Giant Axonal Neuropathy Gene Therapy Well-Tolerated With Some Clinical Benefit

scAAV9-JeT-GAN intrathecal gene therapy was well-tolerated and seemed to slow disease progression in patients with giant axonal neuropathy (GAN), according to data from a phase 1, first-in-human, single-site trial (NCT02362438).

These data were presented at the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 19-22, in Dallas, Texas, by first author Diana Bharucha-Goebel, MD, neuromuscular neurologist, Children's National.

“Critically, patients with GAN present within the first few years of life with gait impairment, and the disease is marked by progressive motor decline, reduced coordination, and effects on vision, swallowing, and respiratory function. Ambulation is typically lost within the first decade of life, and death occurs in the second or third decade of life, typically from respiratory failure,” Bharucha-Goebel and colleagues wrote in the poster.

The trial has dosed 14 participants with GAN with either 3.5x10¹³, 1.2x10¹⁴, 1.8x10¹⁴, or 3.5x10¹⁴ total vector genomes. All participants received corticosteroid immunomodulation, while participants with biallelic null variants (n = 4) received additional T-cell targeted immune modulation. The primary endpoint was safety, as defined by treatment-emergent adverse events (TEAEs) and change in motor function measure (MFM-32) score at 1 year after treatment compared to baseline.Additional immunologic data were collected.

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Investigators found that as of February 2023, there were 644 TEAEsand 144 possible related to scAAV9-JeT-GAN treatment. TEAEs commonly included abnormal vital capacity, upper respiratory infection, acidosis, hyperglycemia, leukocytosis, thrombocytosis, cerebrospinal fluid (CSF) white blood cell pleocytosis, headache, and intracranial hypertension. Out of 43, 1 serious AE of fever and vomiting requiring intravenous fluids was possibly related to treatment. Other frequent serious AEs included urinary tract infection, scoliosis, upper respiratory tract infection, hedache, fracture, and constipation. Two deaths occurred, these were due to pulmonary complications deemed related to GAN and not the gene therapy.

In terms of efficacy, investigators found that the 3 highest dose groups combined had a significantly slowed annual decline in MFM-32 score (P = .002) at 1 year post treatment. Sensory nerve action potential responses also persisted and/or reemerged after gene therapy compared to a declination in natural history, and regenerative clusters in the superficial sensory nerve and on the contralateral side increased in density at 1 year post-treatment. Immunology assessments revealed that CSF white blood cell elevations peaked at months 3-6 post-treatment and were clinically silent and self-limited, anti-AAV9 antibodies peaked at 1:2,560 to 1:327,680 titers, 12 participants had an increased T-cell interferon (IFN)-γ response, and participants receiving T-cell immune suppression had an overall lower IFN-γ response.

“The frequency of serious AEs appears to be more closely linked to baseline disease severity than dose... gene transfer for GAN to marked slowing in disease progression in the combined 3 highest dose cohorts, and this slowing is maintained over long periods of follow up... This data supports further exploration into the impact of scAAV90JeT-GAN in younger or milder individuals with GAN,” Bharucha-Goebel and colleagues concluded.

Read more coverage of the 2023 MDA Conference here.

REFERENCE

Bharucha-Goebel D, Saade D, Todd J, et al. First-in-human intrathecal gene transfer study for Giant Axonal Neuropathy: Assessment of long-term efficacy and review of safety. Presented at: 2023 MDA Conference, March 19-22; Dallas, Texas. Poster #135