BPN14770 Improved Men’s Language, Daily Functions

Tetra Therapeutics’ investigational oral therapy BPN14770 safely and effectively improves cognitive function, particularly language-related domains, and daily functioning in men with fragile X syndrome, according to data from a Phase 2 clinical trial.

“These results offer hope for patients with fragile X syndrome and their families,” Elizabeth Berry-Kravis, MD, PhD, said in a press release. Berry-Kravis is the trial’s principal investigator and a pediatric neurologist at Rush University Medical Center in Chicago, Illinois.

Most clinical outcome measures, including performance-based assessments, parent- and physician-rated scales, and biomarkers “were in favor” of BPN14770, suggesting “a meaningful impact on the global FXS [fragile X syndrome] disease process,” Berry-Kravis added.

The promising findings support further development of the investigational therapy and the launch of a Phase 3 trial to confirm these beneficial effects in a larger patient population that also includes children and women.

The study, “Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial,” was published in the journal Nature Medicine.

BPN14770 works by selectively binding to and partially suppressing the activity of phosphodiesterase 4D (PDE4D), an enzyme known to regulate a brain-signaling molecule involved in learning and memory called cyclic adenosine monophosphate (cAMP).

Notably, cAMP is known to be deficient in fragile X patients, while PDE4D is naturally most active in brain regions important for intellect and that are affected by fragile X.

As such, BPN14770 is expected to increase cAMP levels and prolong its activity, ultimately promoting nerve cell connections that otherwise fail to develop in fragile X patients and improve cognitive function. The therapy  initially was developed by Tetra, which became a subsidiary of Shionogi in May 2020.

“It’s exciting that we have a [therapy] that potentially addresses a core biochemical deficit in [fragile X], a deficiency of cAMP, that has been documented in patients, and which I discovered during my pediatric neurology fellowship 30 years ago,” said Berry-Kravis.

Based on promising preclinical results and Phase 1 clinical data in healthy elderly volunteers, the oral therapy received orphan drug designation in the U.S., which is meant to help speed its development and review.

This prompted the launch of a Tetra-sponsored, exploratory, crossover Phase 2 trial (NCT03569631) that evaluated BPN14770’s safety and effectiveness in 30 men, ages 18–41, with fragile X. The study was conducted at Rush University Medical Center, and it received financial support from the FRAXA Research Foundation.

Including male patients only was expected to “reduce variability in clinical severity and [treatment] response and allow for better detection of efficacy in a small exploratory clinical trial,” the researchers wrote.

Participants were assigned randomly to receive an oral capsule of either BPN14770 (25 mg) or a placebo twice daily for 12 weeks (about three months), after which participants would switch to the opposing regimen for three more months. This crossover study design enables comparison between treatment and placebo in the same participant.

All participants, with a mean age of 31.6 years and mild-to-severe intellectual impairment at study’s start, completed both 12-week treatment periods.

The study’s main goal was to assess the therapy’s safety and tolerability, while secondary goals included cognitive and behavioral changes, as assessed with validated measures.

Results showed that the trial met its main goal, with BPN14770 being generally well-tolerated, leading to few adverse side effects — the most common being vomiting and upper respiratory tract infection. There were no meaningful group differences in terms of adverse events.

Notably, since BPN14770 effects were found to persist during the second 3-month period in patients switching from the investigational therapy to placebo, challenging the detection of significant benefits/differences between groups, secondary goals were evaluated for the first 3-month period only.

Despite the trial’s small size, BPN14770-treated patients had a significant improvement in language, as assessed through both the computer-administered National Institutes of Health-Toolbox Cognitive Battery (NIH-Toolbox, a set of cognitive tests) and a parent/caregiver-completed scale, compared with those on a placebo.

NIH Toolbox scores revealed significant benefits in the men’s ability to pronounce single printed letters or words, to link heard words to the best fitting pictures, and in cognitive function based on past learning experiences.

“In just three months, we saw improvement specifically in the verbal subtests of the NIH Toolbox, coupled with parent rating of improvements, particularly in language,” Berry-Kravis said.

Besides meeting its secondary goal of cognitive improvement, the study also showed that BPN14770 led to significant and clinically meaningful improvements in daily function, as assessed with parent/caregiver scales.

Moreover, scores of other cognitive and behavioral tests, as well as of biomarkers — auditory event-related potentials (timed brain responses to sounds) and eye tracking (social gaze behavior) — showed trends of improvements for the BPN14770 group relative to the placebo group.

“Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning,” the researchers wrote.

“The improvement in language function and communication would be particularly beneficial in participants with FXS and is an area of special need identified by FXS patient advocacy groups,” they added.

Overall, according to the team, the findings support further development of BPN14770.

“Together with evidence of good tolerability, the preliminary indication of cognitive efficacy justifies expanded clinical trials of BPN14770 in FXS,” researchers wrote, adding that future trials “should also include children to explore benefit during neurodevelopment and women, who comprise a genetically heterogeneous population.”

Tetra also is evaluating BPN14770 as a potential treatment for Alzheimer’s disease.