Nirogacestat

Summary

Nirogacestat (CHEMBL1770916) is an approved small-molecule antineoplastic agent (ATC L01XX81); indicated across 7 conditions including neoplasm and desmoid tumor; with CIViC clinical evidence for 2 variant-indication associations (e.g. APC Mutation OR CTNNB1 Activating Mutation in desmoid tumor).

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: L01XX81
• Indications: 7 conditions
• Clinical trials: 29
• Precision-oncology evidence (CIViC): 2 variant–indication associations
• Chemistry: 489.6 Da · C27H41F2N5O

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL1770916
Name	Nirogacestat
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	46224413
ChEBI	CHEBI:229217
ATC	L01XX81
Molecular formula	C27H41F2N5O
Molecular weight	489.6
InChIKey	VFCRKLWBYMDAED-REWPJTCUSA-N

SMILES: CCC[C@@H](C(=O)NC1=CN(C=N1)C(C)(C)CNCC(C)(C)C)N[C@H]2CCC3=C(C2)C(=CC(=C3)F)F

IUPAC name: (2S)-2-[[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]amino]-N-[1-[1-(2,2-dimethylpropylamino)-2-methylpropan-2-yl]imidazol-4-yl]pentanamide

ChEBI definition: A member of the class of imidazoles that is 1H-imidazole substituted by a 1-[(2,2-dimethylpropyl)amino]-2-methylpropan-2-yl group at position 1 and a {N-[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-L-norvalyl}amino group at position 4. It is a γ-secretase inhibitor whose hydrobromide salt is indicated for adult patients with progressing desmoid tumours who require systemic treatment.

Pharmacological roles (ChEBI): antineoplastic agent, γ-secretase modulator.

Also known as: Nirogacestat, PF 03084014, PF 3084014, PF-03084014, PF-3084014, NIROGACESTAT

Parent form; salt/anhydrous children: CHEMBL4298153

Patent coverage: 273 distinct patent families (756 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 682 (90%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Broader ChEMBL bioactivity targets: 2 (assay-derived). Sample: Gamma-secretase, Gamma-secretase-activating protein.

Bioactivity

ChEMBL activities: 8 potent at pChembl ≥ 5 of 8 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
PSEN1	8.92	IC50	1.2	nM	CHEMBL_ACT_29055318
PSEN1	8.92	IC50	1.2	nM	CHEMBL_ACT_6181525
PSEN1	8.89	IC50	1.3	nM	CHEMBL_ACT_18541677
PSEN1	8.21	IC50	6.2	nM	CHEMBL_ACT_18541676
PSEN1	8.21	IC50	6.2	nM	CHEMBL_ACT_19427649
GSAP	8.21	IC50	6.2	nM	CHEMBL_ACT_24984399
PSEN1	8.21	IC50	6.2	nM	CHEMBL_ACT_29055470
PSEN1	7.72	IC50	19.15	nM	CHEMBL_ACT_18541678

Target pathways

No target-pathway data for this drug (no mapped target genes).

Indications & clinical

Indications

2 approved indications. FDA phase 4, plus an anticancer drug’s labelled cancer uses (which ChEMBL often logs at phase 3).

Indication	Phase	MONDO	EFO
neoplasm	3	MONDO:0005070	EFO:0000616
desmoid tumor	3	MONDO:0007608	EFO:0009907

4 diseases in clinical trials (phase 1–3, investigational — not approved indications). Highest ChEMBL trial phase per disease; a non-cancer approved use is occasionally logged at phase 3 here.

Disease (in trials)	Phase	MONDO	EFO
exocrine pancreatic carcinoma	2	MONDO:0005192	EFO:0002618
breast neoplasm	2	MONDO:0021100	EFO:0003869
plasma cell myeloma	2	MONDO:0009693	EFO:0001378
fibromatosis	2	MONDO:0005031	EFO:0000497

1 further indication record had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 29.

Phase distribution

Phase	Trials
PHASE2	11
PHASE1	10
PHASE1/PHASE2	5
PHASE4	1
PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07176689	PHASE4	RECRUITING	Nirogacestat in Premenopausal Females With Desmoid Tumor/Aggressive Fibromatosis (DT/AF)
NCT03785964	PHASE3	COMPLETED	Nirogacestat for Adults With Desmoid Tumor/Aggressive Fibromatosis (DT/AF)
NCT04126200	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM)
NCT04195399	PHASE2	ACTIVE_NOT_RECRUITING	A Study of a New Drug, Nirogacestat, for Treating Desmoid Tumors That Cannot be Removed by Surgery
NCT05573802	PHASE1/PHASE2	RECRUITING	A Study to Investigate Safety and Clinical Activity of Belantamab Mafodotin in Combination With Lenalidomide, Dexamethasone and Nirogacestat in Patients With Transplant Ineligible Newly Diagnosed Multiple Myeloma
NCT05879146	PHASE2	RECRUITING	Evaluation of the Response and Non-response of Nirogacestat in Desmoid Tumors- Clinical Study
NCT05949099	PHASE2	RECRUITING	Study of Cryoablation and Nirogacestat for Desmoid Tumor
NCT07084896	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With Nirogacestat in Participants With RRMM
NCT07150091	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With Nirogacestat, Lenalidomide, and Dexamethasone in Participants With RRMM
NCT07150104	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Sub-study of Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Nirogacestat, Pomalidomide, and Dexamethasone in Participants With RRMM
NCT07170644	PHASE2	ACTIVE_NOT_RECRUITING	A Study of Nirogacestat in Japanese Adults With Desmoid Tumors/Aggressive Fibromatosis (DT/AF)
NCT07539454	PHASE2	NOT_YET_RECRUITING	Nirogacestat in Patients With Kaposi Sarcoma
NCT01981551	PHASE2	COMPLETED	Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis
NCT02109445	PHASE2	TERMINATED	Study Of PF-03084014 In Combination With Gemcitabine And Nab-Paclitaxel In Patients With Metastatic Pancreatic Adenocarcinoma Not Previously Treated With Anticancer Therapies
NCT02299635	PHASE2	TERMINATED	A Study Evaluating PF-03084014 In Patients With Advanced Breast Cancer With Or Without Notch Alterations
NCT02338531	PHASE2	WITHDRAWN	Biomarker Research Study for PF-03084014 in cHEmoresistant Triple-negative Breast cAncer
NCT05090566	PHASE2	TERMINATED	MagnetisMM-4: Umbrella Study of Elranatamab (PF-06863135) in Combination With Anti-Cancer Treatments in Multiple Myeloma
NCT05348356	PHASE2	COMPLETED	Nirogacestat in Ovarian Granulosa Cell Tumors
NCT04722146	PHASE1	ACTIVE_NOT_RECRUITING	A Study of Teclistamab With Other Anticancer Therapies in Participants With Multiple Myeloma
NCT05137054	PHASE1	RECRUITING	A Study to Examine the Effects of Novel Therapy Linvoseltamab in Combination With Other Cancer Treatments for Adult Patients With Multiple Myeloma That is Resistant to Current Standard of Care Treatments
NCT05556798	PHASE1	ACTIVE_NOT_RECRUITING	A Study of Belantamab Mafodotin in Combination With Nirogacestat and Pomalidomide in People With Multiple Myeloma That Has Not Responded to Treatment or Has Come Back After Treatment
NCT00878189	PHASE1	COMPLETED	A Trial In Patients With Advanced Cancer And Leukemia
NCT01876251	PHASE1	TERMINATED	A Study Evaluating The PF-03084014 In Combination With Docetaxel In Patients With Advanced Breast Cancer
NCT02462707	PHASE1	WITHDRAWN	A Study Of PF-03084014 In Japanese Patients With Advanced Solid Tumors
NCT04093596	PHASE1	COMPLETED	Safety and Efficacy of ALLO-715 BCMA Allogenic CAR T Cells in in Adults With Relapsed or Refractory Multiple Myeloma (UNIVERSAL)
NCT04171843	PHASE1	TERMINATED	A Dose-escalation Study to Evaluate the Safety and Clinical Activity of PBCAR269A, With or Without Nirogacestat, in Study Participants With Relapsed/Refractory Multiple Myeloma
NCT07171619	PHASE1	COMPLETED	Evaluate the Effects of Famotidine or Rabeprazole on the PK of Nirogacestat
NCT07259330	PHASE1	COMPLETED	To Determine the Effect of CYP Induction Following Administration of Nirogacestat in Healthy Adult Male Participants
NCT02955446	Not specified	NO_LONGER_AVAILABLE	Compassionate Use Protocol for PF-03084014 in Patients With Advanced Solid Tumor Malignancies

Clinical evidence (CIViC)

Variant × indication × effect (2 predictive associations from 2 curated evidence items):

Variant	Indication	Effect	Therapy	Level	CIViC
APC Mutation OR CTNNB1 Activating Mutation	Desmoid Tumor	Sensitivity/Response	Nirogacestat	CIViC A	EID12023
NOTCH1 L1678P	Adult T-cell Leukemia/lymphoma	Sensitivity/Response	Nirogacestat	CIViC C	EID5921

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.

Related molecules

Related molecules

No competitor molecules sharing a primary target (ChEMBL phase ≥2 or PubChem drug-class).