Rislenemdaz (developmental code names CERC-301, MK-0657) is an orally-active, selective
NMDA receptor subunit 2B (NR2B)
antagonist
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
which is under development by Cerecor in the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
as an adjunctive therapy for
treatment-resistant depression
Treatment-resistant depression is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Definitions of treatment- ...
(TRD).
In November 2013,
phase II clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s were initiated,
and in the same month, rislenemdaz received
Fast Track Designation
Fast track is a designation by the United States Food and Drug Administration (FDA) of an investigational drug for expedited review to facilitate development of drugs that treat a serious or life-threatening condition and fill an unmet medical ...
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 respon ...
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
NMDA receptor. 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, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
and
forebrain
In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the Anatomical terms of location#Directional terms, rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hin ...
. Rislenemdaz binds specifically to the GluN2B subunit in order to prevent endogenous
glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
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 12-17h and 21-26h, 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 low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...
(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's
apimostinel
__NOTOC__
Apimostinel (GATE-202, formerly NRX-1074) is an investigational antidepressant, acting as a novel and selective modulator of the NMDA receptor. It is currently under development for the acute treatment of major depressive disorder (MDD) ...
(NRX-1074) and
4-chlorokynurenine (AV-101) from VistaGen Therapeutics.
Preliminary research
Research into the use of
ketamine
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ne ...
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 pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
using the NR2B antagonist
traxoprodil
Traxoprodil (developmental code name CP-101606) is a drug developed by Pfizer which acts as an NMDA antagonist, selective for the NR2B subunit. It has neuroprotective, analgesic, and anti-Parkinsonian effects in animal studies. Traxoprodil has ...
, 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%. Ho ...
issues and the possibility of it causing
QT prolongation
Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, ...
.
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.
[Paterson B, Fraser H, Wang C, Marcus R. A Randomized, double-blind, placebo-controlled, sequential parallel study of CERC-301 in the adjunctive treatment of subjects with severe depression and recent active suicidal ideation despite antidepressant treatment. Presented at the 2015 National Network of Depression Centers Annual Conference, November-2015, Ann Arbor, MI, USA]
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 ~$25 billion in committed capital, NEA is one of the w ...
(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.
[
]
See also
* List of investigational antidepressants
This is a list of investigational antidepressants, or antidepressants that are currently under development for clinical use in the treatment of mood disorders but are not yet approved. ''Chemical/generic names are listed first, with developmental ...
References
External links
CERC-301 - Cerecor, Inc.
CERC-301 - AdisInsight
{{Ionotropic glutamate receptor modulators
Antidepressants
Carboxylic acids
Experimental drugs
Fluoroarenes
NMDA receptor antagonists
Piperidines
Aminopyrimidines