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short-term repeated dose toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
Justification for type of information:
In general, enzymes are of very low toxicity due to ready biodegradability and very low bioavailability. Data from acute and sub-chronic oral toxicity studies provide evidence that enzymes are of very low toxicological activity (1). Additionally, enzyme preparations have a very long history of being used as processing aids in the production of foods, such as in the dairy, wine, brewing and distilling, starch, and baking industries. Also, enzymes are used in various other industries e.g. detergent, textile, paper, leather, fuel ethanol, and animal feed (2). The production organism used in the manufacture of monoamine oxidase has a long history of safe use.

CDX-616 has not been engineered for gastric stability (low pH and gastric media) and would be digested/hydrolyzed when ingested. Like all proteins, enzymes that have not been engineered for low pH and/or gastric stability, will denature or degrade into amino acids.

The two 14-day toxicity studies of CDX-6114 were designed in compliance with the International Conference on Harmonization (ICH) guidance M3(R2) titled “Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals”, as well as other relevant ICH guidelines, especially ICH-S6(R1). Both studies were conducted in compliance with Good Laboratory Practices (GLP) regulations. These animal toxicology studies were conducted using repeated oral daily dosing of CDX 6114 for up to 14 days in both rats and cynomolgus monkeys. All standard toxicology parameters, including a detailed histological examination of all standard tissues as well as a more extensive evaluation of the gastrointestinal tract, were performed. In both male and female rats and monkeys, oral administration via gavage of 720 mg/kg bw/day of CDX-6114 for 14 consecutive days and showed no drug-related signs of toxicity; therefore, the no observed adverse effect level (NOAEL) was considered to be at least 720 mg/kg bw/day in both species (3).

CDX-7108 is a lipase enzyme developed using the same engineering work structure with manufacturing based on the same manufacturing platform as CDX-616 (aka monoamine oxidase). CDX 7108 was well tolerated in both species at doses up to and including 408 mg/kg bw/day (rats), 424 mg/kg bw/day (monkeys) following 5 consecutive days of dosing, and up to and including 369 mg/kg bw/day in rats and monkeys following 28 days of dosing. No adverse effects were reported for any measured parameter including body weight, body weight gain, food consumption, clinical pathology (hematology, coagulation, clinical chemistry, and urinalysis), ophthalmology or neurobehavior (rats only) and electrocardiography (monkeys only). Furthermore, in both species administered CDX 7108 for 28 days at doses ≤ 369 mg/kg bw/day, there were no CDX-7108 related macroscopic or microscopic findings at the end-of-dosing on Day 28 or in animals held for a 2 week treatment-free recovery period (4).
Finally, monoamine oxidase enzymes are found in terrestrial and aquatic vertebrates (5) and are therefore commonly ingested with food. Based on the weight of evidence presented, further live animal testing to investigate the sub-chronic oral toxicity of monoamine oxidase (aka CDX-616) is scientifically unnecessary as there is sufficient information for deriving an adequate qualitative hazard assessment.

(1) Enzymes REACH Consortium (2010). Data waiving argumentation for technical enzymes.
(3) Study numbers 0440RC130.001, 0437RC130.001, 0440SC130.002 and 0437RC130.001
(4) Study numbers CDX1783-R-2005, CDX1783-R-2021, CDX1783-NHP-2006 and CDX1783-NHP-2022
(5) Setini, A., Pierucci, F., Senatori, O. and Nicotra, A., 2005. Molecular characterization of monoamine oxidase in zebrafish (Danio rerio). Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 140(1), pp.153-161. doi: 10.1016/j.cbpc.2004.10.002.

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Results and discussion

Applicant's summary and conclusion