Clinical Pharmacology Corner Update: FDA Approves EMPLICITI (elotuzumab)

FDA Approves EMPLICITI (elotuzumab) in combination with lenalidomide and dexamethasone for the Treatment of Patients with Multiple Myeloma who have Received One to Three Prior Therapies.

On November 30, 2015, the U.S. Food and Drug Administration (FDA) granted approval to EMPLICITI^TM (elotuzumab) injection in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.  The approved recommended dosage is 10 mg/kg, administered as an intravenous infusion, weekly on Weeks 1 to 8 and every two weeks from Week 9 until disease progression or unacceptable toxicity. Pre-medicate with dexamethasone, diphenhydramine, ranitidine and acetaminophen.

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD)

• MOA: Elotuzumab is a humanized IgG1 monoclonal antibody that targets the SLAMF7 (Signaling Lymphocytic Activation Molecule Family member 7) protein which is expressed on myeloma cells and natural killer cells. Elotuzumab directly activates Natural Killer cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on myeloma cells and facilitates the interaction with Natural Killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity.
• Dose proportionality: Nonlinear pharmacokinetics resulting in greater than proportional increases in area under the concentration-time curve (AUC) indicative of target-mediated clearance.
• Terminal half-life (mean): Thirty-three days.
• Steady State Achieved:  Approximately three months.   

Use in Specific Populations

• The clearance of elotuzumab increased with increasing body weight supporting a weight-based dose.
• Clinically significant differences were not observed in the pharmacokinetics of elotuzumab based on age (37-88 years), gender, race, baseline LDH, albumin, renal impairment ranging from mild to severe (creatinine clearance (CLcr) 15 to 89 mL/min) renal impairment, end-stage-renal disease (CLcr less than 15 mL/min) with or without hemodialysis, and mild (NCI-CTEP) hepatic impairment. The pharmacokinetics of elotuzumab in patients with moderate to severe hepatic impairment is unknown.

Safety and Efficacy

The effectiveness and safety of EMPLICITI was evaluated in a Phase 3, randomized, controlled, open-label, multicenter study in subjects with relapsed/refractory MM who had progressed after 1 to 3 lines of therapies. Subjects (n=646) were randomized to receive elotuzumab (10 mg/kg) in combination with lenalidomide/ dexamethasone (E-Ld) (n=321) or lenalidomide/ dexamethasone alone (Ld) (n=325). The final analysis showed a statistically significant improvement in median PFS time of 4.5 months between Arm E-Ld (19.4 months) and Arm Ld (14.9 months) (Hazard ratio [95% CI]  0.70 [0.57, 0.85], p=0.0004) and overall response rates of 78.5 and 65.5%, respectively. Progression-free survival increased with increasing elotuzumab exposure. However, after controlling for risk factors, patients with elotuzumab average steady state concentrations ≤ 209 µg/mL had PFS similar to those of patients on the active control arm. Exposure-response will be further evaluated in ongoing trials to determine if dose adjustment may be needed for patients with lower elotuzumab exposures as a post marketing commitment with the Agency.

The most common adverse reactions are fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, and pneumonia. At the approved dose, 10% of patients had grade 3 or lower infusion reactions and 1% discontinued elotuzumab due to infusion reactions. Patients on elotuzumab had increased infections relative to active control patients. The rates of grade 3 or higher adverse events or adverse events leading to discontinuations or deaths did not increase with increasing elotuzumab concentration.

---

Full prescribing information is available at http://go.usa.gov/cKUZn.

The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (http://go.usa.gov/cKUDD).

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

We always welcome your thoughts regarding the format, content, and utility of information you receive via this Burst email initiative. Comments may be sent via email to ocp@fda.hhs.gov.

This burst was prepared by the OCP Review Team: Olanrewaju Okusanya, Pharm.D. , MS, Justin Earp, Ph.D., Gene Williams, Ph.D.,  and Nitin Mehrotra, M. Pharm, Ph.D., Division of Clinical Pharmacology V and Division of Pharmacometrics, OCP, Office of Translational Sciences, CDER, FDA.

---

FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov