Ogsiveo Prescribing Information

2.1 Recommended Dosage

The recommended dosage of OGSIVEO is 150 mg administered orally twice daily until disease progression or unacceptable toxicity. Each 150 mg dose of OGSIVEO consists of three 50 mg tablets. OGSIVEO may be taken with or without food.

Instruct patients to swallow OGSIVEO tablets whole and not to break, crush, or chew prior to swallowing.

If a patient vomits or misses a dose, instruct the patient to take the next dose at its scheduled time.

2.2 Dosage Modifications for Adverse Reactions

The recommended dose modifications for OGSIVEO for selected severe adverse reactions are summarized in Table 1 [see Warnings and Precautions (5), Adverse Reactions (6)]. For other severe adverse reactions, life-threatening adverse reactions, or persistent intolerable Grade 2 adverse events, withhold drug until resolved to Grade ≤ 1 or baseline. Only restart at a dose of 100 mg twice daily after considering the potential benefit and likelihood of recurrence of the adverse reaction. Permanently discontinue OGSIVEO for recurrence of severe or life-threatening adverse reaction upon rechallenge at the reduced dose.

5.1 Diarrhea

Diarrhea, sometimes severe, can occur in patients treated with OGSIVEO [see Adverse Reactions (6.1)].

In DeFi, diarrhea occurred in 84% of patients treated with OGSIVEO, and included Grade 3 events in 16% of patients. Median time to first diarrhea event for patients treated with OGSIVEO was 9 days (range: 2 to 434 days). Monitor patients and manage using antidiarrheal medications. Modify dose as recommended [see Dosage and Administration (2.2)].

5.2 Ovarian Toxicity

Female reproductive function and fertility may be impaired in patients being treated with OGSIVEO. Impact on fertility may depend on factors including the duration of therapy and the state of gonadal function at the time of treatment. The long-term effects of OGSIVEO on fertility have not been established. Advise patients on the potential risks for ovarian toxicity before initiating treatment with OGSIVEO [see Use in Specific Populations (8.3)]. Monitor patients for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency, including hot flashes, night sweats, and vaginal dryness.

5.3 Hepatotoxicity

ALT or AST elevations occurred in 30% and 33% of patients who received OGSIVEO in DeFi, respectively. Grade 3 ALT or AST elevations (> 5 × ULN) occurred in 6% and 2.9% of patients, respectively [see Adverse Reactions (6.1)]. Monitor liver function tests regularly and modify dose as recommended [see Dosage and Administration (2.2)].

5.4 Non-Melanoma Skin Cancers

New non-melanoma skin cancers can occur in patients treated with OGSIVEO. In DeFi, cutaneous squamous cell carcinoma and basal cell carcinoma occurred in 2.9% and 1.4% of patients, respectively [see Adverse Reactions (6.1)]. Perform dermatologic evaluations prior to initiation of OGSIVEO and routinely during treatment.

5.5 Electrolyte Abnormalities

Electrolyte abnormalities can occur in patients treated with OGSIVEO. In DeFi, these included decreased phosphate (65%) and decreased potassium (22%). Phosphate <2 mg/dL occurred in 20% of patients who received OGSIVEO. Grade 3 decreased potassium occurred in 1.4% of patients [see Adverse Reactions (6.1)]. Monitor phosphate and potassium levels regularly and supplement as necessary. Modify dose as recommended [see Dosage and Administration (2.2)].

5.6 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, OGSIVEO can cause fetal harm when administered to pregnant women. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose [see Use in Specific Populations (8.1,8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of OGSIVEO was evaluated in 69 patients enrolled in DeFi with progressing desmoid tumor [see Clinical Studies (14)]. Patients received OGSIVEO 150 mg orally twice daily or placebo orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure to OGSIVEO was 20.6 months (range: 0.3 to 33.6).

Serious adverse reactions occurred in 20% of patients who received OGSIVEO. Serious adverse reactions occurring in ≥ 2% of patients were ovarian toxicity (4%).

Permanent discontinuation of OGSIVEO due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation of OGSIVEO in ≥ 2% of patients were diarrhea, ovarian toxicity, increased ALT, and increased AST.

Dosage interruptions of OGSIVEO due to an adverse reaction occurred in 51% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, fatigue, folliculitis, nausea, and ovarian toxicity.

Dose reductions of OGSIVEO due to an adverse reaction occurred in 42% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, folliculitis, hidradenitis, and ovarian toxicity.

The most common (≥ 15% with a difference between arms of ≥ 5% compared to placebo) adverse reactions that occurred in patients receiving OGSIVEO were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea.

Table 2 summarizes the adverse reactions that occurred in DeFi.

a Includes multiple related composite terms.

b Investigator assessment of ovarian toxicity included ovarian failure, premature menopause, amenorrhea, and menopause

c The number of females of reproductive potential in each arm is used as the denominator (OGSIVEO N = 36, Placebo N = 37)

Clinically relevant adverse reactions occurring in < 15% of patients receiving OGSIVEO in DeFi included non-melanoma skin cancers, epistaxis, hidradenitis suppurativa, folliculitis, and influenza-like illness.

Table 3 summarizes laboratory abnormalities in DeFi.

a The denominator used to calculate the rate was 69 for nirogacestat and 72 for placebo based on the number of patients with a baseline value and at least one post-treatment value.

b CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value < Lower Limit of Normal (LLN).

c The denominator used to calculate the rate was 68 for nirogacestat and 69 for placebo based on the number of patients with a baseline value and at least one post-treatment value.

d CTCAE Version 5.0 does not include numeric thresholds for grading of increased urine glucose.

7.1 Effects of Other Drugs on OGSIVEO

7.2 Effects of OGSIVEO on Other Drugs

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action, OGSIVEO can cause fetal harm or loss of pregnancy when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and embryo-fetal death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily [see Data]. There are no available data on the use of OGSIVEO in pregnant women. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Daily oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in decreased fetal body weights, pre- and post-implantation loss, and fetal subcutis edema at doses ≥ 20 mg/kg/day (approximately 0.85 times the recommended dose of 150 mg twice daily based on area under the curve).

8.2 Lactation

Risk Summary

There are no data on the presence of nirogacestat or its metabolites in human milk or the effects of nirogacestat on a breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with OGSIVEO and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

OGSIVEO can cause fetal harm when administered to a pregnant woman (see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating OGSIVEO [see Use in Specific Populations (8.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose.

Infertility

Based on findings in animal studies, OGSIVEO can impair female and male fertility. OGSIVEO has been shown to interfere with folliculogenesis and spermatogenesis in nonclinical studies resulting in changes that included ovarian atrophy [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of OGSIVEO have not been established in pediatric patients. Epiphyseal disorder, manifesting as a widening of the epiphyseal growth plate, has been reported in pediatric patients with open growth plates treated with OGSIVEO.

8.5 Geriatric Use

Of the total number of OGSIVEO-treated patients in the DeFi study, 3 (4%) were 65 years of age and older and none were 75 years of age and older. Clinical studies of OGSIVEO did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger adult patients.

12.1 Mechanism of Action

Nirogacestat is a gamma secretase inhibitor that blocks proteolytic activation of the Notch receptor. When dysregulated, Notch can activate pathways that contribute to tumor growth.

12.2 Pharmacodynamics

Exposure-Response Relationships

There is an exposure-response relationship between nirogacestat exposure and Grade 3 hypophosphatemia with a higher risk of Grade 3 hypophosphatemia at higher exposure.

Cardiac Electrophysiology

At the recommended dosage, a mean increase in the QTc interval > 20 ms was not observed.

12.3 Pharmacokinetics

Nirogacestat pharmacokinetic parameters in patients with desmoid tumors are summarized in Table 6.

* Protein binding values reflect results from separate assays.

Abbreviations: AUC0-tau = area under the time concentration curve to the dosing interval;

Cmax = maximum plasma concentration; Tmax = time to reach Cmax; GMR = geometric mean ratio

Specific Populations

No clinically significant differences in the pharmacokinetics of nirogacestat were observed based on age (18 to 80 years), sex, race (Asian, Black or African American, and White), or mild or moderate renal impairment (eGFR ≥41 mL/min/1.73m2).

Effects of Hepatic Impairment

The mean AUC increased by up to 16% and the mean Cmax decreased by up to 39% in subjects with moderate hepatic impairment identified by Child-Pugh Class B or NCI-ODWG Group C criteria compared to that of subjects with normal hepatic function.

Insufficient data are available to characterize nirogacestat PK in patients with severe hepatic impairment.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A inhibitors: Nirogacestat Cmax increased by 2.5-fold and AUC by 8.2-fold following coadministration of a single dose of OGSIVEO (100 mg) with itraconazole (a strong CYP3A inhibitor). Nirogacestat AUC is predicted to increase by 6.33-, 5.19-, and 3.46-fold following coadministration of multiple doses of OGSIVEO (150 mg BID) with itraconazole, ketoconazole and clarithromycin (strong CYP3A inhibitors), respectively.

Moderate CYP3A inhibitors: Nirogacestat AUC is predicted to increase by 2.73- and 3.18-fold following coadministration of multiple doses of OGSIVEO (150 mg BID) with erythromycin (moderate CYP3A inhibitor) and fluconazole (moderate CYP3A inhibitor), respectively.

Strong CYP3A inducers: Nirogacestat AUC is predicted to decrease by 85% following coadministration of multiple doses of OGSIVEO (150 mg BID) with rifampin (strong CYP3A inducer).

Moderate CYP3A inducers: Nirogacestat AUC is predicted to decrease by 67% following coadministration of multiple doses of OGSIVEO (150 mg BID) with efavirenz (moderate CYP3A inducer).

CYP3A substrates: Midazolam (CYP3A substrate) Cmax is predicted to increase by 1.77-fold and AUC by 2.07-fold following concomitant use with multiple doses of OGSIVEO (150 mg BID).

CYP2C19 substrates: Concomitant use of multiple doses of OGSIVEO (150 mg BID) with a drug that is a sensitive substrate of CYP2C19 decreases the plasma concentrations of these substrates.

P-gp substrates: Exposure to dabigatran (P-gp substrate) Cmax and AUC were not affected by concomitant use with nirogacestat.

Drugs that increase gastric pH: Concomitant administration of proton pump inhibitors (e.g., omeprazole), histamine type 2 (H2)-receptor antagonists (e.g., famotidine), or antacids (e.g., calcium) is expected to reduce concentrations of nirogacestat.

Other Drugs:

No clinically significant differences in nirogacestat pharmacokinetics were predicted when used concomitantly with cimetidine (weak CYP3A inhibitor).

No clinically significant differences were predicted in the pharmacokinetics of the following drugs when used concomitantly with nirogacestat: rosiglitazone (CYP2C8 substrate) or
S-warfarin (CYP2C9 substrate).

In Vitro Studies

Nirogacestat does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6.

Nirogacestat is an inducer of CYP2B6, CYP2C8, CYP2C9, and CYP2C19, but does not induce CYP 1A2.

Transporter systems: Nirogacestat is a P-gp substrate, but not a substrate of BCRP, OATP1B1, and OATP1B3.

Nirogacestat is a P-gp inhibitor, but not an inhibitor of BCRP, MATE1, MATE2-K, OATP1B1, OATP1B3, OAT1, OAT2 and OAT3.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 6-month carcinogenicity study, transgenic rasH2 mice received up to 100 mg/kg/day of oral nirogacestat, resulting in mean exposure levels (AUC) less than those in humans at the recommended dose of 150 mg twice daily. No statistically significant neoplastic findings occurred. The carcinogenic potential of nirogacestat in rats has not been assessed.

Mutagenesis

Nirogacestat was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro chromosome aberration assay in human lymphocytes or in vivo rat bone marrow micronucleus study.

Impairment of Fertility

Nirogacestat resulted in reduced fertility when administered to male and female rats at doses ≥ 5 mg/kg/day (approximately 0.16 times the recommended dose of 150 mg twice daily based on body surface area (BSA), and a lack of fertility when administered to male and female rats at doses ≥ 40 mg/kg/day (approximately 1.3 times the recommended dose of 150 mg twice daily based on BSA). Adverse findings in rats included ovarian atrophy, reduced testes weights, and decreased sperm concentration and motility.

14.1 Desmoid Tumor

The efficacy of OGSIVEO was evaluated in DeFi (NCT03785964), an international, multicenter, randomized (1:1), double-blind, placebo-controlled trial in 142 adult patients with progressing desmoid tumors not amenable to surgery. Patients were eligible if the desmoid tumor had progressed within 12 months of screening. Patients with progressing desmoid tumor that would result in immediate risk to the patient were not eligible.

Patients were randomized to receive 150 mg OGSIVEO or placebo orally twice daily until disease progression or unacceptable toxicity. Patients were stratified by primary tumor(s) location (intra-abdominal versus extra-abdominal). Tumor imaging occurred every 3 months. Crossover was permitted at the time of radiographic progression. The major efficacy outcome was progression-free survival (PFS) based on RECIST v1.1 as assessed by blinded independent central review or on clinical progression by the investigator (and confirmed by independent review). Clinical progression required worsening of symptoms resulting in a global deterioration of health status causing the permanent discontinuation from trial treatment and the initiation of emergent treatment (e.g., radiotherapy, surgery, or systemic therapy including chemotherapy or tyrosine kinase inhibitors) for desmoid tumors. Objective response rate (ORR) was an additional efficacy outcome measure. Worst pain (item 3) was assessed daily using Brief Pain Inventory-Short Form (BPI-SF), an 11-point numerical rating scale ranging from 0 (“no pain”) to 10 (“pain as bad as you can imagine”) and averaged over 7 days prior to each visit.

A total of 142 patients were randomized. The median age was 34 years (range: 18 to 76); 65% were female; race was 83% White, 6% Black, 3% Asian, and other or not reported in 8%; and 73% had an ECOG performance status (PS) of 0, 27% had an ECOG PS of 1, and 0.7% 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 tumor 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 patients received no prior therapy, and 44% received ≥3 prior lines of therapy. Prior therapy included surgery (53%), radiotherapy (23%), and systemic therapy (61%). Thirty-three percent of patients were previously treated with a tyrosine kinase inhibitor and 36% were previously treated with chemotherapy. Fifty percent had a BPI-SF item 3 (worst pain) score of ≥2.

Efficacy results are summarized in Table 7 and Figure 1.

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 with placebo as reference.

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 in DeFi

PFS results were supported by change from baseline in patient-reported worst pain favoring the OGSIVEO arm.

An exploratory analysis of PFS based on only radiographic progression demonstrated a hazard ratio of 0.31 (95% CI: 0.16, 0.62).