Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: T3D Therapeutics, Inc.
T3D-959 is a dual agonist of the peroxisome proliferator activated nuclear receptor delta/gamma, aka PPARδ/γ. It is being developed as an oral therapy for Alzheimer’s disease. In 2013, T3D Therapeutics acquired this compound from DARA BioSciences. In 2010 and 2011, DARA BioSciences had tested DB959 in Phase 1 trials for dyslipidemia and Type 2 diabetes, but subsequently shifted its focus to oncology care products.
The PPAR family of proteins helps regulate blood sugar and triglyceride levels. PPAR activation affects these measures by boosting insulin sensitivity, and this approach has become a mainstay for correcting insulin resistance in diabetes therapy. The rationale for evaluating PPAR agonists in Alzheimer's is based on the hypothesis that sporadic AD is fundamentally an age-related metabolic disease, sometimes called Type 3 diabetes (Sep 2006 conference news; de la Monte and Tong, 2014). Unlike other PPAR-targeted diabetes drugs that have been evaluated in Alzheimer's previously, T3D-959 is not a thiazolidinedione.
The peer-reviewed literature contains three preclinical research reports on T3D-959, by scientists affiliated with T3D Therapeutics. Two report treatment benefits on spatial navigation, memory, and motor performance in rats previously injected with streptozotocin, a pancreatic cancer chemotherapy that poisons insulin-producing beta cells and is used to model diabetes in rodents (Tong et al., 2016; Tong et al., 2016). Another paper reports that T3D-0959 normalized streptozotocin-induced changes in the biomarkers pTau, AβPP, Aβ42, ubiquitin, SNAP-25, synaptophysin, IGF-1 receptor (R), IRS-1, Akt, p70S6K, mTOR, and S9-GSK-3β, also in rats (de la Monte et al., 2017).
In July 2015, a Phase 1/2 study enrolled 36 people with mild to moderate Alzheimer's disease to compare a two-week course of either 3, 10, 30, or 90 mg of T3D-959, taken once daily. This trial did not have a placebo group. It was a biomarker proof-of-mechanism study, in that the primary outcomes were change from baseline of cerebral glucose metabolism as measured by FDG-PET, and change from baseline of functional connectivity between the precuneus/posterior cingulate cortex and hippocampus as measured by resting-state fMRI. The Digit Symbol Substitution Test, ApoE subgroup analysis, blood lipid metabolomics, and ADAS-Cog 11 constituted secondary outcomes. Conducted in Florida and South Carolina, this trial completed in June 2016. Results were published after peer review (Chamberlain et al., 2020). The drug appeared safe, and its plasma pharmacokinetics predicted brain concentrations sufficient to activate PPAR delta. It improved blood markers of insulin sensitivity, and increased brain glucose metabolism in multiple brain regions. Some improvements in ADAS-Cog 11 were found, possibly related to ApoE genotype.
In May 2019, the company announced it had received NIA funding to begin a Phase 2 study called PIONEER (Prospective Therapy to Inhibit and Overcome Alzheimer’s Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration). Starting in March 2021, the trial is expected to enroll 256 people with mild to moderate AD at 41 centers across the U.S. It will compare a six-month course of 15, 30, or 45 mg of T3D-959 to placebo. The primary outcomes are ADAS-Cog11, ADCS-Clinical Global Impression of Change, and safety. Secondary endpoints are the Digit Symbol Coding Test of executive function and plasma Aβ42/40. As of July 2022, the trial was 92 percent enrolled, according to an interim data presentation at the August 2022 AAIC. The drug appeared safe, with no serious adverse events reported, and none that caused treatment to be stopped. The trial is still blinded. Even so, the company claimed a possible treatment effect based on small improvements from baseline in both primary outcomes and on the secondary DCST, in the participants considered as one group including placebo recipients. The trial is slated for completion in mid-2023.
For trial details, see clinicaltrials.gov.
Last Updated: 04 Aug 2022
- Chamberlain S, Gabriel H, Strittmatter W, Didsbury J. An Exploratory Phase IIa Study of the PPAR delta/gamma Agonist T3D-959 Assessing Metabolic and Cognitive Function in Subjects with Mild to Moderate Alzheimer's Disease. J Alzheimers Dis. 2020;73(3):1085-1103. PubMed.
- de la Monte SM, Tong M. Brain metabolic dysfunction at the core of Alzheimer's disease. Biochem Pharmacol. 2014 Apr 15;88(4):548-59. Epub 2013 Dec 28 PubMed.
- Tong M, Deochand C, Didsbury J, de la Monte SM. T3D-959: A Multi-Faceted Disease Remedial Drug Candidate for the Treatment of Alzheimer's Disease. J Alzheimers Dis. 2016;51(1):123-38. PubMed.
- Tong M, Dominguez C, Didsbury J, de la Monte SM. Targeting Alzheimer's Disease Neuro-Metabolic Dysfunction with a Small Molecule Nuclear Receptor Agonist (T3D-959) Reverses Disease Pathologies. J Alzheimers Dis Parkinsonism. 2016 Jun;6(3) Epub 2016 Jun 3 PubMed.
- de la Monte SM, Tong M, Schiano I, Didsbury J. Improved Brain Insulin/IGF Signaling and Reduced Neuroinflammation with T3D-959 in an Experimental Model of Sporadic Alzheimer's Disease. J Alzheimers Dis. 2017;55(2):849-864. PubMed.
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