Oral administration of omipalisib, an investigational inhibitor of PI3K and mTOR cellular signals, can reduce the activity of pro-fibrotic cells in the lungs of patients with idiopathic pulmonary fibrosis (IPF), results from a Phase 1 trial show.
These findings support studies to further explore PI3K and mTOR signals as potential targets to prevent fibrosis progression in this patient population.
The Phase 1 trial data was reported in the study, “A Randomised, Placebo-Controlled Study of Omipalisib (PI3K/mTOR) in Idiopathic Pulmonary Fibrosis,” published in the European Respiratory Journal.
IPF is a life-threatening respiratory disease characterized by uncontrolled activation of pro-inflammatory mechanisms, and consequent progressive lung tissue scaring.
Two therapies have been approved for the treatment of IPF — Esbriet (pirfenidone, marketed by Genentech) and Ofev (nintedanib, marketed by Boehringer Ingelheim) — but these can only slow the rate of pulmonary function decline. Lung transplant is still the only effective strategy that can halt or reverse the decline in pulmonary function.
Studies have suggested that IPF and lung cancer share some biological mechanisms, such as increased cellular metabolism. During fibrosis, cells are more active and require a higher glucose uptake to fulfill their energy demands, similar to what happens with cancer cells.
With this in mind, researchers hypothesized that inhibition of main metabolic cellular signals could represent a potential strategy to halt fibrosis.
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Omipalisib, formerly known as GSK2126458, is an investigational compound that was specifically designed to inhibit PI3K and mTOR signals, which are critical for glucose metabolism, cell growth, proliferation, and survival in cells.
Preclinical results showed that omipalisib can reduce fibroblast proliferation and collagen synthesis — two main features of fibrosis — in lung slices derived from IPF lung tissue. In addition, this inhibitor has already been evaluated as a potential anti-cancer therapy in a Phase 1 trial (NCT00972686), further supporting its therapeutic potential.
Researchers from GlaxoSmithKline, and collaborators at University College London and National Institute for Health Research, in the U.K., evaluated the safety, tolerability, and early efficacy of omipalisib in patients with IPF in a new Phase 1 trial (NCT01725139).
“This is the first study to adopt an experimental medicine approach to evaluating the pharmacology of a novel therapeutic targeting the PI3K/mTOR pathway in IPF,” researchers stated.
The study enrolled 17 patients diagnosed with IPF, 13 of whom were randomly selected to take oral omipalisib while the other four received a placebo twice daily for 7–10 days. The omipalisib dose ranged between 0.25 mg and 2 mg.
Assessment of omipalisib distribution and absorption in the body confirmed that it could effectively reach the lungs. In addition, analysis of lung cells collected through bronchoalveolar lavage (BAL) confirmed that the cells had been exposed to the inhibitor, showing reduced PI3K and mTOR signals.
Participants were also evaluated by fluorodeoxyglucose (FDG) positron-emission tomography (PET) scans, which show spots of increased uptake of glucose and associated high cellular metabolism. The images revealed a reduction in glucose uptake in the lung’s fibrotic areas dependent on the dose of omipalisib given, suggesting a potential therapeutic activity.
During the trial, no serious adverse events were reported or led to early termination of treatment. The most common adverse reactions reported were diarrhea, increased blood glucose levels, lymph node pain, nausea, oral pain, rash, and inflammation of the nose mucosa.
“In conclusion, we have shown that orally dosed omipalisib exerts measurable dose- and exposure-dependent inhibition of PI3K/mTOR pathway in the systemic circulation and lungs of individuals with IPF. Omipalisib also reduces aberrant glucose signaling in fibrotic regions of IPF lungs as measured by FDG PET,” the researchers stated.
Taken together, the results suggest that inhibition of PI3K and mTOR signals could represent a new therapeutic target for the treatment of IPF. The team believes that new inhibitors with improved selectivity may reduce and avoid potential side effects of broader PI3K/mTOR inhibition, while maintaining their therapeutic benefit.