Project: Histamine H4 receptor antagonists; an innovative therapy for the treatment of Vestibular disorders
Development of antagonists for the Histamine H4 Receptor, a new target for symptomatic treatment of vestibular disorders_x000D__x000D_Individuals continuously process three types of sensory inputs: vestibular, visual and somatosensory. These informations are combined in the central vestibular apparatus to form an estimate of orientation and motion of the head and body. While in a normal situation, the stream of informations arriving from contralateral vestibules is processed in a balanced way, a unilateral vestibular disorder leads to an imbalance in the overall neuronal activity causing severe deficits such as vertigo crisis (Hain & Uddin, 2003). Vertigo is characterized by an erroneous sensation of motion accompanied by oscillopsia, postural imbalance and nausea. The incidence of this severe and highly debilitating symptom is extremely broad and connected with age: 1/3 of the population over 40 years old; 85% of the elderly (>80 years old). _x000D_Such symptom is common to several vestibular pathologies such as benign paroxysmal positional vertigo, vestibular neuritis and Meniere’s disease. It can last a few minutes (acute crisis) up to hours or days (chronic vertigo) and hence be highly debilitating. Therapeutic options are mostly restricted to pharmacological treatments (antihistamines, benzodiazepine, and ion channels blockers) which are today largely inefficient to treat vertigo crisis and are often sedative. _x000D__x000D_The aim of Sensorion is to fill this clear unmet medical need and provide doctors (general practitioners, ear-nose & throat specialists, and otoneurologists) and patients with new drugs with superior efficacy to the current options in the treatment of vertigo & dizziness of vestibular origin. It should offer the physician the best choice to safely and rapidly abort vertigo attacks, allowing rapid return to normal function and preventing possible hospitalization (Appendix 1). _x000D_In addition to their capacity to reach the inner ear, these new drugs should be target-specific, modulate vestibular neurons with a fast onset, an increased and lasting efficacy._x000D__x000D_Over the past four years, Sensorion has developed a new technology platform with in-vitro and in-vivo models of vestibular deficits and focused its interest on G protein coupled histamine receptors (GPCR). Sensorion has conducted a series of proof of concept studies leading to the first demonstration of the functional expression in the vestibular system of the recently identified H4R. Furthermore it has demonstrated the potential of H4R reference antagonists (class effect) to modulate vestibular function, suggesting that they are strong candidates for a novel, highly efficient treatment of vertigo crisis caused by peripheral vestibular dysfunction (Desmadryl et al. 2012; EP 2 201 982/WO 2010/072829). Although, the effects observed in vivo with the reference antagonists (JNJ7777120 and VUF6002) have a rather fast onset (max. within 1h), their efficacy is mild (30% effect) and lasted no more than 1-2 hours. More importantly, both parameters (efficacy and duration) appear to be highly variable among all chemically distinct and available compounds tested up to now by Sensorion (7 compounds). This observation leads to the need for Sensorion to further define the best profile of H4R antagonists according to binding kinetics and pharmacokinetics parameters, in order to find a clinical candidate with improved efficacy. _x000D__x000D_To achieve that goal, Sensorion has the opportunity to team up with Griffin Discoveries; a growing and renowned medicinal chemistry company specialized in GPCR and particularly histamine receptors. Griffin discoveries has recently developed two series of H4R antagonists using a rational and unique fragment-based drug design method combined with binding kinetics measurements in addition to PK/PD and compound efficacy. This approach has led to the selection of a first highly selective H4R ligand (GD48) with optimized binding kinetics (affinity, selectivity, residence time) and excellent in vivo pharmacokinetic profile. A second chemically distinct compound series has also been developed and will be further optimized in order to find a compound with the best properties. Such optimized antagonists represent an important opportunity for Sensorion to find a compound with improved efficacy and duration of effect which would be further developed for a vestibular indication._x000D_Based on complementary expertise, knowledge and preclinical studies performed by Sensorion and Griffin discoveries; we believe that a collaborative project would be beneficial for both companies: Sensorion to find a clinical candidate with optimal efficacy (and duration of action) for the symptomatic treatment of vestibular deficits, Griffin discoveries to find new indications for their molecules. Such a project will also lead to the development of new assays that will be valuable to both companies platforms (i.e. kinetic of release), the ‘H4R community’ and on the long term the patients.
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Acronym
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H4 INVEST
(Reference Number: 7935)
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Duration
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21/01/2013 - 01/12/2015
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Project Topic
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Sensorion specializes in the development of innovative therapeutics to treat vestibular disorders. Griffin focuses on the development of histamine H4 receptor antagonists. In this proposal, both SMEs team up to develop a new histamine H4 antagonist for the treatment of vestibular disorders.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 9
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Project partner
