Zopapogene Imadenovec

1 INDICATIONS AND USAGE PAPZIMEOS is indicated for the treatment of adults with recurrent respiratory papillomatosis. PAPZIMEOS™ is a non-replicating adenoviral vector-based immunotherapy indicated for the treatment of adults with recurrent respiratory papillomatosis. ( 1 )

2 DOSAGE AND ADMINISTRATION PAPZIMEOS is for subcutaneous injection only. ( 2.1 ) The recommended dose of PAPZIMEOS is 5×10 11 particle units (PU) per injection administered by subcutaneous injection four ( 4 ) times over a 12-week interval. ( 2.1 ) Prior to the initial administration of PAPZIMEOS, perform a surgical debulking of visible papilloma to establish minimal residual disease. To maintain minimal residual disease during treatment with PAPZIMEOS, remove visible papilloma, if present, prior to the third and fourth administration of PAPZIMEOS. ( 2.1 ) 2.1 Recommended Dosage PAPZIMEOS is for subcutaneous injection only. The recommended dosage of PAPZIMEOS is 5×10 11 particle units (PU) per injection administered as subcutaneous injection four times over a 12-week interval. The recommended dosing schedule for PAPZIMEOS is shown in Table 1 . Table 1: Recommended Treatment Schedule for PAPZIMEOS Administration Administration Interval 1 The second administration should occur no less than 11 days after the initial administration. Initial -- Second 2 weeks after initial administration 1 Third 6 weeks after initial administration Fourth 12 weeks after initial administration Prior to the initial administration of PAPZIMEOS, perform a surgical debulking of visible papilloma to establish minimal residual disease. To maintain minimal residual disease during treatment with PAPZIMEOS, remove visible papilloma, if present, prior to the third and fourth administration of PAPZIMEOS. 2.2 Preparation and Handling PAPZIMEOS is a non-replicating adenoviral vector-based immunotherapy. Follow universal biosafety precautions for handling. PAPZIMEOS is provided as a single-dose vial of sterile frozen suspension. PAPZIMEOS MUST BE RAPIDLY thawed before use and prepared for immediate administration . Once thawed, DO NOT place the PAPZIMEOS vial in a refrigerator, freezer, or on dry ice. Protect PAPZIMEOS from light. DO NOT shake the vial. Recommended Supplies and Materials Freezer for storage of PAPZIMEOS at temperature ≤ -60°C [≤ -76°F] Water bath or dry bead bath set to 37°C [98.6°F] 3 mL sterile syringe Sterile needle (18G to 22G without a filter) to withdraw PAPZIMEOS from the vial Sterile needle for subcutaneous injection (23G to 25G needle, 1/2 - 5/8 inch long) 70% isopropyl alcohol pads Receipt of PAPZIMEOS PAPZIMEOS is provided as a sterile, frozen suspension that has been aseptically filled into single-dose vials fitted with a rubber stopper and aluminum flip-cap seal. Each vial is sealed inside a pouch, which is placed in the carton along with a Package Insert. The PAPZIMEOS carton is shipped frozen at ≤ -60°C [≤ -76°F] in an insulated shipping box containing dry ice. On receipt, the PAPZIMEOS carton must be stored in a freezer at ≤ -60°C [≤ -76°F]. Preparation of PAPZIMEOS for Injection Remove the carton of PAPZIMEOS from the freezer when ready for administration. Take the vial out of the pouch and immediately thaw in a 37°C [98.6°F] water bath or dry bead bath with the vial in an upright position until there are no visible ice crystals in the vial. Exposure of the thawed vial to the 37°C [98.6°F] water bath or dry bead bath should be less than or equal to 5 minutes. Immediately after thawing, wipe the vial with 70% isopropyl alcohol. Flip off the cap and wipe the rubber stopper top. Swirl gently and visually inspect the vial of PAPZIMEOS. PAPZIMEOS should appear as a slightly opalescent to opalescent, colorless liquid, and free of visible particulates. DO NOT use if particulates or discoloration are visible in the suspension. Aseptically withdraw 1 mL of PAPZIMEOS from the thawed vial using a 3 mL syringe with an 18G to 22G needle. DO NOT use a filter needle. Replace the 18G to 22G needle with a subcutaneous injection needle (23G to 25G). Dispose of the used needle and empty vial in a biohazard container. DO NOT hold PAPZIMEOS at room temperature for more than 60 minutes after thawing. DO NOT store thawed PAPZIMEOS vials or filled syringes in a refrigerator, freezer, or on dry ice. Treat any PAPZIMEOS spills with a virucidal agent (such as sodium hypochlorite with 0.5% active chlorine or 6% hydrogen peroxide) for 15 minutes. Dispose of any unused product or waste materials as per facility biohazard waste disposal procedure. 2.3 Administration Administer PAPZIMEOS via subcutaneous injection with the following procedures: Select the lateral regions of the upper arm and thigh for injection. Avoid areas of edema, potential infection, wounds, scars, or the site of a recent subcutaneous injection. Clean the injection site thoroughly with an alcohol swab and allow at least 30 seconds to dry. Inject PAPZIMEOS by inserting the needle at an angle to ensure delivery in the subcutaneous space. Clean the area with an alcohol swab again, DO NOT massage the site of injection. Place potentially contaminated materials from the injection site, including dressings, that may have the patient's bodily fluids/waste, in a sealable bag and dispose into regular trash. These precautions should be followed for 1-2 weeks after injection. Practice proper hand hygiene, such as hand washing, when coming into direct contact with patient body waste. Avoid direct contact with the injection site (e.g., touching or scratching) and dressings for approximately 24 hours following treatment.

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥5%) were injection site reactions, fatigue, chills, pyrexia, myalgia, nausea, headache, tachycardia, diarrhea, vomiting, and hyperhidrosis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Precigen Inc. at 855-743-6777 and [email protected] 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 data described in this section reflects exposure to PAPZIMEOS in one clinical study (Study PRGN-2012-201). A total of 38 adults with recurrent respiratory papillomatosis received a PAPZIMEOS dose of either 1×10 11 PU (n=3), or 5×10 11 PU (n=35) per injection on Days 1, 15, 43, and 85 [see Clinical Studies ( 14 )] . The most common adverse reactions (incidence ≥5%) are summarized in Table 2 . Table 2: Adverse Reactions occurring in ≥5% of Patients in Study PRGN-2012-201 (N=38) *Graded per NCI CTCAE v5.0. There were no Grade >2 adverse reactions. Preferred Term Grade 1-2* n (%) Injection site reaction 37 (97) Fatigue 28 (74) Chills 25 (66) Pyrexia 24 (63) Myalgia 11 (29) Nausea 10 (26) Headache 4 (11) Tachycardia 3 (8) Diarrhea 2 (5) Vomiting 2 (5) Hyperhidrosis 2 (5) Other clinically significant adverse reactions occurring in <5% of patients included vision blurred (3%), injection site bruising (3%), dizziness (3%), dyspnea (3%), and pruritus (3%).

12.3 Pharmacokinetics No biodistribution and vector shedding studies have been conducted with PAPZIMEOS.