# Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse

> **NIH NIH U01** · UNIVERSITY OF KENTUCKY · 2022 · $4,721,164

## Abstract

Cocaine abuse is a major public health problem that directly or indirectly affects most communities and
families. There is still no FDA-approved medication specific for treatment of cocaine dependence or overdose.
Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine
medication a high priority. Accelerating cocaine metabolism that produces biologically inactive metabolites via
the most favorable cocaine-metabolizing pathway—cocaine hydrolysis catalyzed by human
butyrylcholinesterase (BChE) in plasma—is recognized as the most efficient treatment strategy for cocaine
overdose and dependence. Since the catalytic efficiency of wild-type BChE against the naturally occurring (-)-
cocaine is low, we have designed and discovered a set of BChE mutants, known as cocaine hydrolases
(CocHs), with at least 1,000-fold improved catalytic efficiency against (-)-cocaine compared to wild-type BChE.
Preclinical and clinical data for the first one of our previously discovered CocHs has demonstrated the promise
of enzyme therapy approach to the treatment of cocaine dependence. Our more recently designed and
discovered novel CocH entity, denoted as CocH5-Fc(M6), which has not only further improved catalytic
efficiency against cocaine, but also a considerably prolonged biological half-life. It has been demonstrated that
a single dose of CocH5-Fc(M6) can be used to completely block cocaine-induced physiological, behavioral,
and reinforcing effects for a long period of time in animal models. In addition, a stable CHO cell line capable of
efficiently expressing CocH5-Fc(M6) and the corresponding master cell bank (MCB) have been developed
along with establishment of the robust upstream and downstream protein production processes, ready for
large-scale CocH5-Fc(M6) protein production. Built on the encouraging progress of our rational design,
discovery, and development of the highly efficient, long-acting CocH entity CocH5-Fc(M6), the proposed new
project is focused on further development of CocH5-Fc(M6) as a novel therapeutic candidate for cocaine
dependence treatment, including large-scale production of the CocH5-Fc(M6) protein material using the
developed MCB and established robust upstream and downstream protein production processes,
investigational new drug (IND)-enabling studies, and first-in-human (FIH) clinical trials. The obtained clinical
data about the safety, pharmacokinetics, and ex vivo pharmacodynamics of CocH5-Fc(M6) in humans will
enable us to rationally design the most appropriate dosage regimen for future further clinical trials to determine
the clinical efficacy of CocH5-Fc(M6) in cocaine-dependent patients. Thus, this investigation will move a
promising candidate of the highly desired enzyme therapy closer toward FDA approval for cocaine
dependence treatment.

## Key facts

- **NIH application ID:** 10405101
- **Project number:** 5U01DA051079-03
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** CHANG-GUO ZHAN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $4,721,164
- **Award type:** 5
- **Project period:** 2020-08-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405101

## Citation

> US National Institutes of Health, RePORTER application 10405101, Development of a Long-acting Enzyme Therapy for Treatment of Cocaine Abuse (5U01DA051079-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10405101. Licensed CC0.

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