PI3Kγ: A New Approach to Respiratory Relief

Recently approved therapies for cystic fibrosis and chronic obstructive pulmonary disease (COPD) have created significant improvements among patients, but full-capacity lung function remains elusive.

Kither Biotech hopes to remedy that situation using a new approach to cell signaling modulators to inhibit the gamma isoform of phosphatidylinositol 3-kinase (PI3K). Its most advanced program, KIT2014, targets COPD and is expected to begin Phase II trials in 2026. Candidates for cystic fibrosis, idiopathic pulmonary fibrosis (IPF), and other respiratory indications also are in development.

Originally, Kither focused on cystic fibrosis. When a drug with a similar mechanism of action was approved for COPD, the leadership realized their molecule had platform potential and had just gained a smoother approval pathway. “COPD isn’t a single-pathway disease,” Dimitrios Goundis, PhD, CEO, says. “Patients deal with inflammation, mucus, airway constriction, and progressive tissue damage all at once. Targeting multiple mechanisms with one molecule addresses the complexity of the disease.” Therefore, “We deprioritized cystic fibrosis and prioritized COPD.”

Most previously approved PI3K modulators involved the alpha or delta isoforms and are associated with immune-related toxicities and serious adverse events that have limited their application to oncology. Kither’s platform, however, modulates the PI3K gamma signaling pathway to amplify signals that control cells’ metabolism and proliferation. As a prodrug (which is active only after it is metabolized by the cells), therapeutics in this platform are expected to have few, if any, off-target effects, making them safer than most previous PI3K modulators and a potentially viable choice for respiratory indications.

A platform therapeutic

Kither’s most advanced candidate, KIT2014, is notable in that it targets both the phosphodiesterase (PDE) 3 and 4 pathways, unlike therapies currently in use. “By inhibiting both PDE3 and PDE4, KIT2014 elevates cyclic adenosine monophosphate (cAMP) through complementary pathways. This produces bronchodilation through smooth muscle relaxation while reducing neutrophilic inflammation and improving mucociliary clearance,” Goundis explains.

Preclinical studies for COPD reported sustained cAMP elevation in mouse lungs. cAMP affects the smooth muscles in the lungs, helping them work more efficiently. The increased levels caused by KIT2014 reduce mucus accumulation, inflammation, and bronchoconstriction. Reduced neutrophilic chemotaxis, cystic fibrosis transmembrane conductance regulator (CFTR) modulation, and anti-fibrotic activity also were reported in preclinical trials. A Phase I clinical trial was completed in 2025, and the company is preparing to initiate Phase II studies in COPD patients, with once-daily administration of KIT-2014.

As a peptide, KIT2014 is not metabolized by CYP450 enzymes, thus minimizing the risk of drug-on-drug interactions.

For cystic fibrosis, KIT2014 is envisioned as an adjunct to today’s standard of care therapy (currently Trikafta, by Vertex) to enhance CFTR function or, perhaps, as a stand-alone therapy. This candidate has orphan drug designation from the European Medicines Agency, and a Phase II study is being planned for 2026.

Goundis says the platform has potential for several respiratory indications, including COPD, non-cystic fibrosis bronchiectasis, cytokine release syndrome, pulmonary hypertension, and pulmonary fibrosis.

For COPD treatment, it offers dual pathway inhibition, modulating both PDE3 and PDE4. The current standard-of-care options for COPD, ensifentrine and nerandomilast, are single-action small molecules. Ensifentrine is inhaled and inhibits the PDE3 pathway, and nerandomilast is administered orally and selectively inhibits PDE4. Both are administered twice daily.

Kither’s pipeline also includes a candidate for IPF, KITCL27. This PI3K inhibitor is designed as a cell-permeable prodrug in which the molecule is negatively charged to reduce the risk of membrane-crossing and leakage. If leakage does occur, preclinical studies indicate clearance by the kidneys within minutes. In vitro studies suggest KITCL27 may improve the cytostatic effects of both pirfenidone and nintedanib when treating IPF. A next-gen version of this PI3K inhibitor—currently in proof-of-concept studies—is being designed as a small molecule monotherapy for multiple indications.

Another compound, DRIPEP20, also may become a monotherapy for respiratory indications. Still at proof-of-concept, it is a fusion peptide composed of 18 D-amino acids. These acids penetrate cells and mimic amino acids 126-130 of PI3K gamma and, therefore, may block scaffold functions that contribute to airway inflammation and remodeling.

Turin, for better or worse

Kither Biotech spun out of the University of Turin in 2011. At the time, the biotech industry in Italy was still new, so the company provided in vitro and in vivo screening services for pharmaceutical companies to generate cash flow. “That lasted about eight years,” Goundis recalls, “until one of the first biotech venture funds was established in Italy.”

That fund was the catalyst for Kither to begin its own development projects. Attracting funding, though, remained challenging. “Toxicology and scaleup studies aren’t sexy to investors,” Goundis acknowledges, “so the company didn’t get the necessary funds early on. Things changed at the end of 2022, however.”

The Series B fundraising that began then concluded in 2024 with an €18.5 million raise that provided vital funds to accelerate projects. Now Kither is looking to launch a Series B2 or C fundraise to support clinical trials. Current investors include Claris Ventures, ACE Venture, Elysia Capital, Rinvest AG, Club degli Investitori, CDP, IAG, Ersel, and 3B Future Health Fund.

One of Kither Biotech’s challenges may be its location. With more than half the country’s biopharma industry based in and around Milan (90 miles away), public research centers in Rome, and vaccine research centered around Florence, Turin’s biotech industry isn’t top-of-mind for investors or job-seekers. Instead, Turin is better known as the heart of Italy’s automotive industry, as well as home to the 2006 Winter Olympics, and the Shroud of Turin.

Consequently, Goundis admits, “It’s harder to attract talent. However, he stresses, “We’re not constrained by local talent pools. We can work with the best people in respiratory biology, formulation, and regulatory affairs regardless of their location.”

With that in mind, Kither works with a broad range of contractors and consultants for specific projects, yet attracts industry veterans for management. A quick look at the lineup shows most senior executives have more than 30 years’ experience in the industry, typically at large pharma organizations.

Looking Forward

Goundis is looking forward to beginning a Phase II trial for KIT2014 later this year. Beyond that, he says, “Raising funds is the next serious challenge, but we’re in a unique position,” in that the platform’s mechanism of action is well-understood and accepted, and investors appear interested.