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) and one in the U.K. 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 substance use disorders (SUDs)

Overview of Alcohol Use Disorder (AUD) 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.

Overview of Cocaine Use Disorder (CUD) and Treatments:

CUD is a major and escalating public health crisis in the U.S., with over 1.4 million adults meeting the diagnostic criteria for CUD and overdose deaths involving cocaine increasing more than sixfold between 2010 and 2023. CUD is characterized by the compulsive use of cocaine despite its medical, psychological, and behavioral consequences.  Cocaine’s primary mechanism of action, potent blockade of the dopamine transporter, leads to supraphysiologic accumulation of extracellular dopamine in reward-related regions of the brain. This intense and repeated dopaminergic stimulation drives compulsive use that is difficult to reverse through behavioral intervention alone.  Despite decades of research, there are currently no FDA-approved pharmacotherapies for CUD, and existing behavioral treatments such as contingency management and cognitive-behavioral therapy are only moderately effective and are limited by poor adherence. There is an urgent need for a safe, effective, and mechanistically targeted pharmacological treatment for CUD that can reduce cocaine use and cravings without disrupting normal dopamine function in the brain.

NTX-2001 Mechanism:

NTX-2001 is a selective partial agonist of the trace amine-associated receptor 1 (TAAR1) in development for AUD  with planned studies in CUD supported by a grant from NIDA. 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.

In addition, the National Institute on Drug Abuse (NIDA) has awarded Newleos up to $15.5 million to fund the development of NTX-2001 in CUD. The five-year, milestone-based grant funds the development of NTX-2001 through a Phase 1 drug-drug interaction study and a subsequent  Phase 2 efficacy study.

Robust preclinical and human genetic data support TAAR1 agonism as a promising therapeutic approach for treating SUDs.  NTX-2001 was previously studied in multiple clinical trials designed to assess the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple formulations of NTX-2001 at multiple dosing regimens. 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, cognitive delays, language impairment, autism, seizures and behavioral challenges. Dup15q syndrome is a life-long and debilitating disorder that results in life expectancy in the range of 40 years, precludes independent functioning and creates a significant burden for affected individuals and their caregivers.  The prevalence of Dup15q11 is unknown but may be as high as 1 in 5,000 individuals in the general population.  There are currently no disease-modifying treatments approved for management of Dup15q syndrome with affected individuals receiving supportive care focusing on physical and behavioral therapies along with seizure management.

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 and 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 disorders and was found to be safe and well tolerated.