Neurotrope announced that its Phase II trial of Bryostatin-1 in moderate to severe Alzheimer’s disease did not show statistical significance on the primary endpoint, change from baseline to Week 13 in the Severe Impairment Battery (SIB) total score.

In other words, another Alzheimer’s drug bites the dust.

The Phase II trial was designed to evaluate the safety and efficacy of the drug for cognitive deficits in patients with moderate to severe Alzheimer’s. This was defined as a Mini Mental State Exam 2 score of 4 to 15 and patients not currently taking memantine. The patients with randomized one to one to receive either 20 micrograms of Bryostatin-1 or placebo, receiving seven doses for 12 weeks.

Patients who had received memantine (Namenda XR, Namenda, Namenda Titration Pak) were excluded unless they had stopped taking the drug for at least 30 days before enrollment.

An average increase in SIB totals of 1.3 points was observed in the Bryostatin-1 cohort and 2.1 points for the placebo groups at Week 13. The change was not statistically significant.

“We are disappointed in the topline results from the confirmatory Phase II study,” said Charles S. Ryan, Neurotrope’s chief executive officer. “Having just received the data, we are conducting a full review to determine potential next steps and will provide an update of our plans when appropriate. We sincerely thank the patients, physicians, study coordinators and the entire Neurotrope team for their support of this novel study.”

Company shares plunged almost 80% at the news. It is the second time in slightly over two years the drug did not meet its target.

Bryostatin-1 is a kinase C activator, which stimulates synaptic growth factors, amyloid-beta degrading enzymes, and prevents Tau transformation into neurofibrillary tangles. The drug is capable of penetrating the blood-brain barrier and activating PKC-epsilon, a protein kinase that plays a pivotal role in learning and memory. The drug is also being evaluated in Fragile X Syndrome, multiple sclerosis, depression, stroke, Parkinson’s disease and other neurological disorders.

On August 5, the company reported its second-quarter financials. At that time, it reported it had concluded data collection on the Phase II confirmation trial, appointed Michael Ciraolo as general counsel and chief operating officer, and had as of June 30, about $21.2 million in cash and cash equivalents. They projected enough capital to fund operations through at least two more years.

For the last several decades, the dominant theory of Alzheimer’s disease was that it was caused by the accumulation of a protein, beta-amyloid, in the brain. However, failed clinical trial after failed clinical trial suggested that either this theory was just plain wrong or incomplete, that there was something else at work. Neurotrope’s approach was promising if for no other reason than it was something new.

Recently, much Alzheimer’s research is shifting toward the role of the immune system and energy production in the disease. Researchers at Temple University Health System have shown that a type of energy malfunction, called mitochondrial calcium transport remodeling, is involved in the progression of Alzheimer’s disease. This is a mechanism where cells attempt to compensate for decreased energy production and metabolic dysfunction. Initially helpful, this mechanism begins to malfunction, causing drops in mitochondrial function—part of each cell’s energy production system—memory, and cognition. The research was published in the journal Nature Communications.

Problems with calcium regulation and metabolic dysfunction have been associated with Alzheimer’s development and malfunctioning neurons for some time. Intracellular calcium signaling plays an essential role in synaptic transmission and brain cell communication.