NAV

Nogapendekin alfa

Identification

Summary

Nogapendekin alfa is an IL-15 receptor agonist used to treat BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumours.

Generic Name
Nogapendekin alfa
DrugBank Accession Number
DB18740
Background

Nogapendekin alfa is a human IL-15N72D variant. It is one of the active ingredients in Anktiva, a combination product also containing inbakicept, where a single inbakicept is complexed with two nogapendekin alfa components.6 This combination product was approved by the FDA on April 22, 2024, for the treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumours.7 Non-muscle invasive bladder cancer (NMIBC), which accounts for 75% of all bladder tumours, is commonly treated with transurethral resection of the bladder tumour and Bacillus Calmette-Guérin (BCG) immunotherapy; however, NMIBC is associated with a risk of disease recurrence or progression into advanced disease despite initial treatment with BCG.4,5 Nogapendekin alfa, in combination with inbakicept, mimics the actions of IL-15, , stimulating the activation and proliferation of natural killer cells and CD8+ memory T cells, which also synergistically enhance BCG efficacy.4,5

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Interleukin-based products
Protein Chemical Formula
Not Available
Protein Average Weight
12770.45 Da
Sequences
Not Available
Synonyms
  • Fusion protein consisting of il-15n72d and il-15rasu/fc
  • Human interleukin 15 (72-aspartic acid) (human il-15 n72>d isoform)
  • IL-15N72D
  • Il-15n72d:il-15rec-su/fc soluble complex i
  • Inbakicept nogapendekin alfa fusion complex
  • Superagonist interleukin-15:interleukin-15 receptor alphasu/fc fusion complex alt-803
External IDs
  • ALT 803
  • ALT-803
  • ALT803
  • IL-15N72D
  • N-803
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Pharmacology

Indication

Nogapendekin alfa, in combination with inbakicept and Bacillus Calmette-Guérin (BCG), is indicated for the treatment of adult patients with BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumours.6

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Nogapendekin alfa is a human IL-15 superagonist with immunostimulatory properties. In a preclinical bladder cancer model, the administration of inbakicept-nogapendekin alfa protein complex in combination with BCG led to reduced tumour burden and increased infiltration of stimulated CD8 + T cells and NK cells in the bladder.3

Mechanism of action

Interleukin-15 (IL-15) regulates natural killer (NK) and memory T cell homeostasis, making it a notable therapeutic target for cancers and immune disorders such as HIV.1 For example, it is a mediator of NK cell and T cell activation and proliferation.1 IL-15 signals through a heterotrimeric receptor that is composed of the common gamma chain (γc) subunit, the beta chain (βc) subunit, and the IL-15-specific alpha subunit (IL-15Rα).6 IL-15 and IL-15Rα are typically presented by antigen-presenting cells, like monocytes and dendritic cells. These cells present IL-15 in a complex with IL-15Rα to neighbouring immune cells — specifically, natural killer (NK) cells and CD8+ T cells which have the CD122/CD132 receptor complex (shared IL-2/IL-15 receptor; βc and γc).3,6 In other words, IL-15 is trans-presented by the IL-15Rα.6

Nogapendekin alfa is administered as a stable heterodimeric complex with inbakicept, which mimics the biological actions of IL-15.1 Nogapendekin alfa is a human IL-15N72D variant that has an asparagine (Asn) to aspartate (Asp) mutation at amino acid 72 (N72D), which grants the drug increased biological activity and a longer serum half-life compared to free IL-15.1,2,3 The binding of the nogapendekin alfa-inbakicept protein complex to IL-15 receptor promotes the proliferation and activation of NK, CD8+, and memory T cells without the proliferation of immuno-suppressive Treg cells.6 In a carcinogen-induced model of bladder cancer in immunocompetent rats, intravesicular administration of nogapendekin alfa-inbakicept alone or in combination with BCG showed anti-tumour activity.6

TargetActionsOrganism
AInterleukin-2 receptor subunit beta
agonist
Humans
ACytokine receptor common subunit gamma
agonist
Humans
Absorption

Systemic exposure of nogapendekin alfa-inbakicept complex was less than 100 pg/mL following the approved recommended dosage in all patients. This was below the lower limit of quantitation in all patients.6

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
Not Available
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AnktivaSolution400 ug/0.4mLIntravesicalAltor BioScience, LLC, an indirect wholly-owned subsidiary of ImmunityBio, Inc.2024-05-06Not applicableUS flag

Categories

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
7TK323DLA0
CAS number
1622189-43-8

References

General References
  1. Webb GM, Molden J, Busman-Sahay K, Abdulhaqq S, Wu HL, Weber WC, Bateman KB, Reed JS, Northrup M, Maier N, Tanaka S, Gao L, Davey B, Carpenter BL, Axthelm MK, Stanton JJ, Smedley J, Greene JM, Safrit JT, Estes JD, Skinner PJ, Sacha JB: The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques. PLoS Pathog. 2020 Mar 12;16(3):e1008339. doi: 10.1371/journal.ppat.1008339. eCollection 2020 Mar. [Article]
  2. McBrien JB, Mavigner M, Franchitti L, Smith SA, White E, Tharp GK, Walum H, Busman-Sahay K, Aguilera-Sandoval CR, Thayer WO, Spagnuolo RA, Kovarova M, Wahl A, Cervasi B, Margolis DM, Vanderford TH, Carnathan DG, Paiardini M, Lifson JD, Lee JH, Safrit JT, Bosinger SE, Estes JD, Derdeyn CA, Garcia JV, Kulpa DA, Chahroudi A, Silvestri G: Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8(+) cells. Nature. 2020 Feb;578(7793):154-159. doi: 10.1038/s41586-020-1946-0. Epub 2020 Jan 22. [Article]
  3. Rosser CJ, Tikhonenkov S, Nix JW, Chan OTM, Ianculescu I, Reddy S, Soon-Shiong P: Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Guerin (BCG) for the Treatment of Bladder Cancer. Oncoimmunology. 2021 May 3;10(1):1912885. doi: 10.1080/2162402X.2021.1912885. [Article]
  4. de Jong FC, Laajala TD, Hoedemaeker RF, Jordan KR, van der Made ACJ, Boeve ER, van der Schoot DKE, Nieuwkamer B, Janssen EAM, Mahmoudi T, Boormans JL, Theodorescu D, Costello JC, Zuiverloon TCM: Non-muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Guerin. Sci Transl Med. 2023 May 24;15(697):eabn4118. doi: 10.1126/scitranslmed.abn4118. Epub 2023 May 24. [Article]
  5. Chamie K, Chang SS, Kramolowsky E, Gonzalgo ML, Agarwal PK, Bassett JC, Bjurlin M, Cher ML, Clark W, Cowan BE, David R, Goldfischer E, Guru K, Jalkut MW, Kaffenberger SD, Kaminetsky J, Katz AE, Koo AS, Sexton WJ, Tikhonenkov SN, Trabulsi EJ, Trainer AF, Spilman P, Huang M, Bhar P, Taha SA, Sender L, Reddy S, Soon-Shiong P: IL-15 Superagonist NAI in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer. NEJM Evid. 2023 Jan;2(1):EVIDoa2200167. doi: 10.1056/EVIDoa2200167. Epub 2022 Nov 10. [Article]
  6. FDA Approved Drug Products: ANKTIVA (nogapendekin alfa inbakicept-pmln) solution, for intravesical use [Link]
  7. FDA: FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer [Link]
Not Available

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentNon-Small Cell Lung Cancer (NSCLC)1
2Active Not RecruitingTreatmentCervical Cancer / Colorectal Cancer / Gastric Cancer / Hepatocellular Carcinoma / Melanoma / Merkel Cell Carcinoma / Microsatellite Instability / Mismatch Repair Deficient (dMMR) / Non-Small Cell Lung Cancer (NSCLC) / Renal Cell Carcinoma (RCC) / Small Cell Lung Cancer (SCLC) / Squamous Cell Carcinoma of the Head and Neck (SCCHN) / Urothelial Carcinoma1
2Active Not RecruitingTreatmentColorectal Cancer / Small Intestine Cancer1
2Active Not RecruitingTreatmentPancreatic Cancer1
2CompletedTreatmentAcute Myeloid Leukemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SolutionIntravesical400 ug/0.4mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Details1. Interleukin-2 receptor subunit beta
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Interleukin-2 receptor activity
Specific Function
Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2.
Gene Name
IL2RB
Uniprot ID
P14784
Uniprot Name
Interleukin-2 receptor subunit beta
Molecular Weight
61116.59 Da
References
  1. Rosser CJ, Tikhonenkov S, Nix JW, Chan OTM, Ianculescu I, Reddy S, Soon-Shiong P: Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Guerin (BCG) for the Treatment of Bladder Cancer. Oncoimmunology. 2021 May 3;10(1):1912885. doi: 10.1080/2162402X.2021.1912885. [Article]
  2. FDA Approved Drug Products: ANKTIVA (nogapendekin alfa inbakicept-pmln) solution, for intravesical use [Link]
Details2. Cytokine receptor common subunit gamma
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Interleukin-2 binding
Specific Function
Common subunit for the receptors for a variety of interleukins.
Gene Name
IL2RG
Uniprot ID
P31785
Uniprot Name
Cytokine receptor common subunit gamma
Molecular Weight
42286.68 Da
References
  1. Rosser CJ, Tikhonenkov S, Nix JW, Chan OTM, Ianculescu I, Reddy S, Soon-Shiong P: Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Guerin (BCG) for the Treatment of Bladder Cancer. Oncoimmunology. 2021 May 3;10(1):1912885. doi: 10.1080/2162402X.2021.1912885. [Article]
  2. FDA Approved Drug Products: ANKTIVA (nogapendekin alfa inbakicept-pmln) solution, for intravesical use [Link]

Drug created at May 02, 2024 16:18 / Updated at May 15, 2024 05:42