Ultragenyx Pharmaceutical Inc. announced positive topline safety and efficacy data from the first, lowest dose cohort of the ongoing Phase 1/2 study of DTX401, an adeno-associated virus (AAV) based gene therapy for the treatment of glycogen storage disease type Ia (GSDIa). A biologic response, reflected by improved glucose control and increased time to hypoglycemia during fasting, was observed in all three patients, with two patients demonstrating a clinically meaningful improvement in time to hypoglycemia during a controlled fasting challenge. The open-label, multicenter Phase 1/2 study is evaluating the safety, tolerability and therapeutic response of DTX401 in adults with GSDIa. All patients enrolled in the first cohort had null genotypes, with termination mutations or active site mutations, which should result in no residual enzyme activity. Patients in this first cohort each received a single 2.0 × 10^12 GC/kg dose of DTX401, an AAV8 expressing the glucose-6-phosphatase gene (G6Pase-a) under control of the native promoter. Key efficacy assessments include time to hypoglycemia (defined as glucose <60 mg/dL or onset of clinical symptoms) during a controlled in-hospital fasting challenge, impact on biomarkers such as lipids and uric acid, and measurement of glycogen storage in liver by MRI. The first patient in Cohort 1 had a clinically meaningful improvement in time to hypoglycemia from 3.8 hours at baseline to 7.7 hours at Week 12 (103% increase). This patient received a tapering course of steroids, beginning on day 59, to manage a mild asymptomatic elevation in alanine aminotransferase (ALT) levels, which returned to normal levels following the start of the steroid taper. Patient 2 had a clinically meaningful improvement in time to hypoglycemia from 4.1 hours at baseline to 9.0 hours at Week 12 (120% increase). In this instance, the fasting challenge was terminated based on possible hypoglycemia symptoms, and at the time the test was terminated, the patient’s glucose level remained well above 60 mg/dL. This patient received a tapering course of steroids beginning at Week 12 to address a slightly elevated ALT. Patient 3 showed a biologic response, reflected by an improvement in time to hypoglycemia from 5.4 hours at baseline to 6.5 hours at Week 12 (20% increase). As of the primary cutoff date of November 28, 2018, there have been no infusion-related adverse events and no treatment-related serious adverse events reported. All adverse events have been Grade 1 or 2. Patients 1 and 2 had mild elevations in ALT, similar to what has been observed in other programs using AAV-based gene therapy. These two patients successfully completed their tapering steroid regimens. The initial higher dose of steroids in the steroid taper regimen was prospectively reduced to 40 mg/kg to help reduce any risk for hypoglycemia in this particular null genotype population based on the advice of GSDIa experts. DTX401 Cohort 2 Initiation: The independent Data Monitoring Committee (DMC) has completed its review of Week 12 data from Cohort 1 and has concluded that it is safe to proceed to the second dose cohort of the study. Ultragenyx believes a higher dose may be more optimal in achieving the best clinical response and has elected to proceed to the next higher dose given the safety profile observed in the first cohort. In Cohort 2, three patients will be enrolled and will each receive a single dose of 6.0 × 10^12 GC/kg. The first patient in the second dose cohort is expected to be dosed in January 2019, and Cohort 2 data are expected in mid-2019. GSDIa is the most common genetically inherited glycogen storage disease. It is caused by a defective gene for the enzyme G6Pase-a, resulting in the inability to regulate blood sugar (glucose). 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.DTX401 is an investigational adeno-associated virus vector (AAV) type 8 gene therapy designed to deliver stable expression and activity of G6Pase-a under control of the native promoter. DTX401 is administered as a single intravenous infusion and has been shown in preclinical studies to improve G6Pase-a activity and reduce hepatic glycogen levels, a well-described biomarker of disease progression.