Nirogacestat
Nirogacestat, sold under the brand name Ogsiveo, is an anti-cancer medication used for the treatment of desmoid tumors. It is a selective gamma secretase inhibitor that is taken by mouth.
Nirogacestat was approved for medical use in the United States in November 2023. It is the first medication approved by the US Food and Drug Administration for the treatment of desmoid tumors. The FDA considers it to be a first-in-class medication.
Medical uses
Nirogacestat is indicated for adults with progressing desmoid tumors who require systemic treatment.Adverse effects
Nirogacestat treatment has been associated with several notable adverse effects across multiple studies. Hypophosphatemia is a significant and common side effect, with an incidence exceeding 40% in patients with various cancers including desmoid tumors, sarcoma, metastatic breast cancer, and solid organ cancers. Gastrointestinal toxicity is another concern, and glucocorticosteroid pretreatment and post-treatment regimens have shown efficacy in mitigating these effects in clinical trials.Reproductive toxicity has been observed in animal studies, with findings including ovarian atrophy, amenorrhea, premature menopause, reduced testes weight, and decreased sperm concentration and motility; some of these effects may be irreversible. There is a possible risk of non-melanoma skin cancer development. In vivo rat studies showed embryotoxicity, including decreased body weight, implantation loss and subcutis edema at doses lower than the recommended human dose. Additionally, there has been a reported case of eruptive milia in association with nirogacestat therapy.
Nirogacestat have been found to induce grade 1 or 2 adverse effects, with exception of hypophosphatemia at grade 3:
- diarrhea
- nausea and vomiting
- abdominal pain
- fatigue
- maculopapular rash, folliculitis, hidradenitis
- anorexia
- fatigue
- stomatitis
- cough
- alopecia
- upper respiratory tract infection
- dyspnea
- headache
- lymphopenia
- trombocytopenia
- liver toxicity
- hypophosphatemia, hypokalemia
- anaphylaxis
- glycosuria
- proteinuria
Pharmacology
Pharmacodynamics
Nirogacestat works as a gamma secretase inhibitor, which blocks the activation of the Notch receptor, stopping tumor growth.Nirogacestat's indirect action on Notch intracellular domain and amyloid precursor protein due to gamma-secretase inhibition are described in the table below.
Nirogacestat's binding to gamma-secretase assessed with cryogenic electron microscopy showed that it localises in the persenilin 1 catalytic subunit. Four hydrogen bonds are involved in this interaction, where two come from lysine and two from leucine. Its alignment selectively obstructs the site of Notch cleavage by gamma-secretase, which occurs in its β-sheet, allowing inhibition of downstream Notch signalling.
Moreover, nirogacestat's pharmacophore is consistent with other gamma-secretase inhibitors in terms of three dimensional arrangement in the binding cavity. Leucine342 hydrogen bond interaction is shared amongst these compounds
A slight modification of nirogacestat's structure, where the propyl group is substituted by a trifluoropropyl group, results in enhanced binding-pocket occupation and better inhibition.
Pharmacokinetics
Nirogacestat's pharmacokinetic parameters in patients with desmoid tumors are as follows:Drug interactions
Nirogacestat can interfere with several drugs that are metabolised through cytochrome P450 pathways, especially through CYP3A family and CYP2C19. Additionally, gastric acid-neutralising medications impaired its absorption and thus reduced its plasma concentration.Chemistry
Physicochemical properties
Nirogacestat's chemical properties were evaluated in silico and in vitro in mice and are as follows:| Parameter | in silico | in vitro |
| lipophilicity | 4.01 | 2.07 |
| solubility in water | 0.32 | 2.2 ; 11.4 |
| pKa | 6.4, 8.9 | 5.8, 7.1 |
| octanol-water partition coefficient | 4.8 | – |
| topological polar surface area | 71 Ų | – |
Synthesis
Nirogacestat can be synthesised through the following pathway:2-acetyl chloride undergoes cyclisation reaction with ethene to yield 2. Then, 2 reacts with tert-butyl -2-aminopentanoate, yielding 3 that is further hydrolysed to remove the tert-butyl group, yielding 4. To finally obtain nirogacestat, 4 is reacted with 5.
Alternatively, 6 reacts with 7, where the trifluoromethylsulfonate moiety acts as a leaving group and the tert-butyl moiety acts as a protecting group, to avoid the reaction of carboxyl group with amine group in 6. This reaction is performed in iso-propanol and an inorganic acid. Obtained 8 undergoes cyclisation reaction using 9 in a polar aprotic solvent, yielding 10. Then, reaction with 11 creates nirogacestat.
The trifluoromethylsulfonyl group in 7 can be replaced with tert-butyloxycarbonyl group. Reaction of 10 with 11 is conducted a condensing agent, precisely O--1,1,3,3-tetramethyluronium tetrafluoroborate in N,N-diisopropylethylamine.
Formation of several side products should be addressed. The above synthetic pathway allows to minimise side product creation to less than 1%. An important example is adverse cyclisation of the product of reaction of 10 with 11 shown below. To avoid this situation, to the mixture of 10 and 11, compound 6 and hydrobromic acid is added.Compounds 5 and 11 can be synthesised as follows:
A undergoes reduction using diisobutylaluminium hydride in dichloromethane, obtaining B. Then B is condensed with 2,2-dimethylpropan-1-amine with Na(OAc)3BH in DCM on a molecular sieve, yielding 5. To synthesise 11, 5 undergoes reduction with hydrogen on Pd/C in methanol.
Compound 6 and tert-butyl -2-aminopentanoate may be synthesised using an enzyme-driven process, using respectively: ATA ω-transaminase with isopropylamine, pyridoxal phosphate, phosphoric acid and potassium hydroxide; alcohol dehydrogenase, glucose dehydrogenase, glucose monohydrate, NAD+ in phosphate buffer and glycerol. This enzymatic process is used to obtain 6 from 2 while minimising stereoisomer side products.
Crystalline forms
Nirogacestat can exist in several crystalline forms, where the form used clinically is an anhydrous dihydrobromide salt that has a primitive monoclinic Bravais lattice. It exhibits high polymorphic purity of at least 80%. In water, it crystallises as small needles and does not change its lattice, suggesting stability. Other forms can change into form A in methanol, suggesting instability. However, form A in methanol mixed with other reagents changes its lattice. In clinical settings, this transformation is not observed.History
Preclinical studies assessed different functional group configurations of a compound with a common backbone. Initially, N-pyrrolidine was selected for in vivo assay, which demonstrated significant inhibitory activity at gamma-secretase. Further studies aimed to optimise EC50-plasma concentration coefficient, which led to selection of nirogacestat for further studies.The effectiveness of nirogacestat was evaluated in DeFi, an international, multicenter, randomized, double-blind, placebo-controlled trial in 142 adult participants with progressing desmoid tumors not amenable to surgery. Participants were randomized to receive 150 milligrams of nirogacestat or placebo orally, twice daily, until disease progression or unacceptable toxicity. The main efficacy outcome measure was progression-free survival. Objective response rate was an additional efficacy outcome measure. The pivotal clinical trial demonstrated that nirogacestat provided clinically meaningful and statistically significant improvement in progression-free survival compared to placebo. Additionally, the objective response rate was also statistically different between the two arms with a response rate of 41% in the nirogacestat arm and 8% in the placebo arm. The progression-free survival results were also supported by an assessment of patient-reported pain favoring the nirogacestat arm.
As of 2021, nirogacestat was in phase II clinical trials for unresectable desmoid tumors. In addition, a phase III clinical trial, DeFi, was in progress for nirogacestat for adults with desmoid tumors and aggressive fibromatosis.
The FDA granted the application for nirogacestat priority review, fast track, breakthrough therapy, and orphan drug designations. The FDA granted the approval of Ogsiveo to SpringWorks Therapeutics Inc.
Society and culture
Legal status
Nirogacestat was granted breakthrough therapy designation by the FDA in September 2019, for adults with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.In June 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ogsiveo, intended for the treatment of adults with progressing desmoid tumors. The applicant for this medicinal product is SpringWorks Therapeutics Ireland Limited. Nirogacestat was authorized for medical use in the European Union in August 2025.
Research
Neurological disorders
Since gamma-secretase inhibitors are involved in producing amyloid β-peptide from amyloid precursor protein, they may have application in the treatment of Alzheimer's disease. Nirogacestat tested in guiena pig brain showed amyloid β-lowering activity with ED50 for amyloid β in guiena pig brain at 1.83 mg/kg, sc. Another study showed, that IC50 values for cell-free enzyme assay, whole-cell assay and CD25+ B- and T- cells in fetal thymic organ culture are respectively 6.2 nM, 1.2 nm and 1.3 nM.However, human phase II clinical tria of nirogacestatl showed no benefit in altering APP processing by nirogacestat.
Nirogacestat may be useful for treating several other neurological diseases, including hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, inclusion body myositis, multiple sclerosis, mild cognitive impairment and Down's syndrome.
Hematological malignancies
Multiple myeloma
Five clinical trials evaluated efficacy of nirogacestat with other anticancer therapies in multiple myeloma:- UNIVERSAL – nirogacestat and allogeneic CAR-T therapy ALLO-715.
- MajesTEC-2 – nirogacestat an teclistamab
- DREAMM 5 – nirogacestat in combination with belantamab mafodotin and pomalidomide Results showed moderate response rate and allowed reduction of belantamab dose. One important advese effect associated with this treatment regimen were ocular evenets, including keratopathy, decreased corrected visual acuity. DREAMM-5 clinical trial confirmed these findings.
- MagnetisMM-4 – nirogacestat and elranatamab
- PBCAR269A – nirogacestat and allogenic anit-BCMA CAR-T cell therapy, fludarabine and cyclophosphamide
Lymphoblastic leukemia and T-cell lymphoblastic lymphoma
A clinical trial testing nirogacestat's usefulness in treating lymphoblastic malignancies was conducted and its results showed that it inhibited HES4 gene expression in peripheral blood of treated patients. Since this transcription factor is involved in Notch1-mediated T-cell development, this finding justifies further clinical trials to test its efficacy in blood cancers. In vitro studies in Notch1-mutated acute lymphoblastic leukemia cell lines confirmed HES4-inhibition and also presented evidence for decereasing expression of cMyc regulator. Moreover, nirogacestat induced apoptosis markers, that is the active form of caspase-3 and cleaved PARP expression in human acute lymphoblastic leukemia cells.One study tested a novel formulation of nirogacestat and dexamethasone, which were developed to be bound to a modified lecithin nanoparticles, targeting lymphoma cells. In vitro, this allowed to enhance dexamethasone-mediated cell death, through simultaneous glucocorticoid receptor hyperexpression and BCL2 inhibition. It also allowed to increase bone marrow accumulation. The peptide was synthesized from phopsphatidyletholamine bound to stearic acid chains and a pegyl group, an octapeptide and soy lecithin.
Chronic lymphoblastic leukemia
HG3 cell line represents a testing environment for drugs that affect the progression of chronic lymphoblastic leukemia. Nirogacestat is capable of decrease the viability of these cells compared to DMSO in both NOTCH1 wild-type and mutated cells, suggesting a probable treatment regimen for this disease. When combined with a USP28 allosteric inhibition, this regimen was enhanced compared to nirogacestat alone. Both of these findings were statistically significant.Moreover, nirogacestat showed dose-dependent S and G2-M mitotic phase inhibition in Notch1-mutated CLL cells, lowering cell viability.
Diffuse large B-cell lymphoma
Mutations in NOTCH2 genes in diffuse large-B cell lymphoma can cause a relatively common resistance to R-CHOP treatment regimen. Nirogacestat promotes ubiquitin-dependent Notch2 degradation via E3 ligases, stopping mRNA expression of MYC and KRAS genes, which are involved in downstream signalling leading to cell proliferation. Moreover, combination with an AKT inhibitor ipatasertib further enhanced apoptotic promotion in malignant R-CHOP-resistant lymphocytes B. However, the inhibitory constant of nirogacestat in dual KLHL6 and FBXW7 human DLBCL-xenotransplanted mutant mice was over two-times higher, than in the wild type.Acute myeloid leukemia
Nirogacestat's chemoresistance reversion in combination in glasdegib was tested in three in vitro models, each representing a different subtype of acute myeloid leukemia as well as a small pool of patient samples. The results were mixed, where in HL60 cells this combination both reversed quiescence and decreased viability with addition of cytarabine than cytarabine alone. In OCI-AML3 and patient samples, only quiescence reversion was observed, whereas in Kasumi-1 – no differences were found.Reverse transcriptase PCR assay found that nirogacestat in combination with dexamethasone significantly influenced expression of Notch-related genes. This finding shows that nirogacestat poses an ability to reverse glucocorticoid resistance in AML, thereby significantly decreasing tumor mass. Moreover, glucocorticoid administration attenuated nirogacestat-induced gastrointestinal toxicity, by stopping goblet cell metaplasia related to Notch1 suppression, and increasing Math1 gene. Nirogacestat also decreases β-actin expression, disrupting cytosceletal structures. Additionally, nirogacestat treatment exhibits synergistics effects with rapamycin's antileukemic properties.
Splenic marginal zone lymphoma
In vitro studies showed that concomitant nirogacestat administration with decitabine, ibrutinib, idelalisib, and an investigational drug 3-dezaneplanocin A intensively increased cell death in splenic marginal zone malignant lymphocytes.Solid tumors
Colorectal cancer
In mouse with colorectal cancer harboring mutated adenomatous polyposis coli gene, that exhibit enhanced Notch signalling, nirogacestat decreased cell migration, invasion and growth.Pancreatic adenocarcinoma
One study tested nirogacestat alone and with gemcitabine in pancreatic ductal adenocarcinoma patient-derived xenografts in mice and showed that both treatment arms showed regression of cell division and decreased angiogenesis.Phase II clinical trial of nirogacestat in metastatic pancreatic cancer was terminated due to changes in Pfizer's strategy in drug development.
Venous thromboembolism is a serious complication of panceratic cancer that is mediated by interleukin-6, thyroid peroxidase and tissue factor secretion from tumor-associated stromal cells. Nirogacestat, in an in vivo study with mice injected with pancreatic adenocarcinoma cells, showed a steep decrease in these markers. This hyperexpression is also present in human plasma in patients with this malignancy. This effect was shown to be mediated by Jagged-Notch interaction.
Lung adenocarcinoma
Nirogacestat was shown to reverse resistance to tyrosine kinase inhibitors such as gefitinib in EGFR-mutated lung adenocarcinoma, precisely the form where there exists an EGFRT790M/L858R mutation.Breast cancer
Nirogacestat emerged as a possible adjunctive treatment to taxane treatment of triple-negative breast cancer. Notch receptor intracytoplasmic domain being internalized into a singnal-receiving cell, induces a signal transduction pathway associated with pregnane X receptor that causes BCRP, P-glycoprotein and CYP3A4 activation, causing drug resistance. It has a slight preference towards persenilin 2 versus 1 catalytic subunits of gamma-secretase.Nirogacestat's chemoresistance reversion in combination in glasdegib was tested in three in vitro models, each representing a different subtype of acute myeloid leukemia as well as a small pool of patient samples. The results were mixed, where in HL60 cells this combination both reversed quiescence and decreased viability with addition of cytarabine than cytarabine alone. In OCI-AML3 and patient samples, only quiescence reversion was observed, whereas in Kasumi-1 – no differences were found.
Reverse transcriptase PCR assay found that nirogacestat in combination with dexamethasone significantly influenced expression of Notch-related genes. This finding shows that nirogacestat poses an ability to reverse glucocorticoid resistance in AML, thereby significantly decreasing tumor mass. Moreover, glucocorticoid administration attenuated nirogacestat-induced gastrointestinal toxicity, by stopping goblet cell metaplasia related to Notch1 suppression, and increasing Math1 gene. Nirogacestat also decreases β-actin expression, disrupting cytosceletal structures. Additionally, nirogacestat treatment exhibits synergistics effects with rapamycin's antileukemic properties.
In human mitoxantrone-resistant breast carcinoma cell line nirogacestat inhibits their migration, but shows no antiproliferative effects.
In estrogen receptor-positive metastatic breast cancer, a phase I study showed that co-administration of nirogacestat with exemestane inhibited metastasis.
Since angiogenesis associated with tumor development is regulater by YAP/TAZ cytoplasm translocation from nucleus, nirogacestat was tested as a possible inhibitor of cytoplasm transport of these transcription factors. In one study, it was shown that nirogacestat significantly reduced cytoplasmatic concentration of YAP and TAZ, suggesting antiangiogenic activity in breast cancer tumor environment.
Ovarian granulosa cell tumor
Similarly to abovementioned diseases, the mechanism of action of nirogacestat supported the launch of a phase 2 clinical trial. Proposed influence of nirogacestat on these tumors is that overactivation of Notch causes FOXL2 hyperexpression, which is inhibited by this drug. It was confirmed by studying nirogacestat's effect on a cell line, in which a mutation in FOXL2C134W is present that causes enhanced gamma-secretase activity on SMAD-mediated signalling pathway. However, nirogacestat's usefulness in this model is controversial, since some studies show no clinical benefit.Prostate cancer
In vitro studies of nirogacestat in castration-resistant prostate cancer cells showed, that it reversed enzalutamide and docetaxel resistance and itself halted the further development of cancerous malignancy. In PTEN-deficient cancer cells, nirogacestat induced tumor growth arrest by inducing cellular senescence.Hepatocellular carcinoma and squamous cell carcinoma
Nirogacestat has the ability of suppressing hepatocellular carcinoma growth and metastasis, by decreasing Stat3 and Akt signalling activity beside Notch1 inhibition. Concomitant administration of sorafenib further decreased hepatocellular carcinoma spheroids, where this effect is attributed to nirogacestat's ability to reduce Notch1-induced sorafenib resistance via decrasing epithelial-mesenchymal transition, where it is associated with attenuated expression of EMT-related genes, enhanced expression of E-cadherin and inhibition of survival signalling pathways. It also reduced tumor angiogenesis in vivo.Similar mechanisms are responsible for nirogacestat/erlotinib combination's ability to reduce head and neck and oral squamous cell carcinoma cell invasion and tumor growth.