November 30, 2015
The U.S. Food and Drug Administration granted approval for Orphan Drug Empliciti
(elotuzumab) in combination with two other therapies to treat people with multiple myeloma who have received one to three prior medications.
- Elotuzumab is a humanized recombinant monoclonal antibody directed to SLAMF7, a cell surface glycoprotein.
- Elotuzumab consists of the complementary determining regions (CDR) of the mouse antibody, MuLuc63, grafted onto human IgG1 heavy and kappa light chain frameworks.
- Elotuzumab is produced in NS0 cells by recombinant DNA technology.
- Elotuzumab has a theoretical mass of 148.1 kDa for the intact antibody.
Mechanism of Action
- Elotuzumab is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7
- (Signaling Lymphocytic Activation Molecule Family member 7) protein.
- SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities.
- SLAMF7 is also expressed on Natural Killer cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage.
- 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 (ADCC).
- In preclinical models, the combination of elotuzumab and lenalidomide resulted in enhanced activation of Natural Killer cells that was greater than the effects of either agent alone and increased anti-tumor activity in vitro and in vivo.
Elotuzumab exhibits nonlinear pharmacokinetics (PK) resulting in greater than proportional increases in area under the concentration-time curve (AUC) indicative of target-mediated clearance.
The administration of the recommended 10 mg/kg EMPLICITI regimen in combination with lenalidomide/dexamethasone is predicted to result in geometric mean (CV%) steady-state trough concentrations of 194 g/mL (52%).
Safety and Efficacy
The safety and efficacy of Empliciti were tested in a randomized, open-label clinical study of 646 participants whose multiple myeloma came back after, or did not respond to previous treatment. Those taking Empliciti plus Revlimid and dexamethasone experienced a delay in the amount of time before their disease worsened (19.4 months) compared to participants taking only Revlimid and dexamethasone (14.9 months). Additionally, 78.5 percent of those taking Empliciti with Revlimid and dexamethasone saw a complete or partial shrinkage of their tumors compared to 65.5 percent in those only taking Revlimid and dexamethasone.
INDICATIONS AND USAGE
EMPLICITI is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.
DOSAGE AND ADMINISTRATION
The recommended dosage of EMPLICITI is 10 mg/kg administered intravenously every week for the first two cycles and every 2 weeks thereafter in conjunction with the recommended dosing of len
alidomide and low-dose dexamethasone as described below.
Continue treatment until disease progression or unacceptable toxicity.
When EMPLICITI is used in combination with lenalidomide, divide dexamethasone into an oral and intravenous dose and administer as shown in Table.
- In addition to dexamethasone, complete administration of the following medications 45 to 90 minutes prior to EMPLICITI infusion:
- H1 blocker: diphenhydramine (25-50 mg orally or intravenously) or equivalent H1 blocker.
- H2 blocker: ranitidine (50 mg intravenously or 150 mg orally) or equivalent H2 blocker.
- Acetaminophen (650-1000 mg orally)..
DOSAGE FORMS AND STRENGTHS
For Injection: 300 mg or 400 mg lyophilized powder in a single-dose vial for reconstitution.
- Store EMPLICITI under refrigeration at 2C to 8C (36F-46F).
- Protect EMPLICITI from light by storing in the original package until time of use. Do not freeze or shake.
WARNINGS AND PRECAUTIONS
- Infusion reactions: Premedication is required. Interrupt EMPLICITI for Grade 2 or higher and permanently discontinue for severe infusion reaction.
- Infections: Monitor for fever and other signs of infection and treat promptly.
- Second Primary Malignancies (SPM): Higher incidences of SPM were observed in a controlled clinical trial of patients with multiple myeloma receiving EMPLICITI.
- Hepatotoxicity: Monitor liver function and stop EMPLICITI if hepatotoxicity is suspected.
- Interference with determination of complete response: EMPLICITI can interfere with assays used to monitor M-protein. This interference can impact the determination of complete response.
Most common adverse reactions (20% or higher) are fatigue, diarrhea,pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, pneumonia.
Serious adverse events occurred in 65.4% of patients in the elotuzumab-containing arm compared to 56.5% in the lenalidomide plus dexamethasone alone arm.
The FDA granted breakthrough therapy designation for this application, which is granted when a drug is intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints.
Empliciti also received priority review and orphan drug designations. Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition.
Empliciti is marketed by Bristol-Myers Squibb of New York, New York. Darzalex is marketed by Janssen Biotech of Horsham, Pennsylvania. Revlimid is marketed by Celgene Corporation, based in Summit, New Jersey.
*Richardson P.,Jagannath S.,Moreau P.et al.Final Results for the 1703 Phase 1b/2 Study of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma.