Nirogacestat

Identification

Summary

Nirogacestat is a gamma-secretase inhibitor used to treat desmoid tumors

Brand Names
Ogsiveo
Generic Name
Nirogacestat
DrugBank Accession Number
DB12005
Background

Nirogacestat is a small-molecule gamma-secretase inhibitor that was investigated as a potential treatment for desmoid tumors. Desmoid tumors are typically characterized by aberrant activation in Notch signaling.1 Interaction between the notch receptors and their ligands activates proteolytic cleavage by gamma-secretase; therefore, the inhibition of gamma-secretase can potentially inhibit Notch signaling and thus impede the growth of desmoid tumors.2

Nirogacestat was approved under the brand name OGSIVEO on November 27, 2023, by the FDA for the treatment of adult patients with progressing desmoid tumors who require systemic treatment. It was previously granted breakthrough therapy, fast track, and orphan drug designations for the treatment of desmoid tumors, and the final approval was based on positive results obtained in the Phase 3 DeFi trial, where a confirmed objective response rate was observed to be 41% compared to 8% with the placebo.4

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 489.656
Monoisotopic: 489.327917286
Chemical Formula
C27H41F2N5O
Synonyms
  • Nirogacestat
External IDs
  • PF-03084014
  • PF-3084014

Pharmacology

Indication

Nirogacestat is indicated for adult patients with progressing desmoid tumors who require systemic treatment.3

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofProgressive desmoids tumors•••••••••••••••••••••••• •••••••• •••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

There is an exposure-response relationship between nirogacestat exposure and Grade 3 hypophosphatemia with a higher risk of Grade 3 hypophosphatemia at higher exposure.3

At the recommended dosage, a mean increase in the QTc interval > 20 ms was not observed.3

Mechanism of action

Nirogacestat is a gamma secretase inhibitor that blocks proteolytic activation of the Notch receptor. When dysregulated, Notch can activate pathways that contribute to tumor growth.3

TargetActionsOrganism
APresenilin-1
inhibitor
Humans
Absorption

The following pharmacokinetics parameters in patients with desmoid tumors were calculated as follows: Cmax (508 (62) ng/mL), AUC0-tau (u 3370 (58) ng·h/mL), time to steady state (6 days), and Tmax (1.5 (0.5, 6.5) hours).3

Volume of distribution

The apparent volume of distribution [Mean (%CV)] of nirogacestat is 1430 (65) L.3

Protein binding

Nirogacestat has a high level of serum protein binding of 99.6%, with 94.6% to serum albumin and 97.9% to alpha-1 acid glycoprotein.3

Metabolism

Nirogacestat is expected to be metabolized primarily through the N-dealkylation via CYP3A4 (85%), with the involvement of CYP3A4, CYP2C19, CYP2C9, and CYP2D6 in a minor secondary pathway.3

Route of elimination

Nirogacestat is excreted mostly in feces (38%) and urine 17%, with less than 1% of the unchanged drug remains in the urine. It can also be eliminated through expired air (9.7%).3

Half-life

The terminal elimination half-life [Mean (%CV)] of nirogacestat is 23 (37) hr .3

Clearance

The apparent systemic clearance [Mean (%CV)] of nirogacestat is 45 (58) L/hr.3

Adverse Effects
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Toxicity

Based on findings from animal studies and its mechanism of action, nirogacestat can cause fetal harm or loss of pregnancy when administered to a pregnant woman. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and embryo-fetal death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily. There are no available data on the use of nirogacestat in pregnant women. Advise pregnant women of the potential risk to a fetus.3

Due to the high level of protein binding, nirogacestat is not expected to be dialyzable.3

In a 6-month carcinogenicity study, transgenic rasH2 mice received up to 100 mg/kg/day of oral nirogacestat, resulting in mean exposure levels (AUC) less than those in humans at the recommended dose of 150 mg twice daily. No statistically significant neoplastic findings occurred. The carcinogenic potential of nirogacestat in rats has not been assessed.3

Nirogacestat was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro chromosome aberration assay in human lymphocytes or in vivo rat bone marrow micronucleus study.3

Nirogacestat resulted in reduced fertility when administered to male and female rats at doses ≥ 5 mg/kg/day (approximately 0.16 times the recommended dose of 150 mg twice daily based on body surface area (BSA), and a lack of fertility when administered to male and female rats at doses ≥ 40 mg/kg/day (approximately 1.3 times the recommended dose of 150 mg twice daily based on BSA). Adverse findings in rats included ovarian atrophy, reduced testes weights, and decreased sperm concentration and motility.3

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.
DrugInteraction
AbametapirThe serum concentration of Nirogacestat can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Nirogacestat can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Nirogacestat.
AbirateroneThe metabolism of Nirogacestat can be decreased when combined with Abiraterone.
AbrocitinibThe serum concentration of Nirogacestat can be increased when it is combined with Abrocitinib.
Food Interactions
  • Avoid grapefruit products. Nirogacestat is a CYP3A substrate and grapefruit is a known CYP3A inhibitors.
  • Take separate from antacids. take nirogacestat 2 hours before or 2 hours after taking the antacid.
  • Take with or without food.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OgsiveoTablet, film coated100 mg/1OralSpringWorks Therapeutics, Inc.2023-11-27Not applicableUS flag
OgsiveoTablet, film coated50 mg/1OralSpringWorks Therapeutics, Inc.2023-11-27Not applicableUS flag
OgsiveoTablet, film coated150 mg/1OralSpringWorks Therapeutics, Inc.2023-11-27Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as alpha amino acid amides. These are amide derivatives of alpha amino acids.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acid amides
Alternative Parents
Tetralins / N-arylamides / Aralkylamines / N-substituted imidazoles / Imidolactams / Fatty amides / Aryl fluorides / Heteroaromatic compounds / Secondary carboxylic acid amides / Dialkylamines
show 5 more
Substituents
Alpha-amino acid amide / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Carbonyl group
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
QZ62892OFJ
CAS number
1290543-63-3
InChI Key
VFCRKLWBYMDAED-REWPJTCUSA-N
InChI
InChI=1S/C27H41F2N5O/c1-7-8-23(32-20-10-9-18-11-19(28)12-22(29)21(18)13-20)25(35)33-24-14-34(17-31-24)27(5,6)16-30-15-26(2,3)4/h11-12,14,17,20,23,30,32H,7-10,13,15-16H2,1-6H3,(H,33,35)/t20-,23-/m0/s1
IUPAC Name
(2S)-2-{[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]amino}-N-(1-{1-[(2,2-dimethylpropyl)amino]-2-methylpropan-2-yl}-1H-imidazol-4-yl)pentanamide
SMILES
CCC[C@H](N[C@H]1CCC2=CC(F)=CC(F)=C2C1)C(=O)NC1=CN(C=N1)C(C)(C)CNCC(C)(C)C

References

General References
  1. Gounder M, Ratan R, Alcindor T, Schoffski P, van der Graaf WT, Wilky BA, Riedel RF, Lim A, Smith LM, Moody S, Attia S, Chawla S, D'Amato G, Federman N, Merriam P, Van Tine BA, Vincenzi B, Benson C, Bui NQ, Chugh R, Tinoco G, Charlson J, Dileo P, Hartner L, Lapeire L, Mazzeo F, Palmerini E, Reichardt P, Stacchiotti S, Bailey HH, Burgess MA, Cote GM, Davis LE, Deshpande H, Gelderblom H, Grignani G, Loggers E, Philip T, Pressey JG, Kummar S, Kasper B: Nirogacestat, a gamma-Secretase Inhibitor for Desmoid Tumors. N Engl J Med. 2023 Mar 9;388(10):898-912. doi: 10.1056/NEJMoa2210140. [Article]
  2. Shih IeM, Wang TL: Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 2007 Mar 1;67(5):1879-82. doi: 10.1158/0008-5472.CAN-06-3958. [Article]
  3. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
  4. SpringWorks Therapeutics Announces FDA Approval of OGSIVEO™ (nirogacestat) as the First and Only Treatment for Adults with Desmoid Tumors [Link]
PubChem Compound
46224413
PubChem Substance
347828323
ChemSpider
26232306
BindingDB
50458159
RxNav
2670631
ChEMBL
CHEMBL1770916
ZINC
ZINC000038217837
Wikipedia
Nirogacestat

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentDesmoid Tumor1
2Active Not RecruitingTreatmentDesmoid Tumor / Recurrent Desmoid Fibromatosis / Unresectable Desmoid Fibromatosis1
2Active Not RecruitingTreatmentOvarian Cancer / Ovarian Granulosa Cell Tumor1
2CompletedTreatmentDesmoid Tumor1
2Not Yet RecruitingTreatmentTumor1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral150 mg/1
Tablet, film coatedOral50 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11807611No2022-09-082042-09-08US flag
US11612588No2022-07-082042-07-08US flag
US10941118No2019-08-092039-08-09US flag
US10710966No2019-08-092039-08-09US flag
US7795447No2005-08-182025-08-18US flag
US7342118No2005-08-182025-08-18US flag
US11820748No2019-08-092039-08-09US flag
US10590087No2019-08-092039-08-09US flag
US7951958No2005-03-112025-03-11US flag
US11504354No2022-07-082042-07-08US flag
US11845732No2019-08-092039-08-09US flag
US11844780No2022-09-082042-09-08US flag
US11872211No2023-05-192043-05-19US flag
US11884635No2019-08-092039-08-09US flag
US11884634No2019-08-092039-08-09US flag
US11905255No2019-08-092039-08-09US flag
US11925620No2023-05-192043-05-19US flag
US11925619No2023-05-192043-05-19US flag
US11938116No2023-05-192043-05-19US flag
US11957662No2023-05-192043-05-19US flag
US11951096No2023-05-192043-05-19US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility11.4 mg/mLhttps://springworkstx.com/wp-content/uploads/2023/11/OGSIVEO-US-Prescribing-Information-11.27.23.pdf
pKa5.77, 7.13https://springworkstx.com/wp-content/uploads/2023/11/OGSIVEO-US-Prescribing-Information-11.27.23.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.0104 mg/mLALOGPS
logP3.9ALOGPS
logP5.5Chemaxon
logS-4.7ALOGPS
pKa (Strongest Acidic)11.48Chemaxon
pKa (Strongest Basic)10.45Chemaxon
Physiological Charge2Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area70.98 Å2Chemaxon
Rotatable Bond Count11Chemaxon
Refractivity138.14 m3·mol-1Chemaxon
Polarizability54.49 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0007-0226900000-297e245b7e04329da6b5
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-00dr-0024900000-8686d16aacf04b51af17
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-2327900000-05c84a5bcf14ad2a2499
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-000i-0062900000-8eb3ecdb77f12607e92a
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0cdi-5914200000-8587eb418bbeabd46860
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-08fs-0922100000-b8623db4d62485ebdd3e
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-210.7112
predicted
DeepCCS 1.0 (2019)
[M+H]+213.10677
predicted
DeepCCS 1.0 (2019)
[M+Na]+219.0193
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:15274632, PubMed:10545183, PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874, PubMed:28269784, PubMed:20460383). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (PubMed:9738936, PubMed:10593990, PubMed:10899933, PubMed:10811883). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis (PubMed:25394380, PubMed:16959576). Involved in the regulation of neurite outgrowth (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (By similarity).
Specific Function
Aspartic endopeptidase activity, intramembrane cleaving
Gene Name
PSEN1
Uniprot ID
P49768
Uniprot Name
Presenilin-1
Molecular Weight
52667.34 Da
References
  1. Bhattarai A, Devkota S, Bhattarai S, Wolfe MS, Miao Y: Mechanisms of gamma-Secretase Activation and Substrate Processing. ACS Cent Sci. 2020 Jun 24;6(6):969-983. doi: 10.1021/acscentsci.0c00296. Epub 2020 Jun 4. [Article]
  2. Wolfe MS: Structure and Function of the gamma-Secretase Complex. Biochemistry. 2019 Jul 9;58(27):2953-2966. doi: 10.1021/acs.biochem.9b00401. Epub 2019 Jun 25. [Article]
  3. McCaw TR, Inga E, Chen H, Jaskula-Sztul R, Dudeja V, Bibb JA, Ren B, Rose JB: Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance. Oncologist. 2021 Apr;26(4):e608-e621. doi: 10.1002/onco.13627. Epub 2021 Jan 2. [Article]
  4. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...

Components:
References
  1. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: OGSIVEOTM (nirogacestat) tablets, for oral use [Link]

Drug created at October 20, 2016 21:10 / Updated at January 10, 2024 06:22