nirogacestat

Action and Spectrum

Actions and Spectrum: 

Actions: 

Gamma-secretase, an enzyme that cleaves several transmembrane protein complexes, including Notch, is thought to be involved in initiating pathways that contribute to the growth of desmoid tumors. Nirogacestat functions by blocking this enzyme. 

Spectrum: 

Nirogacestat (Ogsiveo) has been approved by the FDA for use in adult patients who need systemic treatment for desmoid tumors that are advancing. The FDA claims that this is the first desmoid tumor treatment that has been approved. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Dyspnea 

Hair loss 

Diarrhea 

Fatigue 

Ovarian problems 

Nausea 

Upper RTI 

Rash 

Cough 

Abdominal pain 

Headache 

Stomatitis 

Decreased phosphate, potassium 

Increased ALT, urine protein, AST, urine glucose 

Black Box Warning

Black Box Warning: 

While taking nirogacestat, stay away from starfruit, grapefruit products, and Seville oranges. 

Contraindication / Caution

Contraindication/Caution: 

Contraindications 

• Hypersensitivity 

Cautions 

• Dehydration and electrolyte imbalance 
• h/o skin cancer 
• Renal impairment 
• Hepatic impairment 
• Drug interactions 
• Pregnancy  
• Breastfeeding 

Pregnancy / Lactation

Pregnancy consideration:  

No data is available regarding the administration of the drug during pregnancy. 

Breastfeeding warnings:  

No data is available regarding the excretion of drug in breast milk. 

Pregnancy category: 

Category A: well-controlled and satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: No data is available for the drug under this category. 

Pharmacology

Pharmacology: 

Gamma-secretase performs cleavage on numerous transmembrane proteins, including Notch, suspected to be involved in triggering pathways that foster the growth of desmoid tumors. 

Research has demonstrated that gamma-secretase cleaves B-cell maturation antigen (BCMA), a therapeutic target with specific expression on multiple myeloma cells. 

Pharmacodynamics: 

While the pathogenesis of desmoid tumors is commonly attributed to disruptions in the Wnt pathway, heightened Notch signaling is increasingly acknowledged as a contributor to disease progression. In a phase I trial employing PF-03084014 for advanced-stage solid tumors resistant to standard therapy, nine patients with desmoid tumors (seven assessable), five patients exhibited partial responses (as per RECIST criteria), and two experienced prolonged disease stabilization.

During subsequent follow-ups, all individuals achieving a partial response maintained this response for durations ranging from 47.9 to 73.6 months, with only one of seven progressing. The average clinical benefit of PF-03084014 was 64 months compared to 13 for all prior interventions. Positive outcomes were also noted in a phase I trial where a single patient with a desmoid tumor was treated with BMS-986115.

Building upon these findings, a phase II trial was initiated, treating 17 patients with unresectable desmoid tumors that had progressed on multiple lines of therapy with PF-03084014. Among the 16 assessable patients, 5 (29%) achieved a partial response (according to RECIST criteria), and 11 patients maintained stable disease with no instances of disease progression.

The success of the gamma-secretase inhibitor PF-03084014 (Nirogacestat) has led to the initiation of a phase III trial in adult patients with desmoid tumors (NCT03785964), recent breakthrough designation by the U.S. Food and Drug Administration, and orphan drug designation by the European Commission. Unraveling the mechanistic changes imposed by gamma-secretase inhibitors in these tumors may facilitate the translation of their promise to other malignancies. 

Pharmacokinetics: 

N/A 

Adminstartion

Administration: 

Nirogacestat is administered orally.  

The prescribed dosage is 150 mg taken by mouth twice daily. Your healthcare provider has the discretion to adjust your dose, temporarily suspend, or permanently discontinue treatment in the event of side effects.  

It can be taken with or without food. Swallow the tablets whole, refraining from breaking, crushing, or chewing them.  

If you are also using an antacid medication, take nirogacestat either 2 hours before or 2 hours after the antacid. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: nirogacestat 

Pronounced: Nye-roh-guh-se-stat 

Why do we use nirogacestat?  

Nirogacestat is currently undergoing exploration primarily for its potential applications in cancer treatment, particularly in cases where there is abnormal activation of the Notch pathway. Ongoing clinical trials and research studies aim to evaluate its effectiveness and safety across different cancer types.