WELIREG (Page 4 of 6)

12.2 Pharmacodynamics

Reductions in plasma levels of erythropoietin (EPO) were observed to be dose- and exposure-dependent at dosages up to 120 mg once daily. The maximum EPO suppression occurred following 2 weeks of consecutive dosing of WELIREG (mean percent decrease from baseline of approximately 60%). Mean EPO levels gradually returned to baseline values after 12 weeks of treatment.

The incidence of Grade 3 anemia increased with higher belzutifan exposure in patients with baseline hemoglobin levels <12 mg/dL [see Warnings and Precautions (5.1)].

Cardiac Electrophysiology

At the recommended dosage, WELIREG does not cause large mean increases (i.e., >20 msec) in the QT interval.

12.3 Pharmacokinetics

The mean steady-state (CV%) Cmax is 1.3 μg/mL (42%) and AUC0-24h is 16.7 μg•hr/mL (52%) in patients with VHL disease-associated RCC. Steady state is reached after approximately 3 days. Cmax and AUC increase proportionally over a dose range of 20 mg to 120 mg (0.17 to 1 times the approved recommended dose).

Absorption

The median Tmax occurs at 1 to 2 hours after administration.

Effect of Food

A high-fat, high-calorie meal (total calories approximately 1000 kcal, 56 g fat, 55 g carbohydrate, and 31 g protein) delayed time to reach peak belzutifan concentration by approximately 2 hours, had no clinically meaningful effect on Cmax , and had no effect on AUC.

Distribution

The mean (CV%) steady-state volume of distribution is 130 L (35%). Plasma protein binding of belzutifan is 45%. The blood-to-plasma concentration ratio of belzutifan is 0.88.

Elimination

The mean (CV%) clearance is 7.3 L/hr (51%) and the mean elimination half-life is 14 hrs.

Metabolism

Belzutifan is primarily metabolized by UGT2B17 and CYP2C19 and to a lesser extent by CYP3A4 [see Clinical Pharmacology (12.5)].

Specific Populations

Patients who are poor metabolizers of UGT2B17 and CYP2C19 had higher belzutifan AUC [see Clinical Pharmacology (12.5)].

There were no clinically significant differences in the pharmacokinetics of belzutifan based on age (19 to 84 years), sex, ethnicity (non-Hispanic, Hispanic), race (White, Black, Asian, Pacific Islander), body weight (42 to 166 kg), mild to moderate renal impairment (eGFR 30-89 mL/min/1.73 m2 estimated by MDRD), or mild hepatic impairment (total bilirubin ≤ ULN with AST > ULN or total bilirubin > ULN to 1.5 x ULN with any AST). The effect of severe renal impairment (eGFR 15-29 mL/min/1.73 m2) and moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and any AST) have not been studied.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effect of Belzutifan on CYP3A Substrates: Coadministration of WELIREG 120 mg once daily with midazolam (a sensitive CYP3A4 substrate) decreased the midazolam AUC by 40% and the Cmax by 34%. Midazolam AUC is predicted to decrease up to 70% in patients with higher belzutifan concentrations (e.g., dual poor metabolizers) [see Clinical Pharmacology (12.5)].

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Belzutifan does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Belzutifan does not induce CYP1A2 or CYP2B6.

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

Belzutifan inhibits MATE2K. Belzutifan does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or MATE1.

12.5 Pharmacogenomics

Patients who are UGT2B17, CYP2C19, or dual UGT2B17 and CYP2C19 poor metabolizers have 2-, 1.6-, or 3.2-fold higher belzutifan steady state AUC0-24h (respectively) compared to patients who are UGT2B17 normal (extensive) metabolizers and CYP2C19 non-poor (ultrarapid, rapid, normal, and intermediate) metabolizers [see Use in Specific Populations (8.7)].

UGT2B17 poor metabolizers who are homozygous for the UGT2B17*2 allele have no UGT2B17 enzyme activity. CYP2C19 poor metabolizers (such as *2/*2, *3/*3, *2/*3) have significantly reduced or absent CYP2C19 enzyme activity. Approximately 15% of White, 6% of Black or African American, and up to 77% of certain Asian populations are UGT2B17 poor metabolizers. Approximately 2% of White, 5% of Black or African American, and up to 19% of certain Asian populations are CYP2C19 poor metabolizers. Approximately 0.4% of White, 0.3% of Black or African American, and up to 15% of certain Asian populations are dual UGT2B17 and CYP2C19 poor metabolizers.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with belzutifan.

Belzutifan was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Belzutifan was not clastogenic in either an in vitro micronucleus assay or an in vivo rat bone marrow micronucleus assay.

Fertility studies in animals have not been conducted with belzutifan. In repeat-dose toxicity studies up to 3-month duration, belzutifan-related findings included degeneration/atrophy of testes and hypospermia and cellular debris of the epididymis in rats administered ≥2 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose of 120 mg daily). Findings in testes and epididymis were associated with decreased sperm count and motility and abnormal sperm morphology at ≥6 mg/kg/day (approximately 0.2 times the human exposure at the recommended dose of 120 mg daily) and did not reverse by the end of the recovery period. Belzutifan had no adverse effects on female reproductive organs in repeat-dose toxicity studies up to 3-month duration; however, belzutifan caused embryo-fetal lethality (post-implantation loss) in pregnant rats given oral doses ≥60 mg/kg/day (approximately 1 time the human exposure at the recommended dose based on AUC) during the period of organogenesis [see Use in Specific Population (8.1)].

14 CLINICAL STUDIES

The efficacy of WELIREG was evaluated in Study 004 (NCT03401788), an open-label clinical trial in 61 patients with VHL-associated RCC diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney as defined by response evaluation criteria in solid tumors (RECIST) v1.1. Enrolled patients had other VHL-associated tumors including CNS hemangioblastomas and pNET. CNS hemangioblastomas and pNET in these patients were diagnosed based on the presence of at least one measurable solid tumor in brain/spine or pancreas, respectively, as defined by RECIST v1.1 and identified by IRC. The study excluded patients with metastatic disease. Patients received WELIREG 120 mg once daily until progression of disease or unacceptable toxicity.

The study population characteristics were: median age 41 years [range 19-66 years], 3.3% age 65 or older; 53% male; 90% were White, 3.3% were Black or African-American, 1.6% were Asian, and 1.6% were Native Hawaiian or other Pacific Islander; 82% had an ECOG PS of 0, 16% had an ECOG PS of 1, and 1.6% had an ECOG PS of 2; and 84% had VHL Type I Disease. The median diameter of RCC target lesions per central independent review committee (IRC) was 2.2 cm (range 1-6.1). Median time from initial radiographic diagnosis of VHL-associated RCC tumors that led to enrollment on Study 004 to the time of treatment with WELIREG was 17.9 months (range 2.8-96.7). Seventy-seven percent of patients had prior surgical procedures for RCC.

The major efficacy endpoint for the treatment of VHL-associated RCC was overall response rate (ORR) measured by radiology assessment using RECIST v1.1 as assessed by IRC. Additional efficacy endpoints included duration of response (DoR), and time to response (TTR).

Table 4 summarizes the efficacy results for VHL-associated RCC in Study 004.

Table 4: Efficacy Results (IRC assessment) for WELIREG for VHL-Associated RCC
Efficacy Outcome Measure WELIREGn=61
+ Denotes ongoing response.
*
All patients with a response were followed for a minimum of 18 months from the start of treatment.
Overall Response Rate, % (n) (95% CI) 49% (30)*(36, 62)
Complete response 0%
Partial response 49%
Duration of Response
Median in months (range) Not reached (2.8+, 22+)
% (n) with DoR ≥ 12 months 56% (17/30)

For VHL-associated RCC, median TTR was 8 months (range 2.7, 19).

Table 5 summarizes the efficacy results for VHL-associated pNET or CNS hemangioblastomas in Study 004.

Table 5. Efficacy Results (IRC assessment) for WELIREG for VHL-Associated Subgroups with CNS Hemangioblastomas or pNET
Endpoint Patients with CNSHemangioblastomasn=24* Patients with pNETn=12*
+ Denotes ongoing response.
*
Number of patients with measurable solid lesions, based on IRC assessment.
Overall Response Rate, % (n) (95% CI) 63%, (15)(41, 81) 83% (10)(52, 98)
Complete response 4% (1) 17% (2)
Partial response 58% (14) 67% (8)
Duration of Response
Median in months (range) Not reached (3.7+, 22+) Not reached (11+, 19+)
% (n) with DoR ≥12 months 73% (11/15) 50% (5/10)

For VHL-associated CNS hemangioblastomas, TTR was 3.1 months (range 2.5, 11). For VHL-associated pNET, median TTR was 8.1 months (range 2.7, 11).

Decreases in size of CNS hemangioblastoma-associated peri-tumoral cysts and syringes were observed.

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