KIT2014 Increased CFTR Modulator Effects in Preclinical Study

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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KIT2014, an experimental treatment that Kither Biotech is developing to treat cystic fibrosis (CF) and other lung diseases, was able to reduce inflammation, relax the airways, and improve the functionality of CFTR modulators in preclinical models, a study shows.

Kither is planning to launch a Phase 1/2a clinical trial of KIT2014 in 2023.

The investigational medicine’s mechanism of action was detailed in the study, “A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases,” published in the journal Science Translational Medicine.

“The publication of these data in a prominent peer-reviewed journal represents an important step as we advance the development of KIT2014 for the treatment of cystic fibrosis,” Vincent Metzler, PhD, Kither’s CEO, said in a press release.

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The activity of cells is influenced by complex interactions among signaling molecules, both inside and outside the cell. Cyclic adenosine monophosphate, or cAMP, is an important intracellular (within-the-cell) signaling molecule. Prior research has shown that increasing cAMP level inside lung cells can help relax the airways and decrease inflammation.

However, increasing lung cAMP levels without inducing substantial side effects has proven challenging.

In this study, an international team that included Kither scientists discovered that a protein called PI3K gamma is a critical regulator of cAMP in structural and inflammatory cells in the lungs. KIT2014, also called PI3K gamma mimetic peptide, is essentially a similar molecule designed to gum-up the machinery that this protein normally works with to keep cAMP levels low, ultimately increasing cAMP levels.

In a mouse model of asthma, the team showed that treatment with KIT2014 induced airway relaxation and reduced inflammation. The team then tested the experimental treatment in airway cells from CF patients.

CF is caused by mutations in gene that provides instructions to make the CFTR protein, which acts like a “gate” on the surface of cells, regulating the movement of water and salt molecules. A recently developed class of medications called CFTR modulators can increase the functionality of this protein in people with certain disease-causing mutations.

In cells with the F508del mutation (the most common CF-causing mutation), co-treatment with KIT2014 increased the effects of existing CFTR modulators by up to 80%.

“Our data of KIT2014 showing an enhancement of the effect of existing CFTR modulators by 80% demonstrate the potential of this peptide, when administered as an inhalation therapy, to improve the condition of many patients still suffering from CF or other respiratory diseases,” said Emilio Hirsch, PhD, senior author of the study and scientific co-founder of Kither.

Added Alessandra Ghigo, PhD, the study’s lead author and scientific co-founder at Kither: “These new data validate KIT2014’s ability to modulate cAMP signal transduction in the lungs, increasing the functionality of CFTR channels, as well as reducing inflammation and bronchoconstriction, properties which are potentially highly beneficial to patients with cystic fibrosis and other diseases like COPD and asthma. We are looking forward to commencing clinical trials for KIT2014.”