Ultragenyx’s Gene Therapy DTX401 Reduces Cornstarch Intake in Patients With Glycogen Storage Disease Type 1a

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Article

Ultragenyx is aiming to submit a marketing application for DTX401 next year.

Eric Crombez, MD, the chief medical officer at Ultragenyx

Eric Crombez, MD

Ultragenyx’s DTX401, an investigational adeno-associated virus serotype 8 (AAV8) vector gene therapy expressing the human G6PC gene, significantly reduced daily cornstarch intake compared to placebo treatment in patients with glycogen storage disease type Ia (GSDIa) who were treated in the phase 3 GlucoGene clinical trial (NCT05139316).1

At 48 weeks posttreatment, the 20 patients in the study treated with DTX401 showed a mean reduction in daily cornstarch intake from baseline of 41.3%, with the 24 patients who received treatment with a placebo showing a mean 10.3% reduction from baseline in daily cornstarch intake at the same time point (P < 0.0001). This measurement constitutes the study's primary end point. Ultragenyx also noted that the group treated with the gene therapy continued to show a mean reduction in cornstarch intake over the 48 weeks and that all patients within the group experienced a reduction in cornstarch intake. Furthermore, at 48 weeks 68% of patients treated with DTX401 showed a 30% or greater reduction in cornstarch intake and 37% of patients treated with DTX401 showed a 50% or greater reduction in cornstarch intake. On the other hand, at 48 weeks just 13% of patients who received the placebo showed a 30% or greater reduction in cornstarch intake and only 4% of patients in the placebo group showed a 50% or greater reduction in cornstarch intake.

The company noted that several of the trial’s key secondary end points were also met. At 48 weeks, those patients treated with DTX401 achieved a mean reduction in cornstarch doses per day of 1.1, while patients who received the placebo showed a mean reduction of just 0.2 (P = 0.0011). Furthermore, improvement in the frequency and quantity of nighttime cornstarch dosing was also observed in the group treated with the gene therapy in comparison to the placebo group. Ultragenyx pointed out that noninferiority (P < 0.0001) of glucose control between the groups was demonstrated.

At 48 weeks posttreatment, the Patient Global Impression of Change (PGIC) was used to measure patient reported outcomes. Patients treated with the gene therapy reported a median score of 2.0 (moderately improved), while patients in the placebo group reported a median score of 1.0 (minimally improved) (P = 0.132). Ultragenyx highlighted that a correlation was observed between 30% or greater reductions in total daily cornstarch intake and moderately or higher improved PGIC scores.

“With these Phase 3 results, the significant reduction in cornstarch intake with continued management of glucose control has the potential to offer meaningful benefit to patients while improving their quality of life on a daily basis,” study investigator Rebecca Riba-Wolman, MD, director of the Glycogen Storage Disease Program & Disorders of Hypoglycemia at Connecticut Children’s Medical Center/University of Connecticut Medical School, said in a statement.1 “GSDIa is a disease that never takes a break, where you must constantly think about your own, or your child's, safety and risk of severe low blood sugar and acidosis throughout the day and especially at night. A treatment that can improve these daily concerns for people with GSDIa without significant risks is essential.”

Ultragenyx characterized the safety profile of DTX401 in the trial as acceptable and expected, with anticipated vector-induced hepatic effects all being nonserious and manageable with a prophylactic corticosteroid regimen. There were no AAV8 class effects of dorsal root ganglion toxicity or cases of thrombotic microangiopathy reported through 48 weeks onstudy in any patient.

The company noted that it expects to report full 48 week data from the trial at a scientific conference before the end of 2024 and that it is aiming to submit a marketing application for DTX401 next year. The gene therapy has previously been evaluated in a phase 1/2 clinical trial (NCT03517085) for patients with GSD1a. The investigational new drug application for the phase 1/2 trial was originally cleared by the FDA in April 2018.2

“This is an incredible milestone for the DTX401 program,” Eric Crombez, MD, the chief medical officer of Ultragenyx, added to the statement.1 “These clinically important and statistically significant results are consistent with our phase 1/2 findings, and the continued improvement in these treated patients reflects the acquired ability to break down glycogen as a source of endogenous glucose from their treated livers. We want to thank the patients, families and treating community for their ongoing participation in this study and their support of progress for the broader GSDIa community.”

In addition to DTX401, Ultragenyx is developing several other gene therapy products. In February 2024 the company reported that UX111, an AAV9 viral vector gene therapy encoding human SGSH, reduced heparin sulfate exposure in the cerebrospinal fluid (CSF), which correlated with stabilized or improved cognitive function in patients with mucopolysaccharidosis type IIIA (also known as Sanfilippo syndrome).3 In January 2024, the company announced that it had completed the dosing of patients with Wilson disease with its investigational AAV9 gene therapy, UX701, in the first stage of the ongoing phase 1/2/3 Cyprus2+ study (NCT04884815).4

Ultragenyx is currently facing a lawsuit filed on behalf of the estate of Henrietta Lacks over the use of the HeLa cell line in the production of AAV vector-based gene therapies.5 In May 2024, United States District Judge Deborah Boardman rejected the company’s motion to dismiss the case.

REFERENCES
1. Ultragenyx announces positive top-line results from phase 3 study of DTX401 gene therapy for glycogen storage disease type Ia (GSDIa). News release. Ultragenyx Pharmaceutical Inc. May 30, 2024. Accessed May 31, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-positive-top-line-results-phase-3-study
2. Ultragenyx Announces Filing and FDA Clearance of an Investigational New Drug Application for DTX401, a Gene Therapy for the Treatment of Glycogen Storage Disease Type Ia. News release. Ultragenyx Pharmaceutical Inc. April 23, 2018. Accessed May 31, 2024. https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-filing-and-fda-clearance-investigational
3. Lau H, Patra K, Wolf M, et al. Reduction of heparan sulfate (HS) exposure in cerebrospinal fluid (CSF) correlates with improved long-term cognitive function in patients with mucopolysaccharidosis type IIIA (MPS IIIA) following treatment with UX111 gene therapy. Presented at: WorldSymposium; February 4-9; San Diego, California. Abstract #LB-35
4. Ultragenyx Announces Completion of Dosing Across Stage 1 Cohorts in Pivotal Phase 1/2/3 Cyprus2+ Study Evaluating UX701 Gene Therapy for the Treatment of Wilson Disease. News release. Ultragenyx Pharmaceuticals. January 25, 2024. Accessed May 31, 2024. https://www.globenewswire.com/news-release/2024/01/25/2817385/20739/en/Ultragenyx-Announces-Completion-of-Dosing-Across-Stage-1-Cohorts-in-Pivotal-Phase-1-2-3-Cyprus2-Study-Evaluating-UX701-Gene-Therapy-for-the-Treatment-of-Wilson-Disease.html
5. Ultragenyx must face Henrietta Lacks family lawsuit over HeLa cell profits. News article. Reuters, Blake Brittain. May 20, 2024. Accessed May 31, 2024. https://www.reuters.com/legal/litigation/ultragenyx-must-face-henrietta-lacks-family-lawsuit-over-hela-cell-profits-2024-05-20/#:~:text=The%20Lacks%20estate%20sued%20Novato,produce%20materials%20for%20gene%20therapy.
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