PARTNERING WITH REMARKABLE RESEARCHERS AND WORLD-CLASS INSTITUTIONS

Tetra is developing a platform of drug products to treat cognitive impairment. The primary focus of our drug development effort is memory improvement. The way we store memories in our brain is by changing the connection between brain cells. These connections are known as synapses. Cognitive impairment occurs when synapses within the brain do not communicate properly at a cellular level. Cognitive problems occur when there is too much activity, or not enough—when neurons do not signal properly. Within brain cells, the substance which controls the way synapses communicate is cyclic AMP, or cAMP.

Tetra’s science builds on previous work by Nobel laureates that identified PDE4 (Phosphodiesterase 4) as a key enzyme that shapes proper cAMP signaling. Specifically, PDE4 limits the spread of cAMP so that spatial and temporal patterning of information is maintained.

The chemistry is a bit complicated. It turns out that PDE4 has 4 subtypes, and drug-induced inhibition of one (or more) of these subtypes can produce nausea or vomiting. To address such undesirable side-effects, Tetra has taken a different approach. Our compound targets only one of the PDE4 enzyme subtypes, and only at specific times of cellular activity. Tetra’s compound is designed to modulate, rather than completely inhibit, PDE4D. The result is that Tetra’s drug improves memory by prolonging cAMP activity. Safety and tolerability are improved because the enzyme is not completely inhibited.

Our lead drug targeting PDE4D, BPN14770, is being developed for treating cognitive impairment in Alzheimer’s disease or schizophrenia with potential applications for Huntington’s disease, Fragile X syndrome, autism, and major depression. Rather than addressing a specific chemical deficit or dysfunction in a specific neural circuit, targeting PDE4D has the potential to augment the fundamental processes underlying learning and memory in the human brain, thereby allowing compensatory brain mechanisms to improve function in the diseased brain.

SELECTED SCIENTIFIC PUBLICATIONS

  • Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D).  Gurney ME, Cogram P, Deacon RM, Rex C, Tranfaglia M. Scientific Reports. 2017 Nov;7(14653).PMID: 29116166  doi: 10.1038/s41598-017-15028-x
  • Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury. Wilson NM, Gurney ME, Dietrich WD, Atkins CM. PLoS One. 2017 May 19;12(5):e0178013. doi: 10.1371/journal.pone.0178013. eCollection 2017. PMID: 28542295
  • Chronic Cognitive Dysfunction after Traumatic Brain Injury is Improved with a Phosphodiesterase 4B Inhibitor. Titus DJ, Wilson NM, Freund JE, Carballosa MM, Sikah KE, Furones C, Dietrich WD, Gurney ME, Atkins CM. J Neurosci. 2016 Jul 6;36(27):7095-108. doi: 10.1523/JNEUROSCI.3212-15.2016. PMID: 27383587
  • Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer’s disease.  Gurney ME, D’Amato EC, Burgin AB.
    Neurotherapeutics. 2015 Jan;12(1):49-56. doi: 10.1007/s13311-014-0309-7.  PMID: 25371167 
  • Discovery of triazines as selective PDE4B versus PDE4D inhibitors.  Hagen TJ, Mo X, Burgin AB, Fox D 3rd, Zhang Z, Gurney ME.   Bioorg Med Chem Lett. 2014 Aug 15;24(16):4031-4. doi: 10.1016/j.bmcl.2014.06.002. Epub 2014 Jun 12.
    PMID: 24998378
  • Structural basis for the design of selective phosphodiesterase 4B inhibitors.  Fox D 3rd, Burgin AB, Gurney ME.
    Cell Signal. 2014 Mar;26(3):657-63. doi: 10.1016/j.cellsig.2013.12.003. Epub 2013 Dec 19.
    PMID: 24361374
  • Small molecule allosteric modulators of phosphodiesterase 4. Gurney ME, Burgin AB, Magnusson OT, Stewart LJ.
    Handb Exp Pharmacol. 2011;(204):167-92. doi: 10.1007/978-3-642-17969-3_7. Review. PMID: 21695640
  • Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.
    Burgin AB, Magnusson OT, Singh J, Witte P, Staker BL, Bjornsson JM, Thorsteinsdottir M, Hrafnsdottir S, Hagen T, Kiselyov AS, Stewart LJ, Gurney ME.  Nat Biotechnol. 2010 Jan;28(1):63-70. doi: 10.1038/nbt.1598. Epub 2009 Dec 27.
    PMID: 20037581
  • Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury. Wilson NM, Gurney ME, Dietrich WD, Atkins CM. PLoS One. 2017 May 19;12(5):e0178013. doi: 10.1371/journal.pone.0178013. eCollection 2017. PMID: 28542295
  • Chronic Cognitive Dysfunction after Traumatic Brain Injury is Improved with a Phosphodiesterase 4B Inhibitor. Titus DJ, Wilson NM, Freund JE, Carballosa MM, Sikah KE, Furones C, Dietrich WD, Gurney ME, Atkins CM. J Neurosci. 2016 Jul 6;36(27):7095-108. doi: 10.1523/JNEUROSCI.3212-15.2016. PMID: 27383587

MEDICINES FOR ALZHEIMER'S DISEASE | TETRA CO-INVESTIGATORS

Dr. James M. O’Donnell is Dean of the School of Pharmaceutical Sciences of SUNY-Buffalo.

Dr. Jos Prickaerts, a neurobiologist, is with the Department of Neuroscience, Maastricht University.

Dr. David Fox III directs Structural Biology at Beryllium in Bainbridge Island, WA.

NIH BLUEPRINT CONSULTANTS

Vince Groppi, PhD / Pharmacology Lead Donna Romero, PhD / Chemistry Lead
Marc Bailie, PhD / Safety and Toxicology Lead Ron White, PhD / DMPK Lead
Jon Lawson, PhD / Process Chemistry Jay Sisco, PhD / Formulation/Drug Product

NIMH PET LIGAND CO-INVESTIGATORS

Robert Innis MD PhD
Victor Pike PhD
Carlos Zarate MD

MEDICINES FOR SCHIZOPHRENIA & DEPRESSION

The Broad Institute

Edward Scolnick MD is a core member of the Broad Institute of MIT and Harvard and chief scientist of Broad’s Stanley Center for Psychiatric Research.

MEDICINES FOR TRAUMATIC BRAIN INJURY

The Miami Project to Cure Paralysis / University of Miami Health System

Coleen Atkins PhD

W. Dalton Dietrich PhD

MEDICINES FOR FRAGILE X SYNDROME

The Fraxa Foundation

Michael Tranfaglia, MD is Medical Director and Chief Scientific Officer of the Fraxa Foundation.

Frauenhofer Institute

Dr. Patricia Cogram