Escient launches to tackle itching and anaphylactoid drug targets

Escient Pharmaceuticals launched today with $40 million in series A funding to develop small-molecule inhibitors of an unusual class of G protein-coupled receptors (GPCRs) implicated in chronic itching conditions.

Nearly 500 U.S. FDA-approved drugs target more than 100 different GPCRs that control physiological processes as varied as appetite, blood pressure, heart rate, immune responses, mood, and vision. Still, hundreds more GPCRs are waiting to be tapped as potential drug targets. One overlooked family of GPCRs, known as Mas-related G protein-coupled receptors (Mrgprs), is what San Diego-based Escient has its eyes set on.

For more than a decade, Xinzhong Dong, a neuroscientist at the Johns Hopkins University School of Medicine, has been studying the role of Mrgprs in the itch response. In 2015, Dong also discovered that Mrgprs play a broader role in the body by producing anaphylactoid, or so-called pseudo-allergic, reactions (Nature DOI: 10.1038/nature14022). These reactions, which can be triggered by a drug, spur symptoms similar to severe allergic reactions but are not caused by an antibody response like a true allergy.

Dong began thinking his work on Mrgprs could form the basis of a new company, and he shared his idea with Alain D. Baron, the former CEO of Elcelyx Therapeutics. Baron says Dong’s Nature paper, along with unpublished data, “prompted the formation of Escient,” of which Dong and Baron are cofounders.

Mrgprs, which are embedded in cell membranes of certain neurons and immune cells, act as “surveillance receptors that recognize offensive stimuli from the internal and external environment,” Baron explains. Beyond that, “What they do is the secret, and that knowledge is really the basis of the company,” he adds.

A handful of published papers offer some clues, however. For instance, mice with a cluster of Mrgpr genes deactivated are relieved of persistent itching from dry skin and contact dermatitis, two chronic itch conditions.

Mice with a particular Mrgpr gene knocked out in mast cells, an immune cell that releases inflammatory molecules, show less swelling than normal when exposed to a compound that causes an anaphylactic reaction.

And a study published by Dong’s lab in March even suggests the receptors may be involved in asthma. Mrgpr genes knocked out in mice reduced the bronchoconstriction and airway sensitivity characteristic of the disease (Nat. Neurosci. 2018, DOI: 10.1038/s41593-018-0074-8).

Escient chief scientific officer and cofounder Marcus F. Boehm says the start-up is focused on studying molecules that normally activate Mrgprs as a starting point for discovering small molecules that could inhibit the receptors instead. Escient isn’t naming its specific Mrgpr targets, or the diseases it aims to treat, but Alain says the company is looking at several neuroimmunology and inflammatory conditions, which may include itch-related disorders.

The Column Group, 5AM Ventures, and Osage University Partners contributed to Escient’s funding, which Baron says will support the company through 2021, the target date for testing its first compound in the clinic.