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Alzheimer Agent T3D-959 Demonstrates Disease-Modifying Effects in Phase 2 PIONEER Trial
The drug showed a strong safety profile and met primary endpoints, showing efficacy in slowing clinical and biological decline and supporting further investigation in a phase 2/3 trial.
John Didsbury, PhD
In a new analysis of the phase 2 PIONEER trial (NCT04251182), treatment with investigational T3D-959 (T3D Therapeutics) resulted in statistically significant impacts on the study’s coprimary end points, in addition to improvements in other Alzheimer disease (AD)-related biomarkers. Results demonstrated a strong safety profile and evidence of slowing of clinical and biological decline.1
Presented at the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 2nd, in Philadelphia, Pennsylvania, PIONEER was a 24-week trial assessing T3D-959 in 250 adults with mild-to-moderate AD per NIA-AA criteria. In total, 141 patients were included in the modified intent-to-treat (mITT) population randomized to placebo (n = 32) or T3D-959 (15 mg: n = 38; 30 mg: n = 39; or 45 mg: n = 32).
Presented by study author John Didsbury, PhD, the president and chief executive officer at T3D Therapeutics, the study met its primary end points of statistical significance on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11) in the 30 mg group (0.73 vs 2.70; P = .073) and Alzhiemer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) in the 15 mg group (0.39 vs 0.86; P = .060). Above all, the therapy was considered safe and well-tolerated.
T3D-959, an oral medicine delivered once a day, is the first PPAR delta-activating compound to be developed for the treatment of AD. Both PPAR delta and PPAR gamma targets are central regulators of glucose and lipid metabolism. PPAR delta has been shown to be highly expressed throughout the central nervous system and enriched in areas of the brain involved in energy homeostasis, e.g. the mediobasal hypothalamus.
In addition to meeting primary end points, treatment with the agent resulted in significant improvements on the secondary end point of plasma amyloid-ß42/40 ratio. Overall, significant effects were seen in the 30 mg (P = .011) and 45 mg (P = .033) groups, with a similar magnitude effect as lecanemab (Leqembi; Eisai), a previously approved antiamyloid therapy, at 6 months.
The higher dosed groups (30 mg and 45 mg) of T3D-959 also showed significant improvement neurodegeneration biomarker neurogranin (30 mg: P = .035; 45 mg: P = .051). In addition, following treatment with T3D-959, changed proteomic markers suggested pluripotent effects on dysregulated AD pathways including inflammation, oxidative stress, and metabolism.
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Previous data from PIONEER was presented at the 2023 Clinical Trials in Alzheimer’s Disease (CTAD) conference. Of the mITT, 55% of subjects had a phosphorylated tau (pTau)217/non-pTau217 ratio greater than 0.015, indicating they had AD pathology and exhibited cognitive decline in the placebo group consistent with AD. The high pTau217 ratio group dosed with 30 mg of T3D-959 (n = 30) demonstrated an improvement of 2 points vs placebo in ADAS-Cog11 with an effect size at 24 weeks equivalent to or better than that observed for antiamyloid plaque antibodies at 76 to 78 weeks.2
Similar to the results presented at AAIC 2024, the data revealed that the ITT population had significant improvement vs placebo in multiple plasma proteomic biomarkers of AD, amyloid plaque formulation, neurodegeneration, inflammation, mitochondrial dysfunction, and oxidative stress as measured by LC-MS. Overall, a 30 mg QD dose was identified as providing optimal safety and efficacy for further investigation in a phase 2/3 clinical trial in patients with mild-to-moderate AD.
At the time of the announced data, Didsbury said in a statement, “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 AD patients and biomarkers to assess."
Click here for more coverage of AAIC 2024.
