I thought it could be worthwhile to provide some information on another promising Fragile-x drug which ultimately didn’t succeed in making it to market.
Seaside Therapeutics is a privately owned US-based biotech. Seaside was initially developing two separate compounds for the treatment of Fragile-x and autism. The first was STX209 (arbaclofen), a selective agonist of **A-B. The second was STX107, a selective mGluR5 antagonist.
In pre-clinical testing, STX209 was shown to reverse both neuropathological and behavioral abnormalities in an Fmr1-knockout mouse model. Based on this positive data, clinical trials of STX209 were initiated.
By 2010 Seaside had announced results from a Phase 2 trial of STX209 in Fragile-x. The trial included 63 adults and children (6-39 years old) in a multi-site, randomised, double blind, placebo- controlled, crossover study conducted in the US over 15 months. Dosing was flexible, with tapering up of the drug every 3–4 days to a maximum of 10 mg twice a day for children and 10 mg three times per day for adults until the optimal tolerated dose was established. The participants were evaluated at 2 and 4 weeks after starting the treatment and then tapered off the treatment over 1–2 weeks. There was a 7-day washout period between the placebo and active treatments. Assessment measures included the Clinical Global Impression Scale (CGIS), the Aberrant Behavior Checklist (ABC), Vineland Adaptive Behavior Scales (Second Edition; VABS), the Social Responsiveness Scale (SRS), the Repetitive Behavior Scale-Revised, the Child and Adolescent Symptom Inventory Anxiety Scale, the Attention Deficit Hyperactivity Disorder Rating Scale-IV, a measure of vocabulary and short-term and working memory, and a Visual Analog Scale (VAS) of the child’s three most problematic behaviors.
The trial failed to meet its primary endpoint, which was the irritability subscale of the ABC. However, on one secondary endpoint, the VAS problem behaviour rating, results were significantly better with the active treatment than with placebo. Another secondary measure, the social avoidance ABC subscale, was also found to be significantly improved during active treatment as compared to placebo. In addition, separate analysis of participants with the worst social impairments showed that they displayed significant improvement during active treatment as compared to placebo.
The research was presented at an International Fragile-x conference by by Elizabeth Berry-Kravis and Randi Hagerman, both of whom are quoted in Neuren’s announcement this week. They described the trial results and parental reports of improvement as “exciting”.
A few months later, Seaside announced positive data from an open-label Phase 2 study of STX209 conducted in patients with autism spectrum disorders (ASD). This time, the primary endpoint of the study, an improvement on the Irritability subscale of the Aberrant Behavior Checklist (ABC-I), achieved statistical significance (p<0.001). In addition, STX209 demonstrated statistically significant improvements across a number of other global and specific neurobehavioral outcomes, including improvements on the Social Withdrawal subscale of the Aberrant Behavior Checklist (ABC-SW, p<0.001), which assesses a core symptom of ASD.
In 2012, Seaside announced that it had struck a deal with Roche. Financial terms were not disclosed. Under the terms of the deal, Seaside agreed to license its STX107 (mGluR5) compound to Roche and Roche took over responsibility for the development and commercialisation of STX107 for Fragile-x and ASD. At this time, Roche was already developing its own mGluR5 drug candidate, RG7090, for Fragile-x. Under the agreement with Roche, Seaside was to complete development of STX209 and Roche took an option to take the drug to market, if successful.
As results of the Phase 2 studies of STX209 in both Fragile-x and ASD were considered to be highly promising, Seaside had commenced a Phase 3 trial of STX209 in Fragile-x and a further Phase 2b trial in ASD.
But the studies were suddenly terminated in 2013. Seaside said that termination wasn’t due to safety issues. At first the company seemed to blame the termination on financial reasons. Demonstrated efficacy then became the issue. According to the VP of Seaside
The FDA requires companies to pick one, and only one, assessment as the “primary endpoint” of the study. In their eyes, the result on that one pre-selected endpoint makes or breaks the study. In our recent autism study, STX209 did not show an advantage over placebo on the primary endpoint of social withdrawal, so the FDA and some news reporters regard it as a negative study. In fact, STX209 did show advantages over placebo on a number of other assessments. Some of these secondary endpoints are just as meaningful as the social withdrawal assessment, or even more so, but in the FDA’s eyes, they don’t make the study a positive study, because they were not pre-selected as the “primary endpoint.
Parents of children who had participated in the trials were devastated. Many saw significant improvement in their children during the trials. They wrote an open letter to Roche, pleading for funding to continue the development of arbaclofen, with no success. They also told their stories on a dedicated website. The following are some examples.
Within the first 2 weeks we had a birthday party for his younger brother and our annual Super Bowl party (both involve guests and noise) he did not however retreat to his room, he stayed with us, he participated. Two weeks after that I sat in my vehicle and cried as I waited for him to walk to the car after school. For the first time ever, he walked out of the school with two other boys (classmates) and they were talking and laughing with one another. It was later that same week that he told my husband that the kids at school were not making fun of him anymore
Now that the medicine is out of her system, MY L is gone. It’s only been 2 weeks since she titrated down. It’s only been 30 hours since she took her last pill. I’ve already seen more meltdowns, more fits, more “I can’ts”, more hitting, and more biting attempts than I saw in the last year combined.
He was like a different child. He enjoyed going to school and being with people. His communication increased and his anxiety descreased. We could run errands. Waiting in lines and getting past automatic doors became doable. The IEP vision statement we came up with started to look like a real possibility. He already had the friend part down. And he is a valued member of his class.
Then we received the devastating news that the STX209 trial was discontinued. Blessedly, we were able to get through the school year before having to start weaning him. But once we did, we started seeing those old behaviors and challenges returning
I waited 10 and a half years for him to tell me he loved me…. With fragile X, you’re like living in a box and someone is holding the lid down. The medication opened the lid and let Parker out….I don’t want to go back to the way life was.
Dr. Mike Tranfaglia, whose son has fragile X but wasn’t in the Seaside trial, said that STX209 appeared to significantly help about a third of patients but also made some patients worse. He said that without being able to tell in advance which patients would benefit, it would be hard for the drug to succeed in a clinical trial and win approval.
Around the same time, Novartis was releasing results of its Phase IIb/III studies with mavoglurant (AFQ056) - an mGluR5 therapy- in separate studies in adolescents and adults with Fragile- x . Both studies failed to meet the primary endpoint of showing significant improvement in abnormal behaviours compared to placebo. Novartis terminated the program.
Late last year, Roche added to the string of disappointing results when it announced that both of its Phase 2 studies for its mGluR5 therapy - RG7090 -had failed to meet both primary and secondary endpoints. It also shut down its Fragile-x program.
Like TBI, clinical development of Fragile-x therapies has proven to be incredibly challenging. To date, no one has successfully completed a Phase 3 trial. This is both Neuren’s opportunity and its challenge. In the context of the recent history of Fragile-x clinical trials, it is inevitable that many will approach this week’s Phase 2a results with cautious optimism. Trofinetide’s success in Phase 2 trials for conditions which represent both ends of the autistic spectrum is certainly encouraging, as are the improvements reported by parents of participants.
But, as we were reminded in this week's announcement, it is only the first step.
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