Selective PDE4D inhibitor shows potential to treat Fragile X autism spectrum disorder

November 07, 2017



Grand Rapids, MI (Nov. 7, 2017) - New preclinical research suggests the potential utility of BPN14770, a selective PDE4D inhibitor currently under development by Tetra Discovery Partners as a prospective treatment for memory and cognitive problems associated with Alzheimer's disease, in the treatment of Fragile X Syndrome (FXS) and possibly other autism spectrum disorders.

Daily treatment of adult male fmr1 C57B16 knockout mice (a standard FXS animal model) for 14 days reduced hyperarousal, and improved social interactions and increased natural behaviors such as nesting and marble burying compared to control FXS mice that received a placebo. At the same time, there was no deleterious effect on behavioral scores in normal wild-type mice treated with BPN14770. The behavioral benefits of BPN14770 in the FXS mice endured for two weeks after drug washout. Microscopic analysis of neurons in the prefrontal cortex from the treated FXS mice showed an improvement in dendritic spine morphology; this finding, combined with the 11 hour half-life of BPN14770 in mice, suggests that the enduring treatment benefits of BPN14770 were not due to slow washout of the drug.

The new research was published online today in Scientific Reports, an online, open-access primary research publication from the publishers of Nature by Tetra Discovery Partners and the company's research collaborators.

"This preclinical study strongly supports PDE4D as a therapeutic target for the treatment of FXS," said Mark E. Gurney, Ph.D., Chairman and Chief Executive Officer of Tetra Discovery Partners. "We have already demonstrated evidence of human safety and tolerability for BPN14770 in a Phase 1 study in healthy young and elderly volunteers. This research suggests BPN14770 may also have utility in the treatment of FXS, which is associated with a spectrum of neuropsychiatric symptoms, mild to severe cognitive impairment and intellectual disability, and potentially also find use in the treatment of other conditions on the autism spectrum."

"The results from these studies are very promising," commented Michael Tranfaglia, M.D., Medical Director and Chief Scientific Officer of the FRAXA Research Foundation. "Inhibition of PDE4 has been validated as a treatment strategy by many research groups in the Fragile X field. However, the current study demonstrates the enhanced therapeutic potential of PDE4D inhibition with BPN14770, which shows the ability to rescue major Fragile X phenotypes not only in acute dosing, but in chronic dosing as well.

"Furthermore, the significant carryover of BPN14770 effects, even two weeks after treatment suggests this drug candidate has genuine long-term beneficial effects on Fragile X pathology," Dr. Tranfaglia continued. "Additionally, tolerance has been a major problem with other drug classes studied as potential treatments for Fragile X syndrome, such as mGluR5 NAMs and GABA-B agonists, but no tolerance was been seen in studies with BPN14770. The selective nature of this compound, which targets only PDE4D, also greatly improves the tolerability of the drug over past-studied, general PDE4 inhibitors, which should facilitate clinical trials in this difficult-to-treat population."
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About Fragile X Syndrome

Fragile X syndrome is a genetic condition that results from the silencing of the X-linked, fragile X mental retardation-1 (FMR1) gene. FXS patients display a range of behavior and other symptoms, including seizures, sleep disorders, anxiety, irritability, hyperactivity, autism, mild-to-severe cognitive impairment and intellectual disability. While FXS occurs in both genders, the condition is more common and generally more severe in males. There is no cure for FXS, and medications may be used to treat seizures, mood problems or other neuropsychiatric symptoms. FXS occurs in approximately 1 in 4,000 males and 1 in 8,000 females.

About 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 disorders including Alzheimer's disease, schizophrenia, and learning/ developmental disabilities such as Fragile X syndrome. BPN14770 has completed three human Phase 1 clinical trials enrolling 147 subjects and has shown excellent safety, oral bioavailability, and preliminary cognitive benefit in elderly subjects. Preparations are under way to initiate a Phase 2 trial of BPN14770 in patients with Alzheimer's disease in the first half of 2018.

About the FRAXA Research Foundation

FRAXA's mission is to find effective treatments and ultimately a cure for fragile X syndrome - the most common inherited cause of autism worldwide. FRAXA funds research and clinical trials at universities all over the world. For more information please visit our website at http://www.fraxa.org.

About Tetra Discovery Partners

Tetra Discovery Partners is a clinical stage biotechnology company developing a portfolio of therapeutic products that will bring clarity of thought to people suffering from Alzheimer's disease and other brain disorders. Tetra uses structure-guided drug design to discover mechanistically novel, allosteric inhibitors of phosphodiesterase 4 (PDE4), an enzyme family that plays key roles in memory formation, learning, neuroinflammation, and traumatic brain injury. Tetra was a recipient of an NIH Blueprint Neurotherapeutics Program cooperative research agreement, and also receives major funding from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, and the National Institute of Mental Health through the Small Business Innovation Research (SBIR) program. Tetra Discovery Partners is headquartered in Grand Rapids, Michigan. For more information, please visit the company's website at http://www.tetradiscovery.com.

Forward-Looking Statements

This press release does not constitute an offer to sell or the solicitation of an offer to buy any securities in a Tetra Discovery Partners stock offering. There will not be any sale of these securities in any state or jurisdiction in which such offering, sale, or solicitation would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

Statements made in this press release that look forward in time or that express beliefs, expectations or hopes regarding future occurrences or anticipated outcomes or benefits are forward-looking statements. A number of risks and uncertainties, such as risks related to product development and commercialization efforts, results of clinical trials, ultimate clinical outcomes, and benefit of Tetra Discovery Partners' products to patients, market, and physician acceptance of Tetra Discovery Partners' products, intellectual property protection, and competitive product offerings, could cause actual events to differ from the expectations indicated in these forward-looking statements. You are cautioned not to put any undue reliance on any forward-looking statement. This press release is neither an offer to sell nor a solicitation of an offer to purchase any particular securities. Any such offer or solicitation will be made only pursuant to definitive legal agreements prepared specifically for such purpose. Tetra Discovery Partners does not assume any obligation to publicly update or revise any forward-looking statements, whether as a result of new events or information, future otherwise.

Contact:

Mark Gurney, Ph.D., Chief Executive Officer
Tetra Discovery Partners
info@tetradiscovery.com

For Media

Joan Kureczka, Kureczka/Martin Associates
Joan@kureczka-martin.com
415-821-2413

Kureczka/Martin Associates

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