Cystinosis Gene Therapy Granted Rare Pediatric Disease Designation by FDA


Preliminary data from an ongoing clinical trial suggest that AVR-RD-04 has been well-tolerated.

AVROBIO’s AVR-RD-04, an investigational gene therapy intended for the treatment of cystinosis, has received rare pediatric disease designation from the FDA.1

AVR-RD-04 functions by genetically modifying patients’ hematopoietic stem cells (HSCs) to express CTNS, the gene that encodes the disease-targeted protein, cystinosin. AVR-RD-04 previously received orphan drug designation from the FDA in March 2020, and it is currently under investigation in a phase 1/2 clinical trial under the name CTNS-RD-04 (NCT03897361).2

“People living with cystinosis need new treatment options to keep cystine from accumulating in the lysosomes of cells, which leads to corneal damage and kidney deterioration, among other complications. Although the current standard of care has improved the outlook for this community, it does not halt disease progression or a wide range of debilitating complications which can severely impact daily lives,” Geoff MacKay, chief executive officer and president, AVROBIO, said in a 2020 statement.2 “We believe lentiviral gene therapy is potentially well suited to comprehensively address these symptoms, since it is designed to restore functional cystinosin throughout the body and brain.” 

Preliminary data from the study, which is being carried out in collaboration with University of California, San Diego (UCSD), suggest that AVR-RD-04 has been well-tolerated, with no therapy-related adverse events (AEs) reported to date.1 The majority of AEs reported were mild to moderate and did not result in clinical sequalae after resolution, and all were determined to be related to myeloablative conditioning, stem cell mobilization, underlying disease, or pre-existing conditions. Additionally, the data indicated that AVR-RD-04 provided benefit in several of the tissues evaluated, including the eyes, skin, gastrointestinal mucosa, and neurocognitive system.

The single-arm, open-label clinical trial will enroll up to 6 patients with cystinosis. The participants will be divided into 3 cohorts. Patients in the first 2 cohorts will be aged 18 years or older, while patients in cohort 3 may be as young as 14 years old. Participants are required to have a history of elevated white blood cell cystine levels and/or a history of cystine crystals present in the eye; a Karnofsky Performance Status or age-dependent Lansky Performance score of at least 60; and adequate hematologic, hepatic, renal, and thyroid function, as well as adequate coagulation, according to pre-defined criteria. Patients who have previously had a kidney transplant must be at least 1-year post-transplant. Exclusion criteria primarily relates to patient health status and treatment history.

Participants will receive marrow cytoreduction with busulfan prior to administration of a single dose of AVR-RD-04. For patients in cohort 3, manufacturing of AVR-RD-04 will include a transduction enhancer referred to as LentiBOOST. The study’s primary end points are incidence and severity of AEs and serious AEs, the number of participants with replication competent lentivirus (RCL), occurrences of insertional mutagenesis and monoclonal expansion, and event-free survival. Secondary end points will include the change in cystine levels, changes in quality of life (QoL) measured by Health-Related QoL, and tests for kidney function, vision, muscle strength, pulmonary function, and neurological and psychometric function. The study is taking place at University of California San Diego and is estimated to be completed in August 2024.

“For people with cystinosis, there are no healthy days,” Nancy J. Stack, president of the Cystinosis Research Foundation, which made a donation to support the trial, said in a statement published at the time the first patient was dosed in late 2019.3 “They must take dozens of pills a day, around the clock, just to stay alive. It is a relentless disease and we urgently need new treatments. We believe that we are now an important step closer to the potential cure that our community has been working toward for many years.”

1. AVROBIO receives rare pediatric disease designation from U.S. Food and Drug Administration (FDA) for first gene therapy in development for cystinosis. News release. AVROBIO, Inc. September 20, 2022. 
2. AVROBIO receives orphan drug designation from U.S. FDA for AVR‑RD‑04 for cystinosis. News release. AVROBIO, Inc. March 9, 2020. 
3. AVROBIO announces first patient dosed in phase 1/2 trial of gene therapy for cystinosis. News release. AVROBIO, Inc. October 8, 2019. 
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