhibition, dysphoria, euphoria, hallucinations, and irritability/lability. He found that 75 percent of trial participants with mild AD on placebo had two emerging symptoms as opposed to 50 percent of patients on 250 mg scyllo-inositol. Looking at single NPI items, the researchers noted that the drug seemed to stem emergence of depression, appetite changes, agitation, and anxiety. Tariot also found a correlation between decline in brain myoinositol and suppression of these behaviors.
Some researchers who attended the symposium were unsure what to make of this. Competition with sodium/myoinositol transporters offers a plausible explanation for how scyllo-inositol lowers the myo isoform in the brain, but how that translates into a behavioral effect was anybody’s guess. Some asked if changes in inositol-phosphate signaling cascades are responsible. Abushakra said that Elan was looking into that. She also said that reductions in osmotic pressure might be at play; myoinositol happens to be a major osmolyte in the brain. On that note, Constantine Lyketsos, Johns Hopkins University, Maryland, reported that patients who responded to the treatment had less cerebroventricular enlargement, which may be related to osmotic changes.
Further analysis suggested that patients who benefited from the drug had milder cognitive deficits and lower tau in the cerebrospinal fluid at baseline than those who did not, noted Lyketsos (see also ARF related news story). This will be helpful in thinking about further clinical development, he suggested. Whether Elan will pursue the drug is unclear. Tariot said scyllo-inositol was under consideration as a potential prevention drug. Abushakra said the company is weighing its options.
Ladostigil is another treatment that might relieve neuropsychiatric symptoms, reported Marta Weinstock, Institute of Drug Research in Jerusalem, Israel. This drug is a pro-drug derivative of rivastigmine, an acetylcholinesterase inhibitor Weinstock helped develop. In the brain, cholinesterases metabolize ladostigil to generate a monoamine oxidase (MAO) inhibitor that boosts levels of dopamine, noradrenalin, and 5-hydroxytryptamine. Weinstock said she expects the drug would reduce anxiety, apathy, and depressive symptoms in AD patients. Ladostigil has just finished a Phase 2 clinical trial sponsored by Avraham Pharmaceuticals, Yavneh, Israel. In this multicenter, double-blind trial, people with mild to moderate AD (MMSE 14-24) took 80 mg of ladostigil twice daily for six months. Cognition and safety were the primary outcomes with behavioral and psychiatric evaluations as secondary measures. The results are expected in the last quarter of 2012.
Weinstock reviewed preclinical data that suggests this drug might help dementia patients. In addition to its MAO and cholinesterase activity, the drug and its metabolites protect cells against oxidative stress and nitric oxide, she said. She believes that the compounds prevent opening of the mitochondrial transition pore, which can trigger apoptosis. In microglial cultures, ladostigil and metabolites seem to tone down release of nitric oxide and inflammatory cytokines. She showed that the drug protected rats against age-related decline in novel object recognition and spatial memory. A three-year Phase 2 trial of low-dose ladostigil (10 mg) in people with mild cognitive impairment is currently recruiting subjects.
Moussa Youdim, Technion-Israel Institute of Technology, Haifa, Israel, described a different type of MAO inhibitor hybrid that also acts as an iron chelator. Youdim noted that iron chemistry creates oxidative stress, and that iron accumulation in the brain has been linked to AD and other neurodegenerative diseases. Amyloid precursor protein (APP) mRNA contains an iron response element that might drive APP synthesis. Youdim reported that several compounds with MAO inhibitor/iron chelator properties reduced APP and β-secretase fragments of APP in 10-month-old APP/PS1 transgenic mice, and attenuated soluble Aβ and amyloid plaque burden.
A different potential therapy that has returned mixed results in the past is vitamin B. David Smith, University of Oxford, England, co-leads the VITACOG trial that indicated B vitamins slow brain atrophy and reduce cognitive decline in people with mild cognitive impairment who also have high plasma homocysteine, a neurotoxin (see ARF related news story). In Stockholm, Smith presented voxel-based morphometry data for a detailed look at atrophy changes. He reported that over the course of the two-year trial, vitamin B slowed atrophy in most areas of the brain examined, including the hippocampus, fusiform gyrus, precuneus, and middle and inferior temporal gyri. Smith said that, overall, the treatment slowed atrophy by about 50 percent. He said the results are evidence of a disease-modifying effect, claiming that, while the treatment may not cure AD, it may prevent it.
Lastly, Giulio Pasinetti from Mount Sinai School of Medicine, New York, discussed the possibility of treating AD with drugs previously approved for entirely different conditions. He is planning a pilot trial to test if carvedilol, an anti-hypertensive, can improve cognition. This will be a six-month, single-site trial recruiting 50 AD patients. Pasinetti and colleagues singled out carvedilol after screening previously approved drugs for Aβ-lowering activity in mice. CRND8 transgenic mice taking 7.5 mg of the drug daily perform better in novel object recognition tests of learning and memory, had reduced Aβ in the brain, and showed improved synaptic plasticity, said Pasinetti. In response to questions, he said he does not know how carvedilol works in this context. Its hypertensive action seems irrelevant because blood pressure in the mice did not change at the doses used. Preliminary evidence suggests a metabolite of the drug may interact with Aβ, he said.—Tom Fagan.