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Monthly infusions of an investigational product that encapsulates dexamethasone sodium phosphate into autologous erythrocytes (EryDex) appeared safe but did not significantly improve neurological symptoms in children with ataxia telangiectasia, an international phase III trial found.

Among 164 kids with the rare progressive neurodegenerative disorder, EryDex showed no difference compared with placebo in scores on the modified International Cooperative Ataxia Rating Scale (mICARS), reported Biljana Horn, MD, of developer Quince Therapeutics in South San Francisco, California, and colleagues.

From baseline to 6 months, the least squares mean difference versus placebo in mICARS scores (range 0-54, with higher scores indicating worse neurological function) were -1.37 (95% CI -2.93 to 0.19) with low-dose EryDex and -1.40 (95% CI -2.96 to 0.15) with high-dose EryDex.

Nor were there significant differences in changes in disease severity, a secondary endpoint measured by the Clinical Global Impression-Change scale, the researchers detailed in .

Ataxia telangiectasia develops in childhood, and symptoms of the inherited multisystem disorder include ataxia, oculomotor apraxia, and involuntary movements. Wheelchair dependence in patients with the classic type of ataxia telangiectasia -- accounting for upwards of 80% of individuals with the condition -- .

"In natural history studies, children with the classical type of ataxia telangiectasia aged younger than 6 years have few clinical signs of neurological deterioration; however, between age 6 and 10 years, there is rapid clinical decline, after which disease progression stabilizes," noted Horn and co-authors.

In trials, this rapid progression could in theory help detect a treatment effect more quickly. "Additionally, treatment of neurodegenerative disorders is often more effective earlier in the disease course before significant neuronal damage occurs," the researchers said.

In a subgroup analysis of the so-called ATTeST trial, children ages 6 to 9 years appeared to benefit with high-dose EryDex, with a least squares mean change in mICARS scores of -2.79 (95% CI -5.09 to -0.48) versus placebo; a smaller ongoing is testing the product exclusively in this age group.

According to Horn and co-authors, corticosteroids can improve neurological symptoms in people with ataxia telangiectasia, but adrenal suppression with long-term use limits its use. This has led to efforts to create novel delivery systems. With EryDex, the dexamethasone is released slowly from erythrocytes over a 4-week period.

Horn and colleagues cited pandemic policies -- the trial was conducted from 2017 to 2021 across a dozen countries -- as a potential for the null findings in their study. Of note, 35% of the participants had delayed and missed treatments.

"In some instances, treatment was delayed because investigators delayed visits to hospital to protect immunocompromised participants in the peak of the pandemic," the authors explained.

Per-protocol analyses supported a treatment effect with both the low and high doses of the investigational product, with least squares mean differences of -2.80 (95% CI -4.67 to -0.93) and -2.21 (95% CI -4.05 to -0.37), respectively, versus placebo.

In an , Yuka Koike, MD, PhD, and Osamu Onodera, MD, PhD, both of Niigata University in Japan, remarked on the challenges of conducting international multicenter trials like ATTeST, as regulatory requirements, implementation inconsistencies, expenses, and language and cultural differences can pose significant challenges to rare disease research.

"The ATTeST study highlights the feasibility of conducting a large international trial for a rare and progressive pediatric neurological disease," they wrote. "In the future, it is hoped clinical trials will be developed that involve fewer patients and lower costs, with less physical and financial burden on patients and their families."

The randomized, double blind, placebo-controlled took place at 22 centers in Australia, Belgium, Germany, India, Israel, Italy, Norway, Poland, Spain, Tunisia, the U.K., and the U.S. Included were children 6 and older who had ataxia telangiectasia with preserved autonomous gait and who weighed more than 15 kg (33 lb).

In total, 175 children started therapy in the study, around half of them boys, with a mean age of 9-10. They were assigned 1:1:1 to monthly infusions with low-dose EryDex (5-10 mg), high-dose EryDex (14-22 mg), or placebo for 6 months.

Unlike ICARS, the has not been validated but was used in the study based on an FDA request "to focus on domains that better predict motor functioning and are more relevant when evaluating disease progression," according to the study authors. Domains on mICARS include posture and gait, kinetic function, and speech.

Adverse events were reported in 73% participants in the low-dose group, 82% of the high-dose group, and 73% of the placebo group. Serious adverse events were observed in 10%, 12%, and 12%, respectively.

Of the potentially steroid-related adverse events, the most common were infections and infestations (37% and 30% with the low- and high-dose treatment vs 22% with placebo), nasopharyngitis (10% and 12% vs 7%), and cough (12% and 16% vs 14%).

On top of pandemic disruptions, the absence of a biomarker for evaluating treatment efficacy was another major limitation of the study, said Horn and colleagues.

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