- Ultragenyx Pharmaceutical on Wednesday released the first data from patients taking the planned Phase 3 dose of gene therapy DTX401 for a condition called glycogen storage disorder 1a. Yet that dose appeared only as effective as a lower dose used in an earlier group of patients.
- The three patients at the higher dose also needed to be treated with steroids to combat liver enzyme elevations, a factor that may have resulted in unexpected hyperglycemia during a fasting challenge.
- Shares fell 12% following the data release Wednesday, which came at a meeting of the Society for the Study of Inborn Errors of Metabolism. Ultragenyx paid $151 million to acquire Dimension Therapeutics for access to DTX401 and other experimental gene therapies.
Gene therapies are almost exclusively being developed for patients with rare, genetically-driven diseases. As a result, companies enroll very small trials that proceed deliberately through dose escalation, and investors closely watch for incremental developments, as Ultragenyx found out this week.
Ultragenyx's DTX401 treats a condition that affects about 6,000 patients worldwide who can't break down glucose, leading to life-threatening episodes of hypoglycemia.
The main treatment is consumption of corn starch every three to five hours, including during the night. The corn starch serves as a glucose reservoir in the intestinal tract. Reduction in corn starch consumption therefore is an endpoint in Ultragenyx's trial.
The first three patients in this Phase 1/2 trial received 2 trillion genome copies per kilogram of body mass of the gene contained by DTX401, which is designed to spur expression glucose-6-phosphatase. They saw their corn starch consumption drop 77%, 72% and 44% after 24 weeks of treatment.
The second set of patients, data for whom was released on Wednesday, received 6 trillion genome copies per kilogram. Two had completed 24 weeks of treatment and saw their corn starch consumption fall 69% and 16%. A third had completed 18 weeks and had a 68% decline in consumption.
Analysts said they expected the higher dose would have resulted in a greater reduction in corn starch, suggesting more work needs to be done to clarify the benefit of a higher dose before proceeding to Phase 3. The company said a possible explanation for the inconsistent response is that patients might have swollen pancreases thanks to chronic corn starch ingestion.
Moreover, the use of steroids to control liver enzyme elevations will need to be fine-tuned. This is not an uncommon issue with gene therapies — for example, Spark Therapeutics used steroids in conjunction with its hemophilia A treatment.
Clarification should come no later than June 2020, because Ultragenyx announced it will be enrolling an expansion cohort of three more patients to be dosed with 6 trillion genome copies per kilogram. The company expects to begin a Phase 3 trial at that dose level next year, which will be influenced by the findings from those additional patients.