Age-based approvals for rare diseases can be devastating

For most of my life, my family has been advocating for therapies to help my twin brother. While the recent approval of a new drug should give us reason to celebrate, there is still more work to do.

My twin brother is 28 years old and has severe Hunter syndrome, also known as mucopolysaccharidosis (MPS) type II. Hunter syndrome is a rare condition caused by the deficiency of an enzyme needed to break down sugars called glycosaminoglycans (GAGs). Due to this enzyme deficiency, GAGs accumulate to toxic levels throughout the body, resulting in progressive multi-organ disease.

Since 2006, the only FDA-approved treatment has been enzyme replacement therapy with idursulfase (Elaprase). While Elaprase addresses some of the somatic symptoms of Hunter syndrome, it does not treat neurological symptoms due to its inability to cross the blood-brain barrier. Consequently, patients suffer from progressive neurodegeneration and early death.

Ever since he received his diagnosis at the age of 2, my brother has gradually lost the ability to communicate verbally and is now fully dependent on others for care. It has been heartbreaking to watch what this disease has taken from him and our family, and we constantly worry about what lies ahead.

The Hunter syndrome community is small, and in recent months, multiple people — many in their teens and early adulthood — have passed away. I have begun to dread opening social media, where I often find news of another devastating loss. We desperately need better treatments that stop both the physical and neurological decline of the disease, so families like mine can focus on living fully instead of worrying about how much time we have left.

This is why the FDA’s recent approval of a new drug for Hunter syndrome should feel like a major achievement. On March 25, the FDA granted accelerated approval for Avlayah (tividenofusp alfa-eknm), a weekly enzyme replacement therapy designed by Denali Therapeutics to cross the blood-brain barrier and treat both neurological and somatic symptoms. This approval represents a major breakthrough as the first new therapeutic innovation for Hunter syndrome in 20 years, and the only FDA-approved therapy designed to treat the neurological symptoms of the disease.

Yet while the approval of Avlayah represents a meaningful milestone, it falls short of a true victory for many families, including my own. Under the current FDA label, Avlayah is approved to treat only pediatric patients with Hunter syndrome through the age of 16.

The FDA’s choice to restrict Avlayah to pediatric patients stems from the phase 1/2 trial of the drug, which included patients ages 3 months to 13 years. However, this reflects the patients available for study during the trial, rather than a clinical determination that only pediatric patients would benefit from treatment.

In fact, scientific evidence suggests patients above the age of 16 would benefit significantly from Avlayah because GAGs accumulate and cause disease progression in adults following the same pathophysiological mechanism seen in children. Since Avlayah reduces this GAG accumulation, its ability to treat disease progression should be the same in both children and adults. This reasoning matches previously approved enzyme replacement therapies for other diseases that do not have an upper age limit and is supported by the ongoing phase 2/3 trial that includes participants up to age 26, signifying Denali Therapeutics recognizes that clinical benefit extends beyond the ages covered by the current FDA-approved label.

Therefore, while accelerated approval helps bring therapies to patients faster, families like mine need the FDA to approve therapies based on what science strongly suggests: Adults with Hunter syndrome can benefit from Avlayah due to its ability to prevent further disease progression and should be given equal access to treatment.

Due to the age restrictions set by the FDA, physicians must prescribe Avlayah off-label to help anyone above age 16. Insurance companies may consequently deny coverage, forcing patients, families, and providers into a lengthy appeals process requiring multiple letters, calls, and meetings with no guarantee of success. During this time-consuming process, patients may experience further physical and neurological decline that may lead to irreversible organ damage.

In addition to harming patient health, this long appeals process also places substantial strain on physicians. According to a 2024 survey from the American Medical Association, physicians and their staff spend on average 13 hours per week writing prior authorization and appeal letters, causing approximately 90% of physicians to report increased burnout from this appeals process alone. If insurance coverage is ultimately denied, patients may face a staggering annual cost between $270,000-$811,000, depending on the dose required by their weight. By limiting Avlayah to pediatric patients, the FDA creates harmful barriers to care which result in substantial health and financial disparities.

Notably, some adults with Hunter syndrome can access Avlayah if they initiated treatment with the drug in a clinical trial as children. Although this continuity of treatment is necessary, it raises ethical concerns around equitable care and justice, as patients with the same disease are treated differently based on whether they had the opportunity and resources to participate in a clinical trial as children. Adults who were not part of the early trials are forced to fight for access, leading to further health and economic disparities within the same patient community.

While Denali is conducting a phase 2/3 trial to confirm clinical benefit in a larger cohort of patients, including participants up to age 26, these confirmatory trials can take years to complete. Patients with Hunter syndrome do not have this time to wait, as disease progression is an ongoing process that can lead to irreversible organ damage. Furthermore, there is no guarantee the FDA will extend the label to include patients of all ages after trial completion. Given the scientific evidence suggests adults will benefit from treatment and that similar therapies are not limited by age, all adults with Hunter syndrome should be given access to Avlayah now without having to wait for additional trials.

With advances in medicine, people with Hunter syndrome and other rare diseases are increasingly surviving into adulthood. While this is a remarkable achievement, rare disease clinical trials, policy discussions, and advocacy initiatives are still centered predominantly around pediatric populations, leaving many adults overlooked. To improve outcomes, we must design clinical trials that enroll patients across the lifespan, ensure patients are not denied therapies based solely on age, and include adults in all rare disease advocacy, policy, and drug development decisions.

Surviving into adulthood should not mean being excluded from hopeful therapies. Like so many others, my brother does not have decades to wait for additional clinical trials with the potential for an expanded FDA label.

Nathan Grant is an M.D./M.B.A. student at Harvard Medical School and Harvard Business School, a researcher at Boston Children’s Hospital, a board member of Project Alive, and the president and founder of Siblings with a Mission.