Ultragenyx Reports Additional Positive Durability Data from AAV Gene Therapy Studies

Ultragenyx Pharmaceutical reported new long-term durability data from the phase 1/2 studies of DTX401 for Glycogen Storage Disease Type Ia and DTX301 for Ornithine Transcarbamylase (OTC) deficiency that were presented at the 14th International Congress of Inborn Errors of Metabolism.

Photo: Eric Crombez, chief medical officer of Ultragenyx Gene Therapies

“With initial patients now in year three following dosing with DTX401 and DTX301 we are seeing the impact of long-term, durable biological responses and the establishment of normal metabolic pathways to allow for the release of glucose from glycogen during periods of fasting for patients with GSDIa and the breakdown of ammonia for patients with OTC deficiency,” said Eric Crombez, chief medical officer of Ultragenyx Gene Therapy. “By directly correcting the underlying genetic cause of disease these gene therapies have the potential to provide meaningful quality-of-life improvements for patients and enable new flexibility and independence to take part in a more active and less-restrictive lifestyle.”

Glycogen Storage Disease Type Ia (GSDIa) is the most severe genetically inherited glycogen storage disease. It is caused by a defective gene coding for the enzyme G6Pase-α, resulting in the inability to regulate blood sugar. Hypoglycemia in patients with GSDIa can be life-threatening, while the accumulation of the complex sugar glycogen in certain organs and tissues can impair the ability of these tissues to function normally. If chronically untreated, patients can develop severe lactic acidosis, progress to renal failure, and potentially die in infancy or childhood. There are no approved pharmacologic therapies. An estimated 6,000 patients worldwide are affected by GSDIa.

Ultragenyx’ DTX401 is an experimental adeno-associated virus type 8 (AAV8) gene therapy designed to deliver stable expression and activity of G6Pase-α under control of the native promoter. DTX401 is administered as a single intravenous infusion and has been shown in preclinical studies to improve G6Pase-α activity and reduce hepatic glycogen levels, a well-described biomarker of disease progression. DTX401 has been granted Orphan Drug designation in both the United States and Europe, and Regenerative Medicine Advanced Therapy (RMAT) and Fast Track designations in the United States.

Longer-term phase 1/2 data presented at ICIEM 2021 demonstrate durability of response, with sustained responses lasting up to 3 years since treatment. Across all 12 patients, the mean reduction in daily cornstarch intake was 69.9 percent ranging from 19-100 percent when comparing baseline to the most recent visit. The nine patients in Cohorts 1, 2, and 3 continue to demonstrate improved glucose control while tapering or discontinuing oral glucose replacement therapy with cornstarch up to 3 years after receiving DTX401. The three patients in Cohort 4 have completed a tapering prophylactic steroid regimen. Two of the three patients have reduced the frequency of daily oral glucose replacement therapy from six times per day at baseline to one (Patient 10) and two (Patient 11) times per day as of their last visit. Across all patients in the phase 1/2 study, to date there have been no infusion-related adverse events, no treatment-related serious adverse events, and no dose-limiting toxicities reported.

OTC deficiency, the most common urea cycle disorder, is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. Individuals with OTC deficiency can build up excessive levels of ammonia in their blood, potentially resulting in acute and chronic neurological deficits and other toxicities. It is estimated that more than 10,000 people are affected by OTC deficiency worldwide, of whom approximately 80 percent are classified as late-onset and represent a clinical spectrum of disease severity. In the late-onset form of the disease, elevated ammonia can lead to significant medical issues for patients. Neonatal onset disease occurs only in males, presents as severe disease, and can be fatal at an early age. Approved therapies, which must be taken multiple times a day for the patient’s entire life, do not eliminate the risk of future metabolic crises. Currently, the only curative approach is liver transplantation.

Ultragenyx’ DTX301 is an investigational AAV8 gene therapy designed to deliver stable expression and activity of OTC following a single intravenous infusion. It has been shown in preclinical studies to normalize levels of urinary orotic acid, a marker of ammonia metabolism. DTX301 was granted Orphan Drug designation in both the United States and Europe.

Longer-term phase 1/2 data presented at ICIEM 2021 demonstrate durable metabolic control and sustained responses. The six patients who previously demonstrated a response remain clinically and metabolically stable, including all three treated at the highest dose, which is the dose that will be used in the phase 3 study. The longest treated responders have demonstrated a durable response up to 4 years after dosing, and up to 3.5 years after discontinuing ammonia-scavenger medications and liberalizing protein-restricted diets.

Two patients were enrolled into Cohort 4 of the DTX301 study and received a tapering prophylactic steroid regimen. Patient 10 is deemed a responder. As of the data cut-off, Patient 11 had completed the prophylactic steroid regimen and is in the process of modifying ammonia-scavenging drugs and or diet. Across all 11 patients in the study, to date there have been no infusion-related adverse events, no treatment-related serious adverse events and no dose-limiting toxicities reported. All treatment-related adverse events have been Grade 1 or 2, except for one episode of grade 3 hyperammonemic crisis related to OTC deficiency.

Author: Rare Daily Staff