Neurotrope's Phase 2 Drug To Treat Alzheimer's Doesn't Clear Threshold For Statistical Significance

After hearing Neurotrope Inc NTRP would announce results of its Phase 2 study of potential Alzheimer’s Disease (AD) treatment Bryostatin-1, biotech investors have waited with baited breath through the weekend.

On Monday, Neurotrope reported positive top-line results from its Phase 2 study of Bryostatin, which met its primary endpoint in patients that completed the full course of treatment, although the results weren't particularly encouraging.

Tested in 147 patients with moderate to severe AD, a population often excluded from clinical trials, Bryostatin was shown to improve outcomes in cognition and ability to handle daily activities.

Of the 147 patients initially enrolled, 113 completed the full 13-week course of treatment, and these 113 (dubbed the “Completer Population”) showed a mean increase on the Severe Impairment Battery (SIB) test -- the primary efficacy endpoint, measuring cognition in patients with severe dementia -- of 1.5 versus a decrease in the placebo group of -1.1.The desired p-value of this endpoint was set at p<0.1, and results showed a p-value of <0.07.

A second set of patients, the modified intent-to-treat (mITT) population, didn't meet the primary endpoint, having not completed the 13-week assessment.

The company will hold a conference call at 8:30 a.m. ET to discuss the data, secondary endpoints, the “somewhat higher incidence of diarrhea” in drug-taking patients versus the placebo, and why only 113 patients out of the initial 147 completed the full course of treatment.

The Disease

Alzheimer's is a type of dementia that causes problems with memory, thinking and behavior. While Alzheimer’s doesn't kill a person directly, as the disease progresses bodily and cognitive functions become increasingly difficult or even impossible.

For the past 20 years, the preeminent theory driving Alzheimer’s treatment research has been the amyloid hypothesis, which presumes that clearing out beta amyloid deposits and tau tangles in the brain is the way to go about treating the disease. In AD patients, these deposits build up in certain parts of the brain, but there is evidence to suggest this isn't the cause of the disease.

Alzheimer’s has defeated 99 percent of biotech drugs designed to treat it. So if AD was pitching a shut-out game, did Neurotrope score a base hit?

The Drug

Neurotrope’s Bryostatin-1 is a multi-modal Protein Kinase C (PKC) epsilon activator that seeks to encourage regeneration of lost brain synapses, as well as clearing amyloid and tau tangles, in AD patients. The compound has been shown, in non-clinical efficacy studies, to spark the growth of synapses in the brain and prevent neuronal death, with a mechanism of action unique among its AD treatment peers.

In Monday’s press release, Neurotrope’s Chief Scientific Officer Dr. Daniel Alkon said, “These results, which show improvement in patients with moderate to severe Alzheimer’s disease, the population that is generally recognized as the most difficult to treat, provide exciting evidence of a new therapeutic approach potentially could rejuvenate synaptic networks in the brain.”

The Doubts

Despite meeting its primary endpoint, it must be said that Neurotrope’s Phase 2 study didn't deliver slam-dunk data. While color provided on the upcoming conference call will illuminate some aspects of the study not explicated in Monday's press release, certain questions will remain as to the true significance of the data.

Why did 34 patients not complete the study? It looks like 12 of the original 147 didn't even receive a dose of Bryostatin-1 or have at least one efficacy evaluation. Expect to hear more detail on those patients that withdrew on the conference call.

What prompted the use of a mITT analysis? Was it simply the fact that some patients failed to complete the full course of treatment, were there randomization errors? At what point was the decision to use mITT made? Meaning, was that intended from the beginning or was the decision to split the population into two sets made after receiving the data, in order to emphasize the efficacy of Bryostatin on patients who complete a full course of treatment?

Sources familiar with the matter tell Benzinga that six patients dropped out of the trial before getting a dose, another six after getting a baseline score, with an additional 22 dropping out after receiving at least one efficacy/safety evaluation.

Neurotrope’s Phase 2 study tested Bryostatin in two doses: 20 ug and 40 ug. The press release makes no mention of the efficacy of the 40ug dose, in any of the three endpoints. The 40 ug dose did better than the placebo, but the 20ug was more efficacious, according to sources. Many will question how an effective drug failed to show more efficacy in a higher dose, and will hope to see that point clarified on the conference call.

Lastly, and perhaps most importantly, the efficacy p-value for the Completer population was p<0.07. While this meets the primary endpoint, being above 0.05 in essence means that in more than one in 20 cases the company’s hypothesis (that its drug is more efficacious than a placebo) could be proven wrong. Some will consider Neurotrope's data not statistically significant, as p<0.05 is the industry standard for statistical significance. Others will highlight that the company has managed to show improvement over the standard of care in a population that others are scared to even attempt to treat.

Would the drug have had a better showing in a longer study, allowing more time for cognition to improve? If it hopes to achieve FDA approval, and be taken seriously by the larger biotech community, the company will have to achieve that p<0.05 benchmark.

Neurotrope certainly feels its Phase 2 results make the case for further study of Bryostatin-1. CEO Dr. Susanne Wilke, in this morning’s press release, said, “Additional development, with a path to Phase 3, is clearly warranted.”

Following further analysis of the data, the company plans to meet with the FDA to discuss Bryostatin-1’s path forward.

Join TheStreet’s Adam Feuerstein on Benzinga’s Premarket Prep Show at 8 a.m. ET, as he shares his first impressions of Neurotrope’s data.

Shares of Neurotrope ran up more than 24 percent to close Friday at $18.81; The stock was down nearly 20 percent in Monday's pre-market session.