A mid-stage study by a tiny company wouldn’t usually attract much attention, but the results unveiled by Neurotrope BioScience have been eagerly anticipated because its drug — derived from a bushy, hermaphroditic sea creature — takes a novel approach.
Big pharma companies have poured billions into drugs that target the toxic molecules amyloid and tau, long seen as the causes of Alzheimer’s. Neurotrope instead took aim at the immediate cause of cognitive decline: destruction of brain synapses and neurons, the physical basis of memory and thought. By preserving neurons and creating new synapses, the team hoped not just to ward off memory loss but perhaps even to help a damaged brain recover, Dr. Daniel Alkon, the company’s president, said in an interview while the trial was underway.
The Phase 2 clinical trial suggests he could be on a promising track. Although the main goal of such a study is to test drug safety, this one also gathered data on how well patients did on a standard test of cognition, called the Severe Impairment Battery, which is used in dementia patients with such serious cognitive deficits they often struggle to answer questions such as, “What is your name?” and “What is the thing you drink coffee from?”
Neurotrope enrolled 147 patients with an average age of 72 and moderately severe to severe Alzheimer’s. Some dropped out, so in the end, 33 got a high dose of the drug (known as Bryostatin-1), given intravenously every two weeks; 38 got a low dose, also every two weeks; and 42 got a placebo.
The patients who received all six low doses did the best; their average improvement after the 12 weeks was 1.5 points on the 100-point cognitive test. Patients receiving a placebo (most were also on standard Alzheimer’s drugs) lost 1.1 points.
Investors were strikingly unimpressed: in early morning trading the stock was down by just over 50 percent, to around $9 a share.
A 2.6-point edge over placebo may fall slightly short of what the Food and Drug Administration would require for approval of a new Alzheimer’s drug, said Dr. Sam Gandy, a neurologist and Alzheimer’s researcher at Mount Sinai School of Medicine who is not affiliated with Neurotrope. He said the FDA typically wants to see a net benefit of at least 3 or 4 points. A longer trial might show if Bryostatin-1 can deliver that; if it indeed preserves and creates synapses, continued use might bring greater benefits, Alkon said.
Although it might seem odd that the lower dose produced greater benefit than the higher dose, that is consistent with what Alkon and his colleagues saw in mouse studies: Because of the way bryostatin acts to boost synapses, less is more, as higher quantities overwhelm neuronal circuits.
One possible red flag: The apparent gains in the low-dose group did not meet the threshold for statistical significance. That means there is a greater probability than researchers generally accept that they were due to chance, rather than to the drug.
Neurotrope’s results have not been published in a scientific journal or presented at a medical meeting, so outside experts have not been able to evaluate that and other important details.
Another concern about the new study is its modest length. In three months, many people with Alzheimer’s deteriorate precipitously, so the fact that the group receiving Bryostatin-1 showed improvement could indeed be due to the drug. On the other hand, some patients might have maintained their status quo during that period even without it.
Also, 12 weeks “might not be long enough to see chronic side effects” that could emerge with long-term use of the drug, said Dr. Howard Fillit, executive director of the Alzheimer’s Drug Discovery Foundation. (If it works, patients would likely have to take Bryostatin-1 for the rest of their lives.) The main adverse event was diarrhea.
The study was unusual for including patients with advanced disease. Most drug companies are testing compounds on patients at earlier and earlier stages of Alzheimer’s, before their brains have lost many synapses. It is also unusual for focusing not on amyloid levels but on loss of synapses. But synapse loss is tied much more closely to the severity of dementia than amyloid plaques and tau tangles are, said Dean Hartley, director of science initiatives at the Alzheimer’s Association.
Neurotrope’s approach uses bryostatin, derived from a moss-like creature named Bugula neritina. In lab animals and cells in dishes, Neurotrope found that its drug increased synapse-boosting molecules called protein kinase C epsilon. That has two effects: it protects neurons from being destroyed by amyloid molecules, and it helps preserve and create synapses.
Bryostatin-1 reversed brain damage in the mice and improved learning and memory. Intriguingly, that happened even when levels of amyloid remained high, suggesting that the compound preserved and created enough synapses in the hippocampus (the brain region that forms new memories) to restore cognitive function and enable synapses to hold their own against the amyloid assault.
“What’s interesting about this compound is it seems to have two mechanisms of action,” Hartley said. “It boosts enzymes that degrade amyloid and also increases synaptogenesis,” the formation of synapses and therefore memories. The latter “adds to our portfolio of potential ways to treat Alzheimer’s.”
Scientists not involved in the study were cautiously optimistic about the results.
It was “not big enough or long enough to show with certainty whether or not this is an effective treatment,” said Maria Carrillo, chief science officer of the Alzheimer’s Association. But “there was a trend towards improvement in memory, thinking and behavior … in a population — people with moderate to severe Alzheimer’s — that has received little attention recently in drug development.”
Though the results are likely to stir excitement, many drugs that seem to be effective in small numbers of patients fail in large clinical trials. Neurotrope CEO Susanne Wilke said a larger trial “is clearly warranted,” but it is not clear if the company, which began trading on the Nasdaq this year, has the financial resources to mount one.
There are four FDA-approved drugs for Alzheimer’s, which affects 5.5 million people in the US: donepezil (sold as Aricept), galantamine (Razadyne), rivastigmine (Exelon), and memantine (Namenda). But none is a cure, and none affects the destruction of neurons and synapses, which causes the disease’s memory loss and cognitive catastrophe.
“We don’t have anything that slows down or prevents the disease,” Hartley said.