. 2023 Oct 20;31:101125. doi: 10.1016/j.omtm.2023.101125

Table 3.

AAV-based therapies clinical holds

Sponsor/Program/Trial identifier #	Target disease	Dates of hold	Reason for hold	Status/Conclusions
Astellas⁴⁰ AT845, FORTIS NCT04174105	Pompe disease-late stage	Jun-22 – Ongoing as of Dec-2022	A serious case of peripheral sensory neuropathy.	The FDA informed the company that it did not have sufficient information to assess the risks to subjects and requires additional information about the recently reported serious adverse event. Hold was lifted in January 2023.
LogicBio⁴¹^,⁴² LB-001 NCT04581785	Methyl-malonic Acidemia (MMA)	Feb-22 – May-22	Two patients (6 months–2 years) developed thrombotic microangiopathy. Serious adverse events appear to be limited to infants, but treating this age is necessary for maximum impact of the therapy.	Next patients will receive the same dose but will be continually assessed. Additional screening and monitoring requirements are in place. Trial will now include additional checks for complement activation and the use of a complement inhibitor if lab test reveals a potential case of thrombotic microangiopathy.
Homology Medicines⁴³^,⁴⁴ HMI-102 NCT03952156	Phenyl-ketonuria (PKU)	Feb-22 – Jun-22	Elevated liver function tests. All are resolved and none required hospitalization.	FDA requested modifications to risk mitigation measures. Clinical protocol adjustments made (inject a T cell inhibitor and steroids). Long-term follow-up is already being conducted (NCT04348708).
Pfizer⁴⁵^,⁴⁶ PF-06939926 NCT03362502	Duchenne muscular dystrophy	Dec-21 – Apr-22	Death of a young patient.	Cause of death was assumed to be more advanced disease and underlying cardiac dysfunction. FDA requested a potency assay and a protocol amendment, and the sponsor did both. Protocol amendment consists of closer monitoring of patients; there will be a 7-day hospitalization period after patients receive the therapy. Still determining strategy for non-ambulatory patients.
Pfizer⁴⁷^,⁴⁸ giroctocogene fitelparovec NCT04370054	Hemophilia A	Nov-21 – Mar-22	Some patients showed higher-than-normal factor levels which increases the risk of blood clots.	Adjusted protocol. Voluntary pause was maintained an additional 7 months (Sep-22) until sponsor had met all necessary conditions, including approval of updated study protocols by regulatory authorities.
Selecta⁴⁹^,⁵⁰ SEL-302, (MMA101 plus ImmTOR) N/A	Methyl-malonic acidemia (MMA)	Nov-21 – Mar-22	Trial has not been initiated yet—no clinical or preclinical issues.	FDA requested further data on CMC linked to the MMA-101 product candidate.
BioMarin⁵¹ BMN 307 NCT04480567	Phenyl-ketonuria	Sep-21 – Ongoing as of Dec-2022	Clinical hold was based on interim safety findings from a preclinical non-GLP pharmacology study. Several mice developed tumors. Lower doses were administered in clinical trials. No issues in humans to date (over 3,000 patients treated).	FDA asked for more animal studies. Delay is expected to last “several quarters.”
Astellas⁵² AT132 (bilparvovec) NCT03199469	X-linked myotubular myopathy	Sep-21 – Ongoing as of Dec-2022	A total of four patient deaths. The first three received the higher dose and developed liver dysfunction and eventual liver failure. Most recent patient died who received a lower dose; cause of death has not been disclosed.	Patient who received this dose had abnormal liver tests despite a normal liver ultrasound and tests prior to dosing. This is the second time this therapy has been put on clinical hold. Hold was lifted in January 2023.
Rocket Pharma⁵³^,⁵⁴ RP-A501 (AAV9.LAMP2B) NCT03882437	Damon disease	May-21 – Aug-21	FDA requested modifications to the trial protocol and revised guidelines for patient selection and management.	Protocol modifications only.
UniQure⁵⁵^,⁵⁶ AMT-061 (Etranacogene dezaparvovec) NCT03569891	Hemophilia B	Dec-20 – Apr-21	One patient developed hepatocellular carcinoma.	Determined not related. The patient had multiple risk factors making them susceptible to the cancer. No other adverse effects have been recorded.
Voyager⁵⁷^,⁵⁸ VY-HTT01 NCT04885114	Huntington’s disease	Oct-20 – Apr-21 – Stopped	Hold placed following IND submission before trial was initiated due to CMC issues.	Updated CMC section of the IND (details vague). The study has since been withdrawn (no participants) and the company has initiated a second-generation product that is in discovery phase (per pipeline on company website).
Lysogene⁵⁹ LYS-SAF302 NCT03612869	Mucopolysaccharidosis Type IIIA (MPS IIIA)	Jun-20 – Ongoing as of Dec-2022	Observations in some patients of localized findings on magnetic resonance images at the intracerebral injection sites. The localized nature of the findings suggests a potential connection to delivery.	At the time of hold, 19 out of 20 patients have been treated, The primary and secondary trial endpoints are based on the analyses of these 19 patients already enrolled. Therefore, company reports that there is no anticipated impact on the current clinical trial timelines. Results of the trial were announced in November 2022. FDA has not approved the therapy and has not lifted the hold.
Passage Bio⁶⁰ PBGM01 NCT04713475	Infantile GM1	Aug-20 – Jan-21	FDA placed on hold and requested additional risk assessments of the biocompatibility of the proposed intra cisterna magna (ICM) delivery device.	No information about resolving the hold was given. Note that the hold was not regarding the therapy but the delivery device.
Voyager⁶¹ VY-AADC NCT03562494	Parkinson’s	Dec-20 – Stopped	Observation of MRI abnormalities in some RESTORE-1 study participants. The clinical implications of this observation are currently unknown and are being evaluated.	No longer in the pipeline. Program end was announced in February 2021.
Sarepta⁶² SRP-9001-103 NCT03199469	DMD	Aug-21 – Oct-21	IND placed on clinical hold as it did not contain sufficient information required under 21 CFR 312.23 to assess the risks to subjects of the proposed studies. An unexpected serious adverse event was reported, of asthenia in a 9-year-old subject, requiring hospitalization and respiratory support after he received therapy in Study SRP-9001-103.	Few details are known as this hold was not disclosed until the FDA advisory committee in May 2023. This was the second clinical hold for this product, the first was in 2018 due to CMC deficiencies (3 months, June -Sept. 2018).