Medicinal Chemistry Expertise

Multiple Sclerosis

Multiple Sclerosis

Califia Bio Inc. has been awarded a $1.7 million NIH Fast Track Phase 2 SBIR grant to validate the efficacy in animal models and establish safety in IND Enabling Safety Studies of a highly selective MLK3 inhibitor, CLFB-1134, for the treatment of the cognitive deficits associated with Multiple Sclerosis (MS).   Although modern treatments for MS are increasingly effective at preventing relapses, patients with MS continue to suffer from progressive neurologic decline that include cognitive deficits. Worsening symptoms such as gait disability, fatigue and cognitive impairment affect up to 70% of patients with MS and have profound long-term impact on daily activities, employment, productivity and quality of life. Market analysis suggests that cognitive impairment affects approximately 1.6 million MS patients.   Neuroimaging studies suggest that these symptoms may derive from degeneration of gray matter in the brain which begins in the earliest stages of MS and progresses independently of the relapses and focal white matter inflammation that are the targets of current immunosuppressive treatments.    Preventing progressive disability is one of the greatest unmet needs in the treatment of MS.

 

Activation of microglia in MS gray matter, which can occur widely even without ongoing relapses, has been associated with loss of synaptic connections and increases in markers of neuronal injury. Activated microglia release the excitatory neurotransmitter glutamate, in addition to radicals and pro-inflammatory molecules that can augment glutamate’s neurotoxic effects. Increased concentrations of these molecules in studies of MS patients suggest a Mixed Lineage Kinase 3 (MLK3) sensitive pathway involved in excitotoxic injury in MS gray matter. Our collaborators at the University of Rochester have demonstrated the ability of MLK inhibition to efficaciously protect hippocampal synaptic architecture and reduce microglial activation in an experimental autoimmune encephalomyelitis (EAE) model of cognitive impairment in MS. The inhibitor used in these studies is non-selective and our current studies will compare the efficacy and safety of a highly selective MLK3 inhibitor, CLFB-1134. From these studies a development compound will be selected for IND enabling safety studies.

 

This research is supported by the National Institute of Neurological Disorders and
Stroke of the National Institutes of Health, under Award Number R44NS092137. The content is
solely the responsibility of the authors and does not necessarily represent the official views of
the National Institutes of Health.