SBIR-STTR Award

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 matching placebos for use in PASS-HD. Upon successful completion, an IND for HD will be ready to submit, approval of which, will allow initiation of clinical testing.

Public Health Relevance Statement:
There are no treatments to slow the progression of Huntington's disease (HD). The recent failure of two promising high-profile clinical trials testing therapies aimed at lowering the production of the huntingtin protein emphasizes the unmet need of HD patients for new drug therapies that approach HD in novel and effective ways. This research supports key pre-clinical trial activities necessary to enable clinical testing of a new neuro- metabolic drug therapy, T3D-959, which acts to restore dysfunctional brain metabolism and function in HD.

Project Terms:
Affect; Age; ages; Elderly; advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Bioenergetics; Brain; Brain Nervous System; Encephalon; capsule; Capsules; Certification; Clinical Trials; Disease; Disorder; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Embryonic Development; Embryo Development; Embryogenesis; Energy Metabolism; Energy Expenditure; Female; Fertility; Fecundability; Fecundity; Glucose; D-Glucose; Dextrose; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Homeostasis; Autoregulation; Physiological Homeostasis; Human; Modern Man; Huntington Disease; Huntington Chorea; Huntington's; Huntington's Disease; Huntington's Disease Pathway; Huntingtons Disease; NIH; National Institutes of Health; United States National Institutes of Health; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Neurons; Neurosciences; Patients; Sham Treatment; sham therapy; Placebos; Play; expectant mother; expecting mother; pregnant mothers; Pregnant Women; Production; Domestic Rabbit; Rabbits; Rabbits Mammals; Oryctolagus cuniculus; Common Rat Strains; Rat; Rats Mammals; Rattus; Records; Research; Development and Research; R & D; R&D; research and development; Research Support; Rodentia; Rodents Mammals; Rodent; social role; Role; Safety; Target Populations; Testing; Toxicology; Genetic Transcription; Gene Transcription; RNA Expression; Transcription; Woman; Work; Guidelines; PPAR gamma; PPAR-γ; PPARgamma; PPARγ; Peroxisome Proliferative Activated Receptor Gamma; Peroxisome Proliferator-Activated Receptor gamma; Peroxisome Proliferator-Activated Receptor γ; Thiazolidinedione Receptor; base; Label; improved; Site; Clinical; Phase; Neurologic; Neurological; Age of Onset; Nuclear Receptors; Chemicals; Failure; Individual; Toxicity Testing; Toxicity Tests; Agonist; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Therapeutic; Therapeutic Agents; Metabolic; programs; PPAR-δ; PPARD protein; PPARdelta; PPARδ; Peroxisome Proliferator-Activated Receptor delta; Peroxisome Proliferator-Activated Receptor δ; PPAR delta; Oral; Protocol; Protocols documentation; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; brain metabolism; mutant; Performance; fat metabolism; lipid metabolism; placebo controlled study; Toxicities; Toxic effect; novel; technological innovation; Pathogenesis; reproductive; HD Gene; Huntingtin; IT15 gene; interesting transcript 15; Huntington gene; Huntingtin Protein; Huntington's disease gene product; Huntington protein; Adverse Experience; Adverse event; Embryo and Fetal Development; Embryonic and Fetal Development; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; Brain region; small molecule; CD3D; T3D; CD3D gene; Dose; Symptoms; Data; randomisation; randomization; randomly assigned; Randomized; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Pathologic; Molecular; Development; developmental; Pathway interactions; pathway; Placebo Control; placebo controlled; open label; open label study; National Institute of Neurological Disorders and Stroke; NINDS; National Institute of Neurological Diseases and Stroke; design; designing; Clinical assessments; Outcome; child bearing; bear children; bearing children; childbearing; neurotoxicity; neuron toxicity; neuronal toxicity; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; mitochondrial dysfunction; commercial application; developmental toxicology; drug candidate; Regimen; phase II trial; phase 2 trial; reproductive toxicity; preclinical trial; pre-clinical trial; brain dysfunction; abnormal brain function; brain impairment; dysfunctional brain; efficacy study

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 matching placebos for use in PASS-HD. Upon successful completion, an IND for HD will be ready to submit, approval of which, will allow initiation of clinical testing.

Public Health Relevance Statement:
There are no treatments to slow the progression of Huntington's disease (HD). The recent failure of two promising high-profile clinical trials testing therapies aimed at lowering the production of the huntingtin protein emphasizes the unmet need of HD patients for new drug therapies that approach HD in novel and effective ways. This research supports key pre-clinical trial activities necessary to enable clinical testing of a new neuro- metabolic drug therapy, T3D-959, which acts to restore dysfunctional brain metabolism and function in HD.

Project Terms:
Affect; ages; Age; advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; Elderly; AD dementia; Alzheimer Type Dementia; Alzheimer disease dementia; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimers Dementia; Primary Senile Degenerative Dementia; primary degenerative dementia; senile dementia of the Alzheimer type; Alzheimer's Disease; Bioenergetics; Brain; Brain Nervous System; Encephalon; capsule; Capsules; Clinical Trials; Dedications; Disease; Disorder; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Embryonic Development; Embryo Development; Embryogenesis; Energy Metabolism; Energy Expenditure; Female; Fertility; Fecundability; Fecundity; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Homeostasis; Autoregulation; Physiological Homeostasis; Human; Modern Man; Huntington Disease; Huntington Chorea; Huntington's; Huntington's Disease; Huntingtons Disease; United States National Institutes of Health; NIH; National Institutes of Health; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Neurosciences; Patients; Placebos; Sham Treatment; sham therapy; Play; Pregnant Women; expectant mother; expecting mother; pregnant mothers; Production; Oryctolagus cuniculus; Domestic Rabbit; Rabbits; Rabbits Mammals; Rattus; Common Rat Strains; Rat; Rats Mammals; Records; Research; research and development; Development and Research; R & D; R&D; Research Support; Rodent; Rodentia; Rodents Mammals; Role; social role; Safety; Target Populations; Testing; Toxicology; Genetic Transcription; Gene Transcription; RNA Expression; Transcription; Woman; Work; Guidelines; PPAR-g; PPAR-γ; PPARgamma; PPARγ; Peroxisome Proliferative Activated Receptor Gamma; Peroxisome Proliferator-Activated Receptor gamma; Peroxisome Proliferator-Activated Receptor γ; Thiazolidinedione Receptor; PPAR gamma; Label; improved; Site; Clinical; Phase; Neurological; Neurologic; Age of Onset; Nuclear Receptors; Chemicals; Failure; Individual; Toxicity Testing; Toxicity Tests; Agonist; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Therapeutic; Therapeutic Agents; Metabolic; programs; PPAR delta; PPAR-δ; PPARD protein; PPARdelta; PPARδ; Peroxisome Proliferator-Activated Receptor delta; Peroxisome Proliferator-Activated Receptor δ; Oral; Protocols documentation; Protocol; Neurodegenerative Disorders; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; brain metabolism; glucose metabolism; mutant; Performance; lipid metabolism; fat metabolism; placebo controlled study; Toxic effect; Toxicities; novel; technological innovation; Pathogenesis; reproductive; Huntington gene; HD Gene; HD protein; Huntingtin; Huntingtin Protein; Huntington protein; Huntington's disease gene product; IT15 gene; interesting transcript 15; Adverse event; Adverse Experience; Embryo and Fetal Development; Embryonic and Fetal Development; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; Brain region; small molecule; CD3D gene; CD3D; T3D; Dose; Symptoms; Randomized; randomisation; randomization; randomly assigned; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Pathologic; Molecular; Development; developmental; Pathway interactions; pathway; Placebo Control; placebo controlled; open label; open label study; National Institute of Neurological Disorders and Stroke; NINDS; National Institute of Neurological Diseases and Stroke; designing; design; Clinical assessments; Outcome; bear children; bearing children; childbearing; child bearing; neuron toxicity; neuronal toxicity; neurotoxicity; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; mitochondrial dysfunction; commercial application; developmental toxicology; drug candidate; Regimen; phase 2 trial; phase II trial; reproductive toxicity; pre-clinical trial; preclinical trial; abnormal brain function; brain impairment; dysfunctional brain; brain dysfunction; efficacy study; data deposition; data submission; new chemical entity; manufacture