Rislenemdaz (developmental code names CERC-301, MK-0657) is an orally active, selective

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

subunit 2B (NR2B)

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

as an adjunctive therapy for

treatment-resistant depression Treatment-resistant depression (TRD) is often defined as major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Inad ...

(TRD). In November 2013, phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s were initiated, and in the same month, rislenemdaz received Fast Track Designation from the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

for TRD. A pilot study was published in 2012, and a phase II trial was completed in 2014, but was deemed insufficient. A second attempt at a phase II trial in 2016 also found that the drug failed to demonstrate efficacy against depression.

Pharmacology

Rislenemdaz is a small-molecule antagonist of the

. The NMDA receptor is composed of several subunits, but rislenemdaz is specific for the GluN2B subunits which are only seen in the

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

and

forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...

. Rislenemdaz binds specifically to the GluN2B subunit in order to prevent endogenous

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

from acting on it. It is considered to be a novel drug for the treatment of MDD and TRD for its immediate onset of efficacy in an oral dosage form. Rislenemdaz and its active metabolite have been shown to have an onset of action of about 1 hour and half-lives of 12–17 h and 21–26 h, respectively. It has been proven to have a very high binding affinity for its target (''K''_i = 8.1 nM). This specificity allows rislenemdaz to mitigate the symptoms of depression without having many adverse effects due to off-target binding.

History

Commercial development

Cerecor acquired the exclusive rights from Merck in 2013 to develop an NMDA receptor antagonist for the treatment of

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

(MDD). This compound acquired from Merck would eventually become rislenemdaz. Funds generated through the IPO of Cerecor in 2015 and a common stock purchase agreement with Aspire Capital Fund in 2016 are being used to further develop the molecule. Cerecor currently holds three families of patents regarding rislenemdaz in the United States as well as several other countries. These patents cover composition of matter, methods of manufacture, methods of use, as well as picture claims to rislenemdaz and any pharmaceutical salts of it. These patents will being to expire in 2022 but some will not expire until 2035. Commercial competitors of the drug include

Naurex Allergan plc is an American, Irish-domiciled pharmaceutical company that acquires, develops, manufactures and markets brand name drugs and medical devices in the areas of medical aesthetics, eye care, central nervous system, and gastroenterology. ...

's apimostinel (NRX-1074) and 4-chlorokynurenine (AV-101) from VistaGen Therapeutics.

Preliminary research

Research into the use of

ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

to treat MDD had already determined that the drug could have effectiveness in rapidly reducing the symptoms of depression. Unfortunately ketamine has powerful dissociative effects, leaving patients in a trance-like state after administration and lending itself to recreational abuse. In 2008 a proof of concept study was conducted by

Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...

using the NR2B antagonist traxoprodil, which proved that drugs similar to ketamine could be used to treat depressive symptoms without causing the dissociative effect seen in that drug. Traxoprodil was eventually dropped from development due to

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

issues and the possibility of it causing

QT prolongation QT or Qt may refer to: Businesses * The Qt Company, a Finnish software developer * QT Hotels & Resorts, an Australasian hospitality provider * QT Inc., an American bracelet manufacturer * QuikTrip, an American convenience store chain People * ...

. The first preclinical study of rislenemdaz was conducted in 2015 and was primarily geared towards assessing the molecule's safety and pharmacokinetic profile in rats and a small group of men. The study showed that rislenemdaz was very orally bioavailable, rapid acting, and that it was safe compared to other similar molecules which had caused neurodegenerative problems in rats. A clinical trial with 135 subjects revealed that rislenemdaz does not have any influence on ECG in humans as is seen in traxoprodil.

Clinical trials

Phase II

Rislenemdaz initiated its first phase II randomized double blind clinical trial
NCT01941043
in November, 2013. This study was funded through a $32 million Series B Financing tranche led by venture capital companies such as

New Enterprise Associates New Enterprise Associates (NEA) is an American-based venture capital firm. NEA focuses investment stages ranging from seed stage through growth stage across an array of industry sectors. With over $25 billion in committed capital, NEA is one of t ...

(NEA), Apple Tree Partners (ATP) and MPM Capital. The trial consisted of 135 patients diagnosed with MDD who were resistant to SSRI/SNRI treatment. The study lasted 28 days and saw patients receiving 8 mg/day doses of rislenemdaz in order to see a change in the Hamilton Depression Rating Scale (HDRS) of the patient by day 7, but no significant changes were noted. However, in March 2015, Cerecor announced that the 8 mg dose for the study did not meet the primary objective for the study, although the study showed the safety and tolerance of rislenemdaz. The company also announced that in a separate study, higher daily doses of drug were able to safely treat patients, indicating that higher doses of drug could be used in future clinical trials. Cerecor conducted a second double blind, randomized, placebo controlled phase II clinical trial
NCT02459236
studying the effects of 12 mg/day and 20 mg/day doses of rislenemdaz on patients with MDD. Numerous changes were made to the study in order to achieve a great likelihood of success and new top-line data from this study in November 2016. However, the study reported in November 2016 that the drug failed to demonstrate

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...

References

External links

CERC-301 - Cerecor, Inc.

CERC-301 - AdisInsight
{{Ionotropic glutamate receptor modulators Carboxylic acids Experimental antidepressants Organofluorides NMDA receptor antagonists Piperidines Aminopyrimidines