New Weekly Infusion for Children with Hunter Syndrome

Avlayah (tividenofusp alfa-eknm) is a hydrolytic lysosomal glycosaminoglycan (GAG)–specific enzyme — a fusion of iduronate-2-sulfatase (IDS) to an IgG1 Fc fragment that binds the transferrin receptor (TfR) so the enzyme can move through the blood–brain barrier by receptor-mediated transcytosis and also reach peripheral tissues. Hunter syndrome (mucopolysaccharidosis type II, MPS II) is an X-linked lysosomal storage disease: without enough IDS, heparan sulfate and dermatan sulfate build up in cells, including in the brain. Older IDS enzyme replacement reaches the body but does not cross that barrier the same way.

Denali’s approval press calls Avlayah the first FDA-approved biologic specifically designed to cross the blood–brain barrier and reach the whole body, including the brain, and the first FDA-approved TfR-enabled medicine built for that crossing. The FDA press calls it the first product approved to address neurologic complications of Hunter syndrome. The US label’s mechanism section describes TfR-mediated delivery across the blood–brain barrier. This is enzyme replacement, not a gene therapy, not a cure, and not something to combine with other Hunter ERTs on the label.

The FDA approved BLA 761485 under accelerated approval on 24 March 2026 (approval letter to Denali Therapeutics Inc.; U.S. License No. 2385). The agency’s public press announcement is dated 25 March 2026. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). That confirmatory work is the ongoing Phase 2/3 COMPASS study (NCT05371613); the approval letter’s accelerated-approval postmarketing requirement 4953-1 is a double-blind, randomized, active (standard-of-care)–controlled trial to verify and describe clinical benefit (sponsor timetable on the letter: trial completion 11/2027, final report 11/2028).

Where this is taking place

Commercial labelled supply today: United States — FDA accelerated approval for neurologic MPS II in the labelled pediatric population (≥5 kg; start before advanced neurologic impairment). Infusions begin in a healthcare setting that can treat anaphylaxis (CPR equipment available). After the patient reaches and tolerates the maintenance dose, the label allows home infusion under healthcare-provider supervision if the clinician recommends it. This is still a supervised IV product under healthcare-provider supervision when given at home.

Outside the United States: As of this draft, no Health Canada NOC/DIN, EC marketing authorisation, MHRA licence, PMDA/MHLW licence, TGA ARTG listing, Swissmedic authorisation, or NMPA decision has been confirmed from primary regulator pages for this article. Denali materials describe COMPASS as supporting future global submissions — that is a development plan, not a foreign licence.

Phase 1/2 supporting accelerated approval — NCT04251026 (USPI “Trial 1”) — multicentre, international, multi-cohort, single-arm, open-label. Sponsor: Denali Therapeutics Inc. CT.gov: ACTIVE_NOT_RECRUITING; actual enrollment 47; estimated completion February 2031. Study director on CT.gov: Sam Lu, MD (Denali). This long-term follow-up is not a new commercial enrolment door.

Confirmatory Phase 2/3 — COMPASS, NCT05371613 — double-blind, randomized 2:1 tividenofusp alfa (DNL310) vs idursulfase (standard-of-care IDS ERT). Sponsor: Denali Therapeutics Inc. CT.gov status: RECRUITING; estimated enrollment 63; start 21 July 2022 (actual); estimated primary completion / completion December 2027. Central contact on CT.gov: Clinical Trials at Denali Therapeutics, clinical-trials@dnli.com. Study director on CT.gov: Jose Alcantara Rodriguez, PharmD (Denali). Cohort A (neuronopathic) and Cohort B (non-neuronopathic); Denali’s approval PR said Cohort A had completed enrollment and Cohort B was still enrolling. Countries with sites on CT.gov include the United States, Canada, United Kingdom, Argentina, Australia, Belgium, Brazil, Czechia, France, Germany, Italy, Netherlands, Spain, Sweden, and Türkiye. A Canadian or EU trial site is not a Canadian or EU marketing authorisation. For families already on labelled US drug, COMPASS is a confirmatory science path — not the default way to “get the brand.”

Ultra-rare reality: the practical US door is a metabolic / lysosomal storage disease centre (or neurology / genetics clinic experienced in MPS II) that can schedule weekly IV infusions, escalate the dose safely, and monitor hemoglobin and urine protein — not a mail-order script written outside that expertise.

Approval matrix

Access by country

• United States: Ask a metabolic / lysosomal / MPS clinic (or genetics–neurology team experienced in Hunter syndrome) about FDA-labelled Avlayah. Labelled under accelerated approval (24 March 2026 letter) for neurologic manifestations of MPS II when started in presymptomatic or symptomatic pediatric patients ≥5 kg before advanced neurologic impairment. Weekly IV with dose escalation to 15 mg/kg maintenance (see dosing). Start in a setting that can treat anaphylaxis. Baseline hemoglobin; watch kidney labs / urine protein. Prior authorisation and specialty distribution still apply. No list price or copay dollars in this article. Denali adverse-reaction line on the USPI: 1-833-ONE-DNLI (1-833-663-3654) or FDA MedWatch 1-800-FDA-1088. Denali’s approval press names Denali Patient Services at 844-DNLI365 (844-365-4365) for treatment-access support — that is company patient-services contact from the sponsor PR, not a dollar figure. This is US commercial labelled supply, not a DIY import.

• Canada: Authorisation not confirmed. COMPASS lists recruiting sites at the University of Alberta (Edmonton), Hospital for Sick Children (Toronto), and McGill University Health Centre (Montreal) — those are trial locations, not a Notice of Compliance. Do not assume SAP, named-patient, or cross-border mail-order of a US vial is available or appropriate. Ask the MPS / metabolic clinic what legal paths exist in Canada when a Canadian label does not yet exist.

• European Union / United Kingdom / Australia / other countries with COMPASS sites: Authorisation not confirmed. Participation in COMPASS or completed Phase 1/2 follow-up is not a commercial label. Regulator authorisation not confirmed in this draft.

• If your regulator has not authorised it: do not import on your own.

Who is eligible (from the US label)

This is a Hunter syndrome (MPS II) conversation — confirmed IDS deficiency / MPS II diagnosis in a centre that already manages the disease. The US indication is specific about timing and weight.

United States (Prescribing Information, revised 3/2026):

• Indication: Treatment of neurologic manifestations of Hunter syndrome (MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment.
• Accelerated approval based on reduction of CSF heparan sulfate. Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
• Limitation of use: Not recommended for use in combination with other enzyme replacement therapies for Hunter syndrome.
• Weight: Safety and effectiveness not established below 5 kg.
• Geriatrics: Trials did not include patients ≥65 years.
• Pregnancy / lactation: No adequate human data — clinic reads the label with you.
• Contraindications: None.
• Not a substitute for hearing care, airway / cardiac monitoring, physiotherapy, school supports, or other MPS II supportive care.

Not labelled on sources confirmed for this draft:

• Health Canada, EMA/EC, MHRA, PMDA, TGA, Swissmedic, or NMPA marketing authorisations (not confirmed here).
• Adults as a free-standing labelled population on the US indication line (the labelled initiation population is pediatric, ≥5 kg, before advanced neurologic impairment). COMPASS includes young adults for confirmatory / global work — that is not the same as a US adult indication on this draft’s sources.
• Combining Avlayah with idursulfase or another IDS ERT.
• A maintenance dose other than the labelled escalation to 15 mg/kg once weekly.

What the pivotal study showed (US label / FDA press)

Efficacy below is from the US Prescribing Information (Section 14) and the FDA 25 March 2026 press announcement — not from an EU or Canadian label (none confirmed). This is a surrogate-endpoint accelerated approval; clinical neurologic benefit is still being confirmed.

Trial 1 — NCT04251026 (USPI):

• Phase 1/2, multicentre, international, multi-cohort, single-arm, open-label.
• 47 pediatric patients with Hunter syndrome (44 neuronopathic; 3 non-neuronopathic); all male; baseline median age 5 years (range 3 months to 13 years).
• 15 ERT-naïve; 32 ERT-experienced (median prior ERT 26 months); 2 with prior HSCT history; 2 with prior gene-therapy history.
• Part 1 dosing ranged; most common dosage (57%) was 15 mg/kg once weekly. Patients on 30 mg/kg weekly did not show additional CSF or urine HS reductions vs 15 mg/kg.
• 46 / 47 completed Part 1 through Week 24; 1 discontinued for an adverse reaction before Week 24.

Surrogate efficacy (CSF HS at Week 24):

• Among 44 patients with Week 24 measurements: mean percent reduction from baseline in CSF HS 91% (95% CI 89%, 92%); min–max percent change 72% to 98%.
• At baseline, 0 / 47 had CSF HS below the upper limit of normal (ULN).
• At Week 24, 93% (41 / 44) had CSF HS below the ULN.

FDA press framing: same Week 24 CSF HS numbers; accelerated approval because CSF HS reduction was judged reasonably likely to predict clinical benefit for neurologic manifestations. FDA noted Denali’s confirmatory randomized trial was more than 95% enrolled at the time of the press announcement.

Pharmacodynamics (label, supportive — relationship to clinical response not established):

• Week 24 reductions from baseline: urine HS 86%, urine DS 91%, total urine GAGs 57%.
• Total urine GAGs below ULN: 2 / 47 (4%) at baseline vs 26 / 38 (68%) at Week 24 among those measured.

Confirmatory path — COMPASS NCT05371613 (not the accelerated-approval efficacy dataset):

• Primary outcomes on CT.gov (Cohort A): percent change in CSF HS at 24 weeks; change in Vineland-3 at 96 weeks.
• Secondary examples: Bayley-III, Vineland ABC, serum NfL, 6-minute walk (Cohort B), urine HS+DS, liver/spleen volume, caregiver global impression.
• Randomized 2:1 Avlayah vs idursulfase. Results are not the basis of the March 2026 accelerated label; they are what continued approval depends on.

Trial-status honesty: NCT04251026 remains in long-term follow-up (ACTIVE_NOT_RECRUITING). COMPASS is RECRUITING for confirmatory science and possible label expansion / ex-US filings — it is not a substitute for US commercial labelled supply when that path exists, and it is not a foreign marketing authorisation.

Dose and how it is given (on-label)

Safety (what the label and FDA press put first)

Boxed warning — hypersensitivity reactions including anaphylaxis: Life-threatening hypersensitivity, including anaphylaxis, has occurred with ERTs including Avlayah — early in treatment and after long exposure. Start in a monitored healthcare setting with CPR support. If severe hypersensitivity / anaphylaxis occurs, discontinue and treat immediately (including epinephrine). Anaphylaxis symptoms reported with Avlayah have included tachycardia, hypotension, wheezing, vomiting, hives, and lip/tongue swelling. In Trial 1, 1 / 47 (2%) had anaphylaxis in the first month.

Infusion-associated reactions (IARs): Common (during or within 24 hours of infusion). More frequent in ERT-naïve patients. Median time to first IAR ~2 weeks; most common in the first 8 weeks, then less frequent — but can still occur later, including ≥2 hours after the infusion ends. Severe IARs in 3 / 47 (6%); 1 patient permanently discontinued for an IAR. Mild/moderate: hold or slow infusion (≥50% rate cut) then retitrate; re-evaluate pretreatment.

Anemia: Reported in 24 / 47 (51%) (includes iron-deficiency anemia and decreased hemoglobin). Higher risk if anemia was already present. Hemoglobin drops often by Week 13; most recovered by Week 24; did not drive discontinuation in the trial; iron supplementation may be used. Obtain hemoglobin at baseline, at 3 months, and periodically as clinically indicated.

Membranous nephropathy: A biopsy-confirmed, steroid-refractory case with immune-complex deposits was reported. Monitor serum creatinine and urinary protein-to-creatinine ratio. If membranous nephropathy is suspected, evaluate and treat; weigh risks and benefits of continuing Avlayah.

Most common adverse reactions (≥20% in Trial 1): IAR (87%), upper respiratory tract infection (60%), ear infection (55%), pyrexia (55%), anemia (51%), cough (47%), vomiting (43%), diarrhea (40%), rash (40%), COVID-19 (38%), rhinorrhea (38%), nasal congestion (36%), fall (23%), headache (23%), skin abrasion (23%), urticaria (21%).

Immunogenicity (label): Anti-drug antibodies detected in 47 / 47 (100%) after treatment; neutralizing antibodies inhibiting enzyme activity in 41 / 47 (87%). Higher ADA titers associated with lower serum drug levels; at the recommended dose, ADA-related PK changes did not show significant effects on CSF HS or urine HS reductions in the evaluated data. Effect of ADAs on safety not fully characterized; effect on clinical effectiveness unknown. Antibodies to other IDS ERTs are expected to cross-react.

Contraindications: none listed.

How to talk to a doctor

Bring the BLA number, the NCT numbers, and the US Prescribing Information if you are in a US clinic. Outside the US, bring honesty that a local label may not exist yet.

1. "I / my child has Hunter syndrome (MPS II) and weighs at least 5 kg. Is Avlayah labelled for neurologic manifestations in this country, and are we before advanced neurologic impairment so the indication fits?"
2. "In the United States, this is accelerated approval based on CSF heparan sulfate. What does that mean for monitoring, and how does COMPASS (NCT05371613) relate to continued approval?"
3. "Walk us through the weekly IV escalation: 3 → 7.5 → 15 mg/kg, ~4-hour infusion, and where the first doses will be given if anaphylaxis occurs."
4. "What is the plan for hemoglobin (baseline and 3 months) and for creatinine / urine protein because of membranous nephropathy risk?"
5. "We will not combine Avlayah with idursulfase or another ERT unless you say the label has changed — the current US limitation says not recommended in combination."
6. "Is prior authorisation started? Who coordinates specialty pharmacy for NDC 84976-001-01?"
7. "If we are outside the US, what legal options exist while HC/EMA/MHRA licences are not confirmed — COMPASS enrolment where still open, local special-access rules, or referral — without DIY import?"
8. "Supportive MPS II care (airway, heart, hearing, development, school/rehab) continues. Avlayah does not replace that."

Research and regulatory team (from sources only — no invented contacts)

• Denali Therapeutics Inc., 161 Oyster Point Boulevard, South San Francisco, CA 94080 — BLA 761485 applicant and licence holder (U.S. License No. 2385); NCT04251026 and NCT05371613 lead sponsor; US manufacturer named on the Prescribing Information.
• Erica Cox, PhD, Executive Director, Regulatory Affairs, Denali — addressee on the FDA accelerated-approval letter (24 March 2026).
• Marty Makary, M.D., M.P.H., FDA Commissioner — quoted in the FDA press announcement (25 March 2026).
• Tracy Beth Hoeg, M.D., Ph.D., Acting CDER Director — quoted in the FDA press announcement on neurologic Hunter syndrome and the CSF HS surrogate.
• Ryan Watts, Ph.D., co-founder and CEO, Denali — quoted in Denali’s 25 March 2026 approval press release.
• Peter Chin, M.D., Chief Medical Officer and Head of Development, Denali — quoted in the same Denali press release.
• Joseph Muenzer, M.D., Ph.D., University of North Carolina at Chapel Hill — named in Denali’s press release as lead investigator of the Phase 1/2 trial.
• Sam Lu, MD, Denali — study director on ClinicalTrials.gov for NCT04251026.
• Jose Alcantara Rodriguez, PharmD, Denali — study director on ClinicalTrials.gov for COMPASS NCT05371613.
• Clinical Trials at Denali Therapeutics — central contact on CT.gov for COMPASS: clinical-trials@dnli.com.
• Denali Patient Services — named in Denali’s approval press release: 844-DNLI365 (844-365-4365).
• Denali adverse-reaction reporting (USPI): 1-833-ONE-DNLI (1-833-663-3654); FDA MedWatch 1-800-FDA-1088.
• COMPASS site facilities (examples on CT.gov; status RECRUITING at last API pull): US — UCSF Benioff Children’s Hospital Oakland; Lurie Children’s (Chicago); Hackensack University Medical Center; UNC Children’s Research Institute (Chapel Hill); Cincinnati Children’s; Children’s Hospital of Philadelphia; UT Houston; University of Utah (Salt Lake City). Canada — University of Alberta (Edmonton); Hospital for Sick Children (Toronto); McGill University Health Centre (Montreal). Additional countries listed on CT.gov as above. Site PIs appear on some CT.gov location records; they are trial investigators, not a national licence office.
• Principal-investigator emails, foreign compassionate-use IDs, or Health Canada / EMA medical-information lines are listed only when they appear on the US label, FDA letter, sponsor primary press, or CT.gov — none invented here.

Bottom line

Avlayah (tividenofusp alfa-eknm) is an FDA accelerated-approved, once-weekly IV IDS enzyme replacement designed to cross the blood–brain barrier (TfR-enabled fusion), labelled 24 March 2026 (BLA 761485) for neurologic manifestations of Hunter syndrome (MPS II) when started in pediatric patients ≥5 kg who are presymptomatic or symptomatic and before advanced neurologic impairment. The March 2026 decision rests on large CSF heparan sulfate reductions in Phase 1/2 (NCT04251026) — mean 91% drop by Week 24, with 93% of measured patients below the ULN. Clinical benefit still has to be verified in confirmatory work, including COMPASS (NCT05371613) / PMR 4953-1. Watch for anaphylaxis/IARs, anemia, and membranous nephropathy. US labelled; other regulators not confirmed. The door is a lysosomal / MPS centre that can deliver weekly monitored IV dosing. The US label does not recommend combining with other Hunter ERTs. Trial sites outside the US are not foreign marketing authorisations.

---

Primary sources

1. FDA press announcement — FDA Approves Drug to Treat Neurologic Manifestations of Hunter Syndrome, Immediate Release 25 March 2026 — https://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-neurologic-manifestations-hunter-syndrome
2. FDA approval package / accelerated approval letter, BLA 761485, Avlayah (tividenofusp alfa-eknm), approval date 24 March 2026 (Denali Therapeutics Inc.; U.S. License 2385) — https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/761485Orig1s000Approv.pdf
3. Avlayah (tividenofusp alfa-eknm) Prescribing Information, revised 3/2026 (FDA labeling) — https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761485s000lbl.pdf
4. DailyMed — AVLAYAH (tividenofusp alfa-eknm) — setid 014d92c1-b643-4680-8ca6-f0b3307da915 — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=014d92c1-b643-4680-8ca6-f0b3307da915
5. Denali Therapeutics press release — Denali Therapeutics Announces U.S. FDA Approval of AVLAYAH™ (tividenofusp alfa-eknm) for Treatment of Hunter Syndrome (MPS II), 25 March 2026 — https://investors.denalitherapeutics.com/news-releases/news-release-details/denali-therapeutics-announces-us-fda-approval-avlayahtm
6. ClinicalTrials.gov NCT04251026 — Phase 1/2 tividenofusp alfa (DNL310) in pediatric Hunter syndrome — https://clinicaltrials.gov/study/NCT04251026
7. ClinicalTrials.gov NCT05371613 — COMPASS Phase 2/3 tividenofusp alfa vs idursulfase — https://clinicaltrials.gov/study/NCT05371613
8. FDA Orphan Drug Designations and Approvals entry — tividenofusp alfa-eknm / Avlayah, marketing approval 03/24/2026 — https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=671118