Alcobra Hopes To Continue Development In Fragile X On Quality Of Life Findings

Having failed a Phase III trial with its lead candidate, metadoxine, in attention deficit/hyperactivity disorder last fall, Alcobra Ltd. unveiled more bad news June 24, reporting that the drug missed its primary endpoint in a Phase II trial in Fragile X syndrome. But the Israeli firm is planning to discuss a new trial with FDA based on positive findings in a pair of secondary endpoints measuring quality of life benefits.

Alcobra had been advancing metadoxine, a non-stimulant that modulates gamma-aminobutyric acid transmission, concurrently in ADHD and Fragile X, but it failed in a Phase III ADHD trial last fall. The firm reported June 24 that metadoxine had again missed the primary efficacy endpoint in the AL014 Fragile X study, reduction in symptom score under the ADHD RS-IV inattentive subscale. In fact, results for that endpoint favored placebo.

Perhaps anticipating further stock-price decline the company experienced last October after the failed ADHD trial, President and CEO Yaron Daniely told a same-day investor call that Alcobra selected the primary endpoint for the Fragile X study with less understanding of the indication than it has today and that success in a pair of secondary endpoints might address factors more important to patients, clinicians and caregivers.

“We selected a pediatric ADHD rating scale as a primary measure for this exploratory study based on the available clinical data for [metadoxine] we had at the time and added several validated additional measures more frequently used in Fragile X studies such as the Vineland [Adaptive Behavioral Scale] and [aberrant behavior checklist (ABC)] as secondary measures. The intent was to explore what signal if any would MDX demonstrate in this population.”

Alcobra is now building a strategy to advance the drug in Fragile X based on achieving statistical and clinical significance in the Vineland Adaptive Behavioral Scale (VABS), which measures aspects of daily living, and the cognitive Test of Attentional Performance for Children (KiTAP) distractibility test, which measures ability to focus on a task despite distractions.

“As individuals with Fragile X syndrome typically have significant intellectual disabilities including impairment in daily living skills, a statistically and clinically significant effect on the VABS daily living skills domain represents a meaningful change in a domain that is highly relevant to this population,” Chief Medical Officer Jonathan Rubin argued on the call.

“The findings of this study are very encouraging, particularly in the context of its size, the large variability in patient ages, IQ, severity and concomitant medication,” Daniely said. “I’d previously set the bar high for this study, stating that in order to pursue this program further a directional benefit at the very least on meaningful clinical outcomes would have to be evident. Well, this study provided two statistically and clinically significant findings on the [intent to treat] population in two important clinical secondary endpoints.”

“The findings on these two distinct assessments certainly pass the bar for demonstrating a positive signal, especially for patients living with Fragile X and their caregivers,” he continued. “We believe that the development of a differentiated [metadoxine] product for the treatment of Fragile X represents a new and attractive value proposition distinct and complementary to our leading ADHD program. We intend to bring the full data of this program to the FDA in the near future and finalize the design of the next study in Fragile X syndrome.”

Impact Of Background Therapy Questioned

The study accepted patients taking up to three psychotropic drugs so long as they were on a stable regimen prior to screening. Alcobra maintains that those background medications might have affected the treatment effect seen in placebo-arm patients, thereby obscuring the clinical benefit of metadoxine.

The company has apparently successfully used a similar argument already with FDA regarding the ADHD program. Alcobra asserts the drug met statistical significance in ADHD if four placebo-arm patients who showed extreme improvement were removed from the sample, because those findings were inconsistent with the rest of the placebo group and historical data. “FDA concurred that positive efficacy results from one short-term Phase II and one short-term Phase III will be sufficient to demonstrate efficacy for approval of metadoxine in this indication,” WBB Securities analyst Stephen Brozak said in a June 24 note.

The benefit in the secondary measures in the Fragile X trial in terms of daily functional behavior like managing time and money and completing domestic chores is particularly notable given the history of trials in the space, Elizabeth Berry Kravis of Rush University Medical Center, the principal investigator on study AL014, pointed out. She noted that previous placebo-controlled trials in adolescents and adults with Fragile X did not show such effects even with longer treatment durations.

There is no FDA-approved therapy for the genetic condition, and patients often receive stimulant therapies that can result in side effects including anxiety and irritability. Metadoxine has had good tolerability in studies to date, she added.

“In the context of recent negative trials of adolescents and adults with Fragile X, which failed to show any significant or even directional improvements on any clinical measure in ITT-based analysis, our trial provided significant findings on the very outcomes that clinicians, patients and their caregivers find meaningful,” Daniely concluded. “Any improvement, let alone with a meaningful clinical effect size in the function of Fragile X patients that impacts their daily lives, performance and skills could be beneficial to this community. We therefore believe that the significant findings on the validated Vineland assessment, supported by the significant cognitive findings, suggest a true finding of benefit in adaptive behavior and function in Fragile X.”

BioMedTracker lists seven suspended trials in Fragile X syndrome, as well as three ongoing clinical programs, including Alcobra and four investigator-initiated trials. Roche discontinued development of basimglurant (RG7090) after two mid-stage studies failed to meet primary and secondary endpoints last September, and Novartis AG shut down its program for mavoglurant (AFQ056) last April after failing in two Phase IIb/III studies.

Alcobra’s stock finished trading on June 24 down 13% to $7.30 per share, a less extreme reaction from the market than it got Oct. 6, 2014, when its share price tumbled by 57% on the news of the Phase III setback in ADHD. Brozak downgraded the company from “buy” to “hold” on the Fragile X data, noting that Alcobra may have a path forward with metadoxine in ADHD, with a plan to submit a pediatric study plan to FDA this quarter for that indication.

After going public in 2013, Alcobra brought its financial holding to about $60 million with a follow-on offering in 2014, which it said would be sufficient to advance metadoxine, which it viewed as virtually a pipeline in a pill, in both ADHD and Fragile X (Also see "Alcobra’s Pipeline In A Pill Aims To Capture The ADHD Market And More" - Pink Sheet, 12 Feb, 2014.). The neuroscience work arose from findings in trials in which the drug failed as a sobering agent for alcohol intoxication; the drug has been available for years as a liver treatment in Russia, China and India.