Leaflet OGSIVEO 50mg film-coated tablets

Ogsiveo 50 mg film‑coated tablets

Ogsiveo 100 mg film‑coated tablets

Ogsiveo 150 mg film‑coated tablets

Ogsiveo 50 mg film‑coated tablets

Each film‑coated tablet contains 50 mg of nirogacestat (as nirogacestat dihydrobromide).

Each film-coated tablet contains 57.8 mg of lactose monohydrate.

Each film-coated tablet contains sunset yellow FCF (E 110).

Ogsiveo 100 mg film‑coated tablets

Each film‑coated tablet contains 100 mg of nirogacestat (as nirogacestat dihydrobromide).

Each film‑coated tablet contains 115.7 mg of lactose monohydrate.

Each film‑coated tablet contains sunset yellow FCF (E 110).

Ogsiveo 150 mg film‑coated tablets

Each film‑coated tablet contains 150 mg of nirogacestat (as nirogacestat dihydrobromide).

Each film‑coated tablet contains 173.5 mg of lactose monohydrate.

Each film‑coated tablet contains sunset yellow FCF (E 110).

For the full list of excipients, see section 6.1.

Film‑coated tablet (tablet).

Ogsiveo 50 mg film‑coated tablets

Round, biconvex, orange film‑coated tablets 8 mm diameter, debossed with “50” on one side.

Ogsiveo 100 mg film‑coated tablets

Round, light orange film‑coated tablets 10 mm diameter, debossed with “100” on one side.

Ogsiveo 150 mg film‑coated tablets

Oval, yellow orange film‑coated tablets 8.5 mm in width, 17.5 mm in length, debossed with “150” onone side.

Ogsiveo as monotherapy is indicated for the treatment of adult patients with progressing desmoidtumours who require systemic treatment.

Ogsiveo should be initiated and monitored by a physician experienced in the use of anticancertherapies.

The recommended dose is 150 mg Ogsiveo twice daily, one dose in the morning and one dose in theevening. This dose should not be exceeded.

Ogsiveo should be continued until disease progression or unacceptable toxicity.

If a dose of Ogsiveo is missed, patients should not take an additional dose. Patients should take thenext prescribed dose.

Dose adjustments for adverse reactions

The recommended dose modifications for selected adverse reactions are provided in Table 1.

For other severe adverse reactions, or in the event of life‑threatening adverse reactions, Ogsiveoshould be withheld until the reaction is resolved to Grade ≤ 1 or baseline. Ogsiveo should only berestarted at a dose of 100 mg twice daily and only after carefully considering the potential benefit andlikelihood of recurrence of the adverse reaction. Ogsiveo should be permanently discontinued forrecurrence of severe or life-threatening adverse reaction upon rechallenge at the reduced dose.

Dose modifications should be made if patients experience the following adverse reactions (gradesrefer to Common Terminology Criteria for Adverse Events):

Table 1: Recommended dose modifications for adverse reactions in patients treated with

Ogsiveo

Adverse reaction Recommended action

Grade 3 diarrhoea persisting for ≥ 3 days Ogsiveo should be withheld until reaction is resolved todespite maximal medical therapy Grade ≤ 1 or baseline, then it should be restarted at adose of 100 mg twice daily.

Ogsiveo should be withheld until reaction is resolved to

Grade 3 folliculitis Grade ≤ 1 or baseline, then it should be restarted at adose of 100 mg twice daily.

Ogsiveo should be withheld until reaction is resolved to

Grade 3 maculopapular rash Grade ≤ 1 or baseline, then it should be restarted at adose of 100 mg twice daily.

Ogsiveo should be withheld until reaction is resolved to

Grade 3 hidradenitis Grade ≤ 1 or baseline, then it should be restarted at adose of 100 mg twice daily.

Adverse reaction Recommended action

Electrolyte abnormalities

Grade 3 hypophosphataemia persisting Ogsiveo should be withheld until reaction is resolved tofor ≥ 7 days despite maximal Grade ≤ 1 or baseline, then it should be restarted at areplacement therapy dose of 100 mg twice daily.

Grade 3 hypokalaemia despite maximal Ogsiveo should be withheld until reaction is resolvedreplacement therapy to Grade ≤ 1 or baseline, then it should be restarted at adose of 100 mg twice daily.

Hepatic abnormalities

Alanine transaminase (ALT) or Ogsiveo should be withheld until ALT, AST, or both are

Aspartate transaminase (AST) ≥ 3 to 5 x resolved to < 3 x ULN or baseline, then it should be

ULN restarted at a dose of 100 mg twice daily.

ALT or AST > 5 x ULN Ogsiveo should be permanently discontinued.

Other adverse reactions

Anaphylaxis or other severehypersensitivity reaction Ogsiveo should be permanently discontinued.

No dose adjustment is recommended for patients who are aged 65 years or over.

Clinical data in patients aged 65 years or over is limited.

No dose adjustment is recommended in patients with mild or moderate renal impairment.

Administration is not recommended in patients with severe renal impairment (see section 5.2).

No dose adjustment is recommended in patients with mild or moderate hepatic impairment.

Administration is not recommended in patients with severe hepatic impairment (see section 5.2).

The safety and efficacy of Ogsiveo in children from 2 to 18 years of age have not been established.

Ogsiveo should not be used in children from birth to less than 2 years of age because of potentialsafety concerns related to structural and functional growth. Currently available data are described insections 4.8 and 5.1, but no recommendation on a posology can be made.

Ogsiveo is for oral use.

The tablets may be taken with or without food. Tablets should not be broken, chewed or crushedbecause there are no data currently available to support other methods of administration.

Patients should avoid consuming grapefruit and grapefruit juice while taking Ogsiveo (seesection 4.5).

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Pregnancy (see sections 4.4 and 4.6)

- Women of childbearing potential not using highly effective contraception (see sections 4.4 and4.6)

- Breast-feeding (see section 4.6)

Diarrhoea was reported in patients receiving nirogacestat (see section 4.8). Patients who experiencediarrhoea during treatment with nirogacestat should be monitored and managed using anti‑diarrhoealmedicinal products. For Grade 3 diarrhoea that persists for ≥ 3 days despite maximal medical therapy,nirogacestat should be withheld until diarrhoea is resolved to Grade ≤ 1 or baseline, then it should berestarted at 100 mg twice daily (see section 4.2).

Dermatologic reactions, including maculopapular rash, folliculitis, and hidradenitis, were reported inpatients receiving nirogacestat (see section 4.8). Patients should be monitored for dermatologicreactions throughout the course of treatment and managed as clinically indicated. For Grade 3dermatologic reactions, nirogacestat should be withheld until resolved to Grade ≤ 1 or baseline, then itshould be restarted at a dose of 100 mg twice daily (see section 4.2).

Ovarian toxicity

Ovarian toxicity was reported in female patients of childbearing potential receiving nirogacestat (seesection 4.8). Ovarian toxicity, identified based on abnormal reproductive hormone levels orperi‑menopausal symptoms, was reported in 75% of women of childbearing potential receivingnirogacestat in the DeFi study. Ovarian toxicity has been reported to resolve in 79% of women ofchildbearing potential during treatment. Follow up information is available for all but two out of27 patients; after stopping treatment, ovarian toxicity was reported to resolve in all women ofchildbearing potential for whom data are available (see section 4.8). Effects of nirogacestat on humanfertility are unknown. Based on findings from animal studies, female fertility may be impaired.

Women of childbearing potential should be advised about the risk of ovarian toxicity before initiatingtreatment with nirogacestat. Patients should be monitored for changes in menstrual cycle regularity orthe development of symptoms of oestrogen deficiency, including hot flashes, night sweats, and vaginaldryness.

Electrolyte abnormalities

Electrolyte abnormalities, including hypophosphataemia and hypokalaemia, were reported in patientsreceiving nirogacestat (see section 4.8). Phosphate and potassium levels should be monitored regularlyand supplemented as necessary. For Grade 3 hypophosphataemia persisting for ≥ 7 days despitemaximal replacement therapy, nirogacestat should be withheld until resolved to Grade ≤ 1 or baseline,then it should be restarted at a dose of 100 mg twice daily (see section 4.2). For Grade 3 hypokalaemiaof any duration, despite maximal replacement therapy, nirogacestat should be withheld until resolvedto Grade ≤ 1 or baseline, then it should be restarted at a dose of 100 mg twice daily (see section 4.2).

Hepatic abnormalities

ALT or AST elevations were reported in patients who received nirogacestat (see section 4.8). Liverfunction tests should be monitored regularly. For ALT or AST ≥ 3 to 5 x ULN, nirogacestat should bewithheld until ALT, AST, or both are resolved to < 3 x ULN or baseline, then it should be restarted ata dose of 100 mg twice daily. For ALT or AST > 5 x ULN, nirogacestat should be permanentlydiscontinued (see section 4.2).

Non‑melanoma skin cancers

Non‑melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma) were reported inpatients receiving nirogacestat (see section 4.8). Skin examinations should be performed prior toinitiation of nirogacestat and routinely during treatment with nirogacestat. Cases should be managedaccording to clinical practices and patients may continue with nirogacestat treatment without doseadjustment.

Embryo‑foetal toxicity - Contraception in males and females

Nirogacestat may cause foetal harm when administered to a pregnant woman (see sections 4.6 and5.3). Patients should be advised of the potential risk to a foetus. Women of childbearing potential musthave a negative pregnancy test prior to initiating nirogacestat treatment. Pregnancy testing duringtreatment with nirogacestat should be considered for women of childbearing potential experiencingamenorrhoea. Women of childbearing potential receiving nirogacestat must use highly effectivecontraceptive methods during treatment with nirogacestat and for 1 week after the last dose ofnirogacestat (see section 4.6). Women of childbearing potential should be advised to inform theirhealthcare provider immediately of a known or suspected pregnancy, and they must stop takingnirogacestat if they become pregnant.

Male patients with female partners of childbearing potential should be advised to use highly effectivecontraceptive methods during treatment with nirogacestat and for 1 week after the last dose ofnirogacestat (see section 4.6).

This medicinal product contains lactose (see sections 2 and 6.1). Patients with rare hereditaryproblems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption shouldnot take this medicinal product.

This medicinal product contains sunset yellow FCF (E110) (see sections 2 and 6.1), which may causeallergic reactions.

Each film‑coated tablet contains less than 1 mmol sodium (23 mg), that is to say essentiallysodium‑free (see section 6.1).

Interaction studies have only been performed in adults.

Nirogacestat is primarily metabolized by CYP3A4 and is a substrate of P‑glycoprotein (P-gp).

Agents that may increase nirogacestat serum concentrations

Effect of moderate and strong CYP3A4 inhibitors

In a clinical study, co‑administration of itraconazole (a strong CYP3A4 inhibitor and P‑gp inhibitor)increased nirogacestat Cmax by 2.5‑fold and AUC by 8.2‑fold. Co‑administration with moderate

CYP3A4 inhibitors is also expected to result in clinically relevant increases in exposure.

Concomitant use with strong inhibitors of CYP3A4 (e.g., clarithromycin, oral ketoconazole,itraconazole) and moderate inhibitors of CYP3A4 (e.g., erythromycin and fluconazole) shouldtherefore be avoided.

Alternative concomitant medicinal products with no or minimal CYP3A4 inhibition should beconsidered. If therapeutic alternatives are not available, Ogsiveo should be immediately interrupted forthe period of time in which a strong or moderate CYP3A4 inhibitor is given.

Patients should avoid consuming grapefruit and grapefruit juice when taking Ogsiveo since theyinclude inhibitors of CYP3A4 (see section 4.2).

Agents that may decrease nirogacestat serum concentrations

Effect of strong and moderate CYP3A4 inducers

The effects of CYP3A4 inducers on nirogacestat exposure have not been evaluated in a clinical study.

Moderate and strong inducers are expected to result in clinically relevant decreases in exposure ofnirogacestat that could lead to reduced efficacy. Concomitant treatment with strong inducers of

CYP3A4 (e.g., carbamazepine, phenytoin, rifampicin, phenobarbital and St. John’s wort) andmoderate CYP3A inducers (e.g., efavirenz and etravirine) should therefore be avoided. In patients forwhom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential shouldbe selected.

Effect of acid‑reducing agents

Nirogacestat has pH‑dependent solubility, with substantially reduced solubility at pH greater than 6.0.

The effects of acid reducing agents (i.e., H2‑receptor antagonists, proton pump inhibitors and antacids)on nirogacestat exposure have not been evaluated in a clinical study, however, co‑administration ofthese medicinal products may reduce the bioavailability of nirogacestat. Concomitant use of Ogsiveowith proton pump inhibitors and H2 blockers is not recommended. However, if concomitant use withacid reducing agents cannot be avoided, Ogsiveo can be staggered with antacids by administering

Ogsiveo 2 hours before or 2 hours after antacid use.

Effects of nirogacestat on the pharmacokinetics of other medicinal products

A drug‑drug interaction study in healthy volunteers investigating the effects of multiple doses ofnirogacestat at a dose of 95 mg once daily on the exposure of midazolam, a sensitive CYP3A4substrate, resulted in a 1.3‑fold increase in midazolam Cmax and a 1.6‑fold increase in midazolam

AUC. The effect of the clinical dose of nirogacestat (150 mg twice daily) on midazolam exposure hasnot been studied and may be different. Ogsiveo should not be used with concomitant administration of

CYP3A4 substrates that have narrow therapeutic indices (e.g., cyclosporine, tacrolimus, digitoxin,warfarin, carbamazepine).

Since no study has been performed investigating the effect of nirogacestat on systemic contraceptivesteroid exposure, it is unknown whether nirogacestat reduces the effectiveness of systemically actinghormonal contraceptives. Women of childbearing potential must use highly effective contraceptivemethods (see section 4.6).

In vitro studies showed that nirogacestat may induce CYP2C8, CYP2C9, CYP2C19, and CYP2B6 andthus there is a risk that nirogacestat can cause decreased exposure of substrates of these enzymes.

When substrates of CYP2C8, CYP2C9, CYP2C19, and CYP2B6 are administered with Ogsiveo,evaluation for reduced efficacy of the substrate should be performed and dose adjustment of thesubstrate may be required to maintain optimal plasma concentrations.

Drug transporter systems

A single-dose drug‑drug interaction study demonstrated that nirogacestat did not affect the exposure ofdabigatran, a P‑gp substrate, which supports the absence of clinically meaningful P‑gp inhibition bynirogacestat.

Women of childbearing potential and men with female partners of childbearing potential should beadvised to avoid pregnancy while on Ogsiveo (see section 4.4).

Women of childbearing potential must use highly effective contraceptive methods during treatmentwith Ogsiveo and for 1 week after the last dose of Ogsiveo (see section 4.4). It is unknown whethernirogacestat reduces the effectiveness of systemically acting hormonal contraceptives. Patients shouldbe advised to use at least one highly effective method of contraception (such as an intrauterine device)or two complementary forms of contraception including a barrier method during treatment with

Ogsiveo and for 1 week after the last dose of Ogsiveo. Women of childbearing potential should beadvised to inform their healthcare provider immediately of a known or suspected pregnancy, and theymust stop taking Ogsiveo if they become pregnant. Women of childbearing potential should notdonate eggs (oocytes) during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo.

Male patients with female partners of childbearing potential must use highly effective contraceptivemethods during treatment with Ogsiveo and for 1 week after the last dose of Ogsiveo (see section 4.4).

Male patients should not donate sperm during treatment with Ogsiveo and for 1 week after the lastdose of Ogsiveo.

Based on findings from animal studies and its mechanism of action, Ogsiveo may cause foetal harmwhen administered to a pregnant woman. Ogsiveo is contraindicated in pregnant women (seesections 4.3 and 5.3). Women of childbearing potential must have a negative pregnancy test prior toinitiating Ogsiveo treatment. Pregnancy testing during treatment with Ogsiveo should be consideredfor women of childbearing potential experiencing amenorrhoea. Patients should be advised of thepotential risk to a foetus. If a patient becomes pregnant while taking Ogsiveo, treatment must bediscontinued. A spontaneous abortion was reported by a woman in the DeFi study who conceivedwhile receiving nirogacestat.

Breast‑feeding

There are no data regarding the presence of nirogacestat or its metabolites in either human or animalmilk or its effects on a breastfed child or on milk production. Because of the potential for seriousadverse reactions in a breastfed child, women must not breastfeed during treatment with Ogsiveo andfor 1 week after the last dose of Ogsiveo (see section 4.3).

Fertility studies were not conducted in humans. The effect of Ogsiveo on fertility in humans is notknown. Based on findings from animal studies, male and female fertility may be impaired (seesection 5.3).

Ogsiveo has no or negligible influence on the ability to drive and use machines. Since fatigue anddizziness may occur in patients taking nirogacestat (see section 4.8), caution should be observed bypatients who experience those adverse reactions when driving or operating machinery.

The most common adverse reactions are: diarrhoea (85%), rash (65%), ovarian toxicity in women ofchildbearing potential (60%), nausea (59%), fatigue (50%), hypophosphataemia (50%),headache (40%), and stomatitis (40%).

The most frequently reported serious adverse reaction was ovarian toxicity (prematuremenopause, 3%). The most common severe adverse reactions were diarrhoea (16%) andhypophosphataemia (13%).

Permanent discontinuation of nirogacestat due to an adverse event occurred in 19% of patients. Themost common adverse reactions leading to discontinuation were diarrhoea (5%), ovariantoxicity (5%), and increased ALT (3%).

The frequency of dose interruption of nirogacestat due to adverse reactions was 59%. The mostcommon adverse reactions leading to dose interruption were diarrhoea (11%), rash maculo-papular (10%), hypophosphatemia (6%) and nausea (5%).

The frequency of dose reduction of nirogacestat due to adverse reactions was 44%. The most commonadverse reactions leading to dose reduction were diarrhoea (9%), rash maculo-papular (6%),stomatitis (3%), and hypophosphatemia (3%).

Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse eventfrequencies identified in 88 patients exposed to nirogacestat 150 mg twice daily during a medianduration of 21.5 months in clinical studies.

The adverse reactions are ranked under heading of frequency using the following convention: verycommon (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to< 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse reactions reported

System organ class Adverse reaction All grades Grades 3-4

Gastrointestinal Diarrhoea Very common Very commondisorders Nausea Very common Common

Stomatitisa Very common Common

Dry mouth Very common --

Skin and subcutaneous Rashb Very common Commondisorders Alopecia Very common --

Folliculitis Very common Common

Hidradenitis Common Common

Dry skin Very common --

Pruritis Very common --

Neoplasms benign, Basal cell carcinoma Common --malignant and Squamous cellc Common --unspecified carcinoma

Metabolism and Hypophosphataemia Very common Very commonnutrition disorders Hypokalaemia Very common Common

Nervous system Headache Very common --disorders Dizziness Very common --

Investigation Proteinuria Very common --

Glycosuria Very common --

Blood and lymphatic Eosinophilia Very common --system disorders

Renal and urinary Renal tubular Common --disorders disorder

Injury, poisoning and Bone fractured Common --proceduralcomplications

Hepatobiliary disorders ALT increased Very common Common

AST increased Very common Common

System organ class Adverse reaction All grades Grades 3-4

Reproductive system and Ovarian toxicitye Very common --breast disorders

Respiratory, thoracic Cough Very common --and mediastinal Upper respiratory Very common --disorders tract infectionf

Dyspnoea Very common --

Epistaxis Very common --

General disorders and Fatigue Very common Commonadministration site Influenza-like illness Very common --conditionsa Stomatitis includes stomatitis, mouth ulceration, oral pain, and oropharyngeal pain.b Rash includes rash maculo-papular, dermatitis acneiform, rash, rash erythematous, rash pruritic, and rashpapular.c Squamous cell carcinoma included squamous cell carcinoma of skin and squamous cell carcinoma.d Bone fracture includes fracture, foot fracture, hand fracture, radius fracture, hip fracture and rib fracture.e Ovarian toxicity includes ovarian failure, premature menopause, amenorrhoea, oligomenorrhoea, menstruationirregular, dysmenorrhoea, heavy menstrual bleeding, vulvovaginal dryness, hot flush, decreased anti-Müllerianhormone (AMH) and increased follicle-stimulating hormone (FSH).f Upper respiratory tract infection (URTI) includes URTI, viral URTI, acute sinusitis, and sinusitis.

- - Represents no cases were reported.

The data described below reflect results of the randomised, double-blind, Phase 3 DeFi study inpatients with desmoid tumours treated with 150 mg BID nirogacestat (N=69) or placebo (N=72) twicedaily.

In the double-blind phase of the DeFi study, diarrhoea was reported in 84% of patients receivingnirogacestat compared to 35% in patients receiving placebo. Grade 3 events occurred in 16% and 1%of patients, respectively (see section 4.4). Grade ≤ 2 diarrhoea resolved in 74% of patients whocontinued on nirogacestat treatment. The median time to first onset of diarrhoea in patients receivingnirogacestat was 9 days (range 2 to 234 days). Diarrhoea led to dose reduction in 10% of patients andtreatment discontinuation in 7% receiving nirogacestat.

In the double‑blind phase of the DeFi study, dermatologic reactions were reported at a higherincidence in patients receiving nirogacestat than in those receiving placebo; they includedmaculo‑papular rash (32% vs 6%), hidradenitis (9% vs 0), and folliculitis (13% vs 0) (see section 4.4).

The median time to rash events was 22 days (range 2 to 603 days). Skin and subcutaneous disordersled to dose reduction in 9% of patients receiving nirogacestat, including maculo‑papular rash in 4%and hidradenitis in 3%. Maculo‑papular rash led to treatment discontinuation in 1%.

Ovarian toxicity

In the double‑blind phase of the DeFi study, 75% of women of childbearing potential receivingnirogacestat reported ovarian toxicity (defined as ovarian failure, premature menopause, amenorrhea,oligomenorrhea, and menopause) compared to no patients receiving placebo. There were three seriousadverse reactions of ovarian toxicity, all premature menopause, representing 11% of all participantsreporting ovarian toxicity. The median time to first onset of ovarian toxicity was 8.9 weeks (range1 day to 54 weeks), and the overall median duration was 18.9 weeks (range 11 days to 215 weeks).

Ovarian toxicity has been reported to resolve in 79% of women of childbearing potential duringtreatment. Follow up information is available for all but two out of 27 patients; after stoppingtreatment, ovarian toxicity was reported to resolve in all women of childbearing potential for whomdata are available. The median time to resolution after discontinuing nirogacestat was 10.9 weeks(range 4 to 18 weeks). Effects of nirogacestat on fertility are unknown (see section 4.4). An exposure-response relationship was identified between nirogacestat and serum follicular stimulating hormone(FSH) levels, with FSH increasing linearly with increasing serum concentrations of nirogacestat.

Electrolyte abnormalities

Electrolyte abnormalities were reported in patients receiving nirogacestat in the double‑blind phase ofthe DeFi study, including hypophosphataemia (43%) and hypokalaemia (12%), compared to 7% and1%, respectively, in patients receiving placebo. Median time to first onset of hypophosphataemia andhypokalaemia was 15 days (range 1 to 833 days) and 15 days (range 1 to 57 days), respectively.

Grade 3 events of hypophosphataemia and hypokalaemia occurred in 3% of patients receivingnirogacestat compared to no patients receiving placebo (see section 4.4). Hypophosphataemia andhypokalaemia led to dose reduction in 4% and 1% of patients receiving nirogacestat, respectively.

Hypophosphataemia led to dose discontinuation in 1% of patients receiving nirogacestat.

Hepatic abnormalities

ALT and AST elevations were reported in 19% and 17%, respectively, of patients receivingnirogacestat in the double‑blind phase of the DeFi study compared to 8% and 11%, respectively, inpatients receiving placebo. Median time to first onset of ALT and AST elevations was 22 days (ALTrange 8 to 924 days; AST range 1 to 1023 days). Grade 3 ALT and AST elevations (> 5 x ULN)occurred in 3% of patients treated with nirogacestat compared to 1% in the placebo arm (seesection 4.4). ALT and AST elevations each led to dose reduction in 1% of patients receivingnirogacestat. ALT and AST elevations led to dose discontinuation in 4% and 3% of patients receivingnirogacestat, respectively.

Non-melanoma skin cancers

Non-melanoma skin cancers were reported at a higher incidence in patients receiving nirogacestat thanin those receiving placebo in the double‑blind phase of the DeFi study, including squamous cellcarcinoma (3% vs 0) and basal cell carcinoma (1% vs 0), with one patient reporting both types ofnon‑melanoma skin cancer (see section 4.4). An additional two cases of non‑melanoma skin cancerwere reported outside of the double‑blind phase of the DeFi study.

Proximal renal tubule effect

Glycosuria and proteinuria were observed in 52% and 46%, respectively, of patients receivingnirogacestat in the double‑blind phase of the DeFi study, compared with 1% and 39%, respectively, inpatients receiving placebo. Median time to onset of glycosuria and proteinuria was 85 days (range 55to 600 days) and 72 days (range 38 to 937 days), respectively. One patient in the DeFi study reportedrenal tubular disorder with increased urinary excretion of uric acid, glucose and phosphate, but noexcess excretion of low molecular weight proteins (beta2‑microglobulin) or any change in renalfunction. The event was managed with dose reduction.

Bone fracture

In the double‑blind phase of the DeFi study, bone fractures were reported in 6% of patients receivingnirogacestat compared with no patients receiving placebo. All reports of bone fracture werenon‑serious and Grade 1 or 2. The median time to first onset of bone fracture events in patientsreceiving nirogacestat was 125 days (range 1 to 739 days). Bone fracture events did not lead to dosereduction or treatment discontinuation in any patient receiving nirogacestat.

Epiphyseal disorder, manifesting as a widening of the epiphyseal growth plate, was reported in 4 of26 (15%) paediatric patients with open growth plates treated with nirogacestat outside of the DeFistudy. The events included epiphysiolysis, hip fracture, epiphyseal disorder, and osteonecrosis. All 4paediatric patients were between the ages of 11 and 12 years. See section 4.2 for information onpaediatric use.

Reporting suspected adverse reactions after authorization of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Signs and symptoms

The symptoms of Ogsiveo overdose are expected to be an extension of its pharmacological actions andmay include diarrhoea, nausea, vomiting, hypophosphataemia, elevated transaminases, and epistaxis.

Due to the high level of protein binding, Ogsiveo is not expected to be dialyzable in patients withnormal serum protein levels. In the event of an overdosage, treatment with Ogsiveo should be stoppedand general supportive measures should be initiated.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents; ATC Code: L01XX81

Nirogacestat is a reversible and non‑competitive inhibitor of gamma secretase that blocks proteolyticactivation of the Notch receptor.

The effects of nirogacestat concentration on QTc interval prolongation were predicted using amodel‑based analysis. The 90% confidence intervals for the predicted mean change in QTcF werebelow 10 msec at the expected Cmax at supratherapeutic doses. Therefore, no clinically significantprolongation in QTcF interval is associated with therapeutic dosing of Ogsiveo.

The DeFi study was an international, multicentre, randomised (1:1), double-blind, placebo‑controlled

Phase 3 study in adult patients with progressing desmoid tumours. Patients with histologicallyconfirmed desmoid tumours that had progressed by ≥ 20% as measured by RECIST v1.1 within12 months of screening and where continued progressive disease did not result in immediatesignificant risk to the patient were eligible. Randomisation was stratified by target tumour location(s)(intra‑abdominal or extra‑abdominal). Patients with multiple target tumours located both in theintra‑and extra‑abdominal location were classified as intra‑abdominal. Patients received 150 mgnirogacestat or placebo orally twice daily in 28‑day cycles until disease progression, death, orunacceptable toxicity. The primary efficacy measure was progression-free survival (PFS). Progressionwas determined radiographically using RECIST v1.1 by a blinded, independent central imagingreview, or as clinically assessed by the investigator and qualified via blinded, independent, centralreview, or by death due to any cause. Additional efficacy measures included objective response rate(ORR), change from baseline in pain at Cycle 10, change from baseline in desmoid tumour‑specificsymptom severity at Cycle 10, change from baseline in role functioning and physical functioning at

Cycle 10, and change from baseline in overall quality of life at Cycle 10. Pain was measured by the7‑day average of item #3 (i.e., worst pain) from the Brief Pain Inventory (BPI) Short Form. Desmoidtumour-specific symptom severity and physical functioning were measured using the GOunder/DTRF

DEsmoid Symptom/Impact Scale (GODDESS).

A total of 142 patients were randomised: 70 to nirogacestat and 72 to placebo. Overall, the median agewas 34 years (range: 18 to 76); 4% were 65 of age or older; 65% were female; race was 83% White,6% Black, 3% Asian, and 8% other; 73% had an ECOG performance status (PS) of 0, 27% had an

ECOG PS of 1, and < 1% had an ECOG PS of 2. Twenty‑three percent of patients had intra-abdominaldisease or both intra‑ and extra‑abdominal disease, and 77% had only extra‑abdominal disease.

Forty-one percent of patients had multifocal disease and 59% had single focal disease. Of 105 patientswith known somatic tumour mutation status, 81% had a CTNNB1 mutation and 21% had an APCmutation. Seventeen percent of patients had a family history of familial adenomatous polyposis (FAP).

Twenty‑three percent of the patients had received no prior therapy and 44% had received ≥ 3 priorlines of therapy. Prior therapy included systemic therapy (61%), surgery (53%), andradiotherapy (23%). Thirty‑six percent of patients were previously treated with chemotherapy and33% were previously treated with a tyrosine kinase inhibitor. Fifty percent had a BPI‑SF item 3 (worstpain) score of ≥ 2 at baseline.

Efficacy results from the ITT population, which included all randomised patients, are presented below.

PFS and ORR improvements were in favour of nirogacestat regardless of baseline characteristicsincluding tumour location and type of prior therapies.

Table 3: Efficacy results in patients with RECIST 1.1 progressing desmoid tumours

Nirogacestat Placebo

N = 70 N = 72

Progression-free survival

Number (%) of patients with event 12 (17) 37 (51)

Radiographic progression a 11 (16) 30 (42)

Clinical progression a 1 (1) 6 (8)

Death 0 1 (1)

Median (months) (95% CI) b NR (NR, NR) 15.1 (8.4, NR)

Hazard ratio (95% CI) 0.29 (0.15, 0.55)p-value c < 0.001

Objective response rate a

ORR, n (%) 29 (41) 6 (8)

Nirogacestat Placebo

N = 70 N = 7295% CI d (29.8, 53.8) (3.1, 17.3)

CR 5 (7) 0

PR 24 (34) 6 (8)p-value e < 0.001

Abbreviations: CI: confidence interval; CR: complete response; ORR: objective response rate; PR: partialresponse; NR: Not Reacheda Assessed by blinded independent central review.b Obtained using Kaplan-Meier Methodology.c p-value was from a one-sided stratified log-rank test.d Obtained using exact method based on binomial distribution.e p-value was from a two-sided Cochran-Mantel-Haenszel test.

Figure 1: Kaplan-Meier curve of PFS

Note: Median and 95% confidence intervals were estimated from the Kaplan-Meier method. Due to the lownumber of events in the nirogacestat arm, the Kaplan-Meier estimate of median time to progression was unableto be estimated.

Patient-reported outcomes

PFS results were supported by change from baseline in patient‑reported worst pain favouring thenirogacestat arm at Cycle 10 (‑1.6 vs ‑0.2; LS mean difference: ‑1.3; 95% confidence interval: ‑2.1 to‑0.6; p < 0.001).

The European Medicines Agency has deferred the obligation to submit the results of studies with

Ogsiveo in one or more subsets of the paediatric population in the treatment of soft tissue sarcoma.

See Section 4.2 for information on paediatric use.

Peak concentrations of nirogacestat are reached approximately 1.5 hours after oral administration.

Nirogacestat absolute bioavailability following oral administration is approximately 19.2% (Range:16.2%‑24.3%).

The blood‑to‑plasma ratio of nirogacestat is estimated to be approximately 0.5 in humans. The serumprotein binding is approximately 99.6% in vitro. Nirogacestat is highly bound to both human serumalbumin and to α‑1 acid glycoprotein but with a greater affinity for α1 acid glycoprotein. Based on thepopulation pharmacokinetic analysis, the apparent oral volume of distribution of nirogacestat indesmoid tumour patients was estimated to be 1430 L.

Nirogacestat is extensively metabolized mainly by CYP3A4. There is incomplete knowledge of majoror active metabolites in vivo due to limitations of detecting non‑radiolabelled metabolites. Numerousminor metabolites have been detected in circulation and excreta.

After a single oral dose of radiolabelled nirogacestat in healthy subjects, approximately 65% of thedose is recovered within 13 days following the administration; 38% is eliminated in faeces, 17% iseliminated in urine, and 10% of the recovered label is found in expired air. Unchanged nirogacestat inthe urine accounts for less than 0.01% and in faeces for less than 0.5% of the administered dose.

The population pharmacokinetic analysis in the desmoid tumour population estimates an apparentterminal elimination half-life of about 23 hours. The apparent oral systemic clearance is approximately45 L/hr.

Linearity/non‑linearity

Nirogacestat exposure increases with escalating single and repeat doses, with proportional increasesover the 50‑150 mg dose range.

Steady‑state conditions are achieved by approximately 7 days following repeat administration. Thepopulation pharmacokinetic analysis estimates an accumulation ratio of approximately 1.5 in desmoidtumour patients.

Effects of hepatic impairment

The pharmacokinetics of nirogacestat were evaluated in patients with moderate hepatic impairment(HI) based on Child‑Pugh classification. Total nirogacestat exposure (AUC) was not affected bymoderate hepatic impairment, but peak exposure (Cmax) was reduced by 28% with a higher volume ofdistribution and longer half‑life.

Effects of renal impairment

The effects of renal impairment on nirogacestat pharmacokinetics have not been evaluated in adedicated clinical study. In a PopPK model, no clinically meaningful relationship was observedbetween renal function tests and nirogacestat pharmacokinetics. There were two subjects with mildand moderate renal impairment, respectively, out of 335 subjects included in the PopPK analysis. Nosubjects with severe renal impairment were included in the PopPK analysis.

In repeat dose toxicity studies in rats and dogs, most of the toxicities were associated with gammasecretase inhibition. The effects included ovarian atrophy, alterations in the estrous cycle, decreasedcellularity in gut‑associated lymphoid tissue, and decreased cellularity of mesenteric lymph nodes. Inthe rat study, growth plate thickening was observed. In addition, all dose levels evaluated in the ratstudy showed chronic progressive nephropathy, pulmonary phospholipidosis, and salivary glandnecrosis in a dose‑dependent manner. In the dog study, treatment‑related effects were present withinthe intestines, spleen, gall bladder, liver, kidney, testes, and ovary. The intestinal and liver findingswere associated with generalized inflammation and associated clinical pathology changes in most ofthe dogs. A NOAEL was not identified in the 3-month oral toxicity studies in rats or dogs. The lowestdose in the rat study was 5 mg/kg/day (human equivalent dose 50 mg/day) and in the dog the lowestdose was 2 mg/kg/day (human equivalent dose of 70 mg/day). Systemic exposures were also belowthe human systemic exposures (AUC) administered 150 mg BID of nirogacestat.

Notch signalling appears to have both an oncogenic and tumour suppressor function. The carcinogenicpotential of nirogacestat was evaluated in a 6‑month transgenic rasH2 mice study. At doses up to100 mg/kg/day an increased incidence of hemangiosarcoma was observed. At 100 mg/kg/day,systemic exposures (AUC) were below (0.2‑fold) those in humans administered 150 mg BIDnirogacestat. The carcinogenic potential in rats has not been assessed.

Nirogacestat reduced fertility indices in both male and female rats, which correlated with ovarianatrophy, reduced testes weights, and decreased sperm motility and effects on sperm morphology. Inaddition, early embryonic loss occurred in fertility studies. In a preliminary embryo‑foetaldevelopment study, nirogacestat induced significant and dose‑related embryo loss, early resorptionsand decreased foetal weights in surviving embryos. These effects occurred at 20 mg/kg/day resultingin systemic exposures below (approximately 0.45‑fold) human exposures after administration ofnirogacestat at 150 mg BID (see section 4.4).

Cellulose, microcrystalline

Lactose monohydrate

Sodium starch glycolate

Magnesium stearate

Macrogol polyvinyl alcohol graft copolymer (E 1209)

Talc (E553b)

Titanium dioxide (E171)

Glycerol monocaprylocaprate type 1/mono/diglycerides (E471)

Polyvinyl alcohol ‑ partially hydrolyzed (E1203)

FD&C yellow #6/sunset yellow FCF aluminium lake (E110)

Iron oxide yellow (E172)

Not applicable.

2 years.

Store below 25°C.

Ogsiveo 50 mg film‑coated tablets

HDPE bottle with child resistant closure and induction seal containing 120 or 180 tablets.

Ogsiveo 100 mg film‑coated tablets

Ogsiveo 150 mg film‑coated tablets

Clear PVC/PVDC blisters with aluminium lidding containing 14 tablets. One pack contains 56 tabletsin 4 blisters.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Merck Europe B.V.

Gustav Mahlerplein 1021082 MA Amsterdam

The Netherlands

EU/1/25/1932/001

EU/1/25/1932/002

EU/1/25/1932/003

EU/1/25/1932/004

Date of first authorization: 14 August 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.