Following data from a small phase IIa study showing its experimental Alzheimer's disease (AD) therapy, PTI-125, led to decreases in key biomarkers of neuroinflammation and neurodegeneration, Cassava Sciences Inc. (formerly Pain Therapeutics) has dosed the first two patients in a phase IIb study of the candidate. Designed to confirm the initial phase II results, which have already attracted big pharma scouts, Cassava's president and CEO, Remi Barbier, said the new study's primary endpoint is improvement in biomarkers of AD from baseline after 28 days of twice-daily treatment.

Company shares (NASDAQ:SAVA) held steady Monday, closing at $1.27.

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. But clinical outcomes have been discouraging at best, featuring a parade of failures from the likes of Biogen Inc., Eisai Co. Ltd., Eli Lilly and Co., and just last week, Neurotrope Inc. (See BioWorld, Sept. 10, 2019.)

Might targeting an altered form of the scaffolding protein filamin A (FLNA), as PTI-125 does, finally offer a more successful avenue to treating the disease? Maybe. In its normal shape, FLNA helps bring multiple proteins together and to ensure they interact properly. But when its altered form interacts with the alpha-7 nicotinic receptor, bad things happen – specifically Alzheimer's and all the pathologies associated with it, Barbier said. The interaction leads to neurodegeneration and brain inflammation, an outcome PTI-125 is designed to arrest.

Identified through a traditional drugs screening program as having high affinity for misshapen FLNA, PTI-125 appears 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, Barbier said.

So far, evidence of those results elucidated in animal studies have appeared to be borne out in the clinic. In the open-label phase IIa, cerebrospinal samples taken before and after 28 days of treatment with the drug found responses among all 13 people with mild to moderate Alzheimer's disease the Austin, Texas-based company studied.

Top-line results included statistically significant decreases in total tau protein, phosphorylated tau, a marker for neurodegeneration, a marker for cognitive decline, an indicator of microglial activation and several proinflammatory biomarkers, all validated biomarkers of AD.

"Our clinical hypothesis is that if you stabilize these biomarkers, cognition and functions of health will also be stabilized," Barbier told BioWorld. "It's inconceivable that you knock down all those biomarkers and nothing happens to the patient." Whether the effect can hold will be shown by the larger phase IIb trial, which like earlier studies of the candidate, is being supported by the NIH. Since 2015, the NIH has committed up to $6.7 million in grants to fund the program.

Blinded, randomized and placebo-controlled, the phase IIb study is expected to enroll 60 patients with mild to moderate Alzheimer's disease over as long as 12 months. Patients will be randomized to one of three groups, to be dosed with PTI-125 100 mg, 50 mg or a matching placebo twice daily for 28 continuous days. The primary endpoint is improvement in biomarkers of AD from baseline to day 28. A projected readout for the trial hasn't been set, though its estimated primary completion is listed as January 2020.

PTI-125 is also advancing alongside an investigational diagnostic to detect the disease, PTI-125Dx. In blinded studies, PTI-125Dx has detected greater-than-10-fold differences between patients with Alzheimer's and age-matched normal controls or young cognitively intact subjects, the company said.

Should either the drug or diagnostic help bring about any of the much-needed progress required by people with Alzheimer's disease and their caretakers globally, the welcome will no doubt extend much beyond this month, World Alzheimer's Month.

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