PUBLICATIONS

Metabolic

May 28, 2026

Medication insights: tividenofusp alfa-eknm (Avlayah)

In March 2026, the Food and Drug Administration (FDA) approved tividenofusp alfa-eknm (Avlayah), a hydrolytic lysosomal glycosaminoglycan (GAG)-specific enzyme, for the treatment of neurologic manifestations of Hunter syndrome (mucopolysaccharidosis type II, or MPS II) when initiated in presymptomatic or symptomatic pediatric patients weighing at least 5 kg prior to advanced neurologic impairment.¹ Because Avlayah is the first approved product to address neurologic complications of MPS II,² Prime Therapeutics (Prime) sought insight from key opinion leader (KOLs) within our Expert Clinical Network (ECN) who specialize in inborn errors of metabolism. This month’s newsletter summarizes KOL feedback on this newly FDA-approved intravenous (IV) therapy for MPS II.¹˒²
Patient experience 

Prime KOLs highlight that Avlayah’s primary advantage is its ability to cross the blood-brain barrier (BBB), enabling treatment of the neuronopathic form of MPS II. In contrast, the currently available enzyme replacement therapy (ERT) (idursulfase [Elaprase]) does not penetrate the BBB and, therefore, does not address these neurological symptoms. Our KOLs anticipate that physicians managing MPS II will strongly consider transitioning patients from Elaprase to Avlayah.

Because central nervous system (CNS) involvement in this disease profoundly impacts quality of life, Prime KOLs emphasize that families affected by neuronopathic MPS II were closely following this drug’s development. Clinical data demonstrating normalization of cerebrospinal fluid (CSF) glycosaminoglycan levels suggest real potential for improved neurocognitive outcomes. Our KOLs feel that the approval of Avlayah is likely to redefine the standard of care, offering the first systemic therapy to treat both somatic and CNS manifestations until a definitive gene therapy becomes widely available. Prime KOLs also add that this therapy could reduce reliance on the invasive intrathecal clinical trials currently used to reach CNS tissues, decreasing procedural risks and improving accessibility.

As with other ERTs, Prime KOLs anticipate that treatment with Avlayah would be lifelong, given that the underlying enzyme deficiency in MPS II is permanent. With long-term therapy, our KOLs expect Avlayah to support improvements in neurocognition, stabilization of musculoskeletal and somatic symptoms, and enhanced functional independence. Based on early clinical trial results, our KOLs further suggest that patients may experience better quality of life and improved daily functioning, with the potential to attend school, work and live semi-independently. Over time, Prime KOLs indicate that Avlayah may significantly alter the natural history of MPS II, bringing outcomes closer to normalcy.
 

Pipeline

Clemidsogene lanparvovec (RGX-121) is an investigational, one-time intracisternal adeno-associated virus serotype 9 (AAV9) gene therapy delivering the iduronate-2-sulfatase (IDS) gene directly to the CNS. While promising, our KOLs comment that questions remain about durability, immune response and systemic (somatic) efficacy, as the administration is CNS-focused. On Feb. 7, 2026, the FDA issued a complete response letter (CRL) regarding the Biologics License Application (BLA) for RGX-121 for the treatment of MPS II. In its CRL, the FDA acknowledged agreement, in principle, with the study protocol but declined approval, citing concerns regarding whether the trial eligibility criteria adequately defined a population with neuronopathic disease, the comparability of the natural history external control to the study population, and the validity of CSF heparin sulfate (HS) D2S6 as a surrogate endpoint. The agency outlined potential next steps, such as conducting an additional study, enrolling more patients with a longer follow-up and incorporating an untreated control arm, all of which would likely be difficult to implement in an ultra-rare disease like MPS II.³ Prime KOLs suggest that combination approaches, such as pairing gene therapy targeting the brain with systemic ERT, may ultimately emerge as an optimal strategy for comprehensive disease management.

Another pipeline agent, pabinafusp alfa (JR-141), is an ERT that also crosses the BBB and is approved in Japan. If approved in the United States, Prime KOLs explain that it would be mechanistically similar to Avlayah. They point out that clinical guidelines from the Society for Inherited Metabolic Disorders (SIMD) or the American College of Medical Genetics and Genomics (ACMG) will likely determine future therapeutic sequencing, if approved.

According to Prime KOLs, patients with neuronopathic disease ultimately require agents that effectively target both CNS and systemic pathology. Until a durable, whole-body gene therapy becomes available, BBB-penetrant ERTs, such as Avlayah, represent the most comprehensive disease-modifying option for MPS II.

Want more information on this topic and more from our KOLs?

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Our Expert Clinical Network is part of our value-based approach to medical and pharmacy benefit management where customers have access to over 175 national and world-renowned key opinion leaders in multiple disease categories. These experts assist clients with challenging prior authorization case reviews, peer-to-peer discussions, drug policy development and formulary guidance. Our ECN supports health plans and providers to make more informed decisions, leading to positive patient outcomes and avoidance of inappropriate care.
References  
  1. Avlayah. Package insert. Denali Therapeutics; 2026.
  2. Office of the Commissioner. FDA approves drug to treat neurologic manifestations of Hunter syndrome. U.S. Food and Drug Administration. March 25, 2026. Accessed April 6, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-treat-neurologic-manifestations-hunter-syndrome 
  3. REGENXBIO announces regulatory update on RGX-121 BLA for MPS II. REGENXBIO Inc. February 9, 2026. Accessed April 13, 2026. https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-announces-regulatory-update-rgx-121-bla-mps-ii 
The information contained in this report is intended for educational purposes only and is not intended to define a standard of care or exclusive course of treatment, nor be a substitute for treatment. All brand names are property of their respective owners.