A new phase IIb readout at odds with earlier data suggesting PTI-125 would diminish key biomarkers of neuroinflammation and neurodegeneration in Alzheimer’s patients has left Cassava Biosciences Inc. President and CEO Remi Barbier looking for answers. The filamin A modulator missed the study's primary endpoint, failing to show a statistically significant ability to decrease levels of tau protein and other biomarkers in cerebrospinal fluid vs. placebo.

"There are two types of failure in our business: There's failure of the drug/science and then there's failure of the study," Barbier told BioWorld. The story of Alzheimer's disease (AD) includes plenty of failures of drugs and science. But this latest outcome is a failure of the study, he said. "Just looking at the placebo group, we know that something is amiss with the study."

Identified through a traditional drugs screening program as having high affinity for misshapen filamin A, PTI-125 has appeared in earlier studies to minimize the toxic interaction of the alpha-7 nicotinic receptor and amyloid beta. It also appears to restore the normal function of the alpha-7, NMDA and brain insulin receptors.

The double-blind, randomized, placebo-controlled phase IIb study enrolled 64 patients with mild to moderate Alzheimer’s disease (AD) to look for an effect from that activity. Its participants were 50 to 85 years of age, with Mini-Mental State Exam scores of 16 to 26. They were randomized to receive PTI-125 in either 100 mg or 50 mg twice-daily, or a matching placebo for 28 continuous days. It built on an open-label phase IIa study that found that CSF samples taken before and after 28 days of treatment with PTI-125 showed responses among all 13 people with mild to moderate AD.

Placebo-treated patients in the trial had huge variability in cerebrospinal fluid (CSF) levels of tau protein and phosphorylated tau, ranging from -54% to +34% and -49% to +253%, respectively, from baseline to day 28. That's unheard of, Barbier said. There's no scientific literature that says levels of tau vary so much over the course of a month, he noted.

In the months ahead, Barbier said his team will analyze the half of each trial participant's CSF sample that they wisely held in reserve before sending the other half off to a respected Swedish lab for analysis. Potential confounding factors that might have stymied the outside lab's analysis, he said, could include sample handling issue, adverse environmental conditions during transport or inattentive lab technicians.

Meanwhile, he said, the company is carrying ahead with development of its blood-based Alzheimer’s diagnostic, Savadx, formerly called PTI-125Dx, and is well financed to carry ahead.

Shares in the Austin, Texas-based venture (NASDAQ:SAVA), which closed yesterday at $8.11, fell 73.9% to $2.12 on May 15.

There are an estimated 5.8 million Americans living with Alzheimer's disease, according to the Alzheimer's Association and as many as 75 million people expected to face AD or other dementias worldwide by 2030, according to the World Health Organization, so the need for effective therapies is acute.

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