Targeting Major Depressive Disorder (MDD) and Substance Use Disorders

A potent, selective kappa opioid receptor (KOR) antagonist was being developed as an adjunctive treatment of major depressive disorder (MDD) and for substance use disorders.

In August 2017, we divested CERC-501 to Janssen Pharmaceuticals, a J&J Company, who are presently conducting a Phase II study.1

1. https://clinicaltrials.gov/ct2/show/NCT03559192

of CERC-501

  • Orally active small molecule that crosses the blood brain barrier
  • Excellent in vivo selectivity for kappa over mu / delta receptors
  • CERC-501 has been observed to have activity in animal models of depression, substance withdrawal, and dependence
  • Generally well-tolerated in five human clinical trials

About MDD

Major depression, also known as unipolar or major depressive disorder, is characterized by a persistent feeling of sadness or a lack of interest in outside stimuli. The unipolar connotes a difference between major depression and bipolar depression, which refers to an oscillating state between depression and mania. Instead, unipolar depression is solely focused on the ”lows”, or the negative emotions and symptoms that patients may experience.

MDD is an incapacitating psychiatric illness that affects millions of people globally and is resistant to treatment in nearly 35% of patients.1 Severe depression tends to be associated with greater functional impairment, a longer duration of illness, a lower likelihood of spontaneous remission, and a greater risk of recurrence. According to the World Health Organization (WHO), MDD will become the second leading cause of disability by 2020 and the primary cause of societal health burden by 2030.2

1. Machado-Vieira R, Salvadore G, Ibrahim LA, Diaz-Granados N, Zarate CA, Jr. Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des. 2009;15(14):1595-1611. 2. Bostwick JM, Pankratz VS. Affective disorders and suicide risk: a reexamination. Am J Psychiatry. 2000;157(12):1925-1932.

Mechanism of Action

Kappa opioid receptors (KORs) and their native ligand dynorphin are localized in areas of the brain that affect reward and stress and may play a key role in mood, stress, and addictive disorders.1,2

Chronic stress leads to increased dynorphin expression, activating KORs and subsequent downstream signaling pathways to inhibit mesolimbic dopamine surge, contributing to negative affective states.3,4

KOR antagonists induce antidepressant-like effects in animal models and attenuate the anxiety behaviors associated with withdrawal. Accordingly, the therapeutic potential of KOR antagonism has been demonstrated in animal models of anhedonia, depression, and anxiety.5,6

Mechanistic validation: Phase 2 data for ALKS-5461, believed to be a “functional” KOR antagonist, in treatment-resistant depression

1. Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 2010;1314:44-55.
2. Knoll AT, Carlezon WA, Jr. Dynorphin, stress, and depression. Brain Res. 2010;1314:56-73.
3. Carr GV, Bangasser DA, Bethea T, Young M, Valentino RJ, Lucki I. Antidepressant-like effects of kappa-opioid
receptor antagonists in Wistar Kyoto rats. Neuropsychopharmacology. 2010;35(3):752-763.  
4. Van't Veer A, Carlezon WA, Jr. Role of kappa-opioid receptors in stress and anxiety-related behavior.
Psychopharmacology (Berl). 2013;229(3):435-452.
5. Mague SD, Pliakas AM, Todtenkopf MS, et al. Antidepressant-like effects of kappa-opioid receptor antagonists in
the forced swim test in rats. J Pharmacol Exp Ther. 2003;305(1):323-330.
6. Rorick-Kehn LM, Witkin JM, Statnick MA, et al. LY2456302 is a novel, potent, orally-bioavailable small molecule
kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders.
Neuropharmacology. 2014;77:131-144.