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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Nirogacestat (DB12005)

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Weight

Average: 489.656
Monoisotopic: 489.327917286

Chemical Formula

C₂₇H₄₁F₂N₅O

Synonyms

• Nirogacestat

External IDs

• PF-03084014
• PF-3084014

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Pharmacology

Indication

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

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Progressive desmoids tumors		••••••••••••	•••••	••••••• •••••••• •••••••	••••••

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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

Target	Actions	Organism
APresenilin-1	inhibitor	Humans

Absorption

The following pharmacokinetics parameters in patients with desmoid tumors were calculated as follows: C_max (508 (62) ng/mL), AUC_0-tau (u 3370 (58) ng·h/mL), time to steady state (6 days), and T_max (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

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Nirogacestat can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Nirogacestat can be increased when combined with Abatacept.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Nirogacestat.
Abiraterone	The metabolism of Nirogacestat can be decreased when combined with Abiraterone.
Abrocitinib	The 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.

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Ogsiveo	Tablet, film coated	50 mg/1	Oral	SpringWorks Therapeutics, Inc.	2023-11-27	Not applicable

Categories

Drug Categories

• Amino Acids
• Amino Acids, Branched-Chain
• Amino Acids, Peptides, and Proteins
• Amyloid Precursor Protein Secretases, antagonists & inhibitors
• Cytochrome P-450 CYP2B6 Inducers
• Cytochrome P-450 CYP2B6 Inducers (strength unknown)
• Cytochrome P-450 CYP2C19 Inducers
• Cytochrome P-450 CYP2C19 Inducers (strength unknown)
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C8 Inducers
• Cytochrome P-450 CYP2C8 Inducers (strength unknown)
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP2C9 Inducers
• Cytochrome P-450 CYP2C9 Inducers (strength unknown)
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Enzyme Inducers
• Cytochrome P-450 Substrates
• Enzyme Inhibitors
• Gamma Secretase Inhibitors and Modulators
• P-glycoprotein inhibitors
• P-glycoprotein substrates

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 / Azacyclic compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds

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Substituents

Alpha-amino acid amide / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzenoid / Carbonyl group / Carboxamide group / Fatty acyl / Fatty amide / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Imidolactam / N-arylamide / N-substituted imidazole / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organofluoride / Organohalogen compound / Organoheterocyclic compound / Organonitrogen compound / Organooxygen compound / Secondary aliphatic amine / Secondary amine / Secondary carboxylic acid amide / Tetralin

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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]

External Links

PubChem Compound

46224413

PubChem Substance

347828323

ChemSpider

26232306

BindingDB

50458159

RxNav

2670631

ChEMBL

CHEMBL1770916

ZINC

ZINC000038217837

Wikipedia

Nirogacestat

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Desmoid Tumor	1
2	Active Not Recruiting	Treatment	Desmoid Tumor / Recurrent Desmoid Fibromatosis / Unresectable Desmoid Fibromatosis	1
2	Active Not Recruiting	Treatment	Ovarian Cancer / Ovarian Granulosa Cell Tumor	1
2	Completed	Treatment	Desmoid Tumor	1
2	Not Yet Recruiting	Treatment	Tumor	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	50 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US11807611	No	2022-09-08	2042-09-08
US11612588	No	2022-07-08	2042-07-08
US10941118	No	2019-08-09	2039-08-09
US10710966	No	2019-08-09	2039-08-09
US7795447	No	2005-08-18	2025-08-18
US7342118	No	2005-08-18	2025-08-18
US11820748	No	2019-08-09	2039-08-09
US10590087	No	2019-08-09	2039-08-09
US7951958	No	2005-03-11	2025-03-11
US11504354	No	2022-07-08	2042-07-08
US11845732	No	2019-08-09	2039-08-09
US11844780	No	2022-09-08	2042-09-08

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	11.4 mg/mL	https://springworkstx.com/wp-content/uploads/2023/11/OGSIVEO-US-Prescribing-Information-11.27.23.pdf
pKa	5.77, 7.13	https://springworkstx.com/wp-content/uploads/2023/11/OGSIVEO-US-Prescribing-Information-11.27.23.pdf

Predicted Properties

Property	Value	Source
Water Solubility	0.0104 mg/mL	ALOGPS
logP	3.9	ALOGPS
logP	5.5	Chemaxon
logS	-4.7	ALOGPS
pKa (Strongest Acidic)	11.48	Chemaxon
pKa (Strongest Basic)	10.45	Chemaxon
Physiological Charge	2	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	3	Chemaxon
Polar Surface Area	70.98 Å2	Chemaxon
Rotatable Bond Count	11	Chemaxon
Refractivity	138.14 m3·mol-1	Chemaxon
Polarizability	54.49 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0007-0226900000-297e245b7e04329da6b5
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00dr-0024900000-8686d16aacf04b51af17
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0udi-2327900000-05c84a5bcf14ad2a2499
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-000i-0062900000-8eb3ecdb77f12607e92a
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0cdi-5914200000-8587eb418bbeabd46860
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-08fs-0922100000-b8623db4d62485ebdd3e
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[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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Details1. Presenilin-1

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]

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