Upstaza (eladocagene exuparvovec) for AADC deficiency
What is Upstaza for AADC deficiency?
Upstaza (eladocagene exuparvovec) is a one-time gene therapy designed to correct the underlying genetic cause of aromatic L-amino acid decarboxylase (AADC) deficiency, which is characterized by developmental delays and movement and behavior problems.
Formerly called PTC-AADC, Upstaza is being developed by PTC Therapeutics, which acquired the therapy’s original developer Agilis Biotherapeutics in 2018.
Upstaza was approved in the European Union and in the U.K. in 2022 to treat AADC deficiency in patients ages 18 months and older. These regulatory decisions made it the first approved disease-modifying therapy for AADC deficiency.
The gene therapy is not approved in the U.S., but PTC has announced plans to file for approval in the country in the company months; the next steps will be determined following a meeting with the U.S. Food and Drug Administration that’s scheduled for December 2023.
How does Upstaza work?
AADC deficiency is caused by mutations in the DDC gene, which provides instructions for making the AADC enzyme. This enzyme is needed to produce certain neurotransmitters, or signaling molecules, that nerve cells use to communicate with each other and the rest of the body. Two such neurotransmitters are serotonin and dopamine.
DDC mutations result in deficient levels of a working AADC enzyme, which means that the brain cannot make enough serotonin and dopamine, leading to the neurological symptoms that are hallmarks of the disease.
Upstaza is a one-time gene therapy that uses a modified and harmless virus, called adeno-associated virus serotype 2 or AAV2, to deliver a healthy copy of the DDC gene to nerve cells. The treatment is expected to increase the production of a working AADC enzyme in cells, which in turn will increase levels of serotonin and dopamine and ease disease symptoms.
How will Upstaza be administered?
In clinical trials, Upstaza was administered directly into the putamen, the area of the brain with the highest AADC activity and where dopamine signaling is key for motor, cognitive, and emotional functions. This is done via a minimally invasive neurosurgical procedure called stereotactic brain surgery, in which previous brain MRI images guide treatment infusion into the putamen on both sides of the brain.
In Europe, the approved dose is a total of 180 billion vector genomes (vg) — which are essentially individual particles of the therapeutic virus — delivered as four 0.08 mL infusions, two per putamen.
Upstaza in clinical trials
Upstaza was investigated in two compassionate use studies in Taiwan and Europe. It also was tested in a Phase 1/2 clinical trial called AADC-010 (NCT01395641) and a Phase 2b trial dubbed AADC-011 (NCT02926066), both conducted in Taiwan.
Compassionate use studies
Early Upstaza compassionate use studies, in which the gene therapy was given to a limited number of AADC deficiency patients before approval, involved eight children in Taiwan and two children in Europe.
Results to date are available from the first four treated children, ages 4 to 6, from the Taiwan study, dubbed AADC-1601. All of the children experienced motor function improvements one year after treatment with a dose of 180 billion vg.
Follow-up data of up to four years or longer from the eight children in Taiwan demonstrated that four of them were able to stand with support and three could sit with support — motor milestones rarely achieved by AADC deficiency patients.
In the European study, a 180 billion vg dose of Upstaza was administered to a boy and a girl older than 10 years at the time of treatment — the oldest to date. These patients had no head control before receiving the gene therapy.
After 1.5 years, both children showed reductions in motor and nonmotor symptoms, and had attained new motor milestones — including head control and being able to reach or grab objects.
AADC-010 Phase 1/2 trial
Launched in 2014, the AADC-010 trial enrolled five boys and five girls, ages 1.7 to 8.4 years, with AADC deficiency. Prior to treatment, none of the patients had met any typical motor milestones, such as head control.
All participants received a 180 billion vg dose of Upstaza, with no surgical complications. One of the children died due to an influenza infection, unrelated to Upstaza, at 10 months after gene therapy treatment. The other nine were followed for a year after receiving the therapy.
One of the study’s main goals was to assess whether treatment with Upstaza led to an increase of at least 10 points in the Peabody Developmental Motor Scales second edition (PDMS-2), indicating improvements in at least five different aspects of motor function.
Results showed that this goal was met: All of the treated participants experienced such a score improvement after one year, with a median increase of 62 points. By one year, all patients had at least partial head control, and five were able to briefly sit up with support. One child who experienced an especially good response was able to sit unassisted and stand with support.
In comparison, among 27 untreated children with AADC deficiency in a comparator group, one developed full head control. None were able to sit or stand.
Upstaza also led to statistically significant improvements on average scores for standardized tests of cognitive and language development, though this was mainly driven by substantial improvements in the one child showing a especially pronounced response.
The trial’s other main goal was to test whether Upstaza led to increases in HVA, a metabolite of dopamine, in the fluid around patients’ brains and spinal cord, called the cerebrospinal fluid or CSF. All but one evaluable patient showed a significant increase in CSF HVA levels. The levels of 5-HIAA, a metabolite of serotonin, did not change significantly following treatment, however.
AADC-011
The AADC-011 study, launched in 2016, tested two doses of Upstaza (180 and 230 billion vgs) in 12 children, as old as 6, with AADC deficiency. The main goals of this trial were the same as those of the AADC-010 study.
Pooled analyses
Results from AADC-011 were pooled with data from AADC-010 and the Taiwan compassionate use study. Across these studies, a total of 30 patients, all younger than age 9, were treated with Upstaza; many of them have been followed for at least 10 years in a long-term extension study.
Pooled analyses from the 26 children who completed at least their one-year assessments showed that the average PDMS-2 score significantly increased, by more than 70 points, after one year.
Significant reductions in the severity of oculogyric crises — a common eye movement disorder in AADC deficiency patients — also were observed after one year, along with significant cognitive and language improvements, and increases in CSF HVA levels.
These gains were sustained for up to five years, with children meeting new motor milestones years after treatment. Such milestones included walking without help or running freely. Further motor development also was observed during five to 10 years of follow-up in the four children who were followed for up to a decade.
Those younger at treatment administration showed the most dramatic long-term improvements.
Because Upstaza is a recently developed therapy and the patients who were treated in the earliest clinical trials are now teenagers, its longer-term outcomes aren’t definitively known yet. Models have suggested that the treatment is likely to substantially extend life expectancy and improve life quality compared with what would be expected for untreated patients.
Ongoing trials
PTC is running a small Phase 2 trial (NCT04903288) testing a device called SmartFlow Magnetic Ressonance Compatible Ventricular Cannula for use in the administration of Upstaza. Three children with AADC deficiency are receiving doses of 180 billion vg.
The study aims to evaluate changes in CSF levels of HVA and other neurotransmitter metabolites, in motor and cognitive function, and quality of life. It also is assessing the number of patients attaining motor milestones or experiencing adverse events. The trial is expected to conclude in 2028.
Common side effects of Upstaza
The most common side effects of Upstaza reported in trials included uncontrolled movements known as dyskinesia, insomnia, and irritability.
Patients also may experience complications related to the surgical procedure or to the anesthesia used when the therapy is administered. Thus, all patients should be closely monitored in the period before, during, and immediately after surgery.
AADC News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare providers with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
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