BTRX-246040

BlackThorn NOPR Antagonist

Our first-in-class nociceptin receptor antagonist (NOPRA)

BTRX-246040, our lead development program, is a first-in-class NOPR antagonist that targets brain networks involved in emotion, reward processing, and motor function. Dysregulation of these systems transcends diagnostic categories.

We are currently evaluating BTRX-246040 in two Phase 2 trials: in patients with major depressive disorder (MDD) with an emphasis on anhedonia, and in patients with Parkinson’s disease (PD) with a focus on apathy and motor dysfunction.

BTRX-246040 for MDD

Depression is one of the most common neurobehavioral health problems in the United States. An estimated 16.2 million U.S. adults age 18 or older had at least one major depressive episode in 2016.1 Depression is often chronic and causes considerable suffering, functional impairment and increased mortality and suicidality. Anhedonia, an inability to feel pleasure, is one of two symptoms required for a diagnosis of depression.2 Depressed patients with more severe anhedonia have a higher risk of mortality.3 Current therapies are not targeted to treat anhedonic dimensions of depression.

In people with depression and symptoms of anhedonia, brain circuits that regulate reward processing are dysregulated.4 Brain regions modulated by NOPR are important for reward and emotion.5 We are targeting the regulation of NOPR circuits to address anhedonic symptoms of depression.

Preclinical studies support our rationale for developing BTRX-246040 for the treatment of depression in patients with anhedonia.6

Our Phase 2a clinical study is a randomized, double-blind, placebo-controlled, multicenter study which is evaluating BTRX-246040 administered once daily for eight weeks in adults (ages 18 to 65 years) with MDD with or without anhedonia. For more information, visit ClinicalTrials.gov.

BTRX-246040 in PD

PD is a common neurodegenerative disorder, affecting approximately 1 million adults in the United States. People with PD often experience depression, apathy and anhedonia.7

NOPRs are highly expressed in brain regions related to Parkinson’s disease and are implicated in modulating both motor and non-motor symptoms.8-11 NOPR antagonism provides a unique approach to potentially improving multiple symptoms of PD. NOPR antagonism may alleviate motor and non-motor PD symptoms by increasing neurotransmission in brain regions involved in the disease pathology.

We have initiated a Phase 2a clinical trial to assess the optimal dose of BTRX-246040 for safety and tolerability in PD patients to be followed by clinical testing of non-motor symptoms of PD.


References:
1. National Institute of Mental Health. Major Depression. https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Accessed May 16, 2018.
2. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, Va: American Psychiatric Publishing; 2013.
3. Fawcett J. The morbidity and mortality of clinical depression. Int Clin Psychopharmacol. 1993 Winter;8(4):217-20.
4. Keedwell PA, Andrew C, Williams SC, Brammer MJ, Phillips ML. The neural correlates of anhedonia in major depressive disorder. Biol Psychiatry. 2005;58(11):843-53.
5. Toll L, Bruchas MR, Calo’ G, Cox BM, Zaveri NT. Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol Rev. 2016;68(2):419-57.
6. Post A, Smart TS, Krikke-Workel J, et al. A selective nociceptin receptor antagonist to treat depression: evidece from preclinical and clinical studies. Neuropsychopharmacology. 2016;41(7):1803-12.
7. Parkinson’s Foundation. Causes and Statistics. www.parkinson.org/understanding-parkinsons/causes-and-statistics. Accessed May 16, 2018.
8. Mollereau C, Mouledous L. Tissue distribution of the opioid receptor-like (ORL1) receptor. Peptides. 2000;21(7):907-17.
9. Marti M, Viaro R, Guerrini R, Franchi G, Morari M. Nociceptin/orphanin FQ modulates motor behavior and primary motor cortex output through receptors located in substantia nigra reticulata. Neuropsychopharmacology. 2009;34(2):341-55.
10. Marti M, Mela F, Fantin M, et al. Blockade of nociceptin/orphanin FQ transmission attenuates symptoms and neurodegeneration associated with Parkinson’s disease. J Neurosci. 2005;25(42):9591-601.
11. Khan MS, Boileau I, Kolla N, Mizrahi R. A systematic review of the role of the nociceptin receptor system in stress, cognition, and reward: relevance to schizophrenia. Transl Psychiatry. 2018;8(1):38.