The investigational treatment BPN14770 improved language skills, cognition, and caregiver-assessed daily functioning ability in adults with fragile X syndrome, top-line results of a Phase 2 clinical trial show.
“We are very excited about the results of this study,” Mark Gurney PhD, said in a press release. Gurney is founder and CEO of Tetra Therapeutics, which is developing BPN14770. Tetra was acquired recently by Shionogi.
One of the molecular features of fragile X is a decrease in levels of the signaling molecule cyclic adenosine monophosphate (cAMP) in the brain. As such, therapies that aim to increase cAMP levels are seen as a viable strategy for fragile X treatment.
BPN14770 blocks the activity of an enzyme called phosphodiesterase 4D (PDE4D), known to affect learning and memory, to increase in cAMP.
“I find it exciting that we have a drug that potentially addresses a core deficit in [fragile X], a decrease in cAMP, that has been documented in patients as well as in the fly and mouse models of the disorder,” said Elizabeth Berry-Kravis, MD, PhD, a pediatric neurologist at Rush University Medical Center, Chicago, Illinois.
The potential therapy has shown promise in preclinical models, and in two Phase 1 clinical trials conducted in people without fragile X (NCT02840279 and NCT02648672). The U.S. Food and Drug Administration granted BPN14770 orphan drug designation as a possible fragile X treatment.
Tetra funded a Phase 2 clinical trial (NCT03569631) to evaluate the therapy in people with the disorder. The study enrolled 30 men ages 18–41. It was conducted at Rush University Medical Center, and it received financial support from the FRAXA Research Foundation.
Participants were given either BPN14770 (25 mg twice per day) or a placebo for 12 weeks. Then, participants originally given a placebo were switched to BPH14770, and vice versa, for 12 additional weeks. This crossover study design enables comparison between treatment and placebo in the same participant.
All 30 participants completed both 12-week treatment periods. However, due to carryover effects (i.e., participants originally given BPN14770 continuing to experience some lingering benefit even after being switched to placebo), the top-line data announced by Tetra concern only the first 12 weeks.
The trial’s main goal was to assess the safety and tolerability of the investigational therapy. Results showed that BPN14770 was generally well-tolerated, with few adverse events.
Cognition was assessed using the NIH-Toolbox, a comprehensive set of neurological assessments. Compared to those on a placebo, participants given BPH14770 experienced significantly greater improvements in two Toolbox language measurements: Oral Reading Recognition (2.8 points) and Picture Vocabulary (5.79). Notably, while Oral Reading Recognition measures the ability to pronounce single printed letters or words, Picture Vocabulary assesses oral vocabulary.
Significant improvements also were seen in the Cognition Crystallized Composite Score (5.29 points higher than placebo), which measures cognition based on past learning experiences.
Caregiver impressions were assessed using a visual analog scale (a scale from 0 to 100). As compared to placebo, clinically significant benefits were seen in caregiver-assessed language (14.04 points) and daily functioning (14.53 points).
“These results offer hope for Fragile X Syndrome patients and their parents,” said Berry-Kravis, the trial’s principal investigator. “The preponderance of clinical outcome measures were in favor of the drug. These included performance-based as well as parent and physician-rated scales which suggests a meaningful impact on the global [fragile X] disease process,” she said.
“These findings validate our approach to treating this disease through a mechanism that addresses a core deficit in the disorder,” Gurney said.
“On behalf of the entire Tetra team, I want to sincerely thank the patients, families and investigators who participated in this study as well as the FRAXA Research Foundation,” he added.
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