The last two years have been tough for Fragile X (FX) research. Many of us in the greater Fragile X community believed that drugs capable of reversing the core symptoms of FX were sitting on the shelf, waiting for consumers eager to improve the quality of their lives. It seemed that all we needed was to complete the drug trials and wait for our physicians to write the prescriptions.

And why not? Virtually every mouse and fruit fly that took these drugs experienced dramatic improvement, and in many cases even reversal of their FX symptoms. There was great anticipation and excitement from the research bench to the bedside, at government agencies funding medical research, among investors on Wall Street and even in the halls of Congress that the Phase III drug trials underway by companies large and small would result in a targeted treatment for FX.

Then the bottom fell out. Primary endpoints were missed and the placebo effect was strong, even though parents reported success. Companies with limited resources closed up shop and big pharma lost interest. Trials were shut down. Supplies, of post-trial medicine that so many were convinced was working, were cut off. Consumers had to confront the reality of withdrawal symptoms and the quest for a replacement drug which could never work as well as this new treatment. Hope and optimism took a serious hit, too, and families were left to wonder whether they would put their loved ones through the drug trial experience again when, and if, another opportunity presented.

Sure, our rock star researchers never gave up hope, continued to believe that they really were onto something and that targeted drug treatment remained a reality. But somehow it seemed that the luster had worn off and the money had dried up.

A Glimmer of Hope

Then, earlier this year, there was a glimmer of hope. After missing their original primary endpoint, the Israeli start-up drug company Alcobra announced that they had a “Plan B”. While the FDA mandates the use of a single primary endpoint{{1}}, Alcobra included a secondary end point{{2}} in their Phase II trials.

What’s more, the secondary end point they used was a tried-and-true measure that assesses adaptive behaviors seen in the daily lives of individuals living with FX.

Lo and behold, when measured by that secondary endpoint, the individuals taking the Alcobra experimental drug showed improvements by an amount that was statistically significant.

This was much welcomed news, but the improvement was demonstrated in the secondary endpoint – NOT the all-important primary endpoint that the FDA was looking to for improvement. Others before Alcobra had been down this road but couldn’t raise the money to start drug trials over with a new endpoint or they just lost interest. Unlike the others, Alcobra pushed forward and held a series of meetings with the FDA. Now, while they still must demonstrate efficacy in a Phase III trial, their candidate drug has been granted Orphan Drug status{{3}} by the FDA. They’ve been given the benefit of a fast track for review and the FDA agreed to allow Alcobra to change their primary endpoint in-between Phase II and Phase III trials. So in Phase III trials likely to get underway next year, the new primary endpoint will be the same one in which statistically significant improvement over placebo has already been shown. Of course, that’s no guarantee that the same findings will be demonstrated in Phase III, but it’s certainly great news.

There’s more good news. Armed with this new lease on life made possible by those meetings with the FDA, Alcobra was able to go back to Wall Street with a new stock offering and was able to quickly raise over 40 million dollars! As a small start-up drug company Alcobra needed this influx of cash to carry out this Phase III trial.

After the hopes of so many were dashed, we are now back to the point where a new drug under study has shown enough promise to make it to Phase III. The FDA has shown interest and flexibility to allow this Phase III to go forward with a modified primary endpoint, instead of starting over from scratch. Even Wall Street responded with the dollars necessary to assure this start-up can see this through.

Only a few days ago, Neuren Pharmaceuticals joined the chorus with a promising press release of their own. They reported back with encouraging results for the Phase II clinical trial of their own study. Suddenly, things are looking up.

It looks like Fragile X research could be experiencing a resurgence.

This all could have easily gone the way of many others that have disappointed us all. But it didn’t… and that’s really good news.

[[1]]Primary endpoint is a validated test which is administered before an experimental drug is given and then again after, to determine whether or not the drug made a difference.[[1]]

[[2]]The secondary endpoint is a second test capable of demonstrating whether and how much a drug under study improved. In this case, Alcobra’s drug’s effect on Fragile X symptoms.[[2]]

[[3]]The Orphan Drug Act (ODA) provides for granting special status to a drug or biological product (“drug”) to treat a rare disease or condition upon request of a sponsor.[[3]]