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 )

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%) AVLAYAH-treated patient, aged 0.5 years, experienced moderate anemia (hemoglobin 9.2 g/dL), which was considered serious due to the patient's age.

Membranous Nephropathy A case of biopsy-confirmed, steroid-refractory membranous nephropathy with immune complex deposits in the kidney was reported in an AVLAYAH-treated patient.