OGSIVEO Film‑coated tablet Ref.[115825] Active ingredients: Nirogacestat
Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: SpringWorks Therapeutics Ireland Limited, Hamilton House, 28 Fitzwilliam Place, Dublin 2, D02 P283, Ireland
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents
ATC Code: L01XX81
Mechanism of action
Nirogacestat is a reversible and non‑competitive inhibitor of gamma secretase that blocks proteolytic activation of the Notch receptor.
Cardiac electrophysiology
The effects of nirogacestat concentration on QTc interval prolongation were predicted using a model‑based analysis. The 90% confidence intervals for the predicted mean change in QTcF were below 10 msec at the expected Cmax at supratherapeutic doses. Therefore, no clinically significant prolongation in QTcF interval is associated with therapeutic dosing of Ogsiveo.
Clinical efficacy and safety
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 histologically confirmed desmoid tumours that had progressed by ≥20% as measured by RECIST v1.1 within 12 months of screening and where continued progressive disease did not result in immediate significant 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 the intra‑and extra‑abdominal location were classified as intra‑abdominal. Patients received 150 mg nirogacestat or placebo orally twice daily in 28‑day cycles until disease progression, death, or unacceptable toxicity. The primary efficacy measure was progression-free survival (PFS). Progression was determined radiographically using RECIST v1.1 by a blinded, independent central imaging review, or as clinically assessed by the investigator and qualified via blinded, independent, central review, 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‑specific symptom 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 the 7‑day average of item #3 (i.e., worst pain) from the Brief Pain Inventory (BPI) Short Form. Desmoid tumour-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 age was 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-abdominal disease 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 patients with known somatic tumour mutation status, 81% had a CTNNB1 mutation and 21% had an APC mutation. 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 prior lines of therapy. Prior therapy included systemic therapy (61%), surgery (53%), and radiotherapy (23%). Thirty‑six percent of patients were previously treated with chemotherapy and 33% were previously treated with a tyrosine kinase inhibitor. Fifty percent had a BPI‑SF item 3 (worst pain) 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 characteristics including tumour location and type of prior therapies.
Table 3. Efficacy results in patients with RECIST 1.1 progressing desmoid tumours:
| Nirogacestat N=70 | Placebo N=72 | |
|---|---|---|
| Progression-free survival | ||
| Number (%) of patients with event | 12 (17) | 37 (51) |
| Radiographic progressiona | 11 (16) | 30 (42) |
| Clinical progressiona | 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-valuec | <0.001 | |
| Objective response ratea | ||
| ORR, n (%) | 29 (41) | 6 (8) |
| 95% CId | (29.8, 53.8) | (3.1, 17.3) |
| CR | 5 (7) | 0 |
| PR | 24 (34) | 6 (8) |
| p-valuee | <0.001 | |
Abbreviations: CI: confidence interval; CR: complete response; ORR: objective response rate; PR: partial response; NR: Not Reached
a 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 low number of events in the nirogacestat arm, the Kaplan-Meier estimate of median time to progression was unable to be estimated.
Patient-reported outcomes
PFS results were supported by change from baseline in patient‑reported worst pain favouring the nirogacestat 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).
Paediatric population
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.
5.2. Pharmacokinetic properties
Absorption
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%).
Distribution
The blood‑to‑plasma ratio of nirogacestat is estimated to be approximately 0.5 in humans. The serum protein binding is approximately 99.6% in vitro. Nirogacestat is highly bound to both human serum albumin and to α‑1 acid glycoprotein but with a greater affinity for α1 acid glycoprotein. Based on the population pharmacokinetic analysis, the apparent oral volume of distribution of nirogacestat in desmoid tumour patients was estimated to be 1430 L.
Biotransformation
Nirogacestat is extensively metabolized mainly by CYP3A4. There is incomplete knowledge of major or active metabolites in vivo due to limitations of detecting non‑radiolabelled metabolites. Numerous minor metabolites have been detected in circulation and excreta.
Elimination
After a single oral dose of radiolabelled nirogacestat in healthy subjects, approximately 65% of the dose is recovered within 13 days following the administration; 38% is eliminated in faeces, 17% is eliminated in urine, and 10% of the recovered label is found in expired air. Unchanged nirogacestat in the 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 apparent terminal elimination half-life of about 23 hours. The apparent oral systemic clearance is approximately 45 L/hr.
Linearity/non‑linearity
Nirogacestat exposure increases with escalating single and repeat doses, with proportional increases over the 50‑150 mg dose range.
Steady‑state conditions are achieved by approximately 7 days following repeat administration. The population pharmacokinetic analysis estimates an accumulation ratio of approximately 1.5 in desmoid tumour patients.
Special populations
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 by moderate hepatic impairment, but peak exposure (Cmax) was reduced by 28% with a higher volume of distribution and longer half‑life.
Effects of renal impairment
The effects of renal impairment on nirogacestat pharmacokinetics have not been evaluated in a dedicated clinical study. In a PopPK model, no clinically meaningful relationship was observed between renal function tests and nirogacestat pharmacokinetics. There were two subjects with mild and moderate renal impairment, respectively, out of 335 subjects included in the PopPK analysis. No subjects with severe renal impairment were included in the PopPK analysis.
5.3. Preclinical safety data
In repeat dose toxicity studies in rats and dogs, most of the toxicities were associated with gamma secretase inhibition. The effects included ovarian atrophy, alterations in the estrous cycle, decreased cellularity in gut‑associated lymphoid tissue, and decreased cellularity of mesenteric lymph nodes. In the rat study, growth plate thickening was observed. In addition, all dose levels evaluated in the rat study showed chronic progressive nephropathy, pulmonary phospholipidosis, and salivary gland necrosis in a dose‑dependent manner. In the dog study, treatment‑related effects were present within the intestines, spleen, gall bladder, liver, kidney, testes, and ovary. The intestinal and liver findings were associated with generalized inflammation and associated clinical pathology changes in most of the dogs. A NOAEL was not identified in the 3-month oral toxicity studies in rats or dogs. The lowest dose in the rat study was 5 mg/kg/day (human equivalent dose 50 mg/day) and in the dog the lowest dose was 2 mg/kg/day (human equivalent dose of 70 mg/day). Systemic exposures were also below the human systemic exposures (AUC) administered 150 mg BID of nirogacestat.
Carcinogenicity
Notch signalling appears to have both an oncogenic and tumour suppressor function. The carcinogenic potential of nirogacestat was evaluated in a 6‑month transgenic rasH2 mice study. At doses up to 100 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 BID nirogacestat. The carcinogenic potential in rats has not been assessed.
Reproductive and developmental toxicity
Nirogacestat reduced fertility indices in both male and female rats, which correlated with ovarian atrophy, reduced testes weights, and decreased sperm motility and effects on sperm morphology. In addition, early embryonic loss occurred in fertility studies. In a preliminary embryo‑foetal development study, nirogacestat induced significant and dose‑related embryo loss, early resorptions and decreased foetal weights in surviving embryos. These effects occurred at 20 mg/kg/day resulting in systemic exposures below (approximately 0.45‑fold) human exposures after administration of nirogacestat at 150 mg BID (see section 4.4).
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