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Pharmacology Review(S) Memorandum CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 207103Orig1s000 PHARMACOLOGY REVIEW(S) MEMORANDUM Ibrance (palbociclib) Date: January 23, 2015 To: File for NDA 207103 From: John K. Leighton, PhD, DABT Acting Director, Division of Hematology Oncology Toxicology Office of Hematology and Oncology Products I have examined pharmacology/toxicology supporting and labeling reviews for Ibrance conducted by Dr. Chen, and secondary memorandum and labeling provided by Dr. Palmby. I concur with Dr. Palmby’s conclusion that Ibrance may be approved and that no additional nonclinical studies are needed for the proposed indication. Reference ID: 3691405 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- JOHN K LEIGHTON 01/23/2015 Reference ID: 3691405 MEMORANDUM Date: January 22, 2015 From: Todd R. Palmby, PhD Pharmacology/Toxicology Supervisor Division of Hematology Oncology Toxicology (DHOT) Office of Hematology and Oncology Products (OHOP) To: File for NDA 207103 Ibrance (palbociclib) Re: Approvability for Pharmacology and Toxicology Indication: in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease Non-clinical pharmacology and toxicology literature and original reports for studies to support NDA 207104 for Ibrance (palbociclib) indicated for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease were reviewed by Wei Chen, PhD. Studies conducted with palbociclib for which reports were submitted to this NDA include pharmacology, pharmacokinetics and ADME, safety pharmacology, general toxicology, genetic toxicology and reproductive and developmental toxicology. Palbociclib is a kinase inhibitor, which has inhibitory activity against cyclin dependent kinase (CDK) 4 and 6. Palbociclib would be the first product approved by the US FDA with a mechanism of action involving inhibition of a cyclin-dependent kinase leading to anti-tumor activity. Palbociclib inhibited CDK4/cyclinD1, CDK4/cyclinD3 and CDK6/cyclinD2 complexes with IC50 values of 11, 9 and 15 nM, respectively. The IC50 values for CDK2/cyclinA, CDK1/cyclinB and CDK5/p25 were greater than 5 M. In vitro, palbociclib blocked progression of the cell cycle from G1 to S phase, thereby reducing proliferation in estrogen receptor (ER)-positive breast cancer cell lines. The combination treatment of palbociclib and antiestrogens in breast cancer cell lines lead to reduced retinoblastoma (Rb) protein phosphorylation and E2F expression, reduced signaling and increased growth arrest compared to treatment with each drug alone. In vivo, the combination treatment of palbociclib and letrozole in an ER-positive breast cancer mouse xenograft model lead to increased inhibition of Rb phosphorylation, downstream signaling and dose- dependent tumor growth inhibition compared to treatment with each drug alone. This data supported the enrollment of patients with ER-positive/HER2-negative advanced breast cancer into the clinical trials that were conducted to support the proposed indication. “Kinase inhibitor” was selected as the Established Pharmacologic Class for palbociclib. This is scientifically valid based on the submitted data and clinically meaningful, since adverse events observed in clinical trials were not unique to palbociclib and did not warrant a distinct Reference ID: 3690854 pharmacologic class to alert prescribers to potential safety concerns that are not associated with other kinase inhibitors. General toxicology studies were conducted with oral palbociclib administration for up to 27 weeks in rats and 39 weeks in dogs. The major adverse effects noted at clinically relevant exposures were in the bone marrow/hematolyphoid system and male reproductive organs in these studies. Additional target organs of toxicity included the gastrointestinal tract, liver, kidney, endocrine/metabolic system, respiratory system and adrenal glands in rats or dogs. Studies of 3-months duration would generally support marketing of a pharmaceutical intended to treat patients with advanced cancer. The studies of 26 and 39 weeks were not required by the US FDA to support submission of an NDA for this indication. FDA requested that the Applicant submit the reports for the 27-week study in rats and the 39-week study in dogs to this NDA after reviewing the 27-week rat study report, submitted to the IND, and noting findings of altered glucose metabolism. Altered glucose metabolism including glycosuria, hyperglycemia and decreased insulin were noted in the 27-week rat toxicology study with palbociclib. Findings in the pancreas (islet cells vacuolation), eye (cataracts, lens degeneration), teeth (degeneration/necrosis of ameloblasts in actively growing teeth), kidney (tubule vacuolation, chronic progressive nephropathy), and adipose tissue (atrophy) were associated with the altered glucose metabolism in these animals. These findings were most prevalent in males at doses ≥30 mg/kg/day (approximately 11 times the human exposure (AUC) at the recommended dose). Some findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present in the 15-week rat study, but at lower incidence and severity. Altered glucose metabolism or associated changes in pancreas, eye, teeth, kidney and adipose tissue were not observed in dogs in repeat-dose toxicology studies up to 39 weeks duration. Hyperglycemia was not observed as an adverse reaction associated with palbociclib administration in clinical trials. There are multiple publications reporting findings from CDK4, CDK6 or CDK4/6 double knockout mice. Mice that do not express CDK4 are viable, but are small in size and infertile. These mice develop insulin deficient diabetes due to a decrease in the number of pancreatic beta islet cells (Rane, Dubus, et al. 1999). A subsequent publication reported that CDK4 is essential for the postnatal proliferation of pancreatic beta cells (Martin, Hunt, et al. 2003). This suggests that inhibition of pancreatic beta cell proliferation during a time when these cells are undergoing expansion may lead to decreased pancreatic beta cell numbers resulting in insulin deficiency. There are potential reasons why altered glucose metabolism occurred in rats administered palbociclib, but was not observed in dogs or in patients in clinical trials and may not be clinically relevant in the indicated patient population. Rodent pancreatic beta cells are dependent on CDK4 for proliferation, while human beta islet cells may have compensatory CDK expression and, therefore, may be able to proliferate normally in the absence of CDK4 or even CDK4/6. Also, the rats used in the repeat-dose toxicology studies Reference ID: 3690854 administered palbociclib were adolescent animals (~8 weeks old at the start of the 27-week study). Beta cell proliferation follows an age-related decline. In humans, beta cell proliferation diminishes shortly after infancy and these cells remain relatively quiescent through adulthood. In rats, this decline occurs slower than in humans, with ~20% of cells proliferating in young animals in the postnatal period, ~10% proliferating during adolescence, ~2% proliferating in early adulthood, 0.07% proliferating in 1 year-old animals and 0.04% proliferating in older animals, approaching the level seen in adult humans. Therefore, the pancreatic beta cells in adolescent rats may be much more sensitive to the effects of palbociclib than in adults, in which beta cells are primarily quiescent. Finally, the altered glucose metabolism and associated findings observed in rats, but not humans, may involve higher relative exposures (AUC) in rats. There is insufficient data at this time to determine if the potential effects of palbociclib on glucose metabolism are clinically relevant. The Applicant has stated that they incorporated appropriate monitoring for these effects in their ongoing and planned clinical trials with palbociclib, so no additional nonclinical studies are necessary at this time. These findings may be important if Ibrance is studied in pediatric patients. There was an imbalance in pulmonary embolisms in patients receiving palbociclib and letrozole compared to patients receiving letrozole alone in clinical trials, with a higher incidence in the palbociclib-treated patients. There were limited findings of thrombosis in repeat-dose toxicology studies conducted with palbociclib. However, based on available literature, there is a mechanistic plausibility for an increased risk of thrombus in patients receiving palbociclib. Mice overexpressing p16(Ink4), a cell cycle inhibitor that promotes senescence by inhibiting CDK4/6 and is upregulated during normal aging, were studied with four different vascular injury models to assess the time to thrombus formation, time to resolution and effect on inflammation-induced vascular dysfunction. The conclusions of
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