CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 200603 PHARMACOLOGY REVIEW(S) Tertiary Pharmacology/Toxicology Review From: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology, OND IO NDA: 200603 Agency receipt date: 12/30/2009 Drug: Lurasidone hydrochloride Applicant: Sunovion Pharmaceuticals (Originally submitted by Dainippon Sumimoto Pharma America, Inc.) Indication: schizophrenia Reviewing Division: Division of Psychiatry Products Background: The pharm/tox reviewer and team leader concluded that the nonclinical data support approval of lurasidone for the indication listed above. Reproductive and Developmental Toxicity: Reproductive and developmental toxicity studies in rats and rabbits revealed no evidence of teratogenicity or embryofetal toxicity. The high doses in the rat and rabbit embryofetal toxicity studies were 3 and 12 times, respectively, the maximum recommended human dose (80 mg) based on a body surface area comparison. Carcinogenicity: Lurasidone was tested in 2 year rat and mouse carcinogenicity studies. These studies were reviewed by the division and the executive carcinogenicity assessment committee. The committee concluded that the studies were adequate and that there was a drug-related increase in mammary carcinomas in female rats at doses of 12 mg/kg and higher and a drug-related increase in mammary carcinomas and adenoacanthomas and pituitary pars distalis adenomas in female mice. The applicant also provided data from various studies showing that lurasidone significantly increases prolactin in several different species including rats and mice. Conclusions: I agree with the division pharm/tox conclusion that this application can be approved from a pharm/tox perspective. The division recommends that lurasidone be labeled with pregnancy category B. This is justified given the lack of effects in the developmental toxicity studies. The carcinogenicity findings are consistent with other members of this class of drugs. Proposed labeling includes wording noting the potential role of elevated prolactin in these tumor findings and also notes the uncertain relevance to human. This is appropriate. 1 The division has decided to use the established pharmacologic class of atypical antipsychotic for lurasidone. This is consistent with other members of the class and is a clinically meaningful term. 2 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- PAUL C BROWN 10/27/2010 Reference ID: 2855588 SUPERVISORY MEMORANDUM NDA# 200603 Drug: Lurasidone Sponsor: Dainippon Sumimoto Pharma America, Inc. (DSP) Indication: Acute treatment of schizophrenia Division: Psychiatry Products Reviewer: Sonia Tabacova, Ph.D. Team Leader: Aisar Atrakchi, Ph.D. Date: October 18, 2010 Dr. Tabacova based her evaluation and conclusion on the nonclinical data submitted by DSP. She concluded that there are no nonclinical concerns that would affect approval of this drug application. I find her assessment adequate and concur with her conclusion and recommendation to approve this application. This memo is a brief overview of the drug profile highlighting the main drug efficacy and safety issues. Lurasidone, the drug substance, is an atypical antipsychotic indicated for the acute treatment of schizophrenia at doses 40-120mg/d. The nonclinical efficacy and safety of lurasidone were investigated in standard animal studies. Dr. Tabacova conducted a thorough and comprehensive review and evaluation and made her recommendations based on the submitted data. Lurasidone’s mechanism of action appears to be antagonism through high affinity binding of the dopamine and serotonin receptors specifically D2, 5HT2A and 5HT7 as well as antagonism of alpha2C adrenergic receptors. Lurasidone showed dose dependent responses in standard animal models of schizophrenia such as methamphetamine-induced hyperactivity, apomorphine-induced stereotypy, and conditioned avoidance response in rats. The drug improved cognition and stabilized mood in a number of learning and memory models in rats, and the incidence and severity of extrapyramidal side effects and CNS depression are lower than for other antipsychotic drugs. There are a number of metabolites of lurasidone; two are with pharmacological effects comparable to that of the parent drug. The potential adverse effects of lurasidone on the CNS, CVS, Respiratory, GI, urinary, and endocrine systems were investigated in a number of in vitro and in vivo safety pharmacology studies in multiple animal species. Many of these effects were extension of the pharmacology of the drug through the dopamine, serotonin and/or adrenergic receptors. Lurasidone caused a significant prolongation of QTc interval (Cmax ≈3ug/ml), in conscious dog but not in the guinea pig or the cat; no effect on BP or QRS duration. Lurasidone inhibited the hERG channel current with an estimated IC50 of 108nM. 1 Lurasidone is rapidly absorbed following oral administration (mean Tmax of 0.7hr but 5hr in the monkey) and its bioavailability is relatively poor (<12% in all species tested). Presence of food seems to improve bioavailability 2-3x. The drug has a large volume of distribution and clearance and T1/2 ranged between 1.6-27hrs. Lurasidone is highly bound to plasma proteins with little free circulating drug and it is widely distributed to body tissues/organs including the brain with marked retention in pigmented tissues like the eyes. It crosses the placenta into the fetus. Lurasidone undergoes extensive metabolism mainly by liver CYP3A4 , and all human metabolites including 2 major ones (>10% of dose), have been found and adequately qualified in 1 or more animal test species. The 2 major human metabolites are ID20219 and ID20220 which have been shown not to be pharmacologically active. Main route of excretion of lurasidone is feces with very little detected in urine. There are no or minimal drug-drug interactions and lurasidone did not inhibit or induce CYP enzymes. The potential toxicity of lurasidone was investigated in single and repeat dose general toxicity studies in rats, monkeys and dogs with oral daily administration up to 6 months in rodent and 1 year in monkeys. Doses tested were up to 100mg/kg/d in the rat, 50mg/kg/d in monkey and, 200mg/kg/d in the dog. The target organs of toxicity include the reproductive system with changes in sex hormones, mammary glands, changes in bone (rat and dog), and increase in prolactin levels in all 3 species. In the 9 month dog study increased incidence of paraventricular contractions was observed in 2/4 200mg/kg/d male group as well as prolongation in the non-corrected QT interval. These dogs had higher plasma levels of lurasidone than other animals in the same dose group. Follow up studies were conducted in the dog up to 2 weeks; no effects of lurasidone were found on PQ, QRS, QT, or cardiac rhythm following 5 or 50mg/kg/d dose. Lurasidone was negative in the standard battery of genetic toxicity tests i.e. the Ames bacterial gene mutation, in vitro chromosomal aberration using Chinese hamster lung cells and the in vivo bone marrow micronucleous test in the mouse. An impurity in the synthetic pathway of lurasidone with a structural alert for gene mutation tested negative in the Ames gene mutation test. In 2 year life time bioassay lurasidone caused tumors in mice and rats. In female mice the incidence of malignant mammary gland tumors and pituitary gland adenomas was significantly increased in all doses tested with the lowest dose representing 1.6x the maximum recommended human dose (MRHD), of 120mg/day based on AUC; no increase in any tumor type in male mice was seen up to 20x in humans at the MRHD. In the rat the incidence of mammary gland carcinoma was significantly increased in females dosed 12 and 50/36mg/kg/d; the NOEL of 3mg/kg/d was only 0.5x the MRHD based on AUC exposure. No increase in tumors in male rats was seen up to the highest dose tested. Rodent mammary and pituitary tumors have been considered to be prolactin mediated and their relevance to human cancer risk is unclear at this time. Lurasidone reduced female rat fertility when administered at daily oral dose of 150mg/kg for 2 weeks premating, during mating, and through gestation day 7. This effect was reversible following 2 week recovery period. The NOEL for decreased fertility is 2 15mg/kg/d which is 1.2x the MRHD based on body surface area. Abnormalities in estrus cycle were observed at 1.5mg/kg/d dose and above; the 0.1mg/kg/d dose was the NOEL which is only 0.01x the MRHD of 120mg/d based on body surface area. There were no drug effects on male fertility up to the highest dose tested of 150mg/kg/d which is 12x the MRHD of 120mg/d. Lurasidone was not teratogenic in rats or rabbit when administered during organogenesis at doses up to 25 and 50mg/kg/d respectively. These doses are 2 and 8x the MRHD of 120mg/d based on body surface area. The drug had no effects on fetal/pup development when administered daily to pregnant rats during organogenesis through weaning up to 10mg/kg/d a dose that is equivalent to the MRHD on a body surface area basis. 3 --------------------------------------------------------------------------------------------------------- This