RP-A501 (AAV9.LAMP2B)

Danon disease is a rare X-linked disorder caused by loss-of-function variants in the LAMP2 gene (Xq24), which encodes lysosome-associated membrane protein 2. It is characterized by a triad of severe cardiomyopathy, skeletal myopathy, and cognitive impairment, and all known pathogenic variants affect at least the LAMP-2B isoform. A mother with a pathogenic variant has a 50% chance of transmitting it in each pregnancy, and an affected father transmits it to all of his daughters and none of his sons. De novo variants account for more than one third of cases in the 2023 international consensus statement, 40% in one study cited by GeneReviews, and half of the probands in a Japanese survey of 20 families. The consensus statement describes penetrance as likely 100% in both sexes. No estimate of incidence or birth prevalence and no newborn or population screening series was found, and GeneReviews states that the general population prevalence is not known. The available prevalence estimates span about two orders of magnitude. Orphanet lists a prevalence below 1 per 1,000,000 and more than 100 families described in the literature. A 2026 congress abstract that applied three methods reported a range from 240 (United States patients with at least 1 instance of ICD-10 code E74.05 in the TriNetX electronic health record database) to 11,807 (loss-of-function LAMP2 variants in population genomic databases). The 2022 proposal for the ICD-10-CM code extrapolated from a hypertrophic cardiomyopathy prevalence of approximately 1 in 500 and a LAMP2 variant frequency of approximately 1% to 4% of those cases to 10,000 to 25,000 cases in the United States (1 in 12,000 to 1 in 50,000 individuals). Rocket Pharmaceuticals stated a prevalence of 15,000 to 30,000 in the United States and Europe in its Form 10-K filed in February 2026, and in October 2026 presented a modeled United States population of 10,000 to 11,000 (about 4,000 male and 6,000 to 7,000 female), derived from a genotype-based analysis of more than 450 patient records and a phenotype-based analysis of claims and health record databases covering more than 310 million lives. The company reported more than 900 identified United States patients as of July 2026 (45% male and 55% female), which it describes as a diagnosis rate under 10%. The frequency of LAMP2 variants in hypertrophic cardiomyopathy, on which several of these estimates rest, also differs by source: 1% to 4% in the consensus statement, below 1% in a 2022 expert consensus table, 2 of 197 index cases (1%) in a French cohort, 2 of 50 probands (4%) in a United States pediatric cohort, 4 of 64 probands (6%) in a Chinese pediatric cohort, and 4 of 2068 participants with unexplained increased left ventricular wall thickness enrolled across 22 countries or regions.

In the consensus statement, the median age at onset is approximately 14 years in males and ranges between 17 and 35 years in females; males typically progress to end-stage hypertrophic cardiomyopathy in the second or third decade of life, and females reach the end stage a decade or more later. In the International Danon Disease Registry (116 participants, 52 male and 64 female; median follow-up 5.82 years), the median age at diagnosis was 12.4 years in males and 21.9 years in females. A heart failure outcome (heart transplantation, left ventricular assist device, or death) occurred in 21 males (40.4%) and 14 females (21.9%), and heart transplantation in 17 males (32.7%) and 13 females (20.3%). Among those who reached the outcome, the median age was 19 years in males and 26 years in females, and the actuarial median time from birth to the outcome was 25 years in males and 63 years in females. The registry table prints deaths in 7 males (13.5%) and 2 females (3.1%) and a total of 6 (5.2%). In a 2011 registry of 82 participants from 36 families, the text gives mean ages at transplantation and at death of 18.1 and 19.8 years in men and 34.5 and 36.0 years in women, and the population table of the same article prints 20.8 and 20.1 years in men and 32.3 and 40.2 years in women; with 63 published cases added, 59.0% of men and 51.6% of women reached transplantation or death. A systematic review of 146 published cases (90 male and 56 female) found the composite of death, heart transplantation, or ventricular assist device in 37% of males at a median age of 21 years and in 32% of females at a median age of 38 years. In a European registry of 57 participants (30 male and 27 female), 17 (30%) died, at a mean age of 23 years in males and 45 years in females; the mean age at first heart failure hospitalization was 18 years in men, and for women it is given as 28 years in the published abstract and 34 years in the body of the accepted manuscript. In a Japanese survey of 39 participants, 20 of the 21 who had died (95%) died of cardiac failure or sudden cardiac arrest, at a mean age of 19 years in males and 37 years in females. Rates of change in untreated males, the reference for the single-arm trials of RP-A501, differ by source. In mixed-effects models of the International Danon Disease Registry, left ventricular mass in males increased by 28.424 g per year of age in 20 participants without a heart failure outcome and by 34.183 g per year in 13 participants with one, left ventricular ejection fraction decreased by 0.888 and 2.461 percentage points per year, and left ventricular mass in females did not change significantly (P=0.5037 and P=0.482). The company's October 2026 presentation cites unpublished data from the same registry: left ventricular mass increasing by 39.86 ± 4.01 g per year and BNP by 42.17 ± 18.46 pg/mL per year in untreated males. An earlier abstract from the registry (112 participants) reported that BNP did not change over time. In a prospective study of 9 males (mean age 11.6 years at enrollment), mean NT-proBNP rose from 932.2 to 1903.6 pg/mL over a mean follow-up of 18.6 months, a statistically significant increase, and mean high-sensitivity troponin T rose from 41.1 to 78.4 ng/L, which was not significant; among the pediatric participants, the average paired differences in left ventricular ejection fraction (-5.9) and left ventricular mass (+64 g) were not statistically significant.

Extracardiac disease is more frequent in males. In the systematic review of 146 cases, males presented with the triad of cognitive impairment, skeletal myopathy, and hypertrophic cardiomyopathy in 42% of cases and females with isolated cardiac disease in 73%; cardiomyopathy was hypertrophic in 96.2% of males, and hypertrophic in 70.3% and dilated in 29.3% of females. In the European registry, all males and 10 of 27 females had at least 1 extracardiac manifestation, clinically significant skeletal myopathy was present in 60% of males and 3% of females, and liver transaminases were elevated in 83% of males and 6% of females. The consensus statement reports mild cognitive impairment and learning difficulties in at least 80% of males and between 6% and 47% of females, supraventricular and ventricular arrhythmias in approximately 60% of individuals, and heart block or sinus node dysfunction requiring a pacemaker in 35% to 50%. A Wolff-Parkinson-White pattern was reported in 68% of men and 27% of women in the 2011 registry and in 19.8% of the 116 participants of the International Danon Disease Registry. A systematic review of ophthalmic findings in 70 patients found retinal abnormalities in 81% and macular involvement in 62%, and in a psychiatric evaluation of 13 participants, 9 (69.2%) met criteria for at least one psychiatric disorder. Quality of life evidence consists of one prospective study of 9 males and one abstract of 10 participants. In the prospective study, average total scores on the Pediatric Cardiac Quality of Life Inventory and on a 23-question pediatric quality of life questionnaire were below 60 of 100 at baseline and at follow-up for both children and parents (on the second instrument, a baseline total of 53.4 ± 17.6 reported by children and 44.9 ± 8.6 reported by parents); the authors cite mean totals between 60 and 80 for children with congenital heart disease not requiring catheter or surgical correction and 68.9 ± 16 for children with cancer on treatment. In the abstract, Kansas City Cardiomyopathy Questionnaire summary scores were lower in participants with an implanted defibrillator than in those without. The authors of both reports state that these instruments are not validated in Danon disease, and no health state utility value, Voice of the Patient report, or published study of caregiver time, work loss, or out-of-pocket cost was found. Caregiver evidence is limited to statements by a patient organization and by families quoted in a company presentation; in the Japanese survey, 10 of 20 mothers (50%) were themselves symptomatic.

No approved therapy treats the cause of the disease. The consensus statement states that there are “no available therapies to specifically treat Danon disease” and that management is largely based on expert opinion and extrapolation from hypertrophic cardiomyopathy guidelines, and no controlled trial of a heart failure drug in Danon disease was found. In the International Danon Disease Registry, 45 of 116 participants (38.8%) had a cardiovascular implantable electronic device, which was a defibrillator in 43 (37.1%), and in the European registry 38 of 57 participants (67%) received an implantable device. In a series of 7 participants, 1 died at age 12 from ventricular fibrillation refractory to defibrillator therapy. Heart transplantation was performed in 30 of 116 registry participants (25.9%), and a 2024 review cites 17.6%. Among 38 recipients from 8 centers, the median age at transplantation was 20.2 years, 2 died, 2 underwent retransplantation, and estimated 5-year graft survival was 87.1% (95% CI 63.6% to 95.9%). In the European registry, 5 of 8 male recipients of a transplant or assist device (62%) died within one year of the procedure, and no death was reported among females receiving a transplant during a mean follow-up of 10.6 years. No cost of illness or healthcare resource utilization study specific to Danon disease was found, and the available cost evidence consists of benchmarks from other populations. For heart transplantation in the United States for all diagnoses, Milliman estimated 2025 billed charges of $1,918,700 per transplant, covering 30 days before transplantation to 180 days after discharge and including $1,220,400 for the hospital transplant admission. Among 2896 pediatric heart transplant recipients (2002 to 2016), total hospitalization costs in 2016 dollars were $906,454 in the second era studied and $767,221 in the third; among 2873 pediatric recipients, total hospitalization costs were $755,345 with a ventricular assist device and $457,086 without mechanical circulatory support. The hospitalization cost of left ventricular assist device implantation in adults was $234,808 in 2011. Median charges per pediatric heart failure-related hospitalization were $72,087 in 2009, the mean cost of an adult hospitalization with primary heart failure was $11,552 in 2014, and adjusted total hospital charges for a defibrillator placement admission were $132,455 in adults without congenital heart disease and $147,002 in adults with it. Adults with obstructive hypertrophic cardiomyopathy in commercial and Medicare supplemental claims had incremental costs of approximately $20,000 per year compared with matched controls, and approximately $35,000 per year when symptomatic. For diagnosis, the 2026 Florida Medicaid independent laboratory fee schedule lists $392.06 for procedure code 81439, a hereditary cardiomyopathy sequencing panel, and a sponsored program offers genetic testing at no charge to patients in the United States aged 40 years or younger with a high suspicion of an inherited cardiomyopathy.