Comment from Kyrsten Lawless

Advocacy Summary: Urgent FDA Incentives for Curative Therapies in Alpha-Mannosidosis and LSDs Submitted by: Kyrsten Lawless, Parent/Advocate Date: April 17, 2026 Core Issue Child (nearly 9 years old) with alpha-mannosidosis on weekly Lamzede (velmanase alfa) ERT for 3 years. ERT only addresses non-CNS symptoms, does not cross the blood-brain barrier, and causes significant side effects (rapid 70 lb weight gain, insatiable hunger, sleep disturbance). Treatments paused due to side effects; bone marrow transplant not viable. Family feels lost with no better options available. 1. Clinical & Human Burden Ultra-rare progressive disease (1 in 500,000–1,000,000 births) causing intellectual disability, skeletal issues, hearing loss, ataxia, recurrent infections, muscle weakness, and psychiatric problems. Lifelong dependency on weekly 4-hour infusions, assistive devices, and full-time care. Urgent need for AAV gene therapies and pharmacological chaperones that cross the BBB, provide sustained enzyme production, and offer one-time or oral disease-modifying treatments. 2. Economic Burden to Medicaid & Taxpayers Lifetime ERT + care costs per patient: $58–72+ million (excluding hospitalizations, surgeries, caregiver support, and lost productivity). Annual costs often exceed $250,000 per patient, with ERT driving the vast majority of expenses. One-time curative therapies would deliver massive long-term savings and reduce reliance on public assistance. 3. Market Failure & Need for Stronger Incentives Orphan Drug Act has helped but is insufficient for ultra-rare LSDs with tiny patient populations. Current high-priced recurring ERTs are profitable for large pharma, but deter investment in one-time AAV gene therapies and chaperones by small biotechs and academic labs. Requested enhancements: targeted grants/public-private partnerships, accelerated pathways (RMAT, Breakthrough), enhanced tax credits, milestone funding, and voucher-linked cost reductions. 4. Strong Preclinical Safety Data in Feline Models Naturally occurring cat model closely mirrors human brain pathology and disease progression. CSF-directed AAV1/AAV6-LAMAN therapy showed excellent safety: no vector-related toxicity, genotoxicity, or inflammation, even at high doses. Demonstrated partial correction of storage lesions and improved survival, including in post-symptomatic animals. 5. Proven Track Record of Feline-to-Human Translation in Other LSDs GM1 gangliosidosis (AAV9): Safe in 2026 NEJM Phase 1/2 trial (n=9); minimal serious vector-related events, transient and manageable side effects. Sandhoff and other LSDs (MPS III, MPS I): Feline/cat models successfully de-risked human intracranial/CSF AAV trials with strong safety profiles (no vector-related fatalities or irreversible damage). 6. Readiness for Alpha-Mannosidosis Advancement Existing feline AAV data (same platform and delivery route) already supports human translation. Patient’s genotype is fully addressable by AAV gene addition. Request: Prioritize IND review, Breakthrough/RMAT designation, and natural history study support (e.g., SPARKLE registry). Call to Action: FDA should expand incentives under the Orphan Drug Act and Rare Pediatric Disease Program to accelerate AAV gene therapies and chaperones for LSDs. This will reduce lifelong costs, caregiver burden, and human suffering while leveraging proven translational science for transformative, potentially curative treatments.