Elotuzumab

Elotuzumab directly activates natural killer cells through both the SLAMF7 pathway and Fc receptors enhancing anti-myeloma activity in vitro. Elotuzumab also targets SLAMF7 on myeloma cells and through interactions with Fc receptors on specific immune cells, promotes the killing of myeloma cells through NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated antibody-dependant cellular phagocytosis (ADCP). In nonclinical models, elotuzumab has demonstrated synergistic activity when combined with lenalidomide, pomalidomide or bortezomib.

Elotuzumab is an immunostimulatory humanised, IgG1 monoclonal antibody that specifically targets the SLAMF7 (signaling lymphocyte activation molecule family member 7) protein. SLAMF7 is highly expressed on multiple myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on natural killer cells (NK), normal plasma cells, and other immune cells including some T cell subsets, monocytes, B cells, macrophages, and pDCs (plasmacytoid dendritic cells), but is not detected on normal solid tissues or haematopoietic stem cells.

The pharmacokinetics (PK) of elotuzumab was studied in patients with multiple myeloma. Elotuzumab exhibits nonlinear PK with decrease in clearance with increase in dose from 0.5-20 mg/kg.

Absorption

Elotuzumab is dosed via intravenous route and therefore is immediately and completely bioavailable.

Distribution

The geometric mean volume of distribution of elotuzumab at the recommended dosing regimen in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone at steady state is 5.7 L (CV: 23%) and 5.6 L (CV: 21%) respectively.

Biotransformation

The metabolic pathway of elotuzumab has not been characterized. As an IgG monoclonal antibody, elotuzumab is expected to be degraded into small peptides and amino acids via catabolic pathways.

Elimination

The geometric mean total clearance of elotuzumab at 10 mg/kg (in combination with lenalidomide and dexamethasone) at steady state is 0.194 L/day (CV: 62.9%). Upon discontinuation of elotuzumab in combination with lenalidomide and dexamethasone or in combination with pomalidomide and dexamethasone, concentrations of elotuzumab will decrease to approximately 3% (approximately 97% washout as estimated by 5 half-lives) of the population predicted steady-state maximal serum concentration by 3 months.

Special populations

Based on a population PK analysis using data from 440 patients, the clearance of elotuzumab increased with increasing body weight supporting a weight-based dose. Population PK analysis suggested that the following factors had no clinically important effect on the clearance of elotuzumab: age, gender, race, baseline LDH, albumin, renal impairment, mild hepatic impairment, and coadministration with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Target-mediated clearance of elotuzumab increased with higher serum M-protein concentrations.

Renal impairment

An open-label study (CA204007) evaluated the pharmacokinetics of elotuzumab in combination with lenalidomide and dexamethasone in patients with multiple myeloma with varying degrees of renal impairment (classified using the CrCl values). The effect of renal impairment on the pharmacokinetics of elotuzumab was evaluated in patients with normal renal function (CrCl >90 mL/min; N = 8), severe renal impairment not requiring dialysis (CrCl <30 mL/min; N = 9), or end-stage renal disease requiring dialysis (CrCl <30 mL/min; N = 9). No clinically important differences in the pharmacokinetics of elotuzumab were found between patients with severe renal impairment (with and without dialysis) and patients with normal renal function.

Hepatic impairment

Elotuzumab is an IgG1 monoclonal antibody, which is principally cleared by catabolism. Thus, hepatic functional impairment is not likely to alter its clearance. The effect of hepatic impairment on the clearance of elotuzumab was evaluated by population PK analyses in patients with mild hepatic impairment (total bilirubin [TB] ≤ the upper limit of normal [ULN] and AST > ULN or TB <1 to 1.5 × ULN and any AST; N = 33). No clinically important differences in the clearance of elotuzumab were found between patients with mild hepatic impairment and patients with normal hepatic function. Elotuzumab has not been studied in patients with moderate (TB >1.5 to 3 × ULN and any AST) or severe hepatic impairment (TB >3 × ULN and any AST).

Elotuzumab only recognizes human SLAMF7 protein. Because elotuzumab does not recognize non-human forms of SLAMF7 protein, in vivo safety data from animal studies are irrelevant. In the same line, no carcinogenicity data are available for elotuzumab in animals, nor were fertility and embryo-foetal toxicity studies performed. Non-clinical safety information primarily consists of limited in vitro human cell/tissue studies where no safety findings were identified.