Results from Alcobra Ltd.'s phase II study of MDX (metadoxine extended release) in the rare neurogenetic disorder fragile X syndrome (FXS) may point in a positive direction for the program, even if the firm's stock went the other way Wednesday.

The company reported statistically significant improvements on two secondary endpoints in the six-week trial in FXS, the most common known cause of inherited intellectual disability – also the leading known genetic cause of autism – characterized by a variety of symptoms from behavioral disorders to learning disabilities. MDX treatment resulted in improvements in the Vineland Adaptive Behavior Scale (VABS) Daily Living Skills assessment (p = 0.044) and in the Test of Attentional Performance for Children (KiTAP) – Distractibility (p = 0.017), functional and cognitive improvements that Alcobra said could have the biggest impact on patients.

Despite the short duration and small size of the study – 62 patients were enrolled and randomized to MDX or placebo – those were "pretty substantial effect sizes," according to principal investigator Elizabeth Berry-Kravis, professor of pediatrics, neurological sciences and biochemistry at Rush University Medical Center.

"It's a pilot study," she acknowledged, "so clearly they have to be confirmed. But if one could demonstrate that sort of an effect size on functions like daily living skills and the ability to kind of stay on task and be able to complete things, that would be . . . a clinically significant benefit," she told investors on a conference call Wednesday morning.

Alcobra President and CEO Yaron Daniely called the findings "very encouraging, particularly in the context of its size, the large degree of variability in patient ages, IQs, severity and concomitant medications."

Wall Street, however, was not convinced, dropping shares of the Tel Aviv, Israel-based company (NASDAQ:ADHD) down 13 percent, or $1.09, to close Wednesday at $7.30. Investors likely interpreted the missed primary endpoint, which used the ADHD RS-IV Inattentive Subscale as its measurement, as an ill omen for ongoing development of MDX in the much larger attention deficit hyperactivity disorder (ADHD) indication. At the very least it could be viewed as yet another failure in FXS, a condition that has proved particularly tricky in terms of finding validated endpoints.

In her presentation, Berry-Kravis highlighted three recent misses by FXS candidates: Novartis AG's AFQ-056 (mavoglurant), an mGlur5 antagonist; Roche AG's RG7090 (RO4917523), an mGluR5 negative allosteric modulator; and Seaside Therapeutics Inc.'s GABA B agonist, arbaclofen. Like Alcobra's study, trials for those candidates enrolled similar patient populations – adolescents and adults with FXS – and tried measuring for benefit using a variety of behavioral and cognitive scales. No statistically significant findings in any of the reported measures in any trials for those three candidates were noted, she said.

Basel, Switzerland-based Novartis said in April 2014 it was discontinuing development of mavoglurant in FXS. Roche, also of Basel, followed suit later that year with RG7090, according to a letter posted by the National Fragile X Foundation. As for Seaside, the Cambridge, Mass.-based firm disappointed patients in May 2013 when it stopped an extension trial of arbaclofen due to lack of funding and appears to have closed up shop altogether. (See BioWorld Today, May 28, 2013.)

MEASURING BEHAVIOR

MDX is a monoamine-independent modulator of GABA transmission, Berry-Kravis, explained. And research has shown that FXS is associated with GABA transmission imbalance.

In animal studies, MDX demonstrated significant improvement in behavioral outcomes, including memory, learning and social interaction. Finding appropriate measures to test whether those findings translate into human subjects is where the difficulty lies, particularly when trying to measure behavioral change in teens and adults, which often is already fixed.

It's hard to change synaptic plasticity or brain wiring, Berry-Kravis said, adding, "It's not clear that behavior is a surrogate for improved plasticity in the brain, particularly when studying older individuals, nor what one can really alter these patterns in a very short time frame in adults or adolescents with a genetic cognitive disorder.

"So these drugs will not really be fully evaluated for their effect on fragile X" until the effects on learning and cognition in children can be completed, she said.

FXS is typically diagnosed around the ages of 3 or 4 and confirmed genetically by the presence of at least 200 CGG trinucleotide repeats in the promoter region of the FMR-1 gene, Berry-Kravis said. It affects roughly 50,000 patients in the U.S., and is more predominant in males. There are no drugs approved specifically for FXS, which means patients usually are prescribed treatment based on their individual symptoms – sometimes antipsychotics for aggression and anxiety, sometimes stimulants for attention deficit – but "these medications are often very hard to balance," she said.

In Alcobra's study, 40 of the 62 subjects were receiving concurrent treatment with at least one psychotropic drug, and 16 of those subjects were being treated with an ADHD drug. The company suggested that those concurrent treatments could have confounded the primary endpoint data. The difference between the MDX-treated group and placebo not only missed statistical significance (p = 0.21), the placebo group also showed greater improvement.

While treatment groups had similar demographics, significantly more placebo-treated subjects took concomitant ADHD medications during the study (p = 0.03), Alcobra said.

Beyond the VABS Daily Living Skills Domain and the KiTAP Distractibility test, the study did not hit any other secondary endpoints. Those included the Aberrant Behavior Checklist and the Repeatable Battery for the Assessment of Neuropsychological Status List Learning test. Related secondary endpoints such as the total ADHD RS score and CGI were similarly nonsignificant. MDX was generally well tolerated and no safety concerns were identified.

"In the context of recent negative trials in adolescents and adults, which failed to show any significant or directional improvements on any clinical measure on ITT-based analyses, our trial provided significant findings on the very outcomes that clinicians, patients and their caregivers find meaningful," CEO Daniely told investors. Those include the "function of patients that impacts their daily lives, performance and skills."

Overall, data are promising enough for Alcobra to forge ahead. Daniely said the next steps will be to request a meeting with the FDA to discuss the phase II outcomes and a proposed design for the next clinical trial, including endpoints.

The firm said it anticipates proposing the VABS Daily Living Skills scale as the primary endpoint. MDX has orphan status in FXS, so the firm could explore various accelerated regulatory pathways, Daniely said.

Piper Jaffray analyst Charles Duncan wrote in a research report that an adaptive phase II/III pivotal trial was likely. "We think we could see a co-primary [endpoint] with the computerized KiTAP test for alertness and other functionality to complement the behavioral VABS test," he added.

Duncan also anticipates a longer treatment duration in the next trial and possibly subgroup analyses. Management noted on the call that the autistic patients in the study tended to perform better than the overall ITT population, as did younger patients enrolled in the trial.

ADHD PLAN PROCEEDING

Alcobra retains full rights to MDX, and is "not proactively seeking" partners for the drug in either the FXS or ADHD indication, Daniely said, though "we have been approached by a number of companies."

He also confirmed that MDX will have differentiated dose forms and dosing regimens for both of those indications, so they can be "independently commercialized and kind of co-exist."

The company completed a phase III study in adult ADHD patients and recently finished a phase II study in adolescent ADHD patients. The FDA has agreed that positive efficacy results from an additional efficacy study in adults with ADHD, plus two pediatric studies, should be sufficient for a new drug application filing.

As of March 31, Alcobra had about $45 million on its balance sheet, which executives said during the first quarter earnings call would fund company activities through 2016, including the completion of the second phase III in adult ADHD.