Vepdegestrant

VEPPANU is indicated for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 (ESR1) -mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy. VEPPANU is a heterobifunctional protein degrader indicated for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 ( ESR1) -mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy. ( 1 )

Tablets: 100 mg blue film-coated, immediate release, round tablet debossed with "VEP" on one side and "100" on the other side. 200 mg blue film-coated, immediate release, oval tablet debossed with "VEP" on one side and "200" on the other side. Tablets: 100 mg and 200 mg ( 3 )

None. None. ( 4 )

QTc Interval Prolongation : Monitor electrocardiograms (ECGs) and electrolytes prior to initiation of treatment with VEPPANU. Correct hypokalemia and hypomagnesemia prior to and during treatment. Repeat ECGs as clinically indicated. Withhold, reduce dose, or permanently discontinue VEPPANU based on severity. ( 5.1 ) Embryo-Fetal Toxicity : VEPPANU can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.2 , 8.1 , 8.3 ) 5.1 QTc Interval Prolongation VEPPANU can cause QT (QTc) interval prolongation [see Clinical Pharmacology ( 12.2 )] . In VERITAC-2, QTc interval prolongation was reported in 10% of patients; Grade 3 occurred in 1.6% of patients. The heart-rate corrected QTc interval using Fridericia's method was greater than 500 msec in 1.6% of patients, and the increase from baseline QTc was greater than 60 msec in 2.6% of patients. VEPPANU dose reduction was required for 0.3% of patients due to QTc interval prolongation [see Adverse Reactions ( 6.1 )] . Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to and during treatment with VEPPANU. Perform an ECG prior to initiation of treatment with VEPPANU, and do not initiate VEPPANU in patients with QTc > 470 msec. Repeat ECG approximately 4 weeks after initiating treatment and as clinically indicated. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, additional ECG monitoring may be necessary. Avoid concomitant use of VEPPANU with strong CYP3A inhibitors or drugs known to prolong the QTc interval. Reduce VEPPANU dose when concomitant use with strong CYP3A inhibitors cannot be avoided [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7.1 , 7.3 ), and Clinical Pharmacology ( 12.2 )] . If concomitant use with other QTc-prolonging agents cannot be avoided, increase the frequency of ECG monitoring. Withhold, reduce dose, or permanently discontinue based on severity [see Dosage and Administration ( 2.3 )] .

5.2 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, VEPPANU can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of vepdegestrant to pregnant rats during the period of organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at maternal exposures below the recommended dose based on area under the curve (AUC). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )] .

The following clinically significant adverse reaction is described elsewhere in the labeling: QTc Interval Prolongation [see Warnings and Precautions ( 5.1 )] Most common ( > 10%) adverse reactions with VEPPANU, including laboratory abnormalities, were decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. at 1-800-983-1329 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 VEPPANU was evaluated in patients with ER-positive, HER2-negative, advanced or metastatic breast cancer following endocrine therapy in VERITAC-2 [see Clinical Studies ( 14 )] . Patients received VEPPANU 200 mg orally once daily (N=312) or fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each subsequent 28-day cycle (N=307). Among patients who received VEPPANU, 33% were exposed for 6 months or longer and 6% were exposed for greater than one year. Serious adverse reactions occurred in 9% of patients who received VEPPANU. The serious adverse reactions included any fracture (1.3%), fall, hypercalcemia, hepatic injury, pneumonia, musculoskeletal pain (0.6% each), and QTc prolonged (0.3%). Fatal adverse reactions occurred in 1.0% of patients who received VEPPANU, including dyspnea, cerebral ischemia, and unknown cause (one patient each). Permanent discontinuation of VEPPANU due to an adverse reaction occurred in 2.9% of patients. Adverse reactions that resulted in permanent discontinuation of VEPPANU included increased alanine aminotransferase (ALT) and dyspnea (0.6% each). Dosage interruptions of VEPPANU due to an adverse reaction occurred in 14% of patients. Adverse reactions which required dosage interruption in >1% of patients included neutropenia (1.9%), anemia, hepatic injury, nausea, fatigue, and musculoskeletal pain (1.3% each). Dosage reductions of VEPPANU due to an adverse reaction occurred in 1.9% of patients. Adverse reactions which required dosage reductions of VEPPANU included electrocardiogram QT prolonged, fatigue and musculoskeletal pain (0.3% each). The most common (≥10%) adverse reactions, including laboratory abnormalities, were decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation. Table 3 and Table 4 summarize adverse reactions and laboratory abnormalities in VERITAC-2, respectively. Table 3: Adverse Reactions (≥10%) in Patients with ER+, HER2-, Advanced or Metastatic Breast Cancer Who Received VEPPANU in VERITAC-2 Adverse reactions were graded using NCI CTCAE version 5.0. Adverse Reaction VEPPANU N=312 Fulvestrant N=307 All Grades % Grade 3 No Grade 4 events were reported. % All Grades % Grade 3 % Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Includes multiple related terms. 30 2.6 23 1 General Disorders and Administration Site Conditions Fatigue 29 1 16

1.3 Gastrointestinal Disorders Nausea 14 0 9 1 Constipation 10 0 3.3 0 Metabolism and Nutrition Disorders Decreased appetite 11 0.3 5 0 Investigations Electrocardiogram QT prolonged 10 1.6 1.3

0.3 Clinically relevant adverse reactions in <10% of patients who received VEPPANU included headache, hot flush, diarrhea, vomiting, bradycardia, and urinary tract infection. Table 4: Select Laboratory Abnormalities (≥10%) that Worsened from Baseline in Patients with ER+, HER2-, Advanced or Metastatic Breast Cancer Who Received VEPPANU in VERITAC-2 Laboratory Abnormality VEPPANU The denominator used to calculate the rate varied between 308 and 310 based on the number of patients with a baseline value and at least one post-treatment value. Fulvestrant The denominator used to calculate the rate varied between 302 and 303 based on the number of patients with a baseline value and at least one post-treatment value. All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Hematology White blood cells decreased 33 0.3 15

0.7 Hemoglobin decreased 24 2.3 20

3.6 Neutrophils decreased 23 2.3 13

0.7 Platelets decreased 10 1.3 11

1.3 Chemistry Aspartate aminotransferase increased 31 1.6 23

1.7 Alanine aminotransferase increased 22 0.6 23

1.0 Alkaline phosphatase increased 21 0 23

0.3 Blood potassium decreased 14 2.6 6

0.3 Bilirubin increased 14 1.0 8 1.3

Strong CYP3A Inhibitors : Avoid concomitant use with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce VEPPANU dosage. ( 2.4 , 7.1 ) Strong CYP3A Inducers : Avoid concomitant use with strong CYP3A inducers. If concomitant use cannot be avoided, increase VEPPANU dosage. ( 2.4 , 7.1 ) Certain P-gp Substrates : Avoid concomitant use with certain P-gp substrates where minimal increases in concentration may lead to serious adverse reactions. ( 7.2 ) Certain UGT1A9 Substrates : Refer to the Prescribing Information for UGT1A9 substrates where minimal increases in concentration may lead to serious adverse reactions. ( 7.2 )

7.1 Effect of Other Drugs on VEPPANU Table 5 describes drug interactions where concomitant use of another drug affects VEPPANU. Table 5: Drug Interactions that Affect VEPPANU Strong CYP3A Inhibitors Prevention or Management Strong CYP3A Inhibitors: Avoid concomitant use of VEPPANU with strong CYP3A inhibitors in patients receiving VEPPANU 200 mg once daily. If concomitant use cannot be avoided, reduce VEPPANU dosage [see Dosage and Administration ( 2.4 )] . Avoid concomitant use with strong CYP3A inhibitors in patients receiving VEPPANU 100 mg once daily. Mechanism and Clinical Effect(s) Vepdegestrant is a CYP3A substrate. Concomitant use with a strong CYP3A inhibitor may increase vepdegestrant plasma concentration [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of VEPPANU-associated adverse reactions. Strong CYP3A Inducers Prevention or Management Avoid concomitant use with strong CYP3A inducers in patients receiving VEPPANU 200 mg once daily. If concomitant use cannot be avoided, increase VEPPANU dosage [see Dosage and Administration ( 2.4 )] . Avoid concomitant use with strong CYP3A inducers in patients receiving VEPPANU 100 mg once daily. Mechanism and Clinical Effect(s) Vepdegestrant is a CYP3A substrate. Concomitant use with a strong CYP3A inducer may decrease vepdegestrant plasma concentration [see Clinical Pharmacology ( 12.3 )] , which may reduce the effectiveness of VEPPANU.

7.2 Effect of VEPPANU on Other Drugs Table 6 describes drug interactions where concomitant use of VEPPANU affects another drug. Table 6: VEPPANU Drug Interactions that Affect Other Drugs Certain P-gp Substrates Prevention or Management Avoid concomitant use with certain P-gp substrates where minimal increases in concentration may lead to serious adverse reactions. Mechanism and Clinical Effect(s) Vepdegestrant is a P-gp inhibitor. Vepdegestrant increases exposure of P-gp substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Certain UGT1A9 Substrates Prevention or Management Refer to the Prescribing Information for UGT1A9 substrates where minimal increases in the concentration may lead to serious adverse reactions. Mechanism and Clinical Effect(s) Vepdegestrant is a UGT1A9 inhibitor. Vepdegestrant increases exposure of UGT1A9 substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates.

7.3 Drugs that Prolong QTc Interval Avoid concomitant use of VEPPANU with other drugs with a known potential to prolong the QTc interval. If concomitant use cannot be avoided: Obtain ECGs when initiating and during concomitant use, and as clinically indicated [see Warnings and Precautions ( 5.1 )] . Withhold VEPPANU if the QTc interval is >480 ms or the change from baseline is >60 ms [see Dosage and Administration ( 2.3 )] . Vepdegestrant causes QTc interval prolongation [see Clinical Pharmacology ( 12.2 )] . Concomitant use of VEPPANU with other drugs that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de Pointes, other serious arrhythmias, and sudden death [see Warnings and Precautions ( 5.1 )] .

Lactation : Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, VEPPANU can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 ) ]. There are no available human data on the use of VEPPANU in pregnant women to inform the drug-associated risk. In an animal reproduction study, oral administration of vepdegestrant to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities at maternal exposures below the recommended dose based on AUC ( see Data ). Advise pregnant women and females of reproductive potential 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 In an embryo-fetal development study in pregnant rats, administration of oral doses of vepdegestrant up to 300 mg/kg/day during the period of organogenesis resulted in embryo-fetal mortality (increased resorptions, post-implantation loss and reduced number of live fetuses) at ≥30 mg/kg/day (approximately 0.3 times the human AUC at the recommended dose). Additional adverse effects at ≥30 mg/kg/day included reduced fetal weight and skeletal abnormalities including delays in skeletal ossification (reduced number of ossification sites, incompletely ossified cervical arches or thoracic centra), skeletal malformations (fusion of sacral centra, hemivertebrae of the sacrum), and/or increased incidence of fetal variations (short cervical ribs, misaligned caudal vertebrae, misshapen cervical arches, and misaligned sacral vertebrae).

8.2 Lactation Risk Summary There are no data on the presence of vepdegestrant or its metabolites in human milk, or its effects on milk production or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women not to breastfeed during treatment with VEPPANU and for 2 weeks after the last dose.

8.3 Females and Males of Reproductive Potential VEPPANU can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify the pregnancy status in females of reproductive potential prior to initiating VEPPANU treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose. Infertility Based on findings from animal studies, VEPPANU may impair fertility in females and males of reproductive potential. The effects of vepdegestrant on fertility were reversible in female animals [see Nonclinical Toxicology ( 13.1 )] .

8.4 Pediatric Use The safety and effectiveness of VEPPANU in pediatric patients have not been established.

8.5 Geriatric Use Of 313 patients who received VEPPANU in the VERITAC-2 study, 39% were 65 years of age or older and 13% were 75 years of age or older. No overall differences in safety or effectiveness of VEPPANU were observed between patients 65 years of age or older compared to younger patients. There is an insufficient number of patients 75 years of age or older to assess whether there are differences in safety or effectiveness.