Valoctocogene Roxaparvovec-Rvox

1 INDICATIONS AND USAGE ROCTAVIAN is an adeno-associated virus vector-based gene therapy indicated for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without antibodies to adeno-associated virus serotype 5 (AAV5) detected by an FDA-approved test. ROCTAVIAN is an adeno-associated virus vector-based gene therapy indicated for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test. ( 1 )

2 DOSAGE AND ADMINISTRATION For one-time single-dose intravenous use only. Treatment with ROCTAVIAN should be under the supervision of a physician experienced in the treatment of hemophilia and/or bleeding disorders. For one-time single-dose intravenous use only. ( 2 ) Perform baseline testing to select patients, including testing for pre-existing antibodies to adeno-associated virus serotype 5 (AAV5), factor VIII inhibitor presence, and liver health assessments. ( 2 ) The recommended dose of ROCTAVIAN is 6 × 10 13 vector genomes (vg) per kg of body weight. ( 2.1 ) Start the infusion at 1 mL/min. If tolerated, the rate may be increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min. ( 2.1 ) For Patient Selection Perform testing for pre-existing antibodies to AAV5 using the FDA approved companion diagnostic. DO NOT administer ROCTAVIAN to patients with a positive test for antibodies to AAV5. Information on FDA-approved tests for the detection of antibodies to AAV5 is available at: http://www.fda.gov/CompanionDiagnostics . Perform factor VIII inhibitor titer testing [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.6) ] . DO NOT administer ROCTAVIAN to a patient with a positive test for factor VIII inhibitor. Perform liver health assessments, which include: Liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total bilirubin and international normalized ration (INR)] Ultrasound and elastography or laboratory assessments for liver fibrosis In case of radiological liver abnormalities and/or liver function test abnormalities (ALT, AST, GGT, ALP or total bilirubin > 1.25 × ULN or INR ≥ 1.4), consider a consultation with a hepatologist to assess eligibility for ROCTAVIAN. Assess patient's ability to receive corticosteroids and/or other immunosuppressive therapy that may be required for an extended period [see Dosage and Administration (2.3) ] . Ensure that the risks associated with immunosuppression are acceptable for the individual patient. DO NOT administer ROCTAVIAN to patients with active acute or uncontrolled chronic infections, known significant hepatic fibrosis (stage 3 or 4 on the Batts-Ludwig scale or equivalent) or cirrhosis, or mannitol hypersensitivity [see Contraindications (4) and Use in Specific Populations (8.8) ] . 2.1 Dose The recommended dose of ROCTAVIAN is 6 × 10 13 vector genomes per kilogram (vg/kg) body weight, administered as a single intravenous infusion. ROCTAVIAN is administered using an infusion pump at a rate of 1 mL/min, which can be increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min. Calculating Dose in Milliliters (mL) and Number of Vials Required Patient dose volume in mL: Body weight in kg multiplied by 3 = dose in mL. The multiplication factor 3 represents the per kilogram dose (6 × 10 13 vg/kg) divided by the amount of vector genomes per mL of the ROCTAVIAN suspension (2 × 10 13 vg/mL). Number of ROCTAVIAN vials to be thawed: Patient dose volume (mL) divided by 8 = number of vials to be thawed (round up to next whole number of vials). The division factor 8 represents the minimum volume of ROCTAVIAN extractable from a vial (8 mL). Table 1: Example of Dose Volume and Number of Vials to be Thawed Patient Weight Patient Dose by Volume (mL) (body weight multiplied by 3) Number of Vials to be Thawed (dose volume divided by 8, then rounded up) 70 kg 210 mL 27 vials (rounded up from 26.25) ROCTAVIAN can be administered only once. 2.2 Preparation for Administration Required Equipment and Materials Flow rate-controlled syringe pump Syringes for ROCTAVIAN administration (the number of syringes will depend on the patient's dose volume and the syringe pump used and should be prepared prior to administration of ROCTAVIAN) 18- to 21-gauge sharp needles High-volume, in-line, low protein binding infusion filter with a pore size of 0.22 microns and maximum operating pressure adequate for the syringe pump or pump settings. Ensure availability of a sufficient number of replacement filters, according to the specifications for maximum filtered fluid volume. Syringe of 0.9% Sodium Chloride Injection, USP sodium chloride 9 mg/mL (0.9%) solution for priming and flushing the infusion line When assembling the infusion system, refer to the compatible materials with ROCTAVIAN suspension listed in Table 2. Table 2: Compatible Infusion System Component Materials Component Compatible Materials Syringes Polypropylene barrel with a synthetic rubber plunger tip Syringe cap Polypropylene Infusion tubing Tubing extensions should not exceed 40 inches in length. Polyethylene 0.22 micron in-line filter Polyvinylidene fluoride filter with polyvinyl chloride body Infusion catheter Polyurethane based polymer Stopcocks Polycarbonate 18 to 21-gauge sharp needles for extraction from vials Do not use filter needles to extract ROCTAVIAN from vials. Stainless steel General Precautions Do not expose ROCTAVIAN to the light of an ultraviolet radiation disinfection lamp. Prepare ROCTAVIAN using aseptic technique. Wear gloves and safety glasses during preparation and administration. Treat spills of ROCTAVIAN with a virucidal agent with proven activity against non-enveloped viruses and blot using absorbent materials. Dispose unused medicinal product and materials that may have come in contact with ROCTAVIAN in accordance with the local biosafety guidelines. Thaw and Inspect 1. Keep each vial in its carton until ready to thaw. ROCTAVIAN is sensitive to light. 2. Thaw ROCTAVIAN at room temperature. Do not thaw or warm vials any other way. Thawing time is approximately 2 hours. 3. Remove the required number of vials from their cartons. 4. Inspect the vials for damage to the vial or cap. Do not use if damaged. 5. Set the vials upright. To achieve optimal thawing, spread them out evenly or place them in racks that have been kept at room temperature. 6. Visually confirm that all vials have been thawed. There should be no visible ice. 7. Very gently invert each vial 5 times to mix. It is important to minimize foaming. 8. Let the suspension settle for approximately 5 minutes before continuing. 9. Visually inspect the fully thawed vials. Do not use a vial if the suspension is not clear, not colorless to pale yellow, or contains visible particles. ROCTAVIAN contains no preservative. For microbiological safety, keep the thawed suspension in the vials until it is time for infusion. If necessary, an intact vial (stopper not yet punctured) that has been thawed at room temperature can be stored refrigerated between 2 to 8°C (36 to 46°F) for up to 3 days, upright and protected from light (e.g., in the original carton). Thawed ROCTAVIAN (in vials or syringes) can be held at room temperature, up to 25°C (77°F), for a maximum of 10 hours including hold time in intact vial, preparation time into the syringes, and duration of infusion. Extraction into Syringes 10. Using 18 to 21-gauge sharp needles, slowly extract ROCTAVIAN from the vials into the infusion-pump syringes. All infusion-pump syringes should be prepared prior to administering ROCTAVIAN. The contents of multiple vials may be combined into a single syringe. Addition of In-line Filter and Priming of the Infusion System 11. Insert the in-line filter close to the infusion site. 12. Prime tubing and filter with ROCTAVIAN. 13. When replacing filters during the infusion, use 0.9% Sodium Chloride Injection, USP, for priming and flushing. Incompatibilities Do not use infusion system components other than those described in Table 2. ROCTAVIAN must not be mixed or diluted with infusion solutions; 0.9% Sodium Chloride Injection, USP is used to prime and flush the infusion line. 2.3 Administration Administer ROCTAVIAN in a setting where personnel and equipment are immediately available to treat infusion-related reactions [see Warnings and Precautions (5.1) ] . Infuse the suspension through a suitable peripheral vein, using an infusion catheter with in-line filter and a programmable syringe pump. Start the infusion at a rate of 1 mL/min. If tolerated, the rate may be increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min. The infusion time depends on infusion volume, rate and patient response and can be, for example, 2 to 5 hours or longer for a patient weighing 100 kg. In the event of an infusion-related reaction during administration [see Warnings and Precautions (5.1) ] , Decrease the infusion rate or stop the infusion. Administer treatment as needed to manage infusion reaction. If the infusion is stopped, restart the infusion at a rate of 1 mL/min and consider maintaining it at a previously tolerated level for the remainder of the infusion. If the infusion needs to be restarted, the infusion should be completed within 10 hours of initial drug product thaw. Discontinue infusion for anaphylaxis. DO NOT administer ROCTAVIAN as an intravenous push or bolus. DO NOT infuse ROCTAVIAN in the same intravenous line with any other products. DO NOT use a central line or port. To ensure the patient receives the complete dose, after the content of the last ROCTAVIAN-containing syringe is infused, flush the infusion line with a sufficient volume of 0.9% Sodium Chloride Injection, USP, through the same tubing and filter, and at the same infusion rate. Maintain venous access during the subsequent observation period [see Warnings and Precautions (5.1) ] . Monitoring Post-Administration Conduct the following tests after ROCTAVIAN administration [see Warnings and Precautions (5.2 , 5.4 , 5.5) ] . Perform regular ALT testing to monitor for elevations. Elevated liver enzymes, especially elevated ALT, may indicate immune-mediated hepatotoxicity and may be associated with decline in factor VIII activity. The monitoring schedule for ALT, and recommendations for corticosteroid use (initiation and taper) are based on the clinical efficacy and safety experience of 112 patients in a clinical study with ROCTAVIAN. Monitor ALT weekly for at least 26 weeks following administration of ROCTAVIAN. See Table 3 for monitoring schedule. Monitor AST and creatine phosphokinase (CPK) as needed to help rule out alternative causes for ALT elevations (including potentially hepatotoxic medications or agents, alcohol consumption, or strenuous exercise). Consider repeating ALT testing within 24 to 48 hours to confirm ALT elevation prior to initiation of corticosteroid treatment and using the same laboratory to measure ALT activity at baseline and over time to minimize the impact of inter-laboratory variability on test results. If ALT ≥ 1.5 × baseline or above ULN consider corticosteroid treatment. For patients who need corticosteroid therapy, the recommended starting dose is 60 mg with a subsequent taper upon return of ALT levels to baseline (see Table 4 below for recommendation on corticosteroid treatment). Monitor ALT weekly, and as clinically indicated, during corticosteroid therapy. Continue to monitor ALT until its return to baseline. Monitor for and manage adverse reactions secondary to corticosteroid use. Refer to the corticosteroid prescribing information for risks and required precautions. Table 3: ALT Monitoring Post-Administration Monitoring of ALT may be accompanied by monitoring of AST and CPK to rule out other causes of ALT elevation. Timeframe Monitoring Frequency Weekly monitoring is recommended, and as clinically indicated, during corticosteroid tapering. First 26 weeks Weekly Weeks 26 to 52 (Year 1) Every 1 to 2 weeks Year 2 Every 3 months After Year 2 Every 6 months Table 4: Recommended Corticosteroid Regimen in Response to ALT Elevations Corticosteroid Regimen (Prednisone or Equivalent Dose of Another Corticosteroid) Starting Dose If ALT continues to rise or has not improved after 2 weeks, increase the corticosteroid dose up to a maximum of 1.2 mg/kg, after ruling out alternative causes for ALT elevation. 60 mg daily for 2 weeks Tapering Taper corticosteroids after ALT levels reach baseline. The taper may be individualized based on the trend of ALT decline, the patient's medical condition, corticosteroid tolerance, and adverse reactions to corticosteroid therapy. 40 mg daily for 3 weeks 30 mg daily for 1 week 20 mg daily for 1 week 10 mg daily for 1 week There is limited information on the benefit of starting a corticosteroid course after the first year of ROCTAVIAN administration. Other immunosuppressive therapies (e.g., tacrolimus, mycophenolate mofetil) may be considered if corticosteroids are contraindicated, ineffective or there are adverse reactions secondary to corticosteroid use necessitating discontinuation. Monitor Factor VIII Activity Monitor factor VIII activity using the same schedule for ALT monitoring in Table 3 [see Warnings and Precautions (5.4) ] . Consider more frequent monitoring in patients with factor VIII activity levels ≤ 5 IU/dL and evidence of bleeding, taking into account the stability of factor VIII levels since the previous measurement. It may take several weeks after ROCTAVIAN infusion before ROCTAVIAN-derived factor VIII activity rises to a level sufficient for prevention of spontaneous bleeding episodes. Therefore, continued routine prophylaxis support with exogenous factor VIII or other hemostatic products used in the management of hemophilia A may be needed during the first few weeks after ROCTAVIAN infusion [see Clinical Pharmacology (12.3) ] . Exogenous factor VIII or other hemostatic products may also be required in case of surgery, invasive procedures, trauma, or bleeds in the event that ROCTAVIAN-derived factor VIII activity is deemed insufficient for adequate hemostasis in such situations. The use of different assays may impact test results; therefore, use the same assay and reagents to monitor patients over time, if feasible [see Warnings and Precautions (5.4) ] . Use of exogenous factor VIII products before and after ROCTAVIAN administration may impede assessment of ROCTAVIAN-derived factor VIII activity. Monitor patients for factor VIII inhibitors (neutralizing antibodies to factor VIII). Test for factor VIII inhibitors especially if bleeding is not controlled, or plasma factor VIII activity levels decrease [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.6) ] . Perform regular liver ultrasound (e.g., annually) and alpha-fetoprotein (AFP) testing in patients with risk factors of hepatocellular carcinoma (e.g., hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic steatohepatitis, advanced age) [see Warnings and Precautions (5.5) ] .

6 ADVERSE REACTIONS The following adverse reactions are also discussed in other sections of the label: Infusion-Related Reactions [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥ 5%) were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain. ( 6 ) Most common laboratory abnormalities (incidence ≥ 10%) were ALT, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), factor VIII activity levels, gamma-glutamyl transferase (GGT) and bilirubin > ULN. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin Pharmaceutical Inc. at 1-866-906-6100, 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 reflect the exposure of 134 adult patients with severe hemophilia A (defined as residual factor VIII activity ≤ 1 IU/dL) to a single dose of 6 × 10 13 vg/kg of body weight of ROCTAVIAN. Patients with detectable pre-existing antibodies to AAV5, active infections, history of thrombosis, immunosuppressive disorders, and liver dysfunction were excluded. All patients had a median follow-up of 162 weeks (range: 66 to 255 weeks) [see Clinical Studies (14) ] . The most common adverse reactions (≥ 5%) to ROCTAVIAN were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain. The most common laboratory abnormalities (≥ 10%) to ROCTAVIAN were ALT, AST, LDH, CPK, factor VIII activity levels, GGT, and bilirubin > ULN. Non-laboratory adverse reactions (≥ 5%) to ROCTAVIAN are listed in Table 5. There were 6 serious adverse reactions related to ROCTAVIAN treatment including ALT elevation, presyncope, maculopapular rash, anaphylaxis, and hypersensitivity reaction. Table 5: Adverse Reactions in ≥ 5% Other adverse reactions include gastroenteritis (2 patients; 1%), rash (2 patients; 1%), diarrhea (6 patients; 4%), and dizziness (3 patients; 2%). of Patients Treated with ROCTAVIAN Adverse Reactions Number of Patients (%) N = 134 All Grades ≥ Grade 3 Nervous system disorders Headache 9 (7%) 0 (0%) Gastrointestinal disorders Nausea 42 (31%) 0 (0%) Vomiting 8 (6%) 0 (0%) Abdominal pain Includes abdominal discomfort, abdominal distension, abdominal tenderness, and abdominal pain upper. 8 (6%) 0 (0%) General disorders and administration site conditions Fatigue Includes fatigue, lethargy, and malaise. 21 (16%) 0 (0%) Infusion-related reactions Infusion-related reactions are not under a specific system organ class and include multiple symptoms that occurred during or within 6 hours after the end of infusion [see Warnings and Precautions (5.1) ]. 9 (7%) 2 (1%) Table 6 lists laboratory abnormalities in patients treated with ROCTAVIAN. Table 6: Laboratory Abnormalities in Patients Treated with ROCTAVIAN Laboratory Abnormalities Number of Patients (%) N = 134 ALT increases > ULN 109 (81%) AST increases > ULN 92 (69%) LDH increases > ULN 77 (57%) CPK increases > ULN 60 (45%) Factor VIII activity levels > ULN Patients with one or more instances of factor VIII activity levels > 170 IU/dL (ULN of the CSA used) or > 150 IU/dL (ULN of the OSA used) [see Warnings and Precautions (5.3) ] . 38 (28%) GGT increases > ULN 24 (18%) Bilirubin increases > ULN 18 (13%) Twelve (9%), 9 (7%) and 1 (1%) of patients experienced > 5-20 × ULN ALT, AST and GGT elevations, respectively. Seven (5%) patients and 5 (4%) patients experienced > 5-10 × ULN and > 10 × ULN CPK increases, respectively. Infusion-related reactions were observed in 9 patients (7%), including hypersensitivity reactions (4%) and anaphylaxis (1%), and have occurred during and/or following ROCTAVIAN administration. Hepatotoxicity as defined by ALT ≥ 1.5 × baseline or ALT > ULN occurred in 107 of 112 (96%) patients. Nine (8%) patients had ALT between > 5-20 × ULN. One hundred (89%) patients had ALT elevations that occurred within the first 26 weeks, 74 (66%) patients had ALT elevations that occurred between weeks 27 to 52, and 72 (64%) patients had ALT elevations that occurred beyond 52 weeks after administration. Thirty-four of 112 (30%) patients had ALT elevations that were associated with a decline in factor VIII activity of ≥ 30%. The majority of patients (82%, 92/112) required corticosteroids for one or more episodes of ALT elevation while 35% (39/112) required alternate immunosuppression. Seventy-six percent, 5%, and 1% of patients used corticosteroids within the first 26 weeks, weeks 27 to 52, and beyond 52 weeks respectively following ROCTAVIAN administration. The most common (≥ 10%) adverse reactions from corticosteroid use (N = 92) included acne (34%), insomnia (27%), mood disorders (20%), cushingoid (20%), rash (18%), weight gain (16%), hypertension (12%), folliculitis (11%), abdominal pain (10%), and vision disorders (10%). Other clinically meaningful adverse events while on corticosteroid therapy included bone fracture (5%), impaired glucose tolerance (5%), herpes zoster (3%), oral candidiasis (3%), and adrenal insufficiency (1%). The most common adverse reactions from alternate immunosuppressant use (N = 39) included hypomagnesemia (15%) and diarrhea (10%). Infections requiring intravenous antimicrobial therapy occurred in 3 (3%) patients while on corticosteroid or other immunosuppressant therapy (N = 97). One case of autoimmune hepatitis was reported during third year follow-up in a patient with history of hepatitis C and steatohepatitis.

12.3 Pharmacokinetics Biodistribution (within the body) and Vector Shedding (excretion/secretion) Valoctocogene roxaparvovec-rvox transgene DNA levels (total amount of vector DNA) in various tissues (evaluated in nonclinical studies), blood, and shedding matrices were determined using a quantitative polymerase chain reaction (qPCR) assay. This assay is sensitive to transgene DNA, including fragments of degraded DNA. It does not indicate whether DNA is present in the vector capsid, in cells or in the fluid phase of the matrix (e.g., blood plasma, seminal fluid), or whether intact vector is present. Plasma and semen matrices were further evaluated by measuring encapsidated (potentially infectious) vector DNA using an immunoprecipitation quantitative PCR assay in Studies 270-201 and 270-301. Nonclinical Data Biodistribution of ROCTAVIAN was assessed in adult male mice. Following intravenous administration of 2.1 × 10 14 vg/kg, the highest vector DNA concentration was detected in the liver, followed by lower levels in the lung, heart, lymph nodes, kidney, spleen, bone marrow, testis, and brain through six months post-administration. The expression of the hFVIII mRNA transcripts were primarily detected in the liver, with no or minimal expression in extrahepatic tissues. Clinical Data ROCTAVIAN biodistribution and vector shedding were investigated on samples from blood, saliva, semen, stool, and urine. Administration of ROCTAVIAN at the dose of 6 × 10 13 vg/kg resulted in detectable vector DNA in blood and all shedding matrices evaluated at the dose of 6 × 10 13 vg/kg, with peak concentrations observed between 1 and 9 days post-administration. The peak vector DNA concentrations were observed in blood, followed by saliva, semen, stool, and urine. The peak concentration observed to date in blood across two clinical studies was 2 × 10 11 vg/mL. The maximum concentration observed in any shedding matrix was 1 × 10 10 vg/mL. After reaching the maximum in a matrix, the transgene DNA concentration declines steadily. In patients treated in two clinical studies, encapsidated (potentially transmissible) vector DNA was detectable in plasma up to 10 weeks after ROCTAVIAN administration. All patients treated in clinical studies achieved the first of 3 consecutive measurements below the lower limit of quantification (LLOQ) for vector DNA in semen by 36 weeks, and all except one patient achieved 3 consecutive measurements below limit of detection (BLOD) or negative by the time of the data cut. The maximum time to the first of 3 consecutive measurements BLOD for encapsidated (potentially transmissible) vector DNA in semen was 12 weeks. In clinical studies, all patients achieved 3 consecutive measurements below the LLOQ for vector DNA in urine and saliva, and 126 (89%) patients achieved 3 consecutive measurements below the LLOQ for vector DNA in stool by the time of the data cut. The maximum time to the first of 3 consecutive LLOQ measurements was 8 weeks for urine, 52 weeks for saliva, and 131 weeks for stool. All patients in the first study achieved 3 consecutive measurements BLOD or negative in urine, saliva, and stool by five-year post-dosing. All patients in the second study achieved 3 consecutive measurements BLOD or negative in urine, and saliva, and 85 (63%) patients achieved 3 consecutive measurements BLOD or negative in stool by three-year data cut. Magnitude and duration of shedding appear to be independent of the patient's attained factor VIII activity.