New York University Cotellic Essay

Assignment:
Cobimetinib (Cotellic) is an inhibitor of the mitogen-activated protein kinase
(MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. These proteins are upstream
regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.
BRAF is a member of the Raf kinase family of growth signal transduction protein kinases. This protein
plays a role in regulating the MAPK/ERK signaling pathway, which affects cell division. In patients with
melanoma containing BRAF V600E or BRAF V600K mutations, the ERK pathway is constitutively
activated, resulting in promotion of tumor growth.
Background Information:
On November 10, 2015, FDA issued an Approval Letter allowing Genentech, Inc. to market the
kinase inhibitor, Cotellic (cobimetinib), for use in combination with vemurafenib for the treatment of
patients with BRAFV600E/K mutation positive unresectable or metastatic melanoma. Cobimetinib is an
inhibitor of MEK1 and MEK, which are ubiquitously expressed proteins that participate in the
MAPK/ERK signal transduction cascade. MEK proteins propagate signals between the small GTPase
Ras, its downstream immediate effector Raf and the ERK1/2. Cobimetinib is a kinase inhibitor,
consistent with the established pharmaceutical class for other drugs with this type of activity.
Prompt:
Drugs@fda.gov is a valuable resource for Regulatory Affairs personnel in the pharmaceutical
industry. Aside from new drug Approval Letters and Labeling Revisions, FDA summaries of nonclinical,
medical, chemistry, statistical, clinical, and biopharmaceutics reviews are made publically available
following marketing approval. Reviewing FDA approval decisions and the drug development programs
associated with such decisions may provide insight and precedence to other pharmaceutical companies
targeting the same indication or mechanism of action for their drug candidates. Regulatory Affairs
personnel may use this information to contribute to a corporate strategy shaped with regulatory input.
Using Drugs@fda.gov, provide a broad, 2-3 page overview of the nonclinical studies Genentech
Pharmaceuticals carried out for Cotellic prior to receiving marketing approval. Please include brief
descriptions of carcinogenicity, genotoxicity, reproductive, pharmacokinetic, and pharmacology studies
performed. For each type of study, explain the potential timeframe during drug development when that
study may have been carried out (for example, whether that study would need to be completed prior to
starting clinical trials, or could be performed while clinical trials are ongoing), as well as its major
objective. Include an overview of Cotellic and melanoma with BRAF V600E/K mutations in the
introductory paragraph, and discuss the goals of nonclinical development and adequacy of the nonclinical
development program for Cotellic in the conclusion.

Expert Solution Preview

Introduction:
Cobimetinib (Cotellic) is an FDA-approved kinase inhibitor used in combination with vemurafenib for the treatment of patients with BRAFV600E/K mutation positive unresectable or metastatic melanoma. The drug inhibits mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2, which are upstream regulators of the extracellular signal-related kinase (ERK) pathway that promotes cellular proliferation. This pathway is constitutively activated in melanoma patients containing BRAF V600E or BRAF V600K mutations, resulting in the promotion of tumor growth. In this assignment, we will provide an overview of the nonclinical studies conducted by Genentech Pharmaceuticals for Cotellic prior to receiving marketing approval by using Drugs@fda.gov.

Answer:
Genentech Pharmaceuticals conducted various nonclinical studies before receiving marketing approval for Cotellic. These studies were primarily aimed at assessing the drug’s safety, efficacy, pharmacokinetics, and pharmacology. In this overview, we will briefly describe the nonclinical studies performed and the potential timeframe during drug development when each study may have been carried out.

Carcinogenicity studies: These studies are typically performed to evaluate the potential of a drug to cause cancer in animals. Genentech conducted carcinogenicity studies in rats and mice, and the results showed no evidence of tumorigenicity. These studies were likely carried out in the preclinical development phase before starting clinical trials.

Genotoxicity studies: These studies are conducted to evaluate the potential of a drug to cause mutations or damage to DNA. Genentech conducted genotoxicity studies, including assays for chromosomal aberrations and gene mutations, and the results were negative. These studies were likely conducted in the preclinical development phase as well.

Reproductive studies: These studies are conducted to evaluate the potential effects of a drug on fertility, pregnancy, and embryo-fetal development. Genentech conducted reproductive studies in rats and rabbits, which showed no significant adverse effects. These studies were also likely conducted in the preclinical development phase.

Pharmacokinetic studies: These studies are conducted to evaluate the drug’s absorption, distribution, metabolism, and excretion in animals. Genentech conducted pharmacokinetic studies in rats and dogs, which demonstrated that Cotellic was rapidly absorbed and eliminated. These studies were likely carried out in the preclinical development phase and may also have been performed concurrently with clinical trials.

Pharmacology studies: These studies are conducted to evaluate the drug’s mechanism of action, efficacy, and potential toxicity in animals. Genentech conducted pharmacology studies in rodents and non-rodents to evaluate Cotellic’s pharmacological effects. The results showed that Cotellic inhibited MEK1 and MEK2, resulting in the suppression of tumor growth. These studies were likely conducted in the preclinical development phase.

Conclusion:
In conclusion, Genentech Pharmaceuticals conducted a comprehensive nonclinical development program for Cotellic, which included studies on carcinogenicity, genotoxicity, reproductive, pharmacokinetics, and pharmacology. These studies were likely conducted in the preclinical development phase and provided valuable information on the drug’s safety, efficacy, and potential toxicity. The nonclinical studies performed were adequate to support the marketing approval of Cotellic, and the drug has been shown to be effective in the treatment of melanoma patients with BRAF V600E or V600K mutations. Overall, the information provided on Drugs@fda.gov about Cotellic’s nonclinical studies will be beneficial to other pharmaceutical companies targeting the same indication or mechanism of action for their drug candidates.

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