# Phase 2 Enabling Studies of a Candidate Drug Therapy (T3D-959) Regulating Neurometabolism for the Treatment of Huntington's Disease

> **NIH NIH R44** · T3D THERAPEUTICS, INC. · 2022 · $1,088,768

## Abstract

The recent failure of two clinical trials in Huntington’s disease (HD) aimed at reducing huntingtin protein
has emphasized the need to find alternative therapeutic avenues to mitigate the pathological effects of the mutant
huntingtin protein that causes this devastating progressive neurodegenerative disorder. T3D-959 is a novel
chemical entity with the potential to improve dysfunctional brain glucose energy and lipid metabolism in
Alzheimer’s disease (AD). A Phase 2 trial in AD subjects is ongoing. Expansion of the therapeutic utility of this
molecule to treat other neurodegenerative diseases is being explored, with Huntington’s disease (HD) of highest
priority based on the particularly strong scientific rationale related to its use in HD and the clinical findings in AD
subjects treated with T3D-959 which are relevant to HD dysfunction. T3D-959 is an orally delivered small
molecule dual nuclear receptor agonist of PPARδ (primary target) and PPARγ (secondary target) that works to
restore and maintain brain metabolic homeostasis. PPARδ plays a key role in neuronal bioenergetic pathways
and is highly expressed in brain regions affected in HD. Of particular significance, is the finding that the mutant
huntingtin protein directly interacts with PPARδ, inhibiting its function. Research on HD has demonstrated a
central role for interference with the function of the transcription regulator PPARδ in contributing to HD
pathogenesis.
 A Phase 2 therapeutic proof of concept trial of T3D-959 in HD subjects has been designed and the study
protocol approved for advancement by the NIH/NeuroNEXT Executive Committee. The Network for Excellence
in Neuroscience Clinical Trials (NeuroNEXT) is a program specifically dedicated to expanding the capability
of NINDS to test promising new neurological therapies. PASS-HD (PPAR delta/gamma Agonist (T3D- 959)
Safety, Tolerability and Efficacy Study in Huntington’s Disease) is a planned randomized, double-blind placebo-
controlled study of T3D-959 (1:1 vs. placebo) in early-stage HD subjects. To initiate this clinical trial, there are
two pre-requisites: First, a GLP fertility and early embryonic development study in rodents and GLP embryofetal
development studies in rodents and non-rodents. These reproductive and developmental toxicology studies are
required by the FDA to support the initiation of the PASS-HD trial and were not required for the active and
approved IND in AD as all subjects are over age 50. Unlike AD, the average age of onset of HD is 35-50 years.
Second, manufacture of capsules containing GMP-grade T3D-959 active pharmaceutical ingredient (API), along
with matching placebo capsules, sufficient to dose 120 subjects once daily for 36-weeks, along with a
contemplated expanded open label access program, is needed. Aim 1: Conduct Segment I and II reproductive
and developmental toxicology studies following ICH guidelines in full compliance with GLP. Aim 2: Production
of GMP-grade T3D-959 API containing capsules and...

## Key facts

- **NIH application ID:** 10480989
- **Project number:** 1R44NS127671-01
- **Recipient organization:** T3D THERAPEUTICS, INC.
- **Principal Investigator:** John Didsbury
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,088,768
- **Award type:** 1
- **Project period:** 2022-09-21 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480989

## Citation

> US National Institutes of Health, RePORTER application 10480989, Phase 2 Enabling Studies of a Candidate Drug Therapy (T3D-959) Regulating Neurometabolism for the Treatment of Huntington's Disease (1R44NS127671-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10480989. Licensed CC0.

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