SPG50 Gene Therapy Warrants Further Study


MELPIDA was well-tolerated in patients and nerve conduction was stable or improved after treatment.

MELPIDA (AAV9/AP4M1; Elpida Therapeutics) gene therapy has been well-tolerated in patients with hereditary spastic paraplegia, type 50 (SPG50).

Initial data from a phase 1 study (NCT05518188) were presented at the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting 2024, held May 7-10 in Baltimore, Maryland, by Souad Messahel, BS, MS, PhD, head, clinical operations, Elpida Therapeutics.

“Our approach utilizes early intervention and higher intrathecal AAV doses than are used in most other intrathecal AAV clinical trials. We speculate that the self-complimentary design of the vector contributes to its potential efficacy, and the relatively modest strength UsP promoter contributes to its safety,” Messahel and colleagues wrote in their poster.

SPG50 is a rare, autosomal recessive disorder caused by biallelic variants in the AP4M1 gene which impact the function of adaptor complex 4 proteins (AP4). Children with SPG50 have a progressive spastic paraplegia that starts in infancy or early childhood, which may evolve into progressive lower-extremity spasticity. Most children become non-ambulatory and wheelchair dependent. There are no current disease-modifying therapies available for SPG50 and standard of care treatment is palliative and aims to prevent secondary complications.

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MELPIDA delivers a functional AP4M1 transgene via an adeno-associated virus (AAV9) vector and has demonstrated safety and meaningful benefits in murine studies. The phase 1 study is recruiting participants with SPG50 between the ages of 4 months and 10 years at UT Southwestern Medical Center in Dallas, Texas. Data have been reported from 4 participants up to 24 months post treatment with MELPIDA, 3 in the United States and 1 treated separately in Canada. Three participants aged 3 to 5 years received 1x1015 vg MELPIDA and the fourth, 5-month-old participant with presymptomatic SPG50 received 4x1014 vg. The authors noted that that patient may be the youngest patient dosed intrathecally with AAV9.

MELPIDA has had a positive safety profile so far, with no negative immune responses and a manageable safety profile, as measured by MRI brain and spine scans, cerebral spinal fluid analysis, complete blood profiles, EKGs, and nerve conduction studies. There has been no evidence of dorsal root ganglion toxicity and nerve conduction was stable or improved after treatment.

Future data will report on efficacy measures being assessed in the study, including Clinical Global Impression of Overall Change, Vineland Adaptive Behavior Scales, Bayley Scales of Infant and Toddler Development, Caregiver Priorities and Child Health Index of Life with Disabilities, Spastic Paraplegia Rating Scale, Gross Motor Function Measure, 3-minute walk test, and SPATAX-EUROSPA Disability Score. After the initial 24 month period of follow-up there will be annual visits for 3 more years.

“Since SPG50 is caused by a monogenic mutation, gene replacement therapy may be a good choice to treat the disease. As AAV9/AP4M1 is expected to provide a fully functional human AP4M1 cDNA copy to participant’s neuronal cells, there is a potential for reducing the neurodegeneration in patients,” Messahel and colleagues concluded their poster. “These preliminary data in humans that demonstrate its safety and tolerability, in addition to proven observations of safety and efficacy of the preclinical in vitro and in vivo studies, justify the clinical development of MELPIDA for the SPG50 population, for which there is a significant unmet medical need.”

Click here to read more coverage of the 2024 ASGCT Annual Meeting.

Messahel S, Chen X, Pirovolakis T, et al. Preliminary Safety Data of a Phase 1/2 Clinical Trial to Support the Use of High Dose Intrathecal AAV9/AP4M1 for the Treatment of Patients with SPG50 Disease. Presented at: ASGCT Annual Meeting 2024, May 7-10; Baltimore, Maryland.
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