Nirogacestat

Nirogacestat is a reversible, non-competitive inhibitor of gamma secretase. By blocking the proteolytic step that activates the Notch receptor, it switches off Notch signalling, a pathway that can drive tumour growth when it is dysregulated.

Mechanism of Action

• Gamma-secretase inhibition: nirogacestat blocks the proteolytic activation of the Notch receptor.
• Notch pathway: dysregulated Notch can activate pathways that contribute to tumour growth, which is the rationale for blocking it.
• Exposure and hypophosphataemia: DrugBank reports a higher risk of grade 3 hypophosphataemia at higher nirogacestat exposure.
• Cardiac electrophysiology: in a model-based analysis, the 90% confidence interval for the predicted mean change in QTcF at the expected peak concentration of supratherapeutic doses stayed below 10 ms, so no clinically significant QTcF prolongation is associated with therapeutic dosing.

Pharmacokinetics

• Absorption: peak concentrations are reached about 1.5 hours after an oral dose. Absolute bioavailability is about 19.2% (range 16.2–24.3%). Exposure rises in proportion to dose between 50 and 150 mg; steady state is reached in about 7 days, with an accumulation ratio of about 1.5.
• Distribution: about 99.6% bound to serum proteins in vitro (albumin and, with greater affinity, alpha-1 acid glycoprotein). The blood-to-plasma ratio is about 0.5 and the apparent volume of distribution in patients about 1,430 L.
• Metabolism: extensively metabolised, mainly by CYP3A4; major or active metabolites in vivo are not fully characterised. Nirogacestat is also a substrate of P-glycoprotein.
• Elimination: after a radiolabelled dose in healthy subjects about 65% was recovered within 13 days (38% in faeces, 17% in urine, and about 10% of the recovered label in expired air); unchanged drug was below 0.01% of the dose in urine and below 0.5% in faeces. Apparent terminal half-life is about 23 hours and apparent oral clearance about 45 L/h.
• Special populations: in moderate hepatic impairment total exposure (AUC) was unchanged and peak exposure (Cmax) was 28% lower, with a larger volume of distribution and longer half-life. Renal impairment has not been studied in a dedicated trial.

• Desmoid tumours: as monotherapy for the treatment of adult patients with progressing desmoid tumours who require systemic treatment.

• Hypersensitivity to nirogacestat or to any of the excipients.
• Pregnancy.
• Women of childbearing potential who are not using highly effective contraception.
• Breastfeeding.

Frequencies are based on 88 patients given 150 mg twice daily for a median of 21.5 months. The most common reactions were diarrhoea (85%), rash (65%), ovarian toxicity in women of childbearing potential (60%), nausea (59%), fatigue (50%), hypophosphataemia (50%), headache (40%) and stomatitis (40%). The most frequent serious reaction was ovarian toxicity (premature menopause, 3%), and the most common severe reactions were diarrhoea (16%) and hypophosphataemia (13%). Treatment was permanently stopped because of an adverse event in 19% of patients (mainly diarrhoea 5%, ovarian toxicity 5% and increased ALT 3%), interrupted in 59% and reduced in 44%.

Very common (≥1/10): diarrhoea, nausea, stomatitis (including mouth ulceration and oral pain), dry mouth, rash (including maculopapular and acneiform rash), alopecia, folliculitis, dry skin, pruritus, hypophosphataemia, hypokalaemia, headache, dizziness, proteinuria, glucosuria, eosinophilia, increased ALT, increased AST, ovarian toxicity (including ovarian failure, premature menopause, amenorrhoea, irregular menstruation and hot flushes), cough, upper respiratory tract infection, dyspnoea, epistaxis, fatigue, influenza-like illness.

Common (≥1/100 to <1/10): hidradenitis, basal cell carcinoma, squamous cell carcinoma (including of the skin), renal tubular disorder, bone fracture.

Grade 3–4 events were very common for diarrhoea and hypophosphataemia, and common for nausea, stomatitis, rash, folliculitis, hidradenitis, hypokalaemia, raised ALT and AST, and fatigue. Within each frequency group the SmPC lists reactions in order of decreasing seriousness. The important serious reactions are ovarian toxicity, severe diarrhoea, electrolyte disturbances, liver enzyme elevation, non-melanoma skin cancers and hypersensitivity, including anaphylaxis.

Nirogacestat is metabolised mainly by CYP3A4 and is a substrate of P-glycoprotein. Interaction studies have been performed only in adults.

• Strong and moderate CYP3A4 inhibitors (clarithromycin, oral ketoconazole, itraconazole; erythromycin, fluconazole): itraconazole raised nirogacestat Cmax 2.5-fold and AUC 8.2-fold, and moderate inhibitors are expected to raise exposure in a clinically relevant way. Avoid the combination and choose alternatives with no or minimal CYP3A4 inhibition. If none is available, Ogsiveo should be interrupted immediately for as long as the inhibitor is given.
• Grapefruit and grapefruit juice: contain CYP3A4 inhibitors; avoid them.
• Strong and moderate CYP3A inducers (carbamazepine, phenytoin, rifampicin, phenobarbital, St John’s wort; efavirenz, etravirine): expected to lower exposure and efficacy. Avoid them and select alternatives with less enzyme induction potential.
• Acid-reducing agents: nirogacestat solubility falls steeply above pH 6.0, so these may reduce its bioavailability. Proton pump inhibitors and H2 blockers are not recommended; if acid reducers cannot be avoided, antacids can be staggered by taking Ogsiveo 2 hours before or 2 hours after the antacid.
• CYP3A4 substrates with a narrow therapeutic range (ciclosporin, tacrolimus, digitoxin, warfarin, carbamazepine): do not use together. In a study with 95 mg once daily, nirogacestat raised midazolam Cmax 1.3-fold and AUC 1.6-fold; the effect at 150 mg twice daily has not been studied.
• CYP2C8, CYP2C9, CYP2C19 and CYP2B6 substrates: nirogacestat may induce these enzymes in vitro. Check for reduced efficacy of the substrate; its dose may need adjusting.
• Hormonal contraceptives: it is unknown whether nirogacestat reduces their effectiveness, so highly effective contraception methods must be used.
• P-glycoprotein substrates: no clinically meaningful P-gp inhibition (dabigatran exposure unchanged).

Treatment should be started and monitored by a physician experienced in the use of anticancer therapies. Ogsiveo is taken by mouth with or without food. The tablets must not be broken, chewed or crushed, and grapefruit and grapefruit juice should be avoided.

Recommended Dose

• 150 mg twice daily, one dose in the morning and one in the evening. This dose must not be exceeded.
• Continue until disease progression or unacceptable toxicity.
• Missed dose: do not take an extra dose; take the next prescribed dose.

Dose Adjustments for Side Effects

For the reactions below, Ogsiveo is withheld until the reaction resolves to grade ≤1 or baseline, and then restarted at 100 mg twice daily:

• Diarrhoea: grade 3 persisting for ≥3 days despite maximal medical therapy.
• Skin reactions: grade 3 folliculitis, maculopapular rash or hidradenitis.
• Electrolytes: grade 3 hypophosphataemia persisting for ≥7 days despite maximal replacement; grade 3 hypokalaemia despite maximal replacement.
• Liver enzymes: ALT or AST ≥3 to 5 times the upper limit of normal (restart once they are below 3 times the upper limit or at baseline). ALT or AST above 5 times the upper limit requires permanent discontinuation.
• Anaphylaxis or other severe hypersensitivity: permanent discontinuation.
• Other severe or life-threatening reactions: withhold until grade ≤1 or baseline, restart only at 100 mg twice daily and only after weighing the benefit against the likelihood of recurrence. Stop permanently if a severe or life-threatening reaction recurs at the reduced dose.

Special Populations

• Elderly: no dose adjustment for patients aged 65 years or over; clinical data in this group are limited.
• Renal impairment: no adjustment in mild or moderate impairment; administration is not recommended in severe impairment.
• Hepatic impairment: no adjustment in mild or moderate impairment; administration is not recommended in severe impairment.
• Children and adolescents: safety and efficacy at 2 to 18 years have not been established. Ogsiveo must not be used from birth to under 2 years of age because of potential safety concerns related to structural and functional growth; no posology can be recommended.

Diarrhoea

Diarrhoea is very common. Patients should be monitored and treated with anti-diarrhoeal medicines. Grade 3 diarrhoea that persists for 3 days or more despite maximal medical therapy calls for withholding the dose and restarting at 100 mg twice daily.

Skin Reactions

Maculopapular rash, folliculitis and hidradenitis have been reported. Patients should be monitored throughout treatment and managed as clinically indicated; grade 3 reactions call for a dose interruption and restart at 100 mg twice daily.

Ovarian Toxicity

Ovarian toxicity, identified from abnormal reproductive hormone levels or peri-menopausal symptoms, was reported in 75% of women of childbearing potential in the DeFi study and resolved during treatment in 79% of them. After treatment stopped it resolved in all women for whom follow-up data exist (all but two of 27). The effect on human fertility is unknown, and animal data suggest female fertility may be impaired. Women of childbearing potential should be told about this risk before starting, and monitored for changes in menstrual regularity and for symptoms of oestrogen deficiency such as hot flushes, night sweats and vaginal dryness.

Electrolyte Abnormalities

Hypophosphataemia and hypokalaemia are very common. Phosphate and potassium should be monitored regularly and replaced as needed. Withhold the dose for grade 3 hypophosphataemia lasting 7 days or more, or grade 3 hypokalaemia, despite maximal replacement.

Hepatic Abnormalities

ALT and AST elevations have been reported. Liver function tests should be monitored regularly. Withhold the dose for ALT or AST at 3 to 5 times the upper limit of normal; stop permanently above 5 times.

Non-Melanoma Skin Cancers

Basal cell and squamous cell carcinoma have been reported. The skin should be examined before treatment and routinely during treatment. Cases are managed according to clinical practice, and treatment can continue without dose adjustment.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy test: women of childbearing potential must have a negative pregnancy test before starting. Testing during treatment should be considered if they develop amenorrhoea. Nirogacestat may cause foetal harm and is contraindicated in pregnancy; if a patient becomes pregnant, treatment must stop. A spontaneous abortion was reported in the DeFi study by a woman who conceived while on treatment.
• Contraception in women: highly effective contraception during treatment and for 1 week after the last dose, using at least one highly effective method (such as an intrauterine device) or two complementary methods including a barrier method. It is unknown whether nirogacestat reduces the effectiveness of hormonal contraceptives. Women should not donate eggs during this period.
• Contraception in men: male patients with female partners of childbearing potential must use highly effective contraception during treatment and for 1 week after the last dose, and should not donate sperm during this period.
• Breastfeeding: contraindicated. There are no data on milk transfer; women must not breastfeed during treatment and for 1 week after the last dose.
• Fertility: not studied in humans; animal data suggest male and female fertility may be impaired.

Excipients

The tablets contain lactose; patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. They also contain sunset yellow FCF (E110), which may cause allergic reactions. Each tablet contains less than 1 mmol (23 mg) of sodium.

Effect on Driving

Ogsiveo has no or negligible influence on the ability to drive and use machines. Because fatigue and dizziness may occur, patients with these symptoms should take care when driving or operating machinery.

Store below 25 °C. No refrigeration is needed. The 50 mg tablets are supplied in bottles with a child-resistant closure and the 100 mg and 150 mg tablets in blisters; not all pack sizes may be marketed.

2 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a physician experienced in anticancer therapy. Ogsiveo is taken at home, so it is supplied to the patient or to the treating clinic on prescription.