Labeling status: investigational product with no approved prescribing information

“RP-A501 is investigational, and its safety and efficacy have not been established.” (opens the source at this quote in a new tab)
“Clinical observations presented here are based on small, uncontrolled studies with varying follow-up.” (opens the source at this quote in a new tab)

“The product is not authorised anywhere in the European Community.” (opens the source at this quote in a new tab)

Thrombotic microangiopathy: phase 1 participant at 1.1 × 10¹⁴ GC/kg, first report in December 2020

“At the higher dose administered (1.1×10¹⁴ gc/kg), one of the two treated patients, who received the higher absolute AAV9 dose and had some degree of pre-existing anti-AAV9 immunity, experienced a non-persistent, immune-related event that was classified as a drug product-related serious adverse event.” (opens the source at this quote in a new tab)
“This was believed to be likely due to complement activation, resulting in reversible thrombocytopenia and acute kidney injury requiring ecumizumab and transient hemodialysis.” (opens the source at this quote in a new tab)
“This patient returned to baseline within three weeks and regained normal kidney function.” (opens the source at this quote in a new tab)

“Patient with enhanced risk due to high weight & vector dose and pre-existing AAV immunity” (opens the source at this quote in a new tab)
“Anticipated SAE of atypical hemolytic-uremic syndrome (aHUS) resulting in reversible thrombocytopenia and acute kidney injury (AKI)” (opens the source at this quote in a new tab)
“AKI required supportive care including eculizumab and transient hemodialysis with full return to baseline kidney function within 2-3 weeks” (opens the source at this quote in a new tab)

Thrombotic microangiopathy: grade and classification of the phase 1 event

“One patient had complement-mediated thrombotic microangiopathy (grade 4) with thrombocytopenia and acute kidney injury.” (opens the source at this quote in a new tab)

“No new drug-related safety events were observed in the low- or higher-dose adult cohorts; the previously disclosed SAE of thrombotic microangiopathy, which has since resolved, was reclassified as a SUSAR.” (opens the source at this quote in a new tab)

“One patient treated with 1.1 x 10¹⁴ GC/kg had complement-mediated thrombocytopenia and acute kidney injury requiring transient hemodialysis that fully recovered.” (opens the source at this quote in a new tab)

Thrombotic microangiopathy: factors the sponsor associated with the phase 1 event, November 2021

“RP-A501 r-AAV dose-dependent toxicity was seen at 1.1x10¹⁴ GC/kg dose levels” (opens the source at this quote in a new tab)
“One of two patients developed thrombotic microangiopathy (TMA)” (opens the source at this quote in a new tab)
“Acute renal failure managed with hemodialysis and eculizumab” (opens the source at this quote in a new tab)
“Baseline LV systolic failure may have contributed” (opens the source at this quote in a new tab)
“Largest patient in clinical trial (>90kg) who received highest total dose (1.06 x 10¹⁶ GC)” (opens the source at this quote in a new tab)

Thrombotic microangiopathy: weight and total vector dose of phase 1 participant 1007

Participant	Age at treatment	Dosing weight	Cohort dose	Total dose
1007	“20 y”	“96.7 kg”	“1.1 x 10¹⁴ GC/kg”	“1.06 x 10¹⁶ GC”

Clinical hold on the phase 1 trial, May 2021

“No new drug-related safety events have been observed in the low- or high-dose adult cohorts of the Phase 1 trial.” (opens the source at this quote in a new tab)
“The U.S. Food and Drug Administration (FDA) has requested the Company to pause patient dosing and modify the protocol and other supporting documents with revised guidelines for patient selection and management.” (opens the source at this quote in a new tab)
“All follow-up study activities will continue and no additional data are requested.” (opens the source at this quote in a new tab)
“Rocket does not anticipate pursuing doses higher than 1.1x10¹⁴ moving forward.” (opens the source at this quote in a new tab)

Discontinuation of the 1.1 × 10¹⁴ GC/kg dose, August 2021

“Given the positive benefit/risk profile in the low dose, and additionally to mitigate safety concerns observed at the higher dose, in agreement with FDA we will no longer treat Danon patients with the higher dose (1.1e14).” (opens the source at this quote in a new tab)
“In agreement with FDA, Rocket will no longer continue dosing patients at the higher dose (1.1e14).” (opens the source at this quote in a new tab)

Lifting of the phase 1 clinical hold, August 16, 2021

“The hold was removed after the Company addressed the FDA’s requests to modify the trial protocol and other supporting documents with revised guidelines for patient selection and management.” (opens the source at this quote in a new tab)
“The Company has initiated steps to resume the program as soon as possible and expects to commence dosing in the low-dose (6.7e13 vg/kg) pediatric patient cohort in the third quarter.” (opens the source at this quote in a new tab)

Risk mitigation adopted after the phase 1 high-dose event

“No further enrollment at HIGHER dose” (opens the source at this quote in a new tab)
“Corticosteroids: Limit daily dose” (opens the source at this quote in a new tab)
“Sirolimus: Minimize renal impact” (opens the source at this quote in a new tab)
“Frequent monitoring for early signs of TMA” (opens the source at this quote in a new tab)
“Rituximab continued” (opens the source at this quote in a new tab)

“Based on the initial efficacy observed in the low dose cohort and to mitigate complement-mediated safety concerns observed in the high dose cohort (related to thrombotic microangiopathy or TMA) and in agreement with the FDA, the Phase 2 study was initiated at the low dose (6.7e13 gc/kg).” (opens the source at this quote in a new tab)
“These measures include exclusion of patients with end-stage HF, and a refined immunomodulatory regimen involving transient B- and T-cell mediated inhibition, with emphasis on preventing complement activation, while also enabling lower steroid doses and earlier steroid taper, with all immunosuppressive therapy discontinued 2-3 months following administration of RP-A501.” (opens the source at this quote in a new tab)

Serious adverse events of interest and platelet changes by phase 1 cohort, data cut September 27, 2022

Measure	Low-dose adult cohort (6.7 × 10¹³ GC/kg)	High-dose adult cohort (1.1 × 10¹⁴ GC/kg)	Low-dose pediatric cohort (6.7 × 10¹³ GC/kg)
Serious adverse events of interest	“n=2 grade 3 steroid myopathy”	“n=1 grade 3 steroid myopathy”“n=1 grade 4 TMA”	“none”
Platelets	“n=2, Grade 1 decrease(to LLN range)”	“n=1, Grade 4 decrease”	“Remain in normal range”

Platelet decreases and transaminase elevations in the phase 1 low-dose adult cohort

“Elevation in transaminases was observed in all three low-dose patients and returned to baseline within the first one to two months post-treatment.” (opens the source at this quote in a new tab)
“There was also a transient and reversible decline in platelets observed in these three patients.” (opens the source at this quote in a new tab)
“These changes were largely responsive to corticosteroids and other immunosuppressive therapies.” (opens the source at this quote in a new tab)

“Reversible platelet decreases and transaminase elevations that returned to baseline within 2 months were seen.” (opens the source at this quote in a new tab)

Complement and platelet monitoring in the phase 1 pediatric cohort

“Platelet counts remained within normal range with modest decreases during days 6-14 post-infusion.” (opens the source at this quote in a new tab)
“Complement soluble membrane attack complex (sC5b-9) increased during days 5-14 post-infusion; no increases >200ng/mL over any 24 hour period were observed; peak values remained <450ng/mL (ULN 250 ng/mL) and were markedly lower than those observed in the adult cohort.” (opens the source at this quote in a new tab)
“Hemoglobin and creatinine levels remained stable during the initial weeks post-infusion.” (opens the source at this quote in a new tab)

“Minimal complement activation” (opens the source at this quote in a new tab)
“No complement-related clinical or laboratory AEs” (opens the source at this quote in a new tab)
“No treatment-related SAEs” (opens the source at this quote in a new tab)

Thrombotic microangiopathy and renal events in the phase 2 trial by cohort, as of August 7, 2026

Grade 3 or higher serious treatment-emergent adverse event related to RP-A501, n (%)	Cohorts 1 and 2, 6.7 × 10¹³ GC/kg (n=4)	Cohort 3, 6.7 × 10¹³ GC/kg with C3 inhibitor (n=2)	Cohort 4, 3.8 × 10¹³ GC/kg (n=3)
Participants with at least 1 event	“3 (75.0)”	“2 (100)”	“1 (33.3)”
Thrombotic microangiopathy	“2 (50.0)”	“1 (50.0)”	“0”
Acute kidney injury	“1 (25.0)”	“1 (50.0)”	“0”
Renal failure	“1 (25.0)”	“0”	“0”

“Grade ≥3 Serious Treatment Emergent Adverse Events Related to RP-A501” (opens the source at this quote in a new tab)
“Patients 2-3, 2-4 and 2-6” (opens the source at this quote in a new tab)

Phase 2 thrombotic microangiopathy cases before May 2025: analyst account of the company conference call

“Regarding the TMA events, one case was linked to a genetic mutation that confers complement sensitivity, and the company has implemented a revised protocol to exclude patients who are genetically predisposed to increased risk for complement activation,” (opens the source at this quote in a new tab)
“Importantly, the patients that did develop TMA earlier in the trial are doing well now from a safety perspective.” (opens the source at this quote in a new tab)

Capillary leak syndrome and death in the phase 2 trial: first disclosure, May 27, 2025

“A patient participating in the Phase 2 pivotal trial of RP-A501 experienced an unexpected Serious Adverse Event (SAE).” (opens the source at this quote in a new tab)
“The SAE involved clinical complications related to a capillary leak syndrome.” (opens the source at this quote in a new tab)
“Upon learning of the initial event, Rocket voluntarily paused further dosing in the study.” (opens the source at this quote in a new tab)
“On May 23, 2025, the FDA placed a clinical hold on the trial to allow for further evaluation.” (opens the source at this quote in a new tab)
“Rocket is deeply saddened to report that this patient has since passed away after an acute systemic infection.” (opens the source at this quote in a new tab)

Capillary leak syndrome: two participants affected, with multi-organ damage

“In May 2025, two patients participating in the Phase 2 pivotal study of RP-A501 each experienced an unexpected SAE.” (opens the source at this quote in a new tab)
“The SAEs involved clinical complications related to a capillary leak syndrome resulting in multi-organ damage; one patient died as a result of these complications following an acute systemic infection.” (opens the source at this quote in a new tab)
“Rocket voluntarily paused further Phase 2 study dosing in the U.S. and EU, and the FDA subsequently placed the trial on clinical hold on May 23, 2025 to allow for further evaluation.” (opens the source at this quote in a new tab)

Capillary leak syndrome: timing of onset and exposure to the C3 inhibitor

“During the conference call, Shah said the patient experienced signs of CLS about a week after receiving RP-A501 in early May.” (opens the source at this quote in a new tab)
“The C3 inhibitor was given pre- and post-RP-A501 treatment in combination with the enhanced prophylactic immunosuppressive regimen of sirolimus, rituximab (marketed as Rituxan® by Genentech, a member of the Roche Group, and Biogen), and prednisone.” (opens the source at this quote in a new tab)
“A second patient also received the modified immunosuppression regimen, including the C3 inhibitor, and also exhibited early signs of CLS but had a reduced course of the C3 inhibitor, which, according to Rocket, further supports its hypothesis that the compound played a role in the development of CLS.” (opens the source at this quote in a new tab)

“Two patients received the immune suppression agent, company CEO Gaurav Shah explained on a conference call Tuesday morning.” (opens the source at this quote in a new tab)
“Rocket was able to reduce the treatment course the second patient received after seeing early signs of capillary leak syndrome in the first.” (opens the source at this quote in a new tab)

Capillary leak syndrome: the added immune suppression agent

“Rocket is conducting a comprehensive root cause analysis and remains in active dialogue with the U.S. Food and Drug Administration (FDA) and other key stakeholders, with the current focus being on the recent introduction of a novel immune suppression agent to the pre-treatment regimen that had been implemented to mitigate complement activation observed in some patients.” (opens the source at this quote in a new tab)
“This novel agent was specific to the AAV9-Danon program.” (opens the source at this quote in a new tab)

“Rocket is carefully evaluating whether a mechanism related to the new agent may have influenced immune responses in an unexpected or paradoxical way,” (opens the source at this quote in a new tab)

“Cohort 3: Males age ≥ 8 years receiving a pegcetacoplan-containing immunomodulatory regimen [N=2 subjects; enrollment closed]” (opens the source at this quote in a new tab)
“Pegcetacoplan was incorporated into the immunomodulation regimen for Cohort 3 but excluded in Cohort 4.” (opens the source at this quote in a new tab)

Capillary leak syndrome: conclusion of the investigation on cause, as stated in the February 2026 annual report

“In August 2025, the FDA lifted the clinical hold on the Phase 2 pivotal study following an investigation which concluded that the SAEs were likely the result of the combination of the C3 component inhibitor introduced into the immunomodulation regimen and RP-A501.” (opens the source at this quote in a new tab)
“As a result, we voluntarily paused further Phase 2 study dosing in the U.S. and EU, and the FDA subsequently placed the trial on clinical hold to allow for further evaluation, which was lifted in August 2025 after the investigation traced the unexpected SAEs to a protocol amendment that added a C3 inhibitor to the immunomodulatory regimen.” (opens the source at this quote in a new tab)

Capillary leak syndrome: mechanism proposed in a 2026 commentary

“The safety review concluded that the severe adverse events were likely the result of the combination of the complement C3 inhibitor introduced into the immunomodulation regimen and the investigational product.” (opens the source at this quote in a new tab)
“A potential mechanism has subsequently been proposed, whereby complement inhibition with the C3 inhibitor may have reduced AAV opsonization and increased vector uptake by endothelial cells, leading to vascular endothelial injury” (opens the source at this quote in a new tab)

Serious events in the two phase 2 participants who received the C3 inhibitor regimen (cohort 3), as of August 7, 2026

Grade 3 or higher serious treatment-emergent adverse event related to RP-A501, n (%)	Cohorts 1 and 2 (n=4)	Cohort 3 (n=2)	Cohort 4 (n=3)
Aplastic anemia	“0”	“1 (50.0)”	“0”
Disseminated intravascular coagulation	“0”	“1 (50.0)”	“0”
Cytokine release syndrome	“0”	“1 (50.0)”	“0”
Hypertransaminasaemia	“0”	“1 (50.0)”	“0”
Pneumothorax	“0”	“1 (50.0)”	“0”
Sepsis	“0”	“1 (50.0)”	“0”
Shock	“0”	“1 (50.0)”	“0”
Retroperitoneal hemorrhage	“0”	“1 (50.0)”	“0”

“In Phase 2 Cohort 3, two patients treated with immunomodulatory regimen containing a C3-inhibitor experienced serious adverse events.” (opens the source at this quote in a new tab)
“Cohort 3 is discontinued and data from the two subjects were not included.” (opens the source at this quote in a new tab)

Description of the fatal event in the October 2026 company release

“Safety findings from the original-dose study, including thrombotic microangiopathy and a fatal serious adverse reaction, informed the recalibrated dose, revised immunomodulation regimen and enhanced safety monitoring now in place.” (opens the source at this quote in a new tab)

Protocol changes when the phase 2 clinical hold was lifted, August 20, 2025

“The FDA authorized the pivotal study to resume first with a recalibrated dose of 3.8 x 10¹³ GC/kg of RP-A501 in three patients, treated sequentially with a minimum four-week interval between each treatment.” (opens the source at this quote in a new tab)
“The revised regimen discontinues prophylactic use of a C3 complement inhibitor, while maintaining sirolimus, rituximab, and steroids.” (opens the source at this quote in a new tab)
“Additionally, the protocol will specify a lower threshold for administering a C5 inhibitor (eculizumab) in response to impending complement activation.” (opens the source at this quote in a new tab)
“To date, six patients with Danon disease have been treated in the Phase 2 study with RP-A501.” (opens the source at this quote in a new tab)

“The modified protocol incorporates a recalibrated RP-A501 dose and an optimized immunomodulatory regimen comprised of rituximab, sirolimus and corticosteroids, together with enhanced eligibility criteria, safety monitoring and risk-mitigation measures.” (opens the source at this quote in a new tab)

Safety in the first three participants dosed at 3.8 × 10¹³ GC/kg under the modified protocol: August and September 2026 statements

“Treatment proceeded sequentially, with a minimum of four weeks between infusions.” (opens the source at this quote in a new tab)
“To date, no thrombotic microangiopathy (TMA), capillary leak syndrome, or other significant safety concerns have been observed in these patients.” (opens the source at this quote in a new tab)

“The clinical data reviewed by FDA included results from the first three patients treated under the modified protocol.” (opens the source at this quote in a new tab)
“All three completed at least four weeks of follow-up and had been discharged following protocol-specified observation.” (opens the source at this quote in a new tab)
“No clinical or laboratory evidence of thrombotic microangiopathy or capillary leak syndrome had been observed.” (opens the source at this quote in a new tab)
“Following its review of the available safety data, the FDA confirmed continued enrollment and dosing under the modified protocol at the recalibrated dose.” (opens the source at this quote in a new tab)

Safety in the first three participants dosed at 3.8 × 10¹³ GC/kg: follow-up through about 3 months, as of September 4, 2026

“No evidence of thrombotic microangiopathy, capillary leak or other complement-mediated events” (opens the source at this quote in a new tab)
“Elevated GGT observed in 1 patient; resolved and patient discharged after 12 days.” (opens the source at this quote in a new tab)
“All 3 patients discharged by 1-2 weeks post-infusion” (opens the source at this quote in a new tab)
“No TMA, capillary leak, or significant complement-mediated adverse events through 3 months in the first three patients” (opens the source at this quote in a new tab)
“Initial safety follow-up is limited for Phase 2 Cohort 4.” (opens the source at this quote in a new tab)
“One RP-A501-related Grade 3 increase in gamma-glutamyltransferase (GGT) was reported and resolved.” (opens the source at this quote in a new tab)
“Safety data as of September 4, 2026.” (opens the source at this quote in a new tab)

Platelet counts and soluble C5b-9 in the first three cohort 4 participants, as of September 4, 2026

“Platelets and Terminal Complement Complex (sC5b9) of the initial 3 patients up to 3 months post-treatment” (opens the source at this quote in a new tab)
“A decrease in platelet count was observed at Week 8-9 in the absence of symptoms or signs suggestive of platelet dysfunction or deficit.” (opens the source at this quote in a new tab)
“All concomitant medications were reviewed to discontinue any potential contributors; it was not deemed clinically significant by the investigator and Sponsor and resolved following medication modifications.” (opens the source at this quote in a new tab)
“The sC5b9 lower limit of detection per the validated assay at the clinical site is <170 ng/mL; reported values of <170 ng/mL are shown as 170 ng/mL.” (opens the source at this quote in a new tab)

Hepatic events in the phase 2 trial by cohort, as of August 7, 2026

Grade 3 or higher serious treatment-emergent adverse event related to RP-A501, n (%)	Cohorts 1 and 2 (n=4)	Cohort 3 (n=2)	Cohort 4 (n=3)
Gamma-glutamyltransferase increased	“0”	“0”	“1 (33.3)”
Hepatic enzyme increased	“1 (25.0)”	“0”	“0”
Hypertransaminasaemia	“0”	“1 (50.0)”	“0”

Hepatic laboratory findings in the phase 1 pediatric cohort

“Transaminases and liver-focused parameters (GGT and bilirubin) were also largely stable.” (opens the source at this quote in a new tab)

“No reported skeletal myopathy or late transaminitis with initial steroid dose-reduction and more rapid taper, and introduction of sirolimus” (opens the source at this quote in a new tab)

Transaminase elevation as a baseline feature of Danon disease in the phase 1 eligibility criteria

“Adequate hepatic function as defined by: AST and ALT ≤10.0×ULN or GGT ≤2.0×ULN (transaminase elevations in DD are considered extensively to result from muscle injury; hence the relatively high upper limit for transaminases and consideration of GGT level, and the presence of additional hepatic eligibility markers of bilirubin and PT/INR).” (opens the source at this quote in a new tab)

Corticosteroid-associated skeletal myopathy in phase 1

“Three patients had glucocorticoid-related exacerbation (grade 3) of Danon disease-related skeletal myopathy.” (opens the source at this quote in a new tab)

“An exacerbation of skeletal myopathy in 3 of the 5 patients resolved with steroid taper.” (opens the source at this quote in a new tab)

“Managed with a steroid-sparing regimen, steroid induced exacerbations of DD-related skeletal myopathy in the pediatric patients were limited relative to those reported in the adult cohort.” (opens the source at this quote in a new tab)

Changes to the immunomodulatory regimen during phase 1 and their stated reasons

“During the study, the immunomodulatory regimen was progressively adapted: steroid doses were reduced to mitigate steroid-induced myopathy, tacrolimus was replaced with sirolimus to reduce the risk of renal toxicity, and rituximab was introduced.” (opens the source at this quote in a new tab)

“All the patients received a transient immunomodulatory regimen of prednisone, tacrolimus or sirolimus, and rituximab.” (opens the source at this quote in a new tab)

Infection: events reported with RP-A501 and its immunomodulatory regimen

“Salmonella Sepsis” (opens the source at this quote in a new tab)

“Rocket is deeply saddened to report that this patient has since passed away after an acute systemic infection.” (opens the source at this quote in a new tab)

“The SAEs involved clinical complications related to a capillary leak syndrome and were followed by a systemic infection and multi-organ damage, ultimately leading to one of the patient’s deaths.” (opens the source at this quote in a new tab)

Infection: vaccination and infection-related eligibility criteria in the phase 1 protocol

“Patient has received meningococcal vaccination recommended by Centers for Disease Control as appropriate for age and health condition (vaccination must be performed at least 6 weeks prior to IP administration).” (opens the source at this quote in a new tab)
“Significant medical conditions including documented human immunodeficiency virus (HIV) infection, active viral or other hepatitis, poorly-controlled hypertension or diabetes, poorly controlled cardiac arrhythmia, or uncontrolled viral, bacterial, or fungal infection.” (opens the source at this quote in a new tab)
“Active or latent tuberculosis.” (opens the source at this quote in a new tab)

Cardiac and neurologic serious events in phase 2 cohorts 1 and 2, as of August 7, 2026

Grade 3 or higher serious treatment-emergent adverse event related to RP-A501, n (%)	Cohorts 1 and 2 (n=4)	Cohort 3 (n=2)	Cohort 4 (n=3)
Cardiac arrest	“1 (25.0)”	“0”	“0”
Posterior reversible encephalopathy syndrome	“1 (25.0)”	“0”	“0”
Rhabdomyolysis	“1 (25.0)”	“0”	“0”

Troponin after infusion in the phase 1 pediatric cohort

“Limited and transient troponin increases were noted, consistent with known AAV9 cardiotropism.” (opens the source at this quote in a new tab)

Heart transplantation 5 months after infusion in the phase 1 participant with reduced ejection fraction: attribution, with baseline ejection fraction given as 32%

“One patient with left ventricular systolic dysfunction at baseline had progressive heart failure and underwent transplantation 5 months after infusion.” (opens the source at this quote in a new tab)

“This patient had more advanced disease than the four other adult/older adolescent patients who received treatment in the low and high dose cohorts, as evidenced by diminished baseline left ventricle ejection fraction (32%) on echocardiogram and markedly elevated left ventricle filling pressure prior to treatment.” (opens the source at this quote in a new tab)
“The patient’s clinical course was characteristic of DD progression.” (opens the source at this quote in a new tab)
“The patient is doing well post-transplant.” (opens the source at this quote in a new tab)

“One adult pt with baseline LV systolic dysfunction required heart transplant at 5m post RP-A501, most likely related to DD progression.” (opens the source at this quote in a new tab)

Heart transplantation 5 months after infusion: clinical course and explant findings presented in November 2021, with baseline ejection fraction given as 35%

“Diminished LV EF (35%)” (opens the source at this quote in a new tab)
“All echocardiographic parameters from local site assessment” (opens the source at this quote in a new tab)
“Markedly elevated LV filling pressure (PCWp 26 mmHg)” (opens the source at this quote in a new tab)
“Prior evidence of fibrosis on MRI” (opens the source at this quote in a new tab)
“Increased frequency of ventricular arrhythmias” (opens the source at this quote in a new tab)
“Uncontrolled arrhythmias resulting in decompensated heart failure” (opens the source at this quote in a new tab)
“Heart transplant (Month 5)” (opens the source at this quote in a new tab)
“Danon Disease progression determined as primary cause” (opens the source at this quote in a new tab)
“Severe fibrosis” (opens the source at this quote in a new tab)
“No evidence of inflammation” (opens the source at this quote in a new tab)

Second heart transplantation in a phase 1 participant, 4.8 years after infusion

“Patient underwent heart transplant at 4.8 years post-RP-A501 infusion; post data cut.” (opens the source at this quote in a new tab)
“Data Extraction Date: July 31, 2026” (opens the source at this quote in a new tab)

Survival during phase 1 follow-up

“At 24 to 54 months, all the patients were alive, with complete resolution of side effects.” (opens the source at this quote in a new tab)

“100% overall survival; median transplant-free survival not reached at median follow-up: 5.7 years (range: 4.3–7.1 years)” (opens the source at this quote in a new tab)

Timing of serious adverse events after infusion in phase 1, data cut September 27, 2022

“All SAEs observed within initial 2-4 months following dosing; reversible with supportive care” (opens the source at this quote in a new tab)
“No additional SAEs observed following initial 2-4 months” (opens the source at this quote in a new tab)

Dorsal root ganglion or sensory neuropathy findings with RP-A501

No evidence found.

Re-administration after anti-AAV9 antibody formation

“Finally, the inability to re-dose due to neutralizing antibody formation remains a major limitation of current AAV platforms, emphasizing the importance of first-dose optimization and long-term durability assessment.” (opens the source at this quote in a new tab)

Regulatory acknowledgment of long-term safety concerns in pediatric use

“Concerns on potential long term safety/efficacy issues in relation to paediatric use: Yes” (opens the source at this quote in a new tab)

Class context, systemic AAV gene therapy: pooled incidence and timing of immune-mediated adverse events

“Random-effects meta-analysis yielded a 30.0% (95% CI, 22.5–38.9; I 2 = 83.1%) overall AE rate, including hepatotoxicity in 23.8% (17.4–31.7; I 2 = 81.7%), myocarditis in 6.2% (4.6–8.1; I 2 = 46%), thrombotic microangiopathy (TMA) in 4.7% (4.4–6.5; I 2 = 18.5%), and treatment-related death in 4.7% (3.0–5.3; I 2 = 46.1%).” (opens the source at this quote in a new tab)
“Hepatotoxicity and myocarditis were generally mild (97% and 96% non-serious), whereas all TMA episodes carried substantial morbidity.” (opens the source at this quote in a new tab)
“Time course analyses revealed TMA clustered in week 1, myocarditis at week 2, and hepatotoxicity up to 6 months post-infusion.” (opens the source at this quote in a new tab)

Class context, onasemnogene abeparvovec (AAV9): thrombotic microangiopathy warning in the prescribing information

“The recommended dose of ZOLGENSMA is 1.1 × 10¹⁴ vector genomes per kilogram (vg/kg) of body weight.” (opens the source at this quote in a new tab)
“Cases of thrombotic microangiopathy (TMA) were reported to occur generally within the first two weeks after ZOLGENSMA infusion in the post-marketing setting” (opens the source at this quote in a new tab)
“TMA is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury.” (opens the source at this quote in a new tab)
“Concurrent immune system activation (e.g., infections, vaccinations) was identified in some cases.” (opens the source at this quote in a new tab)
“Prompt attention to signs and symptoms of TMA is advised, as TMA can result in life-threatening or fatal outcomes.” (opens the source at this quote in a new tab)

Class context, onasemnogene abeparvovec (AAV9): thrombocytopenia warning and platelet monitoring schedule

“Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, were typically observed within the first two weeks after ZOLGENSMA infusion.” (opens the source at this quote in a new tab)
“Monitor platelet counts before ZOLGENSMA infusion and closely monitor platelet counts within the first two weeks following infusion and on a regular basis afterwards (at least weekly for the first month; every other week for the second and third months or until platelet counts return to baseline)” (opens the source at this quote in a new tab)

Class context, onasemnogene abeparvovec (AAV9): thrombotic microangiopathy case reports

“As of July 1, 2020, we had identified 3 infants who developed thrombotic microangiopathy following onasemnogene abeparvovec.” (opens the source at this quote in a new tab)

“This is the first fatal TMA following SMN AAV9 gene therapy in a child carrying a potential predisposing risk factor in the complement factor I gene.” (opens the source at this quote in a new tab)
“We report a fatal case of systemic thrombotic microangiopathy (TMA) following onasemnogene abeparvovec in a 6-month-old child with SMA type 1, emphasizing the need for close monitoring and targeted immunotherapy to optimize early TMA recognition and treatment by AAV gene therapy.” (opens the source at this quote in a new tab)

Class context, fordadistrogene movaparvovec (AAV9) in Duchenne muscular dystrophy: complement activation and thrombotic microangiopathy

“Three participants experienced clinical evidence of TMA.” (opens the source at this quote in a new tab)
“Platelet levels rapidly decreased 7–10 days post infusion, together with C3 and C4 depletion and elevated C5b-9 after ∼7 days.” (opens the source at this quote in a new tab)
“Each affected participant was hospitalized and received supportive care and anti-complement therapy.” (opens the source at this quote in a new tab)
“Anti-AAV9 immunoglobulin M (IgM) and IgG were detected within days post infusion, and participants with TMA demonstrated a particularly rapid rise of neutralizing antibodies and total antibody to AAV9 in the first 1–2 weeks post infusion.” (opens the source at this quote in a new tab)

Class context, systemic AAV9: complement activation with corticosteroids alone compared with rituximab, sirolimus, and corticosteroids

“We describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens.” (opens the source at this quote in a new tab)
“Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.” (opens the source at this quote in a new tab)
“All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens.” (opens the source at this quote in a new tab)
“Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.” (opens the source at this quote in a new tab)
“This study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway.” (opens the source at this quote in a new tab)

Class context, systemic AAV: review of publicly reported thrombotic microangiopathy cases

“While apparently rare based on available information, AAV-associated TMA/aHUS can pose a substantial risk to patients including one published fatality.” (opens the source at this quote in a new tab)
“Reported cases were originally limited to pediatric Duchenne muscular dystrophy patients receiving micro- or mini-dystrophin transgenes via AAV9 but have subsequently been reported in both pediatric and adult patients across a range of disorders, transgenes, promoters, and AAV capsid types.” (opens the source at this quote in a new tab)

Disease context: thrombotic microangiopathy after heart transplantation in a child with Danon disease

“This case describes an uncommon acute complication of diffuse thrombotic angiopathy and associated aHUS/TTP in an 11-year-old girl with Danon disease who underwent orthotopic heart transplant.” (opens the source at this quote in a new tab)
“She had received a single dose of tacrolimus (FK506) and a single dose of antithymocyte globulin.” (opens the source at this quote in a new tab)

Class context, high-dose AAV9: fatal capillary leak syndrome in a participant with Duchenne muscular dystrophy

“Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later.” (opens the source at this quote in a new tab)
“We suggest that a cytokine-mediated capillary leak syndrome developed, which manifested as pericardial effusion on day 5 and ARDS on day 6 and led to worsening of preexisting right ventricle heart failure.” (opens the source at this quote in a new tab)
“Unlike some other patients with DMD in rAAV trials, this patient did not have evidence of thrombotic microangiopathy or of adaptive humoral or cell-mediated immune responses to AAV capsid or transgene products.” (opens the source at this quote in a new tab)

Class context, high-dose AAV9: fatal capillary leak syndrome under prednisolone and sirolimus prophylaxis

“The patient experienced rapid onset of complement activation leading to cytokine-mediated capillary leak syndrome, culminating in refractory shock, multiorgan failure, and death on day 8.” (opens the source at this quote in a new tab)
“A postmortem examination revealed acute circulatory failure as the cause of death without myocarditis or thrombotic microangiopathy.” (opens the source at this quote in a new tab)
“We propose a mechanism driven by the early innate immune response, in which complement-mediated endothelial injury leads to a cytokine-mediated capillary leak syndrome, culminating in refractory shock and multiorgan failure.” (opens the source at this quote in a new tab)
“Importantly, sirolimus did not appear to mitigate early immune response in this patient, consistent with its predominant effects on adaptive immunity rather than the innate and complement-mediated pathways implicated in endothelial injury and capillary leak syndrome after systemic AAV gene transfer.” (opens the source at this quote in a new tab)

Class context: capillary leak, endothelial, and dorsal root ganglion injury named as emerging AAV toxicities at a 2026 workshop

“However, severe and occasionally fatal adverse events affecting vital organs, including the blood, liver, muscle, and heart, have emerged in both clinical trials and real-world post marketing settings.” (opens the source at this quote in a new tab)
“Emerging toxicities, including capillary leak syndrome, endothelial and dorsal root ganglia injuries, were reviewed alongside corresponding preclinical data” (opens the source at this quote in a new tab)

Class context, onasemnogene abeparvovec (AAV9): boxed warning for serious liver injury and acute liver failure

“Cases of acute liver failure with fatal outcomes have been reported.” (opens the source at this quote in a new tab)
“Patients with preexisting liver impairment may be at higher risk” (opens the source at this quote in a new tab)
“Continue to monitor liver function for at least 3 months after infusion, and at other times as clinically indicated” (opens the source at this quote in a new tab)
“Hepatotoxicity (which may be immune-mediated), generally manifested as elevated ALT and/or AST levels.” (opens the source at this quote in a new tab)

Class context, delandistrogene moxeparvovec (AAVrh74): boxed warning for acute serious liver injury and acute liver failure

“Acute serious liver injury, including life-threatening and fatal acute liver failure, has occurred with ELEVIDYS” (opens the source at this quote in a new tab)
“Onset of the liver injury typically begins within 8 weeks after administration of ELEVIDYS.” (opens the source at this quote in a new tab)
“Continue to monitor liver function weekly for the first 3 months after infusion and continue until results are unremarkable” (opens the source at this quote in a new tab)
“Instruct patients to maintain proximity to an appropriate healthcare facility, as determined by the healthcare provider, for at least 2 months following ELEVIDYS infusion” (opens the source at this quote in a new tab)

“Fatal reports of acute liver failure were received from clinical trial and postmarketing data.” (opens the source at this quote in a new tab)
“The patients presented with elevated transaminases and were hospitalized less than two months after treatment with Elevidys.” (opens the source at this quote in a new tab)
“FDA concluded that addition of a Boxed Warning was warranted to highlight the risk of serious liver injury and acute liver failure and alert healthcare providers to obtain prompt consultation with a specialist if acute serious liver injury or impending acute liver failure is suspected, and instruct patients to maintain proximity to an appropriate healthcare facility, as determined by the healthcare provider, for at least 2 months following Elevidys infusion.” (opens the source at this quote in a new tab)

Class context, delandistrogene moxeparvovec (AAVrh74): two fatal cases of acute liver failure

“Both cases occurred in nonambulatory patients (ages 15 and 16 years).” (opens the source at this quote in a new tab)
“Both patients exhibited abrupt elevations in aminotransferases from baseline approximately 4 weeks after delandistrogene moxeparvovec administration.” (opens the source at this quote in a new tab)
“An interdisciplinary expert panel was convened and concluded that no single biomarker or clinical feature consistently predicted the rapid progression of severe ALI to ALF.” (opens the source at this quote in a new tab)

Class context, delandistrogene moxeparvovec (AAVrh74): myocarditis warning and reduced ejection fraction

“Acute, serious, life-threatening myocarditis and troponin-I elevations have been observed within 24 hours to more than 1 year following ELEVIDYS infusion” (opens the source at this quote in a new tab)
“If a patient experiences myocarditis, those with pre-existing left ventricle ejection fraction (LVEF) impairment may be at higher risk of adverse outcomes.” (opens the source at this quote in a new tab)
“Patients with moderate to severe LVEF impairment have not been studied in clinical trials with ELEVIDYS.” (opens the source at this quote in a new tab)
“Monitor troponin-I before ELEVIDYS infusion and weekly for the first month following infusion” (opens the source at this quote in a new tab)

Class context, onasemnogene abeparvovec (AAV9): troponin elevation and cardiac findings in animals

“Increases in cardiac troponin I levels (up to 0.176 mcg/L) have occurred following ZOLGENSMA infusion in clinical trials.” (opens the source at this quote in a new tab)
“Cardiac toxicity was observed in animal studies” (opens the source at this quote in a new tab)
“In toxicology studies conducted in neonatal mice, dose-dependent cardiac and hepatic toxicities were observed following intravenous (IV) administration of onasemnogene abeparvovec” (opens the source at this quote in a new tab)

Class context, systemic AAV: pooled incidence, timing, and outcome of myocarditis

“Seventy-one cases of myocarditis were identified.” (opens the source at this quote in a new tab)
“The pooled incidence rate per 100 patient-years was 8.6 (95% CI, 5.8-10.7; I2=63.2%).” (opens the source at this quote in a new tab)
“All received an intravenous dose >1013 vector genomes per kilogram body weight.” (opens the source at this quote in a new tab)
“Myocardial injury peaked in week 1 after injection (90% [95% CI, 85.7%-96.2%]; I2=43.2%), whereas myocarditis occurred mostly after week 2 (55% [95% CI, 48.7%-65.2%]; I2=33.1%), with no cases after the first month.” (opens the source at this quote in a new tab)
“Most myocarditis/myocardial injury did not have a relevant clinical impact (62, 87%), with only 8 (12%) cases having transient left ventricular dysfunction.” (opens the source at this quote in a new tab)
“The only death occurred in the setting of cytokine-mediated capillary leak syndrome with cardiac dysfunction.” (opens the source at this quote in a new tab)

Class context, systemic AAV: infection warnings in approved product labeling

“Increased susceptibility to serious infections may occur due to concomitant administration of corticosteroid regimen and additional immunosuppressants, and ELEVIDYS.” (opens the source at this quote in a new tab)
“Serious respiratory infections, including with fatal outcomes, have occurred in patients taking immunosuppressant corticosteroids required for ELEVIDYS administration” (opens the source at this quote in a new tab)
“Avoid administration of ELEVIDYS to patients with active infections.” (opens the source at this quote in a new tab)

“Due to activation of humoral and cellular immunity following ZOLGENSMA infusion, patients with underlying active infection, either acute (e.g., respiratory, gastrointestinal) or chronic uncontrolled (e.g., chronic active hepatitis B), could be at an increased risk of serious systemic immune response, potentially resulting in more severe clinical courses of the infection.” (opens the source at this quote in a new tab)
“Postpone ZOLGENSMA in patients with infections until the infection has resolved and the patient is clinically stable.” (opens the source at this quote in a new tab)

Immunomodulation agents, sirolimus: boxed warning on immunosuppression and infection

“Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.” (opens the source at this quote in a new tab)
“Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis.” (opens the source at this quote in a new tab)

Immunomodulation agents, rituximab: hepatitis B reactivation and serious infection warnings

“HBV reactivation can occur in patients treated with RITUXAN, in some cases resulting in fulminant hepatitis, hepatic failure, and death.” (opens the source at this quote in a new tab)
“Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with RITUXAN.” (opens the source at this quote in a new tab)
“Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of RITUXAN-based therapy.” (opens the source at this quote in a new tab)
“RITUXAN is not recommended for use in patients with severe, active infections.” (opens the source at this quote in a new tab)

Immunomodulation agents, eculizumab (C5 inhibitor used for impending complement activation): boxed warning for meningococcal infection

“SOLIRIS, a complement inhibitor, increases the risk of serious infections caused by Neisseria meningitidis” (opens the source at this quote in a new tab)
“Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors.” (opens the source at this quote in a new tab)
“Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of SOLIRIS, unless the risks of delaying therapy with SOLIRIS outweigh the risk of developing a serious infection.” (opens the source at this quote in a new tab)

Immunomodulation agents, pegcetacoplan (C3 inhibitor used in cohort 3 only): boxed warning for infections with encapsulated bacteria

“EMPAVELI, a complement inhibitor, increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B” (opens the source at this quote in a new tab)
“Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors.” (opens the source at this quote in a new tab)

Immunomodulation agents, corticosteroids: myopathy in prednisone labeling

“An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium).” (opens the source at this quote in a new tab)
“This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis.” (opens the source at this quote in a new tab)
“Clinical improvement or recovery after stopping corticosteroids may require weeks to years.” (opens the source at this quote in a new tab)

Class context, intravenous AAV9: dorsal root ganglion findings in animals and in clinical surveillance

“In a 6-month toxicology study conducted in juvenile non-human primates, single IV administration of onasemnogene abeparvovec at the recommended clinical dose level of 1.1 × 10¹⁴ vg/kg, with or without corticosteroid treatment, resulted in microscopic findings in the dorsal root ganglia (DRG), trigeminal ganglia (TG), spinal cord, brainstem, and liver.” (opens the source at this quote in a new tab)
“These microscopic findings were still present at 6 months with decreased severity and incidence.” (opens the source at this quote in a new tab)

“Dorsal root ganglia (DRG) inflammation was observed in NHPs.” (opens the source at this quote in a new tab)
“Patients exhibited no evidence of sensory neuropathy upon clinical examination.” (opens the source at this quote in a new tab)
“Important potential risks include cardiac AEs and DRG toxicity.” (opens the source at this quote in a new tab)

“Degeneration of dorsal root ganglia sensory neurons was also observed, although NHPs exhibited no clinically apparent sensory deficits.” (opens the source at this quote in a new tab)
“The present results and those of another recent study utilizing a different AAV9 variant and transgene indicate that systemic and sensory neuron toxicity may be general properties of i.v. delivery of AAV vectors at high doses, irrespective of the capsid serotype or transgene.” (opens the source at this quote in a new tab)

Class context, onasemnogene abeparvovec (AAV9): vector integration and theoretical tumorigenicity

“There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome.” (opens the source at this quote in a new tab)