CGTLive's Pillars of Progress 2023: Top News in Lysosomal Disorders

For all of 2023, the CGTLive^™ team was following along 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 major medical meetings, the team spent all year bringing the latest information to the website's front page.

Among our areas of focus in 2023 has been lysosomal disorders. This year saw several gene therapies for rare lysosomal storage diseases make progress in the pipeline and show promise in clinical trials. 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 2023.

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.

1. Expert Insights on Gene Therapy for International Batten Awareness Day

• Neuronal ceroid lipofuscinosis (NCL) is a group of 13 rare inherited lysosomal disorders affecting the nervous system which are collectively referred to as Batten disease.
• According to the Batten Disease Support and Research Association (BDSRA), Batten disease is estimated to occur in approximately 2 to 4 in 100,000 births in the United States; however, the BDSRA indicates that the actual occurrence may be even higher.
• Several companies are currently developing gene therapies intended to treat specific forms of Batten disease.

June 6, 2023 — For International Batten Awareness Day, observed annually on June 9, CGTLive™ reached out to experts to inquire about the current treatment landscape for Batten disease and how gene therapy could potentially impact care for this rare disease. Featured are insights from Ineka Whiteman, PhD, head of research and medical affairs, BDSRA Australia, consultant to BDSRA Foundation (USA) and Beyond Batten Disease foundation, and Paulo Falabella, MD, PhD, vice president, clinical development & operations, patient advocacy, rare diseases, REGENXBIO.

"As a monogenic condition, Batten disease is a prime candidate for gene-based therapeutic approaches. Batten disease primarily affects neurons of the brain and retina, so central nervous system (CNS)-targeted gene therapies that restore function of these neurons could potentially rescue the disease course and dramatically improve outcomes for affected individuals."

– Ineka Whiteman, PhD, of BDSRA Australia

2. UX111 Shows Continued Dose-Dependent Efficacy as an MPS IIIA Treatment

• All told, in Cohort 3 of the phase 1/2/3 Transpher A clinical trial (NCT02716246), 10 of 22 patients were treated with a dose of 3 x 1013 vg/kg in the period prior to advanced neurodegeneration occurring.
• These 10 individuals were either younger than 2 years of age, or had baseline Development Quotient (DQ) scores of 60 or higher calculated by the Bayley Scales of Infant and Toddler Development–Third Edition (BSDIII), and ultimately, they reported a rapid reduction of CSF heparan sulfate (HS) levels.
• Importantly, regarding safety, there were no deaths, drug-related serious adverse events, or severe adverse events reported to date in the Transpher A trial.

February 28, 2023 — The administration of the investigational treatment UX111, an intravenously administered self-complementary AAV9-based gene therapy vector encoding hSGSH in development by Ultragenyx to treat patients with mucopolysaccharidosis IIIA (MPS IIIA)—also known as Sanfilippo syndrome type A—is associated with rapid and sustained reductions of relevant cerebrospinal fluid (CSF) biomarker levels in those treated prior to advanced neurodegeneration.

“[MPS IIIA] is caused by a deficiency in the lysosomal enzyme N-sulfoglucosamine sulfohydrolase, resulting in toxic accumulation of lysosomal HS in the brain and other tissues.”

– Kevin M. Flanagan, MD, of Nationwide Children’s Hospital, and colleagues

3. Late-Onset Pompe Disease Gene Therapy Shows Promise in Phase 1/2 Study

• AT845 is intended to deliver a functional copy of the acid alpha-glucosidase (GAA) gene with a muscle-specific promotor via an AAV8 vector with tropism to muscle tissue.
• Among the 4 patients treated with AT845 in the FORTIS trial so far, 3 have ceased treatment with their prior standard of care treatment, enzyme replacement therapy (ERT).
• All patients showed stable forced vital capacity over time following treatment with AT845, including after ERT withdrawal (when applicable).

February 24, 2023 — Astellas Pharma’s AT845, an investigational adeno-associated virus (AAV) vector-based gene replacement therapy intended to treat late-onset Pompe disease (LOPD) has demonstrated encouraging efficacy in interim data from the phase 1/2 FORTIS clinical trial (NCT04174105). The data were presented at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida.

“These data, along with our recent announcement of the clinical hold lift of the FORTIS clinical trial, are very positive developments for the program. The preliminary data presented are encouraging."

– Ha Tran, MD, of Astellas Pharma

4. Gene Therapy Improves Quality of Life in Patients With Glycogen Storage Disease Type 1a

• The open-label, dose-escalation trial evaluated 12 adults (age range, 18-57; mean, 30) with GSD1a treated with a single intravenous infusion of DTX401 for 52 weeks.
• All evaluable patients had significant reductions in daily cornstarch intake at 1 year and at last visit during long-term follow-up.
• All participants are now enrolled in a long-term follow-up study (NCT03970278) and data reported had a cutoff date of March 10, 2023.

May 25, 2023 — DTX401, an investigational AAV8 vector gene therapy expressing the human G6PC gene, showed a positive efficacy and safety profile in all patients with glycogen storage disease type 1a (GSD1a) treated in a phase 1/2 clinical trial (NCT03517085) at 1 year. Data from the trial were presented in a clinical trial symposium at the the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California

“We have not completely restored G6P activity to normal levels, and patients still need some degree of metabolic support, but our hope is that with the activity that we’re providing these patients, they will have a buffer that puts them at lower risk for severe hypoglycemia in the settings of acute illness when they're unable to take oral intake."

– Andrew Grimm, MD, PhD, of Ultragenyx

5. Infantile GM1 Gangliosidosis Gene Therapy Demonstrates Safety and Dose-dependent Biomarker Changes

• PBGM01 is intended to provide a functional copy of GLB1, the disease-targeted gene, via AAVhu68, and is administered to the CNS with an intra-cisterna magna (ICM) injection.
• Following treatment with PBGM01, participants in the trial showed stabilization of MRI severity scores, in contrast to increases seen in natural history data from untreated patients.
• Patients who received the high dose of PBGM01 showed an increase in β-Gal activity in the CSF of 4.7 to 5.2 times baseline.

February 27, 2023 — Passage Bio’s PBGM01, an investigational AAV vector-based gene therapy currently being evaluated in the phase 1/2 Imagine-01 clinical trial (NCT04713475) for the treatment of infantile GM1 gangliosidosis, was shown to have a favorable safety profile and demonstrated dose-dependent changes in biomarkers. The data were presented at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida.

“Future plans and future directions for the Imagine-01 study are really informed by the encouraging safety profile and the early assessment of the dose-dependent response that we're seeing in the biomarkers...”

– Samiah Al-Zaidy, MD, of Passage Bio