PRAX-114 / Praxis Precision Medicines - LARVOL DELTA

A Neuroanatomic and Pathophysiologic Framework for Novel Pharmacological Approaches to the Treatment of Post-traumatic Stress Disorder. (PubMed, Drugs) - "Indeed, investigations and drug development are proceeding in a number of these alternative, non-serotonergic pathways in an effort to improve the management of PTSD. In this manuscript, the authors introduce novel and emerging treatments for PTSD, including drugs in various stages of development and clinical testing (BI 1358894, BNC-210, PRAX-114, JZP-150, LU AG06466, NYV-783, PH-94B, SRX246, TNX-102), established agents and known compounds being investigated for their utility in PTSD (brexpiprazole, cannabidiol, doxasoin, ganaxolone, intranasal neuropeptide Y, intranasal oxytocin, tianeptine oxalate, verucerfont), and emerging psychedelic interventions (ketamine, MDMA-assisted psychotherapy, psilocybin-assisted psychotherapy), with an aim to examine and integrate these agents into the underlying pathophysiological frameworks of trauma-related disorders."

Journal • Review • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder

Clinical specificity profile for novel rapid acting antidepressant drugs. (PubMed, Int Clin Psychopharmacol) - "This review discusses the clinical specificity profile of new antidepressants, namely 4-chlorokynurenine (AV-101), dextromethorphan-bupropion, pregn-4-en-20-yn-3-one (PH-10), pimavanserin, PRAX-114, psilocybin, esmethadone (REL-1017/dextromethadone), seltorexant (JNJ-42847922/MIN-202), and zuranolone (SAGE-217). The main aim is to provide an overview of the efficacy/tolerability of these compounds in patients with mood disorders having different symptom/comorbidity patterns, to help clinicians in the optimization of the risk/benefit ratio when prescribing these drugs."

Journal • CNS Disorders • Cognitive Disorders • Insomnia • Mood Disorders • Psychiatry • Sexual Disorders • Sleep Disorder • Suicidal Ideation

A Clinical Trial of PRAX-114 in Participants With Post-Traumatic Stress Disorder (clinicaltrials.gov) - P2 | N=11 | Terminated | Sponsor: Praxis Precision Medicines | Trial completion date: Feb 2023 ➔ Sep 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2022 ➔ Aug 2022; No longer developing for this indication

Trial completion date • Trial primary completion date • Trial termination • CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

A Clinical Trial of PRAX-114 in Participants With Essential Tremor (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Praxis Precision Medicines | Trial completion date: Oct 2022 ➔ Jun 2022

Trial completion date • Essential Tremor • Movement Disorders

A Clinical Trial of Adjunctive and Monotherapy PRAX-114 in Participants With Major Depressive Disorder (clinicaltrials.gov) - P2 | N=110 | Completed | Sponsor: Praxis Precision Medicines | Active, not recruiting ➔ Completed

Monotherapy • Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Clinical Trial of PRAX-114 in Participants With Essential Tremor (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Praxis Precision Medicines | N=15 ➔ 0 | Recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Essential Tremor • Movement Disorders

A Clinical Trial of Adjunctive and Monotherapy PRAX-114 in Participants With Major Depressive Disorder (clinicaltrials.gov) - P2 | N=110 | Active, not recruiting | Sponsor: Praxis Precision Medicines | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Clinical Trial of PRAX-114 in Participants With Post-Traumatic Stress Disorder (clinicaltrials.gov) - P2 | N=11 | Active, not recruiting | Sponsor: Praxis Precision Medicines | Recruiting ➔ Active, not recruiting | N=80 ➔ 11

Enrollment change • Enrollment closed • CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

A Clinical Trial of PRAX-114 in Participants With Essential Tremor (clinicaltrials.gov) - P2 | N=15 | Recruiting | Sponsor: Praxis Precision Medicines

New P2 trial • Essential Tremor • Movement Disorders

Preference for Extrasynaptic Gabaa Receptors Conveys a Wider Therapeutic Window Between Anxiolytic and Sedative-Like Effects in Rats for the Positive Allosteric Modulator, PRAX-114, Compared With Zuranolone (SOBP 2022) - "The separation between brain concentrations associated with anxiolytic and sedative-like effects was ~2-fold greater for PRAX-114 than zuranolone, supporting our hypothesis that greater extrasynaptic preference results in improved tolerability without compromising anxiolytic efficacy."

Preclinical • CNS Disorders

A Clinical Trial of PRAX-114 in Participants With Major Depressive Disorder (clinicaltrials.gov) - P2/3 | N=216 | Completed | Sponsor: Praxis Precision Medicines | Recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

PRAX-114, an Extrasynaptic-Preferring GABAA Receptor Positive Allosteric Modulator: A Phase 2 Trial Evaluating Multiple Dose Safety, Tolerability, and Preliminary Efficacy in Major Depressive Disorder (SOBP 2022) - "The promising preliminary efficacy data at well-tolerated dose levels support further development of PRAX-114 as a rapid-acting antidepressant with potential to address unmet needs for patients with MDD."

Clinical • P2 data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

PRAX-114, an Extrasynaptic-Preferring GABA-A Receptor Positive Allosteric modulator: A Phase 2 Trial Evaluating Multiple Dose safety, tolerability, and Preliminary Efficacy in Major Depressive Disorder - "Participants in Part B also showed marked improvements in menopausal and mood symptoms over this period, including Day 15 mean decreases from baseline of 60% in the frequency of moderate-to-severe hot flashes and 68% in Meno-D total score. Menopausal and mood symptoms trended toward baseline 2 weeks after study drug discontinuation in Part B. Conclusion The promising preliminary efficacy data at well-tolerated dose levels support further development of PRAX-114 as a rapid-acting antidepressant with potential to address unmet needs for patients with MDD and PMD."

Clinical • Late-breaking abstract • P2 data • CNS Disorders • Depression • Essential Tremor • Major Depressive Disorder • Mood Disorders • Psychiatry

A Clinical Trial of PRAX-114 in Participants With Post-Traumatic Stress Disorder (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: Praxis Precision Medicines

New P2 trial • CNS Disorders • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders. (PubMed, Pharmacol Biochem Behav) - "Recently, however, there has been a resurgence of efforts to bring GABAkines to patients, the FDA approval of the neuroactive steroid brexanolone for post-partum depression in 2019 being the first. Other neuroactive steroids are in various stages of clinical development (ganaxolone, zuranolone, LYT-300, Sage-324, PRAX 114, and ETX-155). These GABAkines and non-steroid compounds (GRX-917, a TSPO binding site ligand), darigabat (CVL-865), an α2/3/5-preferring GABAkine, SAN711, an α3-preferring GABAkine, and the α2/3-preferring GABAkine, KRM-II-81, bring new therapeutic promise to this highly utilized medicinal target in neurology and psychiatry...KRM-II-81 also produces anxiolytic- and antidepressant-like effects in rodent models. Other key features of the pharmacology of this compound are its low sedation rate, lack of tolerance development, and the ability to prevent the development of seizure sensitization."

Journal • Review • Anesthesia • CNS Disorders • Depression • Epilepsy • Mental Retardation • Neuralgia • Pain • Postpartum Depression • Psychiatry • Vascular Neurology

PRAX-114 produces robust increases in EEG beta frequency power, a translational biomarker of GABAA receptor modulation, without dose-limiting sedation (CNS SUMMIT 2021) - "In rats and humans, PRAX-114 produced robust increases in beta-power. In rats, the dose that increased beta-power approximately 1.6-fold was more than 11 times lower than that which previously demonstrated reduced locomotor activity, while also showing antidepressant-like effects. In humans, the 60mg dose achieved large beta-power effects without dose-limiting sedation, suggesting extrasynaptic GABAAR preference is associated with substantial pharmacodynamic effects and favorable tolerability."

Biomarker • Anesthesia • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Praxis Precision Medicines to Host Movement Disorder Day on December 17, 2021 (GlobeNewswire) - "Praxis Precision Medicines, Inc...announced that the Company will host a Movement Disorder Day from 9:00 a.m. to 12:00 p.m. ET on Friday, December 17, 2021 virtually and in New York City...present the development path for PRAX-944 and PRAX-114 in Essential Tremor and will provide a look forward at what’s next with a focus on the upcoming PRAX-944 clinical study in Parkinson’s disease."

Clinical • CNS Disorders • Essential Tremor

PRAX-114, an Extrasynaptic-Preferring GABA-A Receptor Positive Allosteric Modulator: Multiple Dose Safety, Tolerability, Pharmacodynamics and Preliminary Efficacy in Major Depressive Disorder (ACNP 2021) - "Based on combined findings from Phase 1 translational and Phase 2 clinical MDD efficacy trials, the preference of PRAX-114 for extrasynaptic GABA-AR appears to translate into separation of dose-limiting sedative-like side effects from efficacy and pharmacodynamic effects, highlighting the potentially wide therapeutic window for PRAX-114. The observed HAM-A improvement suggests that greater preference for extrasynaptic GABA-AR does not compromise anxiolytic efficacy. The promising preliminary MDD efficacy data at well-tolerated dose levels support further clinical development of PRAX-114 in a randomized controlled trial as a rapid-acting antidepressant with the potential to address unmet needs for patients with MDD."

Clinical • PK/PD data • Alzheimer's Disease • CNS Disorders • Depression • Essential Tremor • Major Depressive Disorder • Mood Disorders • Psychiatry

Preference for Extrasynaptic GABA-A Receptors Conveys a Wider Therapeutic Window Between Anxiolytic and Sedative-Like Effects in Rats for the Positive Allosteric modulator, PRAX-114, Compared With Zuranolone (ACNP 2021) - "When compared side-by side, PRAX-114 had greater preference for extrasynaptic GABAAR than zuranolone (~2-fold and 4-fold greater in terms of potency and efficacy, respectively). The relationships between brain concentrations required to increase β-power, and those associated with anxiolytic effects, were similar for the 2 molecules suggesting that extrasynaptic preference does not limit anxiolytic activity. Interestingly, in the 5-CSRT task, the PRAX-114 EC50 was calculated to achieve a 2.3-fold increase in β-power, whereas the zuranolone EC50 achieved only a 1.6-fold increase in β-power."

Preclinical • Alzheimer's Disease • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

PRAX-114, an Extrasynaptic-Preferring GABA-A Receptor Positive Allosteric Modulator: Multiple Dose Safety, Tolerability, Pharmacodynamics and Preliminary Efficacy in Major Depressive Disorder (ACNP 2021) - "Based on combined findings from Phase 1 translational and Phase 2 clinical MDD efficacy trials, the preference of PRAX-114 for extrasynaptic GABA-AR appears to translate into separation of dose-limiting sedative-like side effects from efficacy and pharmacodynamic effects, highlighting the potentially wide therapeutic window for PRAX-114. The observed HAM-A improvement suggests that greater preference for extrasynaptic GABA-AR does not compromise anxiolytic efficacy. The promising preliminary MDD efficacy data at well-tolerated dose levels support further clinical development of PRAX-114 in a randomized controlled trial as a rapid-acting antidepressant with the potential to address unmet needs for patients with MDD."

Clinical • PK/PD data • Alzheimer's Disease • CNS Disorders • Depression • Essential Tremor • Major Depressive Disorder • Mood Disorders • Psychiatry

Preference for Extrasynaptic GABA-A Receptors Conveys a Wider Therapeutic Window Between Anxiolytic and Sedative-Like Effects in Rats for the Positive Allosteric modulator, PRAX-114, Compared With Zuranolone (ACNP 2021) - "When compared side-by side, PRAX-114 had greater preference for extrasynaptic GABAAR than zuranolone (~2-fold and 4-fold greater in terms of potency and efficacy, respectively). The relationships between brain concentrations required to increase β-power, and those associated with anxiolytic effects, were similar for the 2 molecules suggesting that extrasynaptic preference does not limit anxiolytic activity. Interestingly, in the 5-CSRT task, the PRAX-114 EC50 was calculated to achieve a 2.3-fold increase in β-power, whereas the zuranolone EC50 achieved only a 1.6-fold increase in β-power."

Preclinical • Alzheimer's Disease • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Praxis Precision Medicines Provides Corporate Update and Reports Third Quarter 2021 Financial Results (Yahoo Finance) - "PRAX-114 Phase 2 studies in post-traumatic stress disorder and essential tremor (ET)...expected to initiate in 4Q21....First patient enrolled in PRAX-944 Phase 2b Essential1 Study for treatment of ET; topline results expected in 2H22...Praxis is currently in the second of two cohorts of its PRAX-944 Phase 2a trial for treatment of essential tremor (ET)...Preliminary open-label safety, tolerability and efficacy data is expected in the fourth quarter of 2021, followed by complete open-label and placebo-controlled, randomized withdrawal results in the first half of 2022."

New P2 trial • P2a data • P2b data • CNS Disorders • Essential Tremor

PRAXIS PRECISION MEDICINES : Management’s Discussion and Analysis of Financial Condition and Results of Operations. (form 10-Q) (Market Screener) - "Research and development expenses increased approximately $16.6 million from approximately $9.0 million for the three months ended June 30, 2020 to $25.7 million for the three months ended June 30, 2021....$3.5 million increase in expense related to our PRAX-114 program, driven by an increase in clinical-related and toxicology spend for our Phase 2/3 clinical trial for this program....Research and development expenses increased approximately $27.7 million from $15.9 million for the six months ended June 30, 2020 to $43.6 million for the six months ended June 30, 2021....$4.7 million increase in expense related to our PRAX-114 program, driven by an increase in toxicology and clinical-related spend for our Phase 2/3 clinical trial for this program."

Commercial • CNS Disorders • Depression • Major Depressive Disorder

Praxis Precision Medicines Reports PRAX-114 Perimenopausal Depression (PMD) Phase 2a Proof-of-Concept Trial Results and Announces Plans to Advance to Phase 2b Study in Women with Menopausal and Mood Symptoms (GlobeNewswire) - P2a, N=6; "Praxis Precision Medicines, Inc....reported results from its PRAX-114 Phase 2a Part B proof-of-concept trial for treatment of perimenopausal depression (PMD) and announced plans to advance PRAX-114 to a Phase 2b study in women with menopausal and mood symptoms. Plans for the Phase 2b trial will be disclosed by the end of 2021. In the Phase 2a trial for treatment of PMD, participants treated with a single daily dose of PRAX-114 60 mg suspension formulation (n=6) for 14 days in an outpatient setting showed improvements in menopausal and mood symptoms that were rapid, marked and maintained throughout the two-week treatment period....PRAX-114 is currently being investigated as a monotherapy treatment for MDD in adults in the Phase 2/3 Aria Study and as an adjunctive treatment for MDD in adults in the Phase 2 Acapella Study, with topline results from both trials expected in the first half of 2022."

P2 data • P2a data • Trial status • CNS Disorders • Depression • Major Depressive Disorder

Praxis Precision Medicines Provides Corporate Update and Reports Second Quarter 2021 Financial Results (GlobeNewswire) - “The Company expects to initiate a PRAX-944 Phase 2b study for treatment of essential tremor (ET) in the US in the third quarter of 2021. Topline results are expected in the second half of 2022….Praxis is currently in the second of two cohorts of its PRAX-944 Phase 2a trial for treatment of ET…the company now expects preliminary topline open-label safety, tolerability and efficacy data by the end of 2021. Praxis plans to initiate a PRAX-114 Phase 2 single-dose crossover study for treatment of ET to assess safety, pharmacokinetics (PK) and efficacy in the fourth quarter of 2021. Topline results are expected in the second half of 2022.”

New P2 trial • New P2b trial • P2 data • P2a data • P2b data • CNS Disorders • Essential Tremor