AVLAYAH

1 INDICATIONS AND USAGE AVLAYAH is indicated for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment. This indication is approved under accelerated approval based on the reduction of cerebrospinal fluid heparan sulfate [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Limitations of Use AVLAYAH is not recommended for use in combination with other enzyme replacement therapies for the treatment of Hunter syndrome. AVLAYAH is a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme indicated for the treatment of neurologic manifestations of Hunter syndrome (Mucopolysaccharidosis type II, MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment. ( 1 ) This indication is approved under accelerated approval based on reduction of cerebrospinal fluid heparan sulfate observed in patients treated with AVLAYAH. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). ( 1 ) Limitations of Use AVLAYAH is not recommended for use in combination with other enzyme replacement therapies. ( 1 )

2 DOSAGE AND ADMINISTRATION Administration of AVLAYAH should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. (2.1) Obtain a baseline hemoglobin value in all patients. ( 2.1 ) Recommended AVLAYAH maintenance dosage for pediatric patients who weigh at least 5 kg is 15 mg/kg administered once weekly as an intravenous infusion over approximately 4 hours. ( 2.2 , 2.6 ) Initiate AVLAYAH treatment with a dose escalation regimen. ( 2.2 ) See the full prescribing information for dosage and administration modifications and monitoring. ( 2.3 ) See the full prescribing information for preparation and administration instructions. ( 2.4 , 2.6 ) 2.1 Important Recommendations Prior to AVLAYAH Treatment Initiation Administer AVLAYAH under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1) ] . Initiate AVLAYAH in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1) ]. Consider pretreatment with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions (5.1 , 5.2) ] . Obtain a baseline hemoglobin value in all patients [see Warnings and Precautions (5.3) ] . 2.2 Recommended Dosage The recommended starting dosage of AVLAYAH for pediatric patients weighing at least 5 kg is 3 mg/kg administered once weekly via intravenous infusion. To reduce the risk of infusion-associated reactions (IARs), follow the dose escalation regimen in Table 1 [see Warnings and Precautions (5.2) ] . Administer each dosage level for at least 4 weeks before escalating to the next dosage level. The recommended maintenance dosage of AVLAYAH for pediatric patients who weigh at least 5 kg is 15 mg/kg administered once weekly via intravenous infusion. Table 1: Recommended AVLAYAH Dosage for Pediatric Patients Weighing ≥5 kg a Dosing Week Dosage Level a Do not escalate the dosage level if the current dosage level is not tolerated [see Dosage and Administration (2.3) ] . Week 1 to Week 4 3 mg/kg once weekly Week 5 to Week 8 7.5 mg/kg once weekly Week 9 and beyond 15 mg/kg once weekly (maintenance dosage) 2.3 Dosage and Administration Modifications and Monitoring In the event of a severe hypersensitivity reaction (e.g., anaphylaxis) or a severe IAR, discontinue AVLAYAH and immediately initiate appropriate medical treatment. Consider the risks and benefits of re-administering AVLAYAH following a severe reaction. If the decision is made to re-administer AVLAYAH, re-evaluate pre-treatment medications, slow the infusion rate, and/or reduce the AVLAYAH dose. Monitor patients closely upon re-administration of AVLAYAH [see Warnings and Precautions (5.1 , 5.2) ] . In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, temporarily hold the infusion and/or reduce the infusion rate by at least 50% from the current rate, then titrate up to the recommended infusion rate as tolerated (see Table 3 ) [see Warnings and Precautions (5.1 , 5.2) ]. If the dose has been decreased due to an adverse reaction, evaluate when it is appropriate to increase the dose and follow the recommended dose escalation regimen to achieve the maintenance dosage of 15 mg/kg once weekly [see Dosage and Administration (2.2) ]. 2.4 Preparation Instructions Prepare AVLAYAH using polypropylene syringes and infusion bags composed of polyvinylchloride (PVC) or polyolefins (PO) such as polyethylene (PE) and polypropylene (PP); infusion sets composed of PVC or PE; and filter membranes composed of polyethersulfone (PES). Use aseptic technique during preparation. Reconstitute and dilute AVLAYAH in the following manner: Reconstitution Instructions 1) Determine the number of AVLAYAH vials to be reconstituted based on the patient's weight in kg and the recommended dosage [see Do…

5 WARNINGS AND PRECAUTIONS Infusion-Associated Reactions (IARs) : If a severe IAR occurs, discontinue AVLAYAH and initiate appropriate medical treatment. ( 5.2 ) Anemia : Obtain baseline hemoglobin levels in all patients and monitor 3 months after initiation, and as clinically indicated. Administer appropriate supportive measures for anemia based on clinical judgment. ( 5.3 ) Membranous Nephropathy: Monitor serum creatinine and urinary protein to creatinine ratio. If membranous nephropathy is suspected, conduct diagnostic evaluation and initiate appropriate treatment. ( 5.4 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with enzyme replacement therapies (ERTs), including AVLAYAH [see Adverse Reactions (6) ] . Symptoms of anaphylaxis that have occurred with AVLAYAH have included tachycardia, hypotension, wheezing, vomiting, hives, and lip and tongue swelling. Anaphylaxis has occurred during the early course of ERT and after extended duration of therapy. Administer AVLAYAH under the supervision of a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate AVLAYAH in a healthcare setting with appropriate medical monitoring and support measures including access to cardiopulmonary resuscitation equipment. Prior to AVLAYAH administration, consider pre-treatment with antihistamines, antipyretics, and/or corticosteroids. If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue AVLAYAH and immediately initiate appropriate medical treatment, including use of epinephrine. Consider the risks and benefits of re-administering AVLAYAH following a severe hypersensitivity reaction (including anaphylaxis). If the decision is made to re-administer AVLAYAH, re-evaluate pre-treatment medications (e.g., antihistamines, antipyretics, and/or corticosteroids), slow the infusion rate, and/or reduce the AVLAYAH dose. Monitor patients closely upon re-administration of AVLAYAH. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis, and to seek immediate medical care should symptoms occur. If a mild or moderate hypersensitivity reaction occurs, temporarily hold the infusion and/or reduce the infusion rate by at least 50% from the current rate, then titrate up to the recommended infusion rate as tolerated (see Table 3 ). Re-evaluate the pre-treatment medication regimen [see Dosage and Administration (2.3) ] . If the dose has been decreased due to an adverse reaction, evaluate when it is appropriate to increase the dose and follow the recommended dose escalation regimen to achieve the maintenance dosage of 15 mg/kg once weekly [see Dosage and Administration (2.2) ]. 5.2 Infusion-Associated Reactions Infusion-associated reactions (IARs) have been reported in patients treated with AVLAYAH [see Adverse Reactions (6.1) ] . IARs are defined as adverse reactions occurring during or within 24 hours of the infusion. Symptoms of IARs observed with AVLAYAH can include (but are not limited to) chills, angioedema, hypotension, tachycardia, urticaria, vomiting, wheezing, pyrexia, flushing, erythema, rash, cough, diarrhea, abdominal pain, retching, headache, irritability, and papules. IARs have been reported more frequently in ERT-naïve patients compared to ERT-experienced patients. Cases of infusion-associated reactions occurring 2 hours or more after completion of the infusion have occurred with AVLAYAH. Prior to AVLAYAH administration, consider pre-treatment with antihistamines, antipyretics, and/or corticosteroids to reduce the risk of IARs. IARs may still occur in patients after receiving pre-treatment. Onset of IARs was most common during the first 8 weeks of treatment with a median time to onset of approximately 2 weeks for the first IAR; IARs declined in frequency with continued use of AVLAYAH. IARs may still occur despite …

4 CONTRAINDICATIONS None. None ( 4 )

8.1 Pregnancy Risk Summary There are no available data on the use of AVLAYAH during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal studies to evaluate the potential for embryofetal developmental toxicity and pre- and postnatal developmental toxicity of tividenofusp alfa-eknm have not been conducted. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] Infusion-Associated Reactions [see Warnings and Precautions (5.2) ] Anemia [see Warnings and Precautions (5.3) ] Membranous Nephropathy [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence ≥20%) were IAR, upper respiratory tract infection, ear infection, pyrexia, anemia, cough, vomiting, diarrhea, rash, COVID-19, rhinorrhea, nasal congestion, fall, headache, skin abrasion, and urticaria. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Denali Therapeutics toll-free at 1-833-ONE-DNLI (1-833-663-3654) 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 AVLAYAH was evaluated in male pediatric patients with Hunter syndrome in Trial 1 [see Clinical Studies (14) ] . A total of 47 male patients (age range: 3 months to 13 years) received intravenous AVLAYAH at 3 mg/kg to 30 mg/kg (0.2 to 2 times the approved recommended maintenance dose) weekly, and the majority of patients received 15 mg/kg intravenously weekly after Week 24. The median (minimum, maximum) duration of exposure was 117 (19, 219) weeks. In Trial 1, the most common adverse reactions (≥20%) reported in AVLAYAH-treated patients were infusion-associated reaction (IAR), upper respiratory tract infection, ear infection, pyrexia, anemia, cough, vomiting, diarrhea, rash, COVID-19, rhinorrhea, nasal congestion, fall, headache, skin abrasion, and urticaria. Dose interruptions of AVLAYAH due to an adverse reaction occurred in 91% of patients. The most frequently reported adverse reaction leading to dose interruption was IAR (31 [66%] patients). Other frequently reported adverse reactions leading to dose interruption were COVID-19 (18 [38%] patients), pyrexia (16 [34%]), upper respiratory tract infection (16 [34%]), nasal congestion (6 [13%]), and vomiting (6 [13%]). Dose interruption included skipped infusions due to an adverse reaction as well as temporary infusion pauses with subsequent completion during the same visit. Dose reductions of AVLAYAH due to adverse reactions occurred in 57% of patients; the majority of these reactions were IARs. In Trial 1, one (2%) AVLAYAH-treated patient experienced anaphylaxis, which occurred in the first month of treatment. Table 4 summarizes adverse reactions that occurred in >15% of AVLAYAH-treated pediatric patients with Hunter syndrome. Table 4: Adverse Reactions That Occurred in >15% in AVLAYAH-treated Pediatric Patients With Hunter Syndrome (Trial 1) Adverse Reaction Any Severity N (%) (N = 47) a Infusion-associated reaction includes infusion-related reaction. b Ear infection includes ear infection, otitis media, otitis media acute, otitis externa. c Anemia includes anemia, iron deficiency anemia, and decreased hemoglobin. Infusion-associated reaction a 41 (87%) Upper respiratory tract infection 28 (60%) Ear infection b 26 (55%) Pyrexia 26 (55%) Anemia c 24 (51%) Cough 22 (47%) Vomiting 20 (43%) Diarrhea 19 (40%) Rash 19 (40%) COVID-19 18 (38%) Rhinorrhea 18 (38%) Nasal congestion 17 (36%) Fall 11 (23%) Headache 11 (23%) Skin abrasion 11 (23%) Urticaria 10 (21%) Constipation 8 (17%) Contusion 8 (17%) Gastroenteritis 8 (17%) Infusion site extravasation 8 (17%) Insomnia 8 (17%) Neutropenia 8 (17%) Description of Selected Adverse Reactions Infusion-Associated Reaction Three (6%) AVLAYAH-treated patients experienced severe IARs. One patient permanently discontinued treatment due to an IAR. Anemia Two (4%) AVLAYAH-treated patients experienced severe anemia (defined as hemoglobin <8 g/dL) prior to Week 24. One (2%…