T3D-959, an oral medication in the pipeline of T3D Therapeutics, outperformed a placebo at improving cognitive function in people with mild to moderate Alzheimer’s disease who have a high pTau-217/Non-pTau-217 ratio, a new marker of the disease.
That’s according to top-line results from the Phase 2 PIONEER clinical trial (NCT04251182) that were shared by T3D as late-breaking news at this year’s Clinical Trials in Alzheimer’s Disease conference, held Oct. 24-27 in Boston and virtually.
The presentation was titled “Topline results from the Phase 2 PIONEER trial of oral T3D-959 for the treatment of patients diagnosed with mild-to-moderate Alzheimer’s disease” (#LB03).
High pTau-217/Non-pTau-217 ratio may determine which patients will respond to T3D-959
While the therapy’s cognitive benefits were not seen for the overall trial population — failing one of the study’s main goals — the data suggest that a high pTau-217/Non-pTau-217 ratio, a predictor of early cognitive changes in Alzheimer’s, may help define which patients are most likely to respond to T3D-959.
In addition, multiple biomarkers of Alzheimer’s, neurodegeneration, and inflammation were reduced with T3D-959, and a dose of 30 mg was selected for testing in a future Phase 2b/3 trial in mild-to-moderate Alzheimer’s patients.
“PIONEER positive outcomes achieved the goal to inform the design of a larger and longer Phase 2b/3 trial, with dose selection, a ‘responder’ population of [Alzheimer’s disease] patients and biomarkers to assess,” John Didsbury, PhD, CEO of T3D, said in a company press release.
“The exciting results of this study show potential to modify the course of Alzheimer’s disease in a unique way,” said Michael Weiner, MD, professor emeritus at the University of California, San Francisco, and a principal investigator at the Alzheimer’s Disease Neuroimaging Initiative. “I look forward to seeing these results confirmed and expanded in a larger and longer Phase 2b/3 clinical trial.”
Increasing evidence suggests metabolic abnormalities in brain nerve cells lead to neuroinflammation and affect the cells’ function and balance, thereby accelerating the accumulation of toxic clumps of proteins such as amyloid-beta and tau in the brain. As a result, people with Alzheimer’s experience cognitive and mood changes.
T3D-959 is a brain-penetrating small molecule designed to activate PPAR delta and PPAR gamma, two proteins that control energy balance by fine-tuning the levels of blood sugars and certain fatty molecules. As such, the therapy is expected to improve metabolism and ease Alzheimer’s symptoms.
PIONEER was designed to assess the safety and efficacy of six months of treatment with 15, 30, or 45 mg of T3D-959 against a placebo in 250 adults, ages 50 to 90, with a diagnosis of Alzheimer’s and mild to moderate cognitive impairment.
Results showed T3D-959 was not significantly superior to a placebo at improving patients’ cognitive function, as measured by the Alzheimer’s Disease Assessment Scale 11-task cognitive subscale (ADAS-Cog11), and global function, as assessed by Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change.
This meant the study failed to meet both of its main goals for the whole trial population.
However, a significant cognitive effect was observed with the 30 mg dose in the subgroup of patients who had a high pTau-217/Non-pTau-217 ratio, which indicates higher levels of toxic Tau forms, at study’s start.
The 100 patients with a high pTau-217 ratio and treated with the 30 mg dose of T3D-959 showed a drop of 0.74 points in ADAS-Cog11 scores after six months, indicating better cognitive function. In turn, these scores were increased by 1.27 points in the 29 patients with a high ratio and given a placebo.
This reflected a two-point significant group difference that was “consistent with clinical benefit” for the experimental therapy, the researchers wrote in the abstract. This change was “equivalent to or better than that observed” with more than a year of treatment with anti-amyloid antibodies such as the approved Alzheimer’s therapy Leqembi (lecanemab), T3D stated in the release.
Secondary goal met in study, similar to effect of Leqembi
A secondary goal of superior increase in blood amyloid-beta 42/40 ratio — indicating less toxic amyloid beta forms — also was met with 30 mg of T3D-959 for the whole trial population. The effect was similar to that of Leqembi and two-fold greater in patients with a high p-tau217 ratio.
Treatment with the 30 mg dose also improved the neurodegeneration biomarker neurogranin, as well as biomarkers of inflammation and metabolism.
“Biomarker results suggest potential disease modification with T3D-959,” the researchers wrote.
The therapy was generally well tolerated, with a similar rate of side effects to that of placebo (37.3% vs. 43.1%) and without reports of serious treatment-related side effects.
Also, there were no signs of amyloid-related imaging abnormalities, or ARIAs, a side effect specific to amyloid-clearing antibody-based therapies that can lead to temporary brain swelling and small bleeding spots.
“The outcomes of this trial are encouraging and lay a foundation for advancing the further development of this new molecule to treat Alzheimer’s disease,” said Pierre N. Tariot, MD, who directs Banner Alzheimer’s Institute in Phoenix.
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