FDA Approves Avlayah In Hunter Syndrome Neurologic Manifestations

The U.S. Food and Drug Administration today approved Avlayah (tividenofusp alfa-eknm) for the management of central neurologic manifestations in pediatric patients with Hunter syndrome. Hunter syndrome is a rare, life-threatening, genetic, metabolic, and hereditary disorder affecting both males and females, which causes the progressive physical and mental deterioration of children and adults. Avlayah reduces levels of the modified glycosaminogglycan substrate and associated toxic intermediates in tissues which cause the clinical manifestations of Hunter syndrome. Currently there are no FDA-approved treatments specifically for the central neurologic manifestations of Hunter syndrome. The most common central neurologic features of Hunter syndrome include progressive psychomotor delay, loss of speech, loss of gross and fine motor skills, and in some cases intellectual disability. The most common adverse reactions reported with Avlayah are headache, nasopharyngitis, vomiting, cough, diarrhea, fever, skin and subcutaneous tissue adverse reactions, including Stevens-Johnson syndrome, and decreased white blood cell count.

Novel Mechanism of Action

Avlayah (idursulfase) is the first FDA-approved biologic that can cross the blood-brain barrier to affect the entire body, including the brain. Avlayah is an enzyme replacement therapy indicated for the treatment of the neurologic manifestations of Hunter syndrome (mucopolysaccharidosis type II, or MPS II) in presymptomatic and symptomatic patients 5 years of age or less. If approved, the continued approval of Avlayah for the treatment of Hunter syndrome is contingent upon the results from clinical trials in progress to determine whether patients with Hunter syndrome will experience clinical benefit from Avlayah treatment. These clinical trials are referred to hereafter as the Verification of Efficacy Studies.

Why It Matters

Hunter syndrome (Mucopolysaccharidosis type II or MPS II) is a rare, usually fatal genetic condition that affects physically and mentally, and is frequently life-threatening. Hunter syndrome is caused by a deficiency of the enzyme iduronate-2-sulfatase. Almost all cases of this enzyme deficiency are found in males. The frequency of affected males is estimated as 1 in 100,000 to 1 in 170,000 male births. In severe cases, the accumulation of glycosaminoglycans (GAGs) in cells throughout the body can lead to severe neurologic deterioration. Affected individuals may have physical disabilities and may also have mental disabilities, lose developmentally-based skills and loss of previously acquired skills, exhibit behavioral problems, and other CNS-related problems.

Overcoming a Long-Standing Clinical Challenge

Management of the neurologic manifestations of Hunter syndrome has been particularly problematic due to the lack of effective systemic therapies capable of achieving high concentrations in the brain or spinal cord. Hunter disease is currently treated by intravenous administration of ERT; most such biotherapies fail to cross the blood-brain barrier, and thus do not address the cognitive/behavioral manifestations of the disease. Avlayah uses Denali’s TransportVehicle™ (TV) platform technology to create a series of proprietary compounds that enable large therapeutic molecules such as antibodies, enzymes, and oligonucleotides to be delivered throughout the body, including to the brain, following administration by intravenous injection.

New Regulatory Pathway Set and Clinical Decision-Making

After a long delay Avlayah has received FDA approval allowing its use for treatment of problems of the central nervous system (CNS) and related symptoms. Thus, those who work with people with developmental disabilities as well as those who work with people with psychiatric disabilities will need to determine how Avlayah will fit into the case management plan of each person. Often the case management plan is made up of and governed by services and supports that are mostly symptom focused, behavioral in nature, and medically based with a focus on the treatment of a particular medical organ. Avlayah can become one of the tools used to treat the individual in such a plan. However, it is likely that Avlayah will most impact the treatment plan for people with developmental disabilities and psychiatric disabilities of those providers and payers who participate in the medical utilization review process. Families of people with developmental disabilities will want to know about Avlayah as well.

New Challenges

Individuals and families will want to know what effects treatment for their child or for themselves with Rett Syndrome will have. Payers will struggle to determine whether to cover and set prior authorization levels for a costly medication. Those in the distribution chain will modify their processes to administer the daily dose of liquid medication. Clinicians, particularly medical and clinical psychologists and social workers, will need to educate families as to what to expect from treatment. This education will depend on the age of treatment and the severity of disease; the level of effect of treatment (stabilization of loss, slowing of disease, gain of function) may vary.

Who It Affects

Patients and Family

The decision will most significantly affect patients with Hunter syndrome and their families. Children with the severe, neurodegenerative form of the disease and their families will be most affected by this decision as they grapple with issues of cognitive impairment and behaviour. Patients with the attenuated form of Hunter disease will not be affected by this decision and it will be left to clinicians and caregivers to decide if such a treatment is indicated for individual patients.

Data from clinical trials supported that Avlayah maintained the effects of ERT by producing improvements in neurodevelopmental tests, Bayley Scales of Infant and Toddler Development (BSID) similar to that achieved with the standard ERT regimen administered parenterally by the intravenous route.

Specialist Clinicians

Both medical teams and clinical teams will be involved at different steps of the process, from identifying and considering potential candidates for gene therapy, to counseling families who might be appropriate for consideration for this treatment, to starting patients on the treatment, monitoring how the treatment is having an effect as well as its side effects. Our teams involved will include Pediatric geneticists, metabolic disorder teams, pediatric neurologists, and neurodevelopmental pediatricians, as well as other multidisciplinary teams. In addition, Primary care pediatricians and other clinicians will be involved early on in the screening process to identify families for consideration. Newborn screening is evolving and we are seeing diagnosis occur earlier in life.

As with any drug, our formulation—Avlayah®—may cause side effects. The prescribing physician, such as a pediatric geneticist or pediatric neurologist, who administers Avlayah® to his/her patient(s) should be aware of common adverse reactions such as upper respiratory tract infection and pyrexia (which can include symptoms of sore throat, cough etc). Severe hypersensitivity reactions including anaphylaxis have been reported with Avlayah®. A severe hypersensitivity reaction can occur after administration of the drug.

Healthsystems, Payers, and Advocacy

Other groups and individuals, including healthcare professionals, advocates and support groups, families and caregivers, Healthsystems and payers (e.g. employers, managed care organizations) and Hospitals and outpatient centers where these treatments will be administered and follow-up monitoring performed, will also be important stakeholders in this process. Many of these stakeholders will consider the clinical, cost-effectiveness and long-term outcomes data when making decisions around coverage and reimbursement of Avlayah. In addition to the Rare Pediatric Disease Designation and Breakthrough Therapy Designation, Avlayah was approved under the accelerated approval pathway (AAP) based on evidence of reduction of accumulated glycosaminoglycans (GAGs) in patients with MPS II. Avlayah also received FDA Fast Track and Orphan Drug designations for the treatment of MPS II.

Advocacy groups & patient registries will become more prominent in the gathering of real world evidence and helping families through the access process.

What Changes

• New therapeutic option focused on neurologic symptoms: Clinicians now have an FDA-approved treatment specifically aimed at brain and behavioral manifestations of Hunter syndrome, which may change timing and goals of care for eligible patients. Avlayah is the first ERT approved to treat the CNS manifestations of MPS II.
• Shift in clinical decision-making: Teams will need to assess patients’ neurologic status, age, comorbidities, and care priorities to decide who should start the therapy and when, balancing potential benefits against unknown long-term outcomes and safety considerations.
• Increased demand on care infrastructure and payers: Hospitals, specialty clinics, and insurers should prepare for new administrative, delivery, and coverage challenges, including authorization processes, infusion scheduling, or other administration logistics, and post-marketing surveillance.
• Greater emphasis on early detection and family counseling: The approval reinforces the value and importance of timely diagnosis through newborn screening, clearer prognostic conversations, and shared decision-making so families understand treatment goals, stabilization versus improvement, and realistic monitoring plans.

Clinical and Patient Considerations

For the clinician, the critical questions are which of their patients may be suitable for treatment and at what stage they should be referred for assessment. As these conditions are progressive, treatment is most effective if started early, before irreversible neurological damage occurs. Prioritisation of early screening, swift referral to a specialist and rapid diagnosis is therefore essential.

Discussion with families and caregivers regarding the effects of, and need for, counseling for Huntington disease is a delicate and sensitive task. Families and caregivers will often ask if a particular approach will “cure” Huntington disease, reduce Huntington disease behaviors, or improve cognitive functioning. The therapist needs to be candid regarding the possible neurologic effects of the treatment, side effects, and the need for on-going evaluation and monitoring as the effects of the first FDA approved drug for a rare disease of Huntington disease are unclear. In some cases, it will be helpful to involve other members of the multidisciplinary team such as speech therapy, occupational therapy, a neuropsychologist, a social worker, and/or a palliative care team.

Providers and caregivers should be aware of common and disease-specific side effects as well as effects of biologic therapies that may lead to immune response. Long-term toxicities and the durability of effects on neurologic development also remain an area of interest. Patients should have regular follow-up with the treating physician, as well as neurologist assessment of both current disease activity and neurologic and developmental outcome.

System-Level and Policy Implications

Approvals of high-impact therapies for rare diseases pose significant challenges to the health system and are likely to be subject to prior authorization requirements. Payers are likely to introduce criteria that require evidence of neurologic impairment, specialist input or genetic diagnosis prior to treatment unless alternative pathways are introduced to expedite patient access to these medicines.

Several access disparities exist for families from rural and underserved backgrounds. They already experience long waits to see specialists and travel far for care for this rare cancer. They will demand that policies, health systems, and advocacy organizations address these disparities by establishing access measures like telemedicine, COE’s in regional locations, financial assistance, and transportation.

Regulatory and Reimbursement

Post-approval data will also be of value to some of the various regulatory and reimbursement stakeholders. Real-world evidence generated from patient registries and outcomes data will also help inform future coverage decisions for Galimatep and other emerging therapies targeting rare, life-threatening neurologic diseases.

Looking Ahead

But even after approval, there will be more work to confirm how these treatments work in the real world. Over months and years, more questions will surface, such as who exactly is likely to benefit, how long the effect will last, when to initiate treatment and evidence of value in additional patient populations. These questions will be answered through data from patient registries, clinicians and payers.

Continued R&D

Research and development of treatments for Hunter syndrome is expected to be directed towards several avenues. In addition to therapeutic combinations, gene-directed therapies may be developed that can potentially increase the effectiveness of therapies that target the neurologic manifestations of Hunter syndrome, given the multiple systems that are affected by this disorder. Newborn screening and diagnostic policies and programs are expected to assume a heightened sense of urgency given the positive impact that early treatment has on neurologic outcome.

Clinicians and Healthsystems

This approval will now require updated care pathways and monitoring for both clinicians and treatment systems (such as the EMR) as well as education of families and healthcare staff regarding the treatment as well as the various measures of functional and developmental monitoring which will go beyond standard laboratory values. Families currently receiving treatment for whom an approval is obtained will feel hope renewed, but with a more realistic understanding of what will be required and what to expect regarding access, logistical challenges and long-term follow-up.

Next Up

The FDA is requiring the conduct of a confirmatory clinical trial to verify the clinical benefit of Avlayah for these indications or withdrawal of approval of these indications. For the families of children afflicted with this terrible disease, Avlayah offers hope. Once approved, Avlayah must continue to be monitored for short-term and long-term side effects. Additionally, a safety protocol will be implemented and its effects monitored. The FDA’s approval of Avlayah for the neurologic manifestations of Hunter syndrome offers patients and families affected by this condition a clinically meaningful therapeutic option. The next challenge is to translate FDA approval into timely, equitable and evidence-based treatment that leads to good outcomes for affected children and their families.

References

1. Muenzer J, Burton BK, Harmatz P, et al. An Intravenous Brain-Penetrant Enzyme Therapy for Mucopolysaccharidosis II. N Engl J Med. 2026;394(1):39-50. doi:10.1056/NEJMoa2508681
2. FDA approves drug to treat neurologic manifestations of Hunter Syndrome. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-neurologic-manifestations-hunter-syndrome. Published March 25, 2026. Accessed April 14, 2026.
3. Denali Therapeutics Announces U.S. FDA Approval of AVLAYAH™ (tividenofusp alfa-eknm) for Treatment of Hunter Syndrome (MPS II). https://investors.denalitherapeutics.com/news-releases/news-release-details/denali-therapeutics-announces-us-fda-approval-avlayahtm. Published March 25, 2026. Accessed April 14, 2026.