Voltage-Dependent T-Type Calcium Channel Blockers 

Diverse voltage and ligand gated ion channels mediate Neuron excitation through various ions by sending electrical signals. Calcium is critical for cellular functioning. Voltage-gated calcium channels are primary mediators of depolarization-induced calcium entry into neurons. Calcium ions act as membrane potentiation and signal entities. Multiple genes for calcium channel a1 subunits, co-assembly with a variety of ancillary calcium channel subunits, and alternative splicing generate great diversity of calcium channel subtypes.  These channels fulfill highly specialized roles in specific neuronal subtypes at a particular subcellular loci. Under normal resting conditions, intracellular calcium concentrations lie in 100nM range, but opening of voltage-gated calcium channels results in calcium influx along electrochemical gradient, thus giving rise to a localized elevation of intracellular calcium into the high micromolar range.

Whereas prolonged elevation of intracellular calcium levels is cytotoxic because of the activities that are tightly regulated by intrinsic gating processes and cell signaling pathways. These activities mediate many calcium-dependent processes such as neurotransmitter release, neurite outgrowth, and the activation of calcium-dependent enzymes like calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC). Dysregulation of these processes and associated alterations in calcium channel activity have been linked to different types of neurological disorders.

There are a few approved products acting as calcium channel antagonist. However, the pipeline for Voltage-Dependent T-Type Calcium Channel Blockers is barren in late stage developments. Therefore, the chances of new product entering into the market are quite slim. Only a few companies are developing t-type calcium channel blockers, targeting central nervous system. And majority of the products are in inactive stage. Therefore, more companies are required to develop products, as it holds great potential in CNS disorders.

There are only two products in pipeline activity of mid-stage in phase II developments. Idorsia Pharmaceuticals and Cavion Pharmaceuticals are the key competitors in the respective space. ACT-709478 is being developed as an oral bioavailable drug candidate by Idorsia Pharmaceuticals for Epilepsy of Generalized and Photosensitive. The competition is heated by another company, Cavion developing CX-8998, with same administration route and a potential treatment of Essential tremor; Epilepsy and Parkinson’s disease.

The development of early stage products is taken by Cavion Pharmaceuticals and Sihuan Pharmaceutical with a total of three products.

The present situation demands targeted therapies allowing segregation between sub-types of calcium channels. According to different research studies conducted, the internal and external regulation & modulation mechanism have to be puzzled that would help in achieving new target binding sites, which may have potential in controlling the activity of t-type calcium channels in various pathological conditions. The current scenario has also suggested of no exact clinical model targeting t-type calcium channels for different indications like Parkinson’s disease, Autism etc. that obstructs drug development process at the initial stage. Hence, there is dire need to obtain the exact clinical models.

Vidhi Khosla

Associate Analyst