CGTLive's 2024 Pillars of Progress: Top News in Lysosomal Disorders

For all of 2024, our team was following the clinical development of targeted and novel engineered approaches to the treatment of patients with various medical disorders. These efforts included holding in-depth conversations with experts in the clinical care of these individuals, as well as in cell and gene therapy development, culminating in our coverage of each step of progress that the most exciting cellular and genetic treatments have made along the pipeline.

From major data publications and presentations to FDA decisions and medical meetings, the team spent all year bringing the latest information to the website's front page.

Among our areas of focus in 2024 has been lysosomal disorders. The major news items appeared among the top pieces our team produced—but sometimes smaller stories reach those heights as well because of their clinical impact, their inventive mechanisms, or otherwise. Whatever the reason for the attention these stories got, their place here helps provide an understanding of the themes in lysosomal disorders over the course of 2024.

Here, we'll highlight some of the most-read content on CGTLive's lysosomal disorders page this year. Click the buttons to read further into these stories.

Roche Drops Pompe Gene Therapy Program

“With up to 5 years of follow-up after a single infusion of SPK-8011 we see a result of durable FVIII expression with the majority of participants experiencing levels in the mild hemophilia range. Investigations are ongoing to overcome the challenge of managing a presumed capsid immune response to further reduce variability in FVIII expression following AAV-mediated gene transfer for hemophilia A."
—Stacy Croteau, MD, MMS

In July, Roche discontinued development of its investigational gene therapy SPK-3006, which was being evaluated in the phase 1/2 RESOLUTE trial (NCT04093349) in participants with late-onset Pompe disease. Roche adopted the program into its pipeline along with its acquisition of Spark Therapeutics in December 2019.

AskBio Evaluates ACTUS-101 Gene Therapy for Late-Onset Pompe Disease

“This is an exciting milestone for our company but most importantly, if ACTUS-101 is successful, it could have a meaningful impact on the quality of life for those who suffer from Pompe disease. Further, ACTUS 101 could replace enzyme replacement therapy (ERT) every other week with the potential to be a groundbreaking metabolic treatment for an unforgiving disease now showing up in an increasing number of patients.”
—Sheila Mikhail, JD

ACTUS-101 is an adeno-associated virus (AAV) gene therapy that aims to address the deficiency of acid-alpha-glucosidase (GAA) in patients with Pompe disease. GAA deficiency leads to deleterious progressive accumulation of glycogen in organs and tissues, especially skeletal and cardiac muscle, leading to high morbidity and premature death.

One Big Step Away From BLA Submission for Sangamo’s Fabry Gene Therapy

“The US and European regulatory support for ST-920 and the serious unmet medical need in Fabry disease signal the important role that ST-920 could play in improving the lives of Fabry patients across the globe. We are thankful for the FDA’s support and alignment on a regulatory pathway that could potentially deliver a new treatment option for Fabry disease patients on an expedited, cost-effective timeline."
—Nathalie Dubois Stringfellow, PhD

In February, the FDA aligned with Sangamo Therapeutics on an abbreviated pathway to approval of its gene therapy ST-920 (isaralgagene civaparvovec) for treating Fabry disease following the presentation of data demonstrating disease improvements after treatment from the phase 1/2 STAAR trial (NCT04046224). The FDA advised, in a Type D meeting, that a single study of ST-290 in 25 patients with Fabry without a control arm or head-to-head with enzyme replacement therapy (ERT), in combination with confirmatory evidence, may be an acceptable pathway to a Biologics License Application (BLA).

Discontinued GM1 Gangliosidosis Gene Therapy Shows no Evidence of Clinical Benefit

“While the safety profile of LYS-GM101 appeared acceptable, and the intracisternal route of administration proved feasible, there was little evidence for potential efficacy of the therapy, with limited biochemical correction, and clear clinical decline in all participants.”
—Arunabha Ghosh, MB BChir, PhD, and colleagues

Treatment with LYS-GM101 gene therapy was generally well-tolerated but showed little evidence of a biochemical or clinical benefit in participants with infantile GM1 gangliosidosis treated in a phase 1/2 clinical trial (NCT04273269). Data from the trial, which was discontinued by its sponsor Lysogene, were presented at the 2024 WORLDSymposium, held February 4-9, in San Diego, California, by Arunabha Ghosh, MB BChir, PhD, clinical research fellow – pediatric inherited metabolic diseases, Central Manchester University Hospitals NHS Foundation Trust.

Orchard Therapeutics’ Stem Cell Gene Therapy OTL-201 Reduces Heparan Sulphate Levels in Patients With MPSIIIA

“Treatment was generally well-tolerated, and led to robust, prompt, sustained, multilineage engraftment of genetically modified cells. [There was] physiological and supraphysiological levels of SGHS enzyme in leukocytes, plasma, and CSF with rapid and significant reduction of substrate observed in all compartments... Neurocognitive trial data [is] early, but 4 of 5 patients progressed onto the Kaufman instrument, suggestive of modification of neurological phenotype.”
—Simon Jones, MBChB BSc MRCPCH, and colleagues

Orchard Therapeutics’ OTL-201, an investigational genetically-modified hematopoietic stem cell (HSC) therapy intended to treat mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome), demonstrated the ability to reduce levels of the disease-associated substrate heparan sulphate (HS) in the plasma, urine, and cerebrospinal fluid (CSF) of patients treated in a phase 1/2 clinical trial (NCT04201405). The data were presented in a poster by Simon Jones, MBChB BSc MRCPCH, a consultant in pediatric inherited metabolic disease at St Mary’s Hospital, at the 2024 WORLDSymposium, held February 4-9, in San Diego, California.