cocaine esterase (TNX-1300) / Tonix - LARVOL DELTA

Comparing Efficacy & Safety Of TNX-1300 To Placebo With UC For Treatment Of Acute Cocaine Intoxication In ED Subjects (CATALYST) (clinicaltrials.gov) - P2 | N=3 | Terminated | Sponsor: Tonix Pharmaceuticals, Inc. | N=36 ➔ 3 | Recruiting ➔ Terminated; Tonix has discontinued enrollment and terminated the Phase 2 CATALYST study (TNX-CE-CI202) because enrollment in this emergency department-based study was slower than projected. The study was not discontinued for safety or efficacy reasons.

Enrollment change • Trial termination

Development of cocaine esterase W/O/W nanoemulsions by a novel low-temperature double emulsification approach for cocaine abuse treatment. (PubMed, Int J Biol Macromol) - "Pharmacodynamic studies revealed CocE NEs (3 mg/kg, i.v.) significantly reduced cocaine-induced locomotor sensitization in mice within 45 min, by attenuating cocaine-induced (25 mg/kg, i.p.) dopamine signaling in the brain. CocE NEs represent a promising candidate for the sustained prevention and treatment of cocaine abuse."

Journal

Comparing Efficacy & Safety of TNX-1300 to Placebo with UC for Treatment of Acute Cocaine Intoxication in ED Subjects (CATALYST) (clinicaltrials.gov) - P2 | N=36 | Recruiting | Sponsor: Tonix Pharmaceuticals, Inc. | N=60 ➔ 36 | Trial completion date: Dec 2024 ➔ Mar 2025 | Trial primary completion date: Dec 2024 ➔ Mar 2025

Enrollment change • Trial completion date • Trial primary completion date

Catalytic mechanism, computational design, and crystal structure of a highly specific and efficient benzoylecgonine hydrolase. (PubMed, Int J Biol Macromol) - "Here, BZEase4 was engineered from bacterial cocaine esterase (CocE) by our reactant state-based enzyme design theories (RED), which has a 34,977-fold improved substrate discrimination between BZE and the neurotransmitter acetylcholine (ACh), compared with wild-type CocE. Under the physiological concentrations of BZE and ACh, the reaction velocity of BZEase4 against BZE is 2.25 × 106-fold higher than it against ACh, suggesting BZEase4 has extremely high substrate selectivity for BZE over ACh to minimize the potential cholinergic side-effects. This study provides additional evidence supporting the further development of BZEase4 toward a promising therapeutic for cocaine overdose, a potentially effective and eco-friendly enzymatic method for BZE degradation in the environment."

Journal

A Microbial Cocaine Bioreporter. (PubMed, Sensors (Basel)) - "Further improvement of the sensor's performance was achieved by altering the nucleotide sequence of the PBen gene promoter, the construct's sensing element, using accelerated site-directed evolution. The applicability of ready-to-use paper strips with immobilized bioreporter cells was demonstrated for cocaine detection in aqueous solutions."

Journal

Comparing Efficacy & Safety Of TNX-1300 To Placebo With UC For Treatment Of Acute Cocaine Intoxication In ED Subjects (CATALYST) (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Tonix Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting | Trial completion date: Jun 2024 ➔ Dec 2024 | Initiation date: Dec 2023 ➔ Aug 2024 | Trial primary completion date: Jun 2024 ➔ Dec 2024

Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date

Comparing Efficacy & Safety Of TNX-1300 To Placebo With UC For Treatment Of Acute Cocaine Intoxication In ED Subjects (CATALYST) (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Tonix Pharmaceuticals, Inc.

New P2 trial

Tonix Pharmaceuticals Announces Poster Presentation Involving TNX-1700 in Preclinical Colorectal Cancer Models at the Seventh International Cancer Immunotherapy Conference 2023 (GlobeNewswire) - "TNX-1900 (intranasal potentiated oxytocin), is in development for preventing headaches in chronic migraine, and has completed enrollment in a Phase 2 proof-of-concept study with topline data expected in the fourth quarter of 2023....A Phase 2 study of TNX-1300 is expected to be initiated in the third quarter of 2023."

Enrollment closed • New P2 trial • P2 data • CNS Disorders • Migraine • Pain

Modular Catalysis: Aptamer Enhancement of Enzyme Kinetics in a Nanoparticle Reactor. (PubMed, Biomacromolecules) - "We explored this concept with cocaine esterase and anticocaine aptamers having varying K values, both encapsulated in MS2 virus-like particles...This beneficial effect was lost when either aptamer binding was too tight or the aptamers were not constrained to be close to the catalyst. This work demonstrates a modular way to enhance catalysis by independently controlling substrate capture and release to the processing enzyme."

Journal

Unlocking the strength of inducible promoters in Gram-negative bacteria. (PubMed, Microb Biotechnol) - "We validate the improvement in OFF state control and inducibility by demonstrating production of the toxic and aggregate-prone cocaine esterase enzyme CocE. We further demonstrate portability of the promoters to additional Gram-negative species Pseudomonas putida and Vibrio natriegens. Our results represent a significant improvement over existing protein expression systems that will enable advances in protein production for various biotechnology applications."

Gram negative • Journal • Infectious Disease

An Open-Label, Randomized Pilot Study Comparing the Safety of a Single Dose of TNX-1300 to Usual Care (UC) Alone for the Treatment of Signs and Symptoms of Acute Cocaine Intoxication in Male Emergency Department (ED) Subjects (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Tonix Pharmaceuticals, Inc. | N=45 ➔ 0 | Recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal

An Open-Label, Randomized Pilot Study Comparing the Safety of a Single Dose of TNX-1300 to Usual Care (UC) Alone for the Treatment of Signs and Symptoms of Acute Cocaine Intoxication in Male Emergency Department (ED) Subjects (clinicaltrials.gov) - P2 | N=45 | Recruiting | Sponsor: Tonix Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open

Cocaine esterase occurrence in global wastewater microbiomes and potential for biotransformation of novel psychoactive substances. (PubMed, Environ Microbiol Rep) - "In addition, in silico predictions indicated that carfentanil, 4F-MDMB-BINACA, 5F-MDMB-PICA, MDMB-4en-PINACA and mitragynine might also undergo microbial hydrolysis, in a similar fashion of cocaine degradation by cocaine esterase. In conclusion, it was demonstrated the microbial potential to hydrolyze drugs of abuse in wastewater environments, contributing to the critical evaluation of potential metabolites as biomarkers for microbial and human transformation of drugs in wastewater."

Clinical • Journal

An Open-Label, Randomized Pilot Study Comparing the Safety of a Single Dose of TNX-1300 to Usual Care (UC) Alone for the Treatment of Signs and Symptoms of Acute Cocaine Intoxication in Male Emergency Department (ED) Subjects (clinicaltrials.gov) - P2; N=45; Not yet recruiting; Sponsor: Tonix Pharmaceuticals, Inc.

New P2 trial

Efficient Cocaine Degradation by Cocaine Esterase-Loaded Red Blood Cells. (PubMed, Front Physiol) - "Unfortunately, the native enzyme was highly unstable and the corresponding mutagenized derivatives, RBP-8000 and E196-301, although improving in vitro thermo-stability and in vivo half-life, were a partial solution to the problem...Thus, our in vitro data show that E196-301-loaded RBCs could act as efficient bioreactors in degrading cocaine to non-toxic metabolites to be possibly considered in substance-use disorder treatments. This approach should now be investigated in a preclinical model of cocaine use disorder to evaluate if further protein modifications are needed to further improve long term enzyme stability."

Journal

Evaluation of the cholinesterase activity of a potential therapeutic cocaine esterase for cocaine overdose. (PubMed, Drug Alcohol Depend) - "Given the fact that clinically relevant dose of RBP-8000 displays insignificant cholinesterase activity relative to endogenous cholinesterases in human, administration of RBP-8000 is unlikely to produce any significant cholinergic side-effects. This study provides supplemental evidences in support of further development of RBP-8000 towards a clinically used pharmacotherapy for cocaine overdose."

Journal

Tonix Pharmaceuticals reports third quarter 2019 financial results and operational highlights (Gurufocus) - "TNX-1300 (double-mutant cocaine esterase): Met with FDA to discuss and reach agreement on the design of toxicology studies for TNX-1300 to support a Phase 2 clinical study....Tonix‘s programs for treating addiction conditions also include TNX-1300 (double-mutant cocaine esterase), which is in Phase 2 development for the treatment of cocaine intoxication."

FDA event

Tonix Pharmaceuticals Reports Second Quarter 2019 Financial Results and Operational Highlights (GlobeNewswire, Tonix Pharmaceuticals Holding Corp.) - Pipeline Expanded in Addiction Medicine with Cocaine Antidote TNX-1300 and Potential New Alcohol Use Disorder Indication for TNX-102 SL .

Clinical • New trial

Tonix Pharmaceuticals Expands Pipeline with Mid-Stage Biologic Candidate TNX-1300 for Cocaine Intoxication (GlobeNewswire, Tonix Pharmaceuticals Holding Corp.) - "Tonix Pharmaceuticals Holding Corp....announced today that it has in-licensed a Phase 2 asset, TNX-1300 (T172R/G173Q double-mutant cocaine esterase 200 mg, i.v. solution)* for the treatment of cocaine intoxication....designated as a breakthrough therapy by the U.S. Food and Drug Administration (FDA). TNX-1300, formerly RBP-8000, is a recombinant enzyme that efficiently degrades and metabolizes cocaine in cocaine abusers, as demonstrated in a Phase 2 randomized, double-blind, placebo-controlled clinical study, providing support of the use of TNX-1300 as a treatment for cocaine intoxication."

Breakthrough therapy designation • Clinical • FDA event • Licensing / partnership