RARE Daily

Tetra Therapeutics Announces Positive Topline Results from Phase 2 Study in Fragile X Syndrome

November 4, 2020

Rare Daily Staff

Shionogi subsidiary Tetra Therapeutics reported positive topline results from its phase 2 exploratory study in adult patients with Fragile X syndrome. 

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism, with a prevalence of 1 in 3,600 to 4,000 males and 1 in 4,000 to 6,000 females in the United States. Individuals with Fragile X syndrome often have a range of behavioral challenges, such as cognitive impairment, anxiety, mood swings, hyperactivity, attention deficit, poor sleep, self-injury, and heightened sensitivity to various stimuli, such as sound. They are also prone to comorbid medical issues including seizures and sleep disturbance.

Fragile X syndrome results from mutations in the FMR1 gene, which blocks expression of the Fragile X Mental Retardation Protein (FMRP), an important protein in GABA synthesis. Extrasynaptic GABA levels are abnormally reduced, and there is also dysregulation of GABA receptors, which causes tonic inhibition: the brain becomes inundated with signals and loses the ability to separate background noise from critical information. There are no FDA-approved therapies for Fragile X syndrome, and treatment primarily consists of behavioral interventions and pharmacologic management of symptoms.

Tetra’s lead candidate, BPN14770, is a first-in-class phosphodiesterase allosteric inhibitor and increases the levels of cAMP, a key signaling molecule in the brain that is deficient in FXS patients. In preclinical studies, BPN14770 promoted the maturation of connections between neurons, which are impaired in patients with FXS, for which it has Orphan Drug designation from the U.S. Food and Drug Administration.

This unique mechanism of action has the potential to improve cognitive and memory function in devastating CNS disorders, including FXS, Alzheimer’s disease and other dementias, learning/developmental disabilities and schizophrenia.

Tetra’s single-center, randomized, placebo-controlled, two-way crossover study, BPN14770 demonstrated excellent safety as well as benefits on cognitive function and behavior in 30 patients with FXS.

“In addition to being safe and well tolerated, treatment with BPN14770 led to significant cognitive improvement, specifically in the language domains, and we also saw a clinically meaningful benefit in overall daily functioning,” said Mark Gurney, founder and CEO of Tetra. “These findings validate our approach to treating this disease through a mechanism that addresses a core deficit in the disorder.”

The Phase 2 clinical trial was a randomized, placebo-controlled, two-way crossover study.  Each period was 12 weeks in duration with no washout between periods.  The study enrolled 30 adult male subjects age 18-41 years with FXS due to greater than 200 CGG repeats in the FMR1 gene.  Subjects received daily oral doses of 25 mg twice a day of BPN14770 or placebo. Parents/caregivers and physician raters were blinded to treatment. Study enrollment occurred between July 9, 2018 and July 31, 2020.  All subjects completed both treatment periods, although carryover effects limited the primary statistical analysis to Period 1.  The following results, therefore, describe the outcomes for patients who received BPN14770 during Period 1, compared to those who received placebo.

Cognitive assessments using the NIH-Toolbox revealed significant benefit in Oral Reading Recognition (LSMean Difference +2.81), Picture Vocabulary (+5.81), and Cognition Crystallized Composite Score (+5.31).  Parent/Caregiver ratings using 100 point Visual Analog Scales revealed benefit that was judged to be clinically significant in Language (LSMean Difference +14.04) and Daily Functioning (+14.53). The benefit of BPN14770 was maintained up to 12 weeks after the crossover from drug to placebo.  BPN14770 was very well tolerated in the phase 2 trial with few adverse events.

“These results offer hope for Fragile X syndrome patients and their parents” said Elizabeth Berry-Kravis, pediatric neurologist, Rush University Medical Center, and 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 FXS disease process.  I find it exciting that we have a drug that potentially addresses a core deficit in FXS, a decrease in cAMP, that has been documented in patients as well as in the fly and mouse models of the disorder.”

Photo: Mark Gurney, founder and CEO of Tetra


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