About OGSIVEO

OGSIVEO is the first and only FDA-approved therapy for adult patients with progressing desmoid tumors who require systemic treatment.

OGSIVEO is the first approved gamma secretase inhibitor, a novel mechanism of action in the desmoid tumor treatment landscape

  • OGSIVEO is believed to block proteolytic activation of the Notch receptor1
  • When dysregulated, Notch can activate pathways that contribute to tumor growth1

OGSIVEO was studied in the largest completed* Phase 3 trial in adult patients with desmoid tumors

DeFi: An international, multicenter, randomized (1:1), double-blind, placebo-controlled, Phase 3 study of OGSIVEO in patients with progressing desmoid tumors not amenable to surgery. Patients had treatment-naïve, refractory, or recurrent disease (N=142).1,2

  • All patients had histologically confirmed desmoid tumors that had progressed ≥20% by RECIST v1.1 within 12 months before screening2
  • If patients had multiple target tumors that were located in the intra- and extra-abdominal locations, they were classified as intra-abdominal2
  • Patients were randomized to receive 150 mg OGSIVEO or placebo orally twice daily until disease progression or unacceptable toxicity1
  • Tumor imaging occurred every 3 months1

Completed double-blind, randomized, Phase 3 trial in adult patients with desmoid tumors.1,2

Imaging-based progression or completion of the primary analysis.2

Eligible patients were given the option to enroll in the open-label extension phase.2

BID, twice daily; DeFi, Desmoid Fibromatosis; RECIST, Response Evaluation Criteria in Solid Tumors.

Primary End Point

Progression-Free Survival1,2

  • Progression-free survival was defined as the time from randomization until the date of imaging-based or clinical progression or death2
  • Progression-free survival was based on RECIST v1.1 as assessed by blinded independent central review or on clinical progression by the investigator (and confirmed by independent review)1
  • 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 (eg, radiotherapy, surgery, or systemic therapy including chemotherapy or tyrosine kinase inhibitors) for desmoid tumors1

Key Secondary Efficacy End Points§

Objective Response Rate1,2

  • Objective response rate was defined as complete response or partial response according to RECIST v1.1.2

Worst Pain Intensity (change from baseline at Cycle 10‖)1,2

  • Patient-reported worst pain intensity was assessed daily using item 3 of the 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 visit1,2

These are the secondary efficacy end points included in the OGSIVEO Prescribing Information. Additional secondary efficacy end points were evaluated in the DeFi study.1,2

Each cycle was 28 days.2

BPI-SF, Brief Pain Inventory-Short Form; DeFi, Desmoid Fibromatosis; RECIST, Response Evaluation Criteria in Solid Tumors.

Baseline characteristics in the DeFi study were consistent with the population of patients with desmoid tumors and included different prior treatments, genetic mutations, and tumor locations1,2

All patients experienced tumor progression ≥20% as measured by RECIST v1.1 within 12 months prior to treatment initiation.2

Female:male ratio
approximately 2:1 ¹
patients hadextra-abdominal tumors ¹ 3 in 4
Patients with treatment histories ¹ different

4 in 10 had multifocal tumors1

Baseline demographics and disease-related characteristics1,2
OGSIVEO (n=70)Placebo (n=72)
Age, median (min, max)33.5 years (18, 73)34.5 years (18, 76)
Sex, n (%)
Male25 (36%)25 (35%)
Female45 (64%)47 (65%)
Females of reproductive potential*37 (53%)37 (51%)
Race, n (%)
White64 (91%)54 (75%)
Black or African American4 (6%)5 (7%)
Asian 1 (1%)3 (4%)
Other1 (1%)10 (14%)
Family history of FAP, n (%)11 (16%)13 (18%)
Somatic mutations, n (%)52 (74%)53 (74%)
APC11 (16%)11 (15%)
CTNNB143 (61%)42 (58%)
No identified mutation01 (1%)
Not analyzed18 (26%)18 (25%)
Target tumor location, n (%)
Intra-abdominal17 (24%)18 (25%)
Extra-abdominal53 (76%)54 (75%)
Multifocal disease, n (%)27 (39%)31 (43%)
Desmoid tumor treatment status, n (%)
Treatment-naïve18 (26%)14 (19%)
Refractory/recurrent following prior treatment52 (74%)58 (81%)
Prior therapies, n (%)
Surgery31 (44%)44 (61%)
Radiation16 (23%)16 (22%)
Systemic therapy43 (61%)44 (61%)
Chemotherapy24 (34%)27 (38%)
Tyrosine kinase inhibitor23 (33%)24 (33%)

In the DeFi study, 50% of patients had a BPI-SF item 3 (worst pain) score of ≥2.1

Defined in the trial protocol as females between menarche and confirmed menopause (ie, 12 months since last menstruation) with intact ovarian function. Based on the investigator’s judgment.2

APC, adenomatous polyposis coli; BPI-SF, Brief Pain Inventory-Short Form; CTNNB1, catenin beta 1; DeFi, Desmoid Fibromatosis; FAP, familial adenomatous polyposis; RECIST, Response Evaluation Criteria in Solid Tumors.

OGSIVEO demonstrated powerful efficacy in the DeFi study1

OGSIVEO significantly improved progression-free survival1

Primary End Point:Patients receiving OGSIVEO achieved a 71% reduction in the risk of disease progression or death vs placebo (HR=0.29; 95% CI: 0.15, 0.55; P<0.001*)1

  • Median PFS in the OGSIVEO arm was not reached (95% CI: NR, NR) compared with 15.1 months (95% CI: 8.4, NR) in the placebo arm1,†,‡,§
    • PFS events occurred in 12 patients (17%) in the OGSIVEO arm and 37 patients (51%) in the placebo arm1
  • The Kaplan-Meier estimated median PFS for OGSIVEO could not be estimated due to the low number of events2

P-value was from a one-sided stratified log-rank test with placebo as reference.1

Progression-free survival was defined as the time from randomization until the date of imaging-based or clinical progression or death. Progression-free survival was 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 (eg, radiotherapy, surgery, or systemic therapy including chemotherapy or tyrosine kinase inhibitors) for desmoid tumors.1,2

Data cut-off as of April 7, 2022 for PFS.2

Obtained using Kaplan-Meier methodology.1

CI, confidence interval; HR, hazard ratio; NR, not reached; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.

OGSIVEO demonstrated a statistically significant response vs placebo1

Key Secondary Efficacy End Point:OGSIVEO treatment resulted in a 41% objective response rate with a 7% complete response rate1

Median time to objective response was 5.6 months with OGSIVEO (range: 2.6 to 19.4 months) vs 11.1 months with placebo (range: 2.8 to 16.4 months).2,#

Analysis Limitations

  • Time to objective response was an exploratory end point in the DeFi study
  • This end point was not powered for statistical analysis and should be considered descriptive only
  • Therefore, the results require cautious interpretation and could represent chance findings
  • These data are not included in the OGSIVEO Prescribing Information

Objective response rate was defined as CR or PR according to RECIST v1.1. Assessed by blinded independent central review.1,2

Partial response was defined as a ≥30% decrease in the sum of the longest diameters of target tumors.2

Complete response was defined as disappearance of all target and non-target tumors.2

Desmoid tumors can have an unpredictable course and may exhibit spontaneous regression.3

Obtained using exact method based on binomial distribution.1

P-value was from a two-sided Cochran-Mantel-Haenszel test.1

Median time to objective response was calculated as time in months from first dose until date of the first documented response (CR or PR).2

CI, confidence interval; CR, complete response; DeFi, Desmoid Fibromatosis; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors.

OGSIVEO provided consistent PFS and ORR results regardless of baseline characteristics2,4

PFS and ORR improvements favored OGSIVEO across subgroups defined according to:2,4

Sex
Family history of FAP
Genetic mutation status
Tumor location
Focality (single or multifocal)
Type of previous treatments
Desmoid tumor treatment status

Analysis Limitations

  • These results are from prespecified subgroup analyses of PFS and ORR
  • DeFi was not powered to assess statistical differences between subgroups and these analyses should be considered descriptive only
  • Therefore, the results require cautious interpretation and could represent chance findings
  • These data are not included in the OGSIVEO Prescribing Information

OGSIVEO reduced patient-reported pain1

PFS results were supported by change from baseline in patient-reported worst pain favoring the OGSIVEO arm1,*

Patient-reported worst pain intensity was assessed daily using item 3 of the 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.1,2

BPI-SF, Brief Pain Inventory-Short Form; DeFi, Desmoid Fibromatosis; FAP, familial adenomatous polyposis; ORR, objective response rate; PFS, progression-free survival.

OGSIVEO safety profile1

Warnings and Precautions1

Diarrhea
Diarrhea, sometimes severe, can occur in patients treated with OGSIVEO. 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.

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. Monitor patients for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency, including hot flashes, night sweats, and vaginal dryness.

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. Monitor liver function tests regularly and modify dose as recommended.

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. Perform dermatologic evaluations prior to initiation of OGSIVEO and routinely during treatment.

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. Monitor phosphate and potassium levels regularly and supplement as necessary. Modify dose as recommended.

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.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; DeFi, Desmoid Fibromatosis; ULN, upper limit of normal.

Most adverse events were Grade 1 or 2 and occurred within 1 month of starting OGSIVEO2

  • 95% of adverse events were Grade 1 or 2 in the OGSIVEO arm of the DeFi trial2
  • The first onset of adverse events in most patients treated with OGSIVEO occurred during Cycle 1 (within 28 days)2
  • Serious adverse reactions occurred in 20% of patients who received OGSIVEO. Serious adverse reactions occurring in ≥2% of patients were ovarian toxicity (4%)1
  • The most common adverse reactions (≥15% with a difference between arms of ≥5% compared to placebo) that occurred in patients receiving OGSIVEO were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, and dyspnea1

Adverse reactions (≥15%) in patients with desmoid tumor who received OGSIVEO with a difference between arms of ≥5% compared to placebo in DeFi1

 
OGSIVEO (n=69)
Placebo (n=72)
Adverse Reaction
All Grades
Grade 3
All Grades
Grade 3
Gastrointestinal
Diarrhea
84%
16%
35%
1.4%
Nausea
54%
1.4%
39%
0
Stomatitis*
39%
4%
4%
0
Abdominal pain*
22%
1.4%
14%
1.4%
Reproductive system
Ovarian toxicity*,†
75%‡
0
0
0
Skin and subcutaneous tissue
Rash*
68%
6%
14%
0
Alopecia
19%
0
1.4%
0
General
Fatigue*
54%
2.9%
38%
0
Nervous system
Headache*
30%
0
15%
0
Respiratory
Cough*
20%
0
6%
0
Dyspnea
16%
0
6%
0
Infections
Upper respiratory tract infection*
17%
0
2.8%
0
  • In the DeFi trial, the median duration of exposure for OGSIVEO was 20.6 months (range: 0.3 to 33.6 months)1
  • 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 illness1

Includes multiple related composite terms.1

Investigator assessment of ovarian toxicity included ovarian failure, premature menopause, amenorrhea, and menopause.1

The number of females of reproductive potential in each arm is used as the denominator (OGSIVEO N=36, placebo N=37).1

DeFi, Desmoid Fibromatosis.

Additional safety and tolerability data from the DeFi trial

Laboratory abnormalities (≥15%) that worsened from baseline in patients with desmoid tumor who received OGSIVEO in DeFi1

 
OGSIVEO (n=69)
Placebo (n=72)
Laboratory Abnormality
All Grades
Grade 3 or 4
All Grades
Grade 3 or 4
Decreased phosphate*,†
65%
Not Applicable
11%
Not Applicable
Increased urine glucose‡,§
51%
Not Applicable
0
Not Applicable
Increased urine protein‡
40%
0
25%
0
Increased aspartate aminotransferase*
33%
2.9%
18%
1.4%
Increased alanine aminotransferase*
30%
6%
21%
1.4%
Decreased potassium*
22%
1.4%
4.2%
0

Discontinuation, dosage interruptions, and dose reductions in DeFi1

  • 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 denominator used to calculate the rate was 69 for OGSIVEO and 72 for placebo based on the number of patients with a baseline value and at least one post-treatment value.1

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).1

The denominator used to calculate the rate was 68 for OGSIVEO and 69 for placebo based on the number of patients with a baseline value and at least one post-treatment value.1

CTCAE Version 5.0 does not include numeric thresholds for grading of increased urine glucose.1

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; DeFi, Desmoid Fibromatosis.

Ogsiveo tablet container

OGSIVEO offers convenient oral dosing1

  • 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
Dosage Modifications

Recommended dose modifications for adverse reactions1,*

Adverse Reaction
Severity
OGSIVEO Dosage Modifications
Diarrhea persisting for ≥3 days despite maximal medical therapy
Grades 3 or 4
Withhold OGSIVEO until resolved to Grade ≤1 or baseline, then restart at a dose of 100 mg twice daily.
ALT or AST increased
Grade 2
(≥3 to 5 x ULN)
Withhold OGSIVEO until ALT, AST, or both are resolved to <3 × ULN or baseline, then restart at a dose of 100 mg twice daily.
Grades 3 or 4 (>5 x ULN)
Permanently discontinue.
Hypophosphatemia persisting for ≥3 days despite maximal replacement therapy
Grades 3 or 4
Withhold OGSIVEO until resolved to Grade ≤1 or baseline, then restart at a dose of 100 mg twice daily.
Hypokalemia despite maximal replacement therapy
Grades 3 or 4
Withhold OGSIVEO until resolved to Grade ≤1 or baseline, then restart at a dose of 100 mg twice daily.

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.1

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

Drug Interactions

Effects of other drugs on OGSIVEO1

  • Strong or moderate CYP3A inhibitors: OGSIVEO is a CYP3A substrate. Strong or moderate CYP3A inhibitors increase OGSIVEO exposure, which may increase the risk of OGSIVEO adverse reactions. Avoid concomitant use of OGSIVEO with strong or moderate CYP3A inhibitors, including grapefruit products, Seville oranges, and starfruit
  • Strong or moderate CYP3A inducers: OGSIVEO is a CYP3A substrate. Strong or moderate CYP3A inducers decrease serum OGSIVEO exposure, which may reduce the effectiveness of OGSIVEO. Avoid concomitant use of OGSIVEO with strong or moderate CYP3A inducers
  • Gastric acid reducing agents: OGSIVEO is poorly soluble at pH ≥6. Gastric acid reducing agents may decrease serum OGSIVEO exposure, which may reduce the effectiveness of OGSIVEO. Avoid concomitant use with proton pump inhibitors and H2 blockers. If concomitant use cannot be avoided, OGSIVEO can be staggered with antacids (eg, administer OGSIVEO 2 hours before or 2 hours after antacid use)
  • For additional information about potential drug interactions with OGSIVEO, see Table 4 (Section 7.1) and Table 5 (Section 7.2) of the full Prescribing Information

Important Safety Information

Indication 

OGSIVEO is indicated for adult patients with progressing desmoid tumors who require systemic treatment.

Important Safety Information

Warnings and Precautions

Diarrhea: Diarrhea, sometimes severe, can occur in patients treated with OGSIVEO. Diarrhea occurred in 84% of patients treated with OGSIVEO, and included Grade 3 events in 16% of patients. Median time to first diarrhea event was 9 days (range: 2 to 434 days). Monitor patients and manage using antidiarrheal medications. Modify dose as recommended.

Ovarian Toxicity: Female reproductive function and fertility may be impaired in patients treated with OGSIVEO. Impact on fertility may depend on factors like duration of therapy and state of gonadal function at time of treatment. Long-term effects of OGSIVEO on fertility have not been established. Advise patients on the potential risks for ovarian toxicity before initiating treatment. Monitor patients for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency, including hot flashes, night sweats, and vaginal dryness.

Hepatotoxicity: ALT or AST elevations occurred in 30% and 33% of patients, respectively. Grade 3 ALT or AST elevations (>5 x ULN) occurred in 6% and 2.9% of patients. Monitor liver function tests regularly and modify dose as recommended.

Non-Melanoma Skin Cancers: New cutaneous squamous cell carcinoma and basal cell carcinoma occurred in 2.9% and 1.4% of patients, respectively. Perform dermatologic evaluations prior to initiation of OGSIVEO and routinely during treatment.

Electrolyte Abnormalities: Decreased phosphate (65%) and potassium (22%) occurred in OGSIVEO-treated patients. Phosphate <2 mg/dL occurred in 20% of patients. Grade 3 decreased potassium occurred in 1.4% of patients. Monitor phosphate and potassium levels regularly and supplement as necessary. Modify dose as recommended.

Embryo-Fetal Toxicity: 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 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.

Adverse Reactions

The most common (≥15%) adverse reactions were diarrhea (84%), ovarian toxicity (75% in the 36 females of reproductive potential), rash (68%), nausea (54%), fatigue (54%), stomatitis (39%), headache (30%), abdominal pain (22%), cough (20%), alopecia (19%), upper respiratory tract infection (17%), and dyspnea (16%).

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

The most common laboratory abnormalities (≥15%) were decreased phosphate, increased urine glucose, increased urine protein, increased AST, increased ALT, and decreased potassium.

Drug Interactions

CYP3A Inhibitors and Inducers: Avoid concomitant use with strong or moderate CYP3A inhibitors (including grapefruit products, Seville oranges, and starfruit) and strong or moderate CYP3A inducers.

Gastric Acid Reducing Agents: Avoid concomitant use with proton pump inhibitors and H2 blockers. If concomitant use cannot be avoided, OGSIVEO can be staggered with antacids (e.g., administer OGSIVEO 2 hours before or 2 hours after antacid use).

Consult the full Prescribing Information prior to and during treatment for important drug interactions.

Use in Specific Populations

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.

Please click here for full Prescribing Information.

Important Safety Information

ALT, alanine aminotransferase; APC, adenomatous polyposis coli; AST, aspartate aminotransferase; BID, twice daily; BPI-SF, Brief Pain Inventory-Short Form; CI, confidence interval; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; CTNNB1, catenin beta 1; DeFi, Desmoid Fibromatosis; FAP, familial adenomatous polyposis; FDA, US Food and Drug Administration; HCP, healthcare professional; HR, hazard ratio; NR, not reached; ORR, objective response rate; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; ULN, upper limit of normal.

References
  1. OGSIVEO. Prescribing Information. SpringWorks Therapeutics, Inc.
  2. Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a gamma-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388(10):898-912.
  3. Penel N, Chibon F, Salas S. Adult desmoid tumors: biology, management and ongoing trials. Curr Opin Oncol. 2017;29(4):268-274.
  4. Data on file. SpringWorks Therapeutics, Inc.