Upstaza leads to long-term benefits for patients in prediction model

Upstaza 'potentially life-changing' for patient survival, quality of life: Study

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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In this gene therapy illustration, a strand of DNA is shown on a couch while a therapist sits on a chair nearby.

Treatment with Upstaza (eladocagene exuparvovec) is estimated to prolong survival and lead to life quality gains for aromatic l-amino acid decarboxylase (AADC) deficiency patients relative to standard supportive care.

These are the findings of a recent study that used existing clinical data to model possible long-term outcome trajectories for people with the disease.

The analysis gives insight into how the one-time gene therapy from PTC Therapeutics might alter the disease course long term, given that treated patients so far haven’t yet been followed long enough for scientists to truly know its long-term impacts.

The study, “Long-Term Outcomes of Eladocagene Exuparvovec Compared with Standard of Care in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Modelling Study,” was published in Advances in Therapy.

AADC deficiency is caused by mutations in the DDC gene, which lead to a lack of working AADC, an enzyme critical for the production of important brain signaling chemicals, or neurotransmitters.

Abnormally low production of these neurotransmitters critically compromises brain function, leading to severe neurological symptoms such as a failure to meet developmental milestones like walking and talking.

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Case report supports Upstaza for children older than 10 years

Upstaza provides healthy copy of DDC gene via one-time infusion into brain

Upstaza provides patients with a healthy copy of DDC, enabling them to make more working AADC enzyme. It’s delivered as a one-time infusion directly into a brain region called the putamen, which is especially impacted by the disease.

It is the only disease-modifying treatment approved for AADC deficiency patients in the European Union and the U.K., where it was cleared for patients 18 months and older last year. In the U.S., a similar regulatory application is expected to be filed this year.

Upstaza was evaluated in a compassionate use study dubbed AADC-1601, a Phase 1/2 clinical trial called AADC-010 (NCT01395641), and a Phase 2b study dubbed AADC-011 (NCT02926066), all conducted in Taiwan.

Cumulatively, these studies involved 30 children, ages 19 months to 8.5 years, with AADC deficiency who had failed to achieve head control.

Data indicated that up to 10 years after receiving Upstaza, treated children attained and continued to reach motor milestones that patients usually don’t achieve. Cognitive improvements, reductions in symptoms, healthy weight gain, and improved caregiver life quality were also observed in the years after the infusion.

Because these patients are still being followed, it is not yet known how Upstaza influences longer-term outcomes and whether it will prolong survival for patients, who are at a high risk of death in their first decade of life.

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AAN 2023: Children reaching motor milestones 10 years after Upstaza

Model compares long-term benefits of Upstaza with those of supportive care

Now, researchers in Taiwan and at PTC and Open Health created a model that would compare the long-term benefits of Upstaza against those of best supportive care (BSC) for AADC deficiency patients in a U.K. healthcare setting.

BSC consists of standard treatments used to alleviate symptoms but which don’t fundamentally address the cause of the disorder or restore neurotransmitter production.

Upstaza’s efficacy was based on motor milestone data from the previous Upstaza clinical studies. BSC efficacy was informed by findings from 49 patients in a natural history patient database who had similar clinical and demographic features as those involved in the trials.

Because AADC deficiency is so rare, the researchers also used additional sources to help predict life quality and healthcare resource utilization.

Given that “no long-term survival data for patients with AADC deficiency was available from clinical trials or from the literature,” the researchers used data from children with cerebral palsy as a proxy for predicting patients’ long-term survival in the model.

The model accounted for two phases based on children’s motor development, including a development phase (up to 12 years), during which motor milestone progression is expected to increase, and a long-term phase thereafter, where motor milestones stabilize and are not expected to progress further.

Results indicated that patients’ median estimated survival was 40 years with Upstaza compared with 15.5 years with BSC, indicating that the gene therapy is estimated to extend survival by 24.5 years.

Estimated survival at the end of the developmental phase (12 years) was 86% with Upstaza and 61.9% with BSC. After 20 years, these rates were 74% for Upstaza and 36.8% for BSC.

With BSC, most years of life were lived in a state where no motor milestones were achieved. For Upstaza-treated patients, the model predicted the highest achieved motor milestone by the end of the developmental phase would be sitting unassisted for 20.9% of patients, standing with support for 24%, and walking with assistance for 22.1%.

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Upstaza to be available at low or no cost for eligible patients in England

Upstaza associated with life quality benefits

The gene therapy was also associated with life quality benefits, with an estimated additional 20.21 quality-adjusted life years, or QALYs, relative to BSC. A QALY refers to a year living in perfect health.

“The magnitude of QALY gains reflects the innovative and potentially life-changing impacts of [Upstaza], far exceeding QALY gains historically observed for specialty therapies,” the researchers wrote.

Data also showed that “disease management costs for both treatments are driven by follow-up visit costs due to the large interdisciplinary team of specialists needed to treat patients with AADC deficiency,” the team wrote.

Long-term healthcare utilization costs were estimated to be higher for Upstaza-treated patients: £632,829 (about $778,800) compared with £402,431 ($495,300) with BSC. This difference was “driven by the additional survival of patients and so the increase in the number of specialist visits over a longer period,” the researchers wrote.

Overall, “this study provides a model that can explore the long-term outcomes for patients with AADC deficiency and indicates survival… and quality of life benefits … from treatment with [Upstaza] compared to BSC,” the team concluded.

Among the study’s limitations, the researchers noted differences between cerebral palsy and AADC deficiency, which may have resulted in over- or underestimations of the real survival of Upstaza-treated patients.