U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 11/23

Name-        ZYNYZ

Acive  Ingredient -  Retifanlimab- dlww

Pharmacological clssificiation-        To treat metastatic recurrent locally advanced                                                               Market cell carcinor                           

 Date of Approval-         22 March 2023

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                            ZYNYZ safely and effectively.

See full prescribing information for ZYNYZ. ZYNYZ™ (retifanlimab-dlwr) injection, for intravenous use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE ZYNYZ is a programmed death receptor-1 (PD-1)–blocking antibody indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma. (1)

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

(1, 14) DOSAGE AND ADMINISTRATION The recommended dosage of ZYNYZ is 500 mg as an intravenous infusion over 30 minutes every 4 weeks. (2.1) See full Prescribing Information for dosage modifications for adverse reactions (2.2) and preparation and administration instructions.

(2.3) DOSAGE FOR

(3) CONTRAINDICATIONS None.

(4) WARNINGS AND PRECAUTIONS_______________ • Immune-Mediated Adverse Reactions (5.1) o Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis,

immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, and immune-mediated dermatologic adverse reactions, and solid organ transplant rejection. o Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. o Withhold or permanently discontinue ZYNYZ and administer corticosteroids based on the severity of reaction. (2.2) • Infusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue ZYNYZ based on severity of reaction. (2.2, 5.2) • Complications of Allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1–blocking antibody. (5.3) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.4, 8.1, 8.3) ADVERSE REACTIONS The most common (= 10%) adverse reactions are fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Incyte Corporation at 1-855-463-3463 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2)

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions Advise patients that ZYNYZ can cause immune-mediated adverse reactions including the following [see Warnings and Precautions (5.1)]:

• Pneumonitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pneumonitis, including new or worsenin

• Colitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of colitis, including diarrhea, blood or mucus in stools, or severe abdominal pain.

• Hepatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatitis.

• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, or type 1 diabetes mellitus.

• Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.

• Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately if they develop a new rash.

• Other immune-mediated adverse reactions: - Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms [see Warnings and Precautions (5.1)].

Infusion-Related Reactions Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].

Complications of Allogeneic HSCT or Solid Organ Transplant Rejection Advise patients to contact their healthcare provider immediately if they develop signs or symptoms of post-allogeneic HSCT complications or of solid organ transplant rejection [see Warnings and Precautions (5.1, 5.3)].

Embryo-Fetal Toxicity Advise females of reproductive potential that ZYNYZ can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)].

Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of ZYNYZ [see Use in Specific Populations (8.3)].

Lactation Advise female patients not to breastfeed while taking ZYNYZ and for 4 months after the last dose [see Use in Specific Populations (8.2)].

Manufactured by: Incyte Corporation Wilmington, DE 19803 U.S. License No. 2228 ZYNYZ and the ZYNYZ logo are trademarks of Incyte. © 2023 Incyte Corporation. All rights reserved. 1

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Retifanlimab-dlwr binds to the PD-1 receptor, blocks interaction with its ligands PD-L1 and PD-L2, and potentiates T-cell activity. 12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for safety and effectiveness of retifanlimab-dlwr have not been fully characterized. 12.3 Pharmacokinetics The pharmacokinetics of retifanlimab-dlwr were evaluated in patients with various solid tumors, including patients with MCC. Retifanlimab-dlwr exposures (maximum concentration [Cmax] and area under the curve [AUC]) increased proportionally over a dosage range from 375 mg to 750 mg (0.75- to 1.5-fold of the approved recommended dose). Following administration of retifanlimab-dlwr at 500 mg every 4 weeks, steady-state concentrations were achieved at Cycle 6 (approximately 6 months) and systemic accumulation was 1.3-fold. Distribution The geometric mean volume of distribution at steady state for retifanlimab-dlwr is 6.0 L (coefficient of variation [CV]: 20%). Elimination The elimination half-life of retifanlimab-dlwr at steady state is 19 days (CV: 29%). Clearance of retifanlimab-dlwr after the first dose was 0.31 L/day (CV: 36%) and decreased over time by approximately 23%, resulting in a steady-state clearance of 0.24 L/day. Specific Populations The following factors have no clinically meaningful effect on the pharmacokinetics of retifanlimab-dlwr: age (18 to 94 years), sex, body weight (35 to 133 kg), race (White, Black, Asian), albumin level (21 to 54 g/L), Eastern Cooperative Oncology Group (ECOG) score (0 to 2), tumor burden (sum of the target lesion diameters: 10 to 360 mm), HIV status, renal function (estimated glomerular filtration rate = 26 mL/min/1.73 m2), or mild hepatic impairment (total bilirubin less than or equal to the ULN and AST greater than ULN or total bilirubin greater than ULN and less than or equal to 1.5 times ULN and any AST). The pharmacokinetics of retifanlimab-dlwr have not been studied in patients with moderate or severe hepatic impairment. 14 Reference ID: 5145703

12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of ZYNYZ or of other retifanlimab products. ADAs were tested in 104 patients with MCC who received ZYNYZ. The incidence of retifanlimab treatment-emergent ADAs was 2.9% (3/104) using a bridging enzyme-linked immunosorbent assay following a median exposure time of 169 days. Neutralizing antibodies were detected in 2 of 3 patients with treatment-emergent ADAs. The effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of retifanlimab products is unknown. 13 NONC

USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, ZYNYZ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of ZYNYZ in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death (see Data). Human IgG4 immunoglobulins (IgG4) are known to cross the placenta; therefore, retifanlimab-dlwr has the potential to be transmitted from the mother to the developing fetus. Advise 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 Animal reproduction studies have not been conducted with ZYNYZ to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering ZYNYZ during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to retifanlimab-dlwr may increase the risk of developing immune-mediated disorders or altering the normal immune response. 12 Reference ID: 5145703 8.2 Lactation Risk Summary There is no information regarding the presence of retifanlimab-dlwr in human milk, or its effects on the breastfed child or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to ZYNYZ are unknown. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose of ZYNYZ. 8.3 Females and Males of Reproductive Potential ZYNYZ can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating ZYNYZ [see Use in Specific Populations (8.1)]. Contraception Advise females of reproductive potential to use effective contraception during treatment with ZYNYZ and for 4 months after the last dose. 8.4 Pediatric Use The safety and effectiveness of ZYNYZ have not been established in pediatric patients. 8.5 Geriatric Use Of the 65 patients with metastatic or recurrent locally advanced MCC treated with ZYNYZ, 79% were 65 years or older, and 37% were 75 years or older. Clinical studies of ZYNYZ did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.

11 DESCRIPTION Retifanlimab-dlwr is a programmed death receptor-1 (PD-1)–blocking antibody. Retifanlimab-dlwr is a humanized IgG4 kappa monoclonal antibody produced in Chinese hamster ovary cells. Retifanlimab-dlwr has an approximate molecular weight of 148 kDa. ZYNYZ (retifanlimab-dlwr) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution for intravenous use. The solution is free from visible particles. Each single-dose vial contains 500 mg of retifanlimab-dlwr in 20 mL of solution. Each mL contains 25 mg of retifanlimab-dlwr, glacial acetic acid (0.18 mg), polysorbate 80 (0.1 mg), sodium acetate (0.57 mg), sucrose