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 with approximately 20 million adults suffering from GAD in the 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. A substantial portion of GAD patients remain inadequately 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 roughly half of all 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 potential first-in-class GABA_A-γ1 positive allosteric modulator (PAM). GABA_A is the major inhibitory neurotransmitter in the brain and positive allosteric modulation of the GABA_A receptor is a well-validated approach for managing GAD symptoms. Nonselective GABA_A PAMs such as benzodiazepines, while robust anxiolytics, modulate GABA_A 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 GABA_A-γ1 receptor subunit, thereby sparing brain networks associated with the safety liabilities of benzodiazepines.

NTX-1955 Clinical Development:
Newleos is currently conducting two Phase 1b studies in the European Union (EU) to assess the pharmacology and proof-of-mechanism for NTX-1955 in GAD. NTX-1955 has shown dose-dependent anxiolytic activity in several gold-standard preclinical models used in anxiety research matching benzodiazepines’ efficacy 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 receptor occupancy studies, demonstrating that it is safe, well tolerated, brain penetrant and selective to GABA_A-γ1.

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

Overview of Social Anxiety Disorder and Treatments:
SAD is a common and chronic anxiety disorder affecting approximately 15-20 million adults in the U.S. SAD has two primary subtypes: generalized SAD, characterized by pervasive fear, anxiety and avoidance across a wide range of social situations, and performance-only SAD, in which symptoms are limited to specific performance-based situations such as public speaking.  Across subtypes, SAD is characterized by fear of negative evaluation, anticipatory anxiety, panic symptoms, and avoidance behaviors that interfere with daily functioning. SAD can also manifest with physical symptoms such as blushing, trembling, sweating, gastrointestinal distress, and tachycardia. A substantial proportion of patients with generalized SAD remain inadequately managed by available pharmacological therapies, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). These first-line serotonergic therapies are ineffective or poorly tolerated in many patients, and treatment is often limited by side effects such as emotional blunting and sexual dysfunction, contributing to underuse, discontinuation, and persistent unmet need.

NTX-1472 Mechanism:
NTX-1472 is a potential best-in-class, highly selective, brain-penetrant vasopressin 1a (V1a) receptor antagonist. V1a is the receptor for arginine vasopressin (AVP), a neuropeptide that plays a key role in modulating anxiety and stress. V1a receptors are highly expressed in regions of the brain that are essential for social and threat processing, such as the lateral septum, central amygdala, and bed nucleus of the stria terminalis.

NTX-1472 Clinical Development:
Newleos is currently conducting the Phase 2 SOAR study, a randomized, double-blind, placebo-controlled, multi-center study designed to assess the safety, tolerability, and efficacy of NTX-1472 in adults with SAD. 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.

NTX-2001 for the treatment of alcohol use disorder (AUD)

Overview of Alcohol Use Disorder and Treatments:
AUD affects nearly 30 million people in the U.S. and is associated with more than 95,000 deaths each year, making it one of the leading preventable causes of death. AUD is characterized by compulsive alcohol consumption, where persistent, compulsive behaviors result in life threatening medical consequences. The underlying neuropathology of AUD includes dysregulated dopamine signaling (exaggerated dopamine release and impaired control of mesolimbic circuits) and aberrant neurocircuitry signaling satiety. Despite the prevalence and burden of AUD, fewer than 10 percent of those with AUD receive any form of treatment. There are only three FDA-approved pharmacotherapies to treat AUD, and these drugs are only moderately effective and thus limited in their use. There is an urgent need for novel, mechanistically targeted treatments that can more effectively reduce alcohol consumption and cravings while minimizing side effects.

NTX-2001 Mechanism:
NTX-2001 is a selective partial agonist of the trace amine-associated receptor 1 (TAAR1) in development for AUD. TAAR1 is a G protein-coupled receptor expressed in key brain regions that modulate dopaminergic circuits, including reward reinforcement and satiety.  Consistent with expression patterns of TAAR1, NTX-2001 has been shown to modulate dopaminergic neurotransmission in the midbrain (nucleus) accumbens reward circuit. TAAR1 agonism acts by normalizing dopaminergic neurotransmission in a state-dependent manner, thereby reducing excessive or increasing insufficient dopamine signaling. 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:
Newleos is currently conducting a Phase 1b proof-of-concept study in the U.S. to determine the effects of NTX-2001 on alcohol consumption compared to placebo in the alcohol drinking paradigm (ADP), a well-established, translational paradigm to simulate alcohol consumption, among other quantitative measures of drinking behavior. The study will also assess the safety, tolerability and pharmacokinetics of NTX-2001 in individuals with AUD.

Robust preclinical and human genetic data support TAAR1 agonism as a promising therapeutic approach for treating SUDs.  NTX-2001 was previously studied in eight clinical trials involving healthy volunteers and individuals with schizophrenia or schizoaffective disorder designed to assess efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics. NTX-2001 was studied in multiple formulations at multiple dosing regimens, with approximately 645 participants receiving the study intervention (either NTX-2001 or placebo).  Across all these studies, NTX-2001 was consistently safe and well tolerated.

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 GABA_A receptor.  Individuals with Dup15q syndrome have extra copies of the α5 GABA_A receptor, which is involved in the control of inhibitory synaptic development and neuronal excitability. Excess α5 GABA_A 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 GABA_A 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

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