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PHARMACOLOGY REVIEW(S) Comments on N 22-562 Carbaglu Carglumic Acid from Abby Jacobs, AD Date: 3/15/10

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PHARMACOLOGY REVIEW(S) Comments on N 22-562 Carbaglu Carglumic Acid from Abby Jacobs, AD Date: 3/15/10 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-562 PHARMACOLOGY REVIEW(S) Comments on N 22-562 Carbaglu carglumic acid From Abby Jacobs, AD Date: 3/15/10 1. I concur that there are no pharm/tox issues with approval and the labeling of pharm/tox portions is acceptable, with the changes suggested by the reviewer. 2. I do not concur with the postmarketing requests a. There is no need for a chronic study in nonrodents in addition to the rodent chronic study -The number of animals per group will be small -There are human data sufficient for approval. -The animals tested will not have the condition of hyperammonemia, and thus adverse effects observed at high doses may not be relevant to the patient population -the drug is lifesaving - the number of persons having this condition is rather small b. There is no need for a carcinogenicity study The animals tested will not have the condition of hyperammonemia, and thus adverse effects observed at high doses may not be relevant to the patient population -the drug is lifesaving and - the number of persons having this condition is rather small Application Submission Type/Number Type/Number Submitter Name Product Name -------------------- -------------------- -------------------- ------------------------------------------ NDA-22562 ORIG-1 ORPHAN EUROPE CARBAGLU (CARGLUMIC ACID) --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- ABIGAIL ABBY C C JACOBS 03/15/2010 MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH FROM: David B. Joseph, Acting Pharmacology Team Leader DATE: March 11, 2010 SUBJECT: NDA 22,562 (serial # 000 dated June 17, 2009) Sponsor: Orphan Europe, SARL Drug Product: Carbaglu (carglumic acid) Comments: 1. Carbaglu (carglumic acid, or N-carbamoyl-L-glutamic acid) was developed for the treatment of hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency. Carglumic acid is a structural analog of N-acetyl-L-glutamate (NAG), which is an obligatory allosteric activator of mitochondrial carbamoyl phosphate synthetase 1 (CPS 1), the first enzyme of the urea cycle. NAG is synthesized by the enzyme NAGS. In the absence of NAGS, NAG is not produced and plasma levels of ammonia are elevated due to impaired function of the urea cycle. NAGS deficiency is the rarest of the hereditary urea cycle disorders. The time of onset of clinical signs in NAGS deficiency patients is variable, ranging from shortly after birth through adulthood. The neonatal onset of NAGS deficiency is severe, with death expected to occur within a few days. Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS 1. 2. The nonclinical dataset did not identify any safety issues that would impact the approvability of carglumic acid. The most notable findings in the nonclinical data were the high mortality in orally-treated neonatal rats, and the impaired growth and survival of rat pups in a peri- /post-natal developmental study. In a 2-week oral toxicity study, administration of 2000 mg/kg/day produced deaths in most rat pups (neonates) within 2-3 days, whereas drug- related deaths were not observed at lower dose levels (250-1000 mg/kg/day). The lethal dose in this study is 8 times the maximum recommended starting dose for Carbaglu (250 mg/kg), based on a bodyweight comparison (mg/kg). Since the cause of hyperammonemia in neonates is usually unknown and because of the length of time needed to obtain a diagnosis, it is expected that carglumic acid will be administered in neonates with hyperammonemia as an adjunctive treatment with other ammonia lowering therapies (e.g., sodium phenylbutyrate). In this scenario, treatment with carglumic acid would likely continue until a cause of hyperammonemia is identified (e.g., a specific urea cycle enzyme deficiency). Therefore, the observed toxicity in orally-treated neonatal rats and in the offspring of carglumic acid-treated rats is a safety concern. Page 2 However, this concern can be addressed in the labeling (see the Pharmacology/Toxicology review by Dr. Yuk-Chow Ng). 3. General toxicology studies were conducted in rats only, although the Agency did request submission of a chronic toxicity study in a nonrodent species. The Sponsor has not provided any convincing rationale for the omission of toxicity studies in a nonrodent species. This deficiency is discussed in detail in Dr. Ng’s review. I concur with Dr. Ng’s recommendation that the Sponsor should conduct a chronic (9-month) oral toxicity study in a nonrodent species, as a post-marketing requirement. 4. I concur with Dr. Ng’s recommendation that the Sponsor should conduct a 2-year carcinogenicity study in a single species, as a post-marketing requirement. The Sponsor has committed to performing this study following the approval of Carbaglu. Recommendations: There are no nonclinical issues which preclude the approval of Carbaglu for treatment of hyperammonemia due to NAGS deficiency. I concur with Dr. Ng’s recommendation for approval, and with the recommendations for post-marketing nonclinical studies, as described above. __________________________________ ____________ David B. Joseph, Ph.D. Date Acting Pharmacology Team Leader Division of Gastroenterology Products cc: NDA 22,562 DGP DGP/CSO DGP/Dr. Joseph DGP/Dr. Ng OND IO/Dr. Jacobs Application Submission Type/Number Type/Number Submitter Name Product Name -------------------- -------------------- -------------------- ------------------------------------------ NDA-22562 ORIG-1 ORPHAN EUROPE CARBAGLU (CARGLUMIC ACID) --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- DAVID B JOSEPH 03/11/2010 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION NDA NUMBER: 22-562 SERIAL NUMBER: 000 DATE RECEIVED BY CENTER: 6/17/2009 PRODUCT: Carbaglu® INTENDED CLINICAL POPULATION: Patients with hyperammonemia associated with N-Acetylglutamate synthase deficiency SPONSOR: Orphan Europe Paris, France DOCUMENTS REVIEWED: Vol. 1-15 REVIEW DIVISION: Division of Gastroenterology Products PHARM/TOX REVIEWER: Yuk-Chow Ng, Ph.D. ACTING PHARM/TOX TEAM LEADER: David B. Joseph, Ph.D. DIVISION DIRECTOR: Donna Griebel, M.D. PROJECT MANAGER: Roland Girardet, MHS, MS, MBA TABLE OF CONTENTS EXECUTIVE SUMMARY .............................................................................................. 3 2.6 PHARMACOLOGY/TOXICOLOGY REVIEW................................................. 13 2.6.1 INTRODUCTION AND DRUG HISTORY................................................................. 13 2.6.2 PHARMACOLOGY....................................................................................................... 17 2.6.2.1 Brief summary ...................................................................................................................... 17 2.6.2.2 Primary pharmacodynamics ................................................................................................. 18 2.6.2.3 Secondary pharmacodynamics ............................................................................................. 19 2.6.2.4 Safety pharmacology ............................................................................................................ 19 2.6.2.5 Pharmacodynamic drug interactions..................................................................................... 20 2.6.3 PHARMACOLOGY TABULATED SUMMARY....................................................... 20 2.6.4 PHARMACOKINETICS/TOXICOKINETICS .......................................................... 20 2.6.4.1 Brief summary ...................................................................................................................... 20 2.6.4.2 Methods of Analysis.............................................................................................................21 2.6.4.3 Absorption ............................................................................................................................ 21 2.6.4.4 Distribution........................................................................................................................... 25 2.6.4.5 Metabolism........................................................................................................................... 28 2.6.4.6 Excretion............................................................................................................................... 31 2.6.4.7 Pharmacokinetic drug interactions........................................................................................ 31 2.6.4.8 Other Pharmacokinetic Studies............................................................................................. 32 2.6.4.9 Discussion and Conclusions ................................................................................................
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