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
pK_a	6.4, 8.9	5.8, 7.1
octanol-water partition coefficient	4.8	–
topological polar surface area	71 Å²	–

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 Na₃BH 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.