Allos plans for pivotal Phase 3 study of arbaclofen for fragile X

Positive findings in trial would support applications for FDA approval

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Allos Pharma has met with the U.S. Food and Drug Administration (FDA) to optimize the design of a planned Phase 3 trial to test its investigational oral therapy arbaclofen in individuals with fragile X syndrome.

The trial is intended to confirm promising findings from a previous Phase 3 study in children with the neurodevelopmental disease. Should these results also be positive, they’ll back the company’s applications for regulatory approval of arbaclofen for fragile X — an indication for which there are no approved treatments to date.

“We are extremely pleased with the outcome of the meeting with the FDA and grateful for their engagement, guidance and support as we advance our Phase 3 trial for fragile X syndrome,” Randall Carpenter, MD, Allos’ co-founder, said in a company press release.

“We remain committed to providing a new treatment option for patients and families affected by this debilitating disorder, and believe that arbaclofen has the potential to make a significant, positive impact on their lives,” Carpenter said.

The pharmaceutical company did not provide any information as to when the new trial could potentially launch.

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Fragile X patients experience a range of neurological symptoms, including developmental delays, behavioral disturbances, problems with social functioning, and seizures.

Evidence suggests that disruptions in the signaling of GABA, a messenger molecule nerve cells use to communicate, drives excessive nerve cell firing (excitability) that underlies some of the symptoms of fragile X.

Formerly known as STX209, arbaclofen was originally developed by Seaside Therapeutics, which stopped clinical testing of the treatment in 2013 due to resource limitations. The therapy was licensed to Allos in 2020.

Allos’ co-founders, Carpenter and Mark Bear, PhD, had previously founded Seaside and advanced arbaclofen through Phase 3 studies in fragile X.

Arbaclofen works to activate GABA-B receptors, which are proteins GABA normally interacts with to exert its effects. In doing so, the treatment essentially mimics the activity of GABA at these receptors — but it’s 10 times more potent than GABA itself, according to the company.

Ultimately, the therapy is expected to reduce nerve cell excitability, thereby easing fragile X symptoms. This hypothesis is supported by studies in animal models and a proof-of-concept Phase 2 trial (NCT00788073) that had been conducted by Seaside.

A previous Phase 3 trial (NCT01325220), launched by Seaside in 2011, evaluated the treatment’s effects on behavior in children with fragile X, ages 5-11. A total of 172 children were enrolled and received oral arbaclofen (5 mg or 10 mg) or a placebo, 2-3 times daily for eight weeks, or about two months.

A similar trial (NCT01282268), also Phase 3, tested arbaclofen against a placebo among 125 adolescents and adults with fragile X, ages 12-50.

In both studies, the main efficacy goal was to assess changes in social avoidance — a behavioral abnormality common in fragile X patients. Evaluations were made using the social avoidance subscale of the caregiver-reported, fragile X-specific Aberrant Behavior Checklist (ABC) scale.

Results indicated that neither trial met this goal, with no significant differences between the arbaclofen and placebo groups in terms of social avoidance changes.

However, data on secondary measures, such as other ABC subscales, showed arbaclofen was superior to a placebo at easing other abnormal behaviors, such as irritability, in children with fragile X.

Importantly, despite the testing, the researchers weren’t sure whether the observed numerical changes in ABC scores were clinically relevant.

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Arbaclofen Improved Behavior of Almost Half of Children in Phase 3 Trial

Fragile X patients, families eager for new trial

Allos last year presented new analyses from the pediatric trial after defining what clinically meaningful change would translate to in certain ABC subscales. Specifically, the focus was on irritability, social avoidance, and social unresponsiveness (lethargy).

With these thresholds in place, it was observed that significantly more children given arbaclofen (45%) saw clinically meaningful improvements across the ABC subscales relative to those given a placebo (4%).

“The robust efficacy observed in children provides clarity on effective dosage, inclusion criteria, trial duration, safety, and [efficacy goals], increasing confidence that the pivotal Phase 3 trial will yield positive results,” Allos stated in the release.

Additionally, the company noted that feedback from the recent FDA meeting, along with input from the Clinical Trial Committee of the National Fragile X Foundation (NFXF), will also inform the trial’s design.

“The expert clinician members of our Clinical Trial Committee have provided input and guidance to optimize the design of the clinical trial and enthusiastically support performing this study,” said Hilary Rosselot, executive director of NFXF.

“NFXF looks forward to working in partnership with Allos to better the lives of individuals with Fragile X Syndrome and their families,” Rosselot said.

The robust efficacy observed in children provides clarity on effective dosage, inclusion criteria, trial duration, safety, and [efficacy goals], increasing confidence that the pivotal Phase 3 trial will yield positive results.

Allos’ licensing of arbaclofen in 2020 was met with enthusiasm from fragile X families who had participated in the earlier Seaside-sponsored trials and faced disappointment when its development stopped.

“We support the dedicated work of Drs. Bear and Carpenter and the rest of the Allos team to move ahead with arbaclofen to treat core symptoms in children with fragile X,” said Katie Clapp, president and co-founder of the FRAXA Research Foundation, adding, “Many, many families are waiting eagerly to have access to arbaclofen again!”