The University of Buffalo (UB) and Tetra Therapeutics have co-developed a drug called BPN14770 that in preclinical research deters the effects of amyloid beta, a key calling card protein of Alzheimer’s that is toxic to nerve cells. Phase I results in healthy elderly volunteers suggest benefits. They drug will now be studied in Phase II clinical trial. 

What is BPN14770

BPN14770 is a novel therapeutic agent that selectively inhibits phosphodiesterase-4D (PDE4D) to enhance early and late stages of memory formation. This unique mechanism of action has the potential to improve cognitive and memory function in devastating CNS disorders including Fragile X Syndrome, Alzheimer’s disease and other dementias, learning/developmental disabilities and schizophrenia. Preclinical animal models show that BPN14770 has the potential to promote the maturation of connections between neurons, which is impaired in patients with Fragile X Syndrome, and to protect connections between neurons which otherwise are lost in patients with Alzheimer’s disease. Tetra has completed two Phase 1 double blind, placebo-controlled, dose-ranging studies of the safety and pharmacokinetics of single ascending doses and multiple ascending doses of BPN14770 in healthy volunteers. Evidence for cognitive benefit was found in elderly subjects. Tetra currently is conducting an investigational Phase 2 study of BPN14770 in adults with Fragile X Syndrome, an indication for which BPN14770 has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA). BPN14770 is currently approved for investigational use only by the U.S. FDA and is not currently approved for marketing in any territory.  It was co-developed by Tetra Therapeutics and Rush University Medical Center.

What were the Preclinical Study Results?

Studies using mice found that the drug inhibits the activity of phosphodiesterase-4D (PDE4D), an enzyme that plays a key role in memory formation, learning neuroinflammation and traumatic brain injury. PDE4D lowers the cyclic adenosine monophosphate (cAM)—a messenger molecule that signals physiological changes such as cell division, change, migration and death—in the body leading to physical alternations in the brain. cAMP has numerous beneficial functions, including improved memory. By inhibiting PDE4D, BPN14770 increases cAMP signaling in the brain which ultimately protects against the toxic effects of amyloid beta.

Commercial Sponsor: Tetra Therapeutics

Tetra Therapeutics was founded in 2011 with SBIR funding from the National Institute of Mental Health (NIMH). By 2015, they had raised a total of $19M in NIH grants, contracts and venture capital. In 2018, they achieved Orphan Drug designation for BPN14770 for Fragile X Syndrome. By the end of 2018, they had accumulated another $50 million in venture investments in two separate rounds a well as initiate a Phase II clinical trial for BPN14770 in Fragile X Syndrome. By 2019 they initiated the PICASSO AD clinical trials—a Phase II study of BPN14770 for Alzheimer’s Disease.

Japanese Pharma Shionogi Invests

At the end of 2018 it was announced that Japanese pharmaceutical company Shionogi Ltd. entered into a partnership with Tetra to accelerate the development of BPN14770 clinical development in Fragile X and early Alzheimer’s disease.  Deal term summary included a overall value of $160 million plus royalties, including $5 million in upfront payments and $35 million in equity investment (e.g. Shionogi is now a partial owner of Tetra). Shionogi gained access to regional license for the Alzheimer’s drug candidate for Japan, Korea and Taiwan.

PICASSO Study for Alzheimer’s Disease

The study commenced in April 2019 and will run through June 2020 according to Clinicaltrials.gov. A randomized, parallel assignment, double-blind, placebo controlled, 3-arm parallel design study to study the effects of BPN14770 in patients with early stage Alzheimer’s Disease. The study will include 255 participants.

University of Buffalo (UB) Participation

UB partnered with Tetra for a study, which suggested that BPN14770 could be capable of triggering multiple biological mechanisms capable of protecting the brain from memory deficits, neuronal damage and biochemical impairments reported Ying Xu, a research associate within UB’s Department of Pharmaceutical Sciences. Their study was published in the September 5 edition of the Journal of Pharmacology and Experimental Therapeutics.

UB Researchers

James M. O’Donnell, Dean of the School of Pharmacy and Pharmaceutical Sciences

Ying Xu, Co-lead Investigator and Research Associate Professor, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences

Call to Action: For those interested in clinical pipeline addressing Alzheimer’s Disease the PICASSO study should be on the watch list.

Source: University at Buffalo

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