Topline results provide “clinical evidence of a modification of multiple AD pathologies associated with amyloid plaque burden,” said John Didsbury, PhD, chief executive officer of T3D Therapeutics Inc., the company developing the drug.
While the primary cognitive endpoints were not met in the overall study population, the data suggest that a “high plasma pTau-217/non–pTau-217 ratio, a marker of AD pathology, likely defines an AD population responsive to T3D-959 therapy,” Dr. Didsbury said.
He said it’s important to note that no PET imaging (amyloid/tau) or biomarkers were used as entry criteria and, in hindsight, some participants likely did not have AD, which likely played a role in the negative primary outcome.
The findings from the PIONEER study were presented at the annual Clinical Trials on Alzheimer’s Disease conference.
‘Surprised and shocked’
The PPAR family of proteins helps regulate blood sugar and triglyceride levels. The rationale for evaluating PPAR agonists in AD is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease.
T3D-959 is the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma, which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD.
The PIONEER tested three doses of T3D-959 (15 mg, 30 mg, and 45 mg) vs. placebo in 250 adults with mild to moderate AD (Mini-Mental State Examination [MMSE] 14-26, Clinical Dementia Rating (CDR)-Global 0.5-2.0, and Sum of Boxes [CDR-SB] ≥ 3.0). T3D-959 or placebo was taken once daily for 24 weeks.
In the overall population, the primary endpoints – Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Global Impression of Change (CGIC) – were not met.
“Plain and simple, when we saw this data, we were surprised and shocked,” said Dr. Didsbury, and wondered, “How can placebo be doing so well on a 6-month AD trial?”
“We suspect the presence of non-AD subjects in the trial based on the lower-than-typical number of ApoE4 positive subjects, increased cognitive performance and learning effects observed, and only 45% of trial subjects having a low pTau-217 ratio, a biomarker indicating that they would have no AD pathology plasma,” he explained.
Plasma baseline pTau-217 ratio correlates with AD risk and severity and is a marker of AD pathology; in the subgroup with high pTau-217 ratio, the ADAS-Cog11 endpoint was met in the 30-mg T3D-959 group vs. the placebo group (–0.74 vs. 1.27; P = .112), “consistent with clinical benefit,” Dr. Didsbury noted.
The secondary endpoint of change in plasma amyloid-beta (Ab)42/40 ratio was also met in the 30-mg T3D-959 group – increasing at week 24 with T3D-959 vs. decreasing with placebo (P = .0206), with even greater improvement in the high pTau-217 ratio group. In this group, improvement of Ab42/40 ratio was nearly twofold greater than the overall group.
T3D-959 had a similar magnitude of effect on Ab42/40 as lecanemab (Leqembi) at 6 months, the researchers point out in their late-breaking abstract.
Biomarkers of all three AD diagnostic criteria (amyloid/tau/neurodegeneration) were improved, as well as markers of inflammation, insulin resistance, and dysfunctional lipid metabolism – results that demonstrate “peripheral targeted engagement,” Dr. Didsbury said.
“Along with the strong safety profile of T3D-959, the evidence supports a larger study evaluating T3D-959 30 mg/day in patients with mild to moderate AD and a baseline plasma p-Tau-217/non–pTau-217 ratio of ≥ 0.015,” the researchers conclude in their abstract.