Antidote Therapeutics Progresses Optimization of the Nicotine-degrading Enzyme, NicA2, for Potential Use in Treating Nicotine Addiction
- Category: Proteins and Peptides
- Published on Monday, 05 August 2019 19:16
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- A new study, now published in BMC Biotechnology, demonstrates successful protein engineering resulting in a longer-acting enzyme, increased catalytic activity and reduced immunogenicity in vivo
- No drug-related toxicities were observed in a 30-day pilot toxicology study in rats
- Results provide a viable path toward a drug candidate suitable for human therapeutic use in treating nicotine addiction
GAITHERSBURG, MD, USA I August 05, 2019 I Antidote Therapeutics, Inc., (ATI) announced today the publication of the successful protein engineering of proprietary variants of the nicotine-degrading enzyme, NicA2, for potential therapeutic use in smoking cessation and other nicotine addiction disorders.
Published in BMC Biotechnology,1 study results demonstrate that novel variants increase catalytic activity of the NicA2 enzyme leading to a three-fold improvement in lowering brain nicotine levels, and the circulating half-life has been lengthened over eight-fold compared to the naturally occurring enzyme as studied in rats. Additionally, reduced immunogenic potential has been demonstrated in a human transgenic HLA mouse model. Furthermore, no toxicities were observed in a month-long repeated-dose rat study with continuous administration of nicotine.
Smoking and tobacco use are the largest preventable causes of death in the U.S. and globally, and a critical need exists for new treatments to combat nicotine addiction and its adverse health effects.2.3.4 Antidote Therapeutics is optimizing and developing the NicA2 enzyme as a novel therapeutic approach that degrades nicotine, the main addictive component of tobacco, minimizing brain exposure and reducing its reinforcing effects.
“An optimized nicotine-degrading enzyme is intended to enhance nicotine elimination so that addictive, reinforcing levels of nicotine are not reached in the brain of the treated smoker, even if they may continue to smoke during a quit attempt or relapse,” says Matthew W. Kalnik, Ph.D., President and Chief Executive Officer of ATI. “Only one in five smokers achieve long-term abstinence using standard of care therapies, leaving the majority still smoking and seeking alternatives. Our goal is to develop an optimized, long-acting nicotine-degrading enzyme that can provide a new tool for the medical community to use in an integrated treatment and relapse prevention plan for smoking or nicotine addiction associated with use of e-cigarettes.”
Over five million smokers in the U.S. with smoking-related diseases, such as cardiovascular or respiratory disease, or lung and other cancers, continue to smoke.2,3,4 By blocking nicotine’s effects, acute disease outcomes exacerbated by nicotine are expected to improve whether or not patients fully abstain from smoking. By removing brain-related nicotine-reinforcement, more patients may reduce smoking or stop all together.
The study was supported in part by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH).5 Using systematic mutational analysis of the active site of NicA2, the study yielded ten variants that increased the enzyme’s catalytic activity at the relatively low nicotine concentrations found in the blood of smokers. In addition, PEGylation substantially increased the enzyme’s circulating half-life and reduced its immunogenic potential. One of the most improved variants (ATI-3009) is approximately three-fold more potent than wild-type enzyme at reducing nicotine distribution to brain in rats, with the promise of smaller, less frequent doses.
About Antidote Therapeutics, Inc.
Antidote Therapeutics, Inc. is a biotechnology company with a portfolio of first-in-class nicotine-blocking drugs to treat diseases caused or worsened by nicotine. In addition to NicA2, the company is developing ATI-1013, a fully human monoclonal antibody to nicotine, for treatment of Buerger’s Disease, Critical Limb Ischemia and nicotine addiction.
- February 2019 – ATI enters into a collaboration with the National Cancer Institute (NCI) to further develop ATI-1013 to a successful filing of an Investigational New Drug (IND) application. The scope of the collaboration includes manufacturing process development, IND-enabling pharmacology and toxicology studies, and production of ATI-1013 for use in clinical trials.
- September 2018 - U.S. Food and Drug Administration (FDA) grants Orphan Drug Designation for ATI-1013 for the treatment of Buerger’s Disease.
- July 2018 - Pre-clinical proof of concept for NicA2 publishes in BMC Biotechnology6.
Antidote Therapeutics is advancing its compounds for clinical development and is currently seeking partnerships and funding. Interested parties may contact the company for further information, please visit http://www.antidotetx.com.
1BMC Biotechnology, Optimization of a nicotine degrading enzyme for potential use in treatment of nicotine addiction
2Reitsma MB, Fullman N, Ng M, Salama JS, Abajobir A, Abate KH, et al. Smoking prevalence and attributable disease burden in 195 countries and territories, 1990-2015: a systematic analysis from the global burden of disease study 2015. Lancet. 2017;389(10082):1885–906.
3World Health Organization. WHO report on the global tobacco epidemic, 2017: monitoring tobacco use and prevention policies. 2017.
4USHHS, The Health Consequences of Smoking—50 Years of Progress, A Report of the Surgeon General (2014). https://www.cdc.gov/tobacco/data_statistics/sgr/50th-anniversary/index.htm
5 R43DA044064 Protein Engineering of a Biologic Drug Candidate.
SOURCE: Antidote Therapeutics