NTX-1955 for the treatment of generalized anxiety disorder (GAD)

Overview of Generalized Anxiety Disorder and Treatments:
GAD is the second most common mental health disorder among adults (~20 million adults in U.S. alone).  GAD is characterized by restlessness, irritability, feeling on edge, being easily startled, and panic attacks.  GAD can also be characterized by physical ailments such as muscle tension, fatigue, irritability, gastrointestinal symptoms, and headaches.  Most GAD patients are poorly managed by approved pharmacological therapies such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and benzodiazepines. Specifically, while first-line SSRIs and SNRIs are ineffective in most patients, second-line benzodiazepines, while highly efficacious, are not recommended for long-term use due to sedation, potential for misuse and dependence, and cognitive impairment.

NTX-1955 Mechanism:
NTX-1955 is a first-in-class GABAA-γ1 positive allosteric modulator (PAM) in development for GAD. GABAA is the major inhibitory neurotransmitter in the brain and positive allosteric modulation of the GABAA receptor is a well-validated approach for managing GAD symptoms. Nonselective GABAA PAMs such as benzodiazepines, while robust anxiolytics, modulate GABAA receptors throughout the entire brain, including in brain regions that lead to cognitive and sedative side effects. In contrast, NTX-1955 is designed to selectively engage GABAergic transmission in the amygdala, which is at center of the brain’s regulation of anxiety and highly enriched for the GABAA-γ1 receptor subunit, thereby sparing brain networks associated with the safety liabilities of benzodiazepines. .

NTX-1955 Clinical Development:
NTX-1955 has shown dose-dependent anxiolytic activity in gold-standard preclinical anxiety models without the side effect profile seen with classical benzodiazepines. Further, NTX-1955 has completed multiple Phase I studies, including Single Ascending Dose, Multiple Ascending Dose, drug-drug interaction and target engagement studies, demonstrating that it is safe, well tolerated, brain penetrant and selective to GABAA-γ1.

NTX-1472 for the treatment of social anxiety disorder (SAD)

Overview of Social Anxiety Disorder and Treatments:
Approximately 20 million adults in the United States are diagnosed with SAD every year, totaling approximately 7.1% of the population. 1 SAD is characterized by fear, anxiety and avoidance that interfere with relationships, daily routines, work, school or other activities.  SAD is more common among teens and adolescents, with higher prevalence among females.  Many patients and caregivers feel currently available treatment options fall short due to lack of efficacy, unwanted side effects and potential for addiction. 2

NTX-1472 Mechanism:
NTX-1472 is a best-in-class, highly selective, brain-penetrant vasopressin 1a (V1a) receptor antagonist in development for SAD. V1a is the receptor for arginine vasopressin (AVP), a neuropeptide that modulates amygdala activation to threatening stimuli and anxious moods. V1a receptors are expressed at high levels in multiple regions of the brain that modulate social behaviors and anxiety, such as the central amygdala, lateral septum, and bed nucleus of the stria terminalis.

NTX-1472 Clinical Development:
NTX-1472 has completed Phase 1 Single Ascending Dose, Multiple Ascending Dose, and drug-drug interaction studies and was found to be safe and well tolerated.

References

  1. Anxiety and Depression Association of America (2022)
  2. Jefferies & Ungar (2020)

NTX-2001 for the treatment of substance use disorder (SUD)

Overview of Substance Use Disorders:
SUD is a mental health condition characterized by a problematic pattern of substance use that causes distress and/or impairs a person’s life. 1  SUD can be mild, moderate or severe.  Over 21 million Americans had a diagnosis of SUD in 2022.  The most prevalent SUDs include alcohol, opioids, cocaine, methamphetamine and tobacco use disorders, which are typically managed by interventions such as detoxification, medication and behavioral therapies. 2  Although medications are available, there remains a need for more effective treatment options with better safety and tolerability profiles. 3

NTX-2001 Mechanism:
NTX-2001 is a selective partial agonist of the trace amine-associated receptor 1 (TAAR1) in development for SUD. TAAR1 is a G protein-coupled receptor (GPCR) expressed in the nuclei of the dopaminergic and serotonergic system, as well as in the amygdala, hypothalamus, subiculum, and rhinal cortices. 4 Consistent with expression patterns of TAAR1, NTX-2001 has been shown to modulate dopaminergic (DA) neurotransmission in the midbrain/nucleus accumbens reward circuit. TAAR1 agonism acts by “normalizing” dopaminergic neurotransmission in a state-dependent way, meaning it reduces excessive or increases insufficient dopamine signaling. 5 TAAR1 activation modulates dopamine neurotransmission in addiction circuits, leading to the inhibition of the rewarding and reinforcing effects of drugs from different classes including psychostimulants, opioid and alcohol.

NTX-2001 Clinical Development:
Robust preclinical and human genetic data support TAAR1 agonism as a promising therapeutic approach for treating SUDs.  NTX-2001 has completed Phase 1 Single Ascending Dose, Multiple Ascending Dose, and drug-drug interaction studies and was found to be safe and well tolerated.

References

  1. https://my.clevelandclinic.org/health/diseases/16652-drug-addiction-substance-use-disorder-sud
  2. https://www.precedenceresearch.com/substance-abuse-treatment-market;
  3. https://wwwnc.cdc.gov/travel/yellowbook/2024/additional-considerations/substance-use
  4. Wu, R., Liu, J., & Li, J.-X. (2022). Trace amine-associated receptor 1 and drug abuse. Advances in Pharmacology 93: 373–401.
  5. Halff, E. F., Rutigliano, G., Garcia-Hidalgo, A., & Howes, O. D. (2023). Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders. Trends in Neurosciences, 46(1): 60–74.

NTX-1511 for the treatment of rare neurodevelopmental disorders

Overview of Dup15q syndrome:
Dup15q syndrome is a rare genetic neurodevelopmental disorder caused by maternal copy number gains of the 15q11.2-q13.1 region on chromosome 15, and is characterized by hypotonia, motor impairment and cognitive delays.  The prevalence of Dup15q11 is unknown, but may be as high as 1 in 5,000 individuals in the general population. 1 There are currently no disease-modifying treatments approved for management of Dup15q syndrome.

NTX-1511 Mechanism:
NTX-1511 is a selective negative allosteric modulator (NAM) of the α5 subunit of the GABAA receptor.  Individuals with Dup15q syndrome have extra copies of the α5 GABAA receptor, which is involved in the control of inhibitory synaptic development and neuronal excitability. Excess α5 GABAA receptor function is believed to contribute to the neurodevelopmental pathophysiology of Dup15q syndrome. NTX-1511 has the potential to impact Dup15q pathophysiology by reducing the functional consequences of GABAA receptor genes duplication/triplication.

NTX-1511 Clinical Development:
NTX-1511 has completed Phase 1 Single Ascending Dose, Multiple Ascending Dose, drug-drug interaction and patient studies in neuropsychiatry and neurodevelopmental disorder, and was found to be safe and well tolerated.

References

  1. https://medlineplus.gov/genetics/condition/15q11-q13-duplication-syndrome/
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