A NOVEL MECHANISM TO MODULATE THE ENDOCANNABINOID SYSTEM
The ECS is composed of two major G-protein couple receptors named cannabinoid receptor type-1 (CB1) and type-2 (CB2), a class of endogenous signalling lipids (endocannabinoids) and a series of enzymes involved in their biosynthesis and degradation.
The two most abundant and well-studied endocannabinoids are anandamide (AEA) and 2-arachidonoyl glycerol (2-AG). At the synaptic level, upon the arrival of an action potential, neurotransmitters are released from presynaptic neurons into the synaptic cleft.
Increase of intracellular Ca2+ concentration in the postsynaptic neurons activates the biosynthetic enzymes for AEA and 2-AG, which are released in the synaptic cleft. Endocannabinoids activate CB1 receptors expressed on pre-synaptic neurons blocking the release of further neurotransmitters (negative feedback, retrograde signaling). Finally, endocannabinoids are transported intracellularly where they are degraded by specific enzymes.
Although data from independent laboratories have clearly suggested the existence of an endocannabinoid membrane transport mechanism (reviewed in Nicolussi & Gertsch, 2015), this has remained elusive for many years.
Thanks to the prolonged support of NCCR TransCure and other founding agencies, the research group of Prof. Jürg Gertsch at the University of Bern has successfully identified the molecular entities responsible for endocannabinoid transport across cell membranes (as yet unpublished) and generated the first-in-class selective endocannabinoid reuptake inhibitors (SERIs).
First generation SERIs have been instrumental in uncovering a new pharmacological modulation of the endocannabinoid system resulting from the inhibition of endocannabinoid cell reuptake (Chicca et al., PNAS 2017; Reynoso-Moreno et al., 2018).
SERIs’ mechanism of action enables restoration of the full spectrum of endocannabinoid biological activities.
THE POTENTIAL FOR TREATMENT
Preclinical and clinical evidence links altered functioning of the endocannabinoid system with different diseases related to CNS and peripheral organs. The strongest evidence correlates with anxiety, stress and mood-related disorders and inflammatory diseases.
One of the reasons for altered functioning of the endocannabinoid system is the higher expression of the degrading enzymes in pathophysiological conditions that generate endocannabinoid deficiency. SERIs exert the maximal pharmacological effect during disease conditions (time-limited) and in the tissue or brain region primarily involved in the disease (space-specific).
The competitive, non-covalent and reversible mechanism of action of SERIs exerts pro-homeostatic effects on the endocannabinoid system and limits the risk of an excessive, prolonged and ubiquitous accumulation of endocannabinoids. This results in a key potential differentiation from other approaches to modulating the ECS.
The endocannabinoid system is a key neuromodulator system in the CNS and it is involved in regulating neurotransmitter release of major neuronal circuits. Modulation of the endocannabinoid system can enable restoration of normal functioning of the brain by rebalancing dysregulated neurotransmission in CNS disorders.
SERIs’ mechanism of action can translate into a better safety profile for short and long term use and an improved therapeutic control of the symptoms associated with anxiety, mood and stress-related disorders.
SERIs represent a novel therapeutic approach to treat CNS disorders characterized by altered functioning of the endocannabinoid system and endocannabinoid deficiency through a fine-tuned, pro-homeostatic modulation of this system.
THE MEDICAL NEED
Synendos targets neuropsychiatric disorders, in particular anxiety and mood related disorders with the potential to treat serious symptoms that present across a number of neuropsychiatric conditions. These include Post Traumatic Stress Disorder (PTSD).
Within this area there have been no new treatments with a novel mode of action for over 25 years. Existing treatments, such as anti-depressants (e.g., Selective Serotonin Reuptake Inhibitors (SSRIs)) and anti-psychotics, have suboptimal efficacy and significant limitation in safety. The leading cause of discontinuation of treatment is due to side effects and lack of tolerability.
PTSD affects 1-8% of the population worldwide, with higher rates in women and represents a significant burden on patients and society. At present, there is little effective and well tolerated pharmacotherapy for PTSD, with only two SSRIs (paroxetine and sertraline) approved. As second- and third-line treatments, there are other antidepressants/mood stabilizers that have a broader pharmacology and even less favorable safety profile than SSRIs.
Synendos has conducted market research with over 40 KOLs across the major markets, exploring the unmet needs in PTSD and the attractiveness of the profile associated with a novel SERI agent. This has confirmed the need for a novel mode of action, differentiated from SSRIs and antipsychotics and with a safety profile that allows for longer term treatment in a wider patient population than is possible with existing treatments. This is the profile that our SERI molecules are aiming to achieve, restoring a healthy endocannabinoid balance in a form that can be administered orally and is well-tolerated.
SERIs DESIGN AND DEVELOPMENT
The design and development of second generation SERIs began in 2012 with an in silico ligand polypharmacophore screening of >12 million compounds, followed by an effective medicinal chemistry programme (in collaboration with a CRO).
In total, more than 800 purchasable and newly synthesized compounds were tested with the identification of three lead compounds. An additional characterization of the safety and efficacy profile of these three lead compounds led to the identification of SYT-510 as our preclinical drug candidate with two possible follow up/back up compounds.
An innovative screening platform based upon the exclusive access to the mechanism of endocannabinoid cell reuptake will in future enable Synendos to develop new generation of inhibitors (target-based) and new classes of modulators with unique pharmacological features in the endocannabinoid system.