NAV

Isatuximab

Identification

Summary

Isatuximab is a chimeric monoclonal antibody targeted against surface CD38 glycoproteins for the treatment of multiple myeloma in patients who have failed previous therapies.

Brand Names
Sarclisa
Generic Name
Isatuximab
DrugBank Accession Number
DB14811
Background

Isatuximab (formerly SAR650984) is a humanized, IgG1-derived monoclonal antibody (mAb) produced from a Chinese hamster ovary (CHO) cell line.9,2 Structurally, isatuximab is comprised of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains.9 It is a cytolytic antibody targeted against CD38, a glycoprotein found on the surface of some immune cells that is highly expressed by malignant plasma cells in multiple myeloma.9 Along with daratumumab, another anti-CD38 mAb, isatuximab constitutes a novel treatment modality for patients with difficult-to-treat multiple myeloma.

Following three consecutive years on the yearly "Antibodies to watch" list published in "mAb", a peer-reviewed scientific journal dedicated to antibody research,6,7,8 isatuximab was granted Orphan Drug designation and approved on March 2nd, 2020, for the treatment of multiple myeloma.9,10 It is manufactured by Sanofi-Aventis U.S. under the brand name Sarclisa.10

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
148000.0 Da
Sequences
Not Available
Synonyms
  • Isatuximab
  • isatuximab-irfc
External IDs
  • Hu 38SB19
  • SAR 650984
  • SAR-650984
  • SAR650984
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Pharmacology

Indication

Isatuximab is indicated in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma in adults who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.9 It is also indicated in combination carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.9

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatMultiple myeloma (mm)Regimen in combination with: Pomalidomide (DB08910), Dexamethasone (DB01234)••••••••••••••••••••••••• •• ••••• ••• ••••• ••••••••• ••••••••• •••••••••••• ••• • •••••••••• ••••••••••••••••••• ••••••••• ••••••••
Used in combination to treatRefractory multiple myelomaRegimen in combination with: Dexamethasone (DB01234), Carfilzomib (DB08889)••••••••••••••••••••••••• • •• • ••••• ••••• •• ••••••••••••••••• ••••••••• ••••••••
Used in combination to treatRelapsed multiple myelomaRegimen in combination with: Carfilzomib (DB08889), Dexamethasone (DB01234)••••••••••••••••••••••••• • •• • ••••• ••••• •• ••••••••••••••••• ••••••••• ••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Isatuximab results in the apoptosis of malignant plasma cells via inhibition of a surface protein key to their survival and proliferation.9 It has a relatively long residence time in the body, taking approximately 2 months to clear following the final dose, and may therefore be infused on a weekly or bimonthly schedule.9 Isatuximab is given in combination with pomalidomide due to a synergy that exists between the two - isatuximab can induce a depletion in host NK lymphocytes, yet the ADCC effect of anti-CD38 mAbs has been shown to be superior in patient samples with a high ratio of NK to myleoma cells.5 Pomalidomide, another antineoplastic agent, has the ability to induce and enhance NK lymphocyte activity1,5 and thus works synergistically to enhance isatuximab-mediated killing of myeloma cells.2

Isatuximab is formulated as an intravenous infusion and its administration may result in infusion-related reactions characterized most commonly by dyspnea, cough, chills, and nausea.9 All noted reactions started during the first infusion and 98% resolved on the same day. Reactions may be mitigated by pre-medication with acetaminophen, H2 antagonists, diphenyhdramine, and/or dexamethasone.9 Patients with grade 1 or 2 reactions may restart the infusion at a slower rate following resolution of symptoms, but patients experiencing a grade 3 or higher reaction (e.g. hypertension, bronchospasm) should discontinue therapy indefinitely.9

Isatuximab can generate false positive results for indirect antglobulin tests (indirect Coombs tests), immunofixation tests, and serum protein electrophoresis.9

Mechanism of action

Multiple myeloma is a blood cancer characterized by an overproduction of malignant plasma cells in the bone marrow. A unique characteristic of myeloma cells is their dense and uniform expression of CD38 surface glycoproteins - these proteins, also expressed in relatively minor quantities on other lymphoid and myeloid cells, have been identified as performing several critical cellular functions, and this, along with their relative abundance on myeloma cells, has made them an attractive target for multiple myeloma treatment. CD38 was first identified as an activation marker, but has subsequently demonstrated roles in adhesion to endothelial CD31 proteins, as an accessory component of the synapse complex, and as an ectoenzyme involved in the metabolism of extracellular NAD+ and cytoplasmic NADP. The products of CD38’s ectoenzymatic activity include the calcium-mobilizing compound adenosine diphosphate ribose (ADPR), which can be further metabolized by CD203a/PC-1 and CD73 to adenosine, an immunosuppressive molecule that may play a role in tumour cell evasion of the immune system.2

Isatuximab is an IgG1-derived monoclonal antibody targeted against CD38 proteins.9 Its activity against CD38 results in a number of downstream effects, including direct apoptosis of the affected cell and activation of immune mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC), all of which result in potent anti-tumour activity.9,2 Via allosteric antagonism, isatuximab also inhibits CD38 ectoenzymatic activity, preventing the immunosuppressive effects of its downstream products.

Isatuximab may also exert its effects via downstream promotion of lysosome-dependent cell death, upregulation of reactive oxygen species, and restoration of antitumor immune effector cell functions.2

TargetActionsOrganism
UADP-ribosyl cyclase 1
binder
antibody
Humans
Absorption

When administered at the recommended dose and schedule, the steady-state Cmax and AUC were found to be 351 µg/mL and 72,600 μg∙h/mL, respectively.9 It takes approximately 8 weeks for isatuximab to reach steady-state. Over a dosage range of 1 mg/kg to 20 mg/kg given every 2 weeks AUC increases in a greater than dose-proportional manner, whereas over a dosage range of 5 mg/kg to 20 mg/kg every 4 weeks (followed by every 2 weeks) AUC was found to increase proportionately with dose. Steady-state AUC is lower in patients with increased body weight, but not to the extent that dose adjustments are required.9 Tmax ranges from approximately 2 to 5 hours, increasing with dose and with repeated dosing.3

Volume of distribution

The predicted volume of distribution of isatuximab is 8.13 L.9

Protein binding

Not Available

Metabolism

Isatuximab metabolism is likely to involve catabolism to smaller proteins and peptides.9

Route of elimination

Not Available

Half-life

Not Available

Clearance

Total clearance decreases with increasing dose and with multiple dosing.9 At steady-state, it takes approximately 2 months to eliminate ≥99% of isatuximab from plasma following the last dose.9

Adverse Effects
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Toxicity

There is no known antidote for isatuximab, nor does there appear to be any clinical experience with overdose.9 Symptoms of overdosage are likely to be consistent with isatuximab's adverse effect profile and may therefore include significant infusion-site reactions, gastrointestinal disturbances, and may increase the risk of infection. Treatment of overdose should involve careful monitoring of the patient and symptomatic and supportive measures as clinically indicated.9

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Isatuximab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Isatuximab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Isatuximab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Isatuximab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Isatuximab.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
SarclisaInjection, solution, concentrate20 mg/mlIntravenousSANOFI WINTHROP INDUSTRIE2020-12-23Not applicableEU flag
SarclisaInjection, solution, concentrate500 mg/25mLIntravenoussanof-aventis U.S. LLC2020-03-02Not applicableUS flag
SarclisaInjection, solution, concentrate20 mg/mlIntravenousSANOFI WINTHROP INDUSTRIE2020-12-23Not applicableEU flag
SarclisaSolution500 mg / 25 mLIntravenousSanofi Aventis2020-07-03Not applicableCanada flag
SarclisaInjection, solution, concentrate100 mg/5mLIntravenoussanof-aventis U.S. LLC2020-03-02Not applicableUS flag

Categories

ATC Codes
L01FC02 — Isatuximab
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
R30772KCU0
CAS number
1461640-62-9

References

General References
  1. Moreno L, Perez C, Zabaleta A, Manrique I, Alignani D, Ajona D, Blanco L, Lasa M, Maiso P, Rodriguez I, Garate S, Jelinek T, Segura V, Moreno C, Merino J, Rodriguez-Otero P, Panizo C, Prosper F, San-Miguel JF, Paiva B: The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma. Clin Cancer Res. 2019 May 15;25(10):3176-3187. doi: 10.1158/1078-0432.CCR-18-1597. Epub 2019 Jan 28. [Article]
  2. Morandi F, Horenstein AL, Costa F, Giuliani N, Pistoia V, Malavasi F: CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma. Front Immunol. 2018 Nov 28;9:2722. doi: 10.3389/fimmu.2018.02722. eCollection 2018. [Article]
  3. Mikhael J, Richardson P, Usmani SZ, Raje N, Bensinger W, Karanes C, Campana F, Kanagavel D, Dubin F, Liu Q, Semiond D, Anderson K: A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma. Blood. 2019 Jul 11;134(2):123-133. doi: 10.1182/blood-2019-02-895193. Epub 2019 Mar 12. [Article]
  4. Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, Solanki M, Meng R, Lee H, Wiederschain D, Zhu C, Rak A, Anderson KC: Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab. Cells. 2019 Nov 26;8(12). pii: cells8121522. doi: 10.3390/cells8121522. [Article]
  5. van de Donk NWCJ, Usmani SZ: CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance. Front Immunol. 2018 Sep 20;9:2134. doi: 10.3389/fimmu.2018.02134. eCollection 2018. [Article]
  6. Kaplon H, Reichert JM: Antibodies to watch in 2018. MAbs. 2018 Feb/Mar;10(2):183-203. doi: 10.1080/19420862.2018.1415671. Epub 2018 Jan 16. [Article]
  7. Kaplon H, Reichert JM: Antibodies to watch in 2019. MAbs. 2019 Feb/Mar;11(2):219-238. doi: 10.1080/19420862.2018.1556465. Epub 2018 Dec 22. [Article]
  8. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  9. FDA Approved Drug Products: Sarclisa (isatuximab-irfc) for intravenous injection [Link]
  10. FDA News Release: Isatuximab Approval [Link]
  11. FDA Approved Drug Products: SARCLISA® (isatuximab-irfc) injection, for intravenous use (Nov 2023) [Link]
RxNav
2282018
Wikipedia
Isatuximab
FDA label
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Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentMultiple Myeloma (MM)6
3CompletedTreatmentMultiple Myeloma (MM)1
3Not Yet RecruitingTreatmentMultiple Myeloma (MM)1
3Not Yet RecruitingTreatmentNewly Diagnosed Multiple Myeloma1
3RecruitingTreatmentMultiple Myeloma (MM)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solution, concentrateIntravenous100 mg/5mL
Injection, solution, concentrateIntravenous20 MG/ML
Injection, solution, concentrateIntravenous500 mg/25mL
SolutionIntravenous100 mg / 5 mL
SolutionIntravenous500 mg / 25 mL
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Details1. ADP-ribosyl cyclase 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
Antibody
General Function
Transferase activity
Specific Function
Synthesizes the second messagers cyclic ADP-ribose and nicotinate-adenine dinucleotide phosphate, the former a second messenger for glucose-induced insulin secretion. Also has cADPr hydrolase activ...
Gene Name
CD38
Uniprot ID
P28907
Uniprot Name
ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1
Molecular Weight
34328.145 Da
References
  1. FDA Approved Drug Products: Sarclisa (isatuximab-irfc) for intravenous injection [Link]

Drug created at May 20, 2019 14:28 / Updated at November 08, 2023 12:09