Top 10 Pulmonary Fibrosis Stories of 2018

Throughout 2018, Pulmonary Fibrosis News provided you daily coverage of key discoveries, potential treatments, and clinical trials related to pulmonary fibrosis (PF).

As we look forward to bringing more news to patients, family members, and caregivers dealing with PF in 2019, here are the Top 10 most-read articles of 2018, with a brief description of what made them interesting to the PF community.

No. 10 — “Dental Workers Could Be at Risk of Developing Pulmonary Fibrosis, Study Reports”

In March, the U.S. Centers for Disease Control and Prevention (CDC) reported that dentists and other dental healthcare personnel may be at risk of developing idiopathic pulmonary fibrosis (IPF) at work. Of the 894 patients treated for IPF between September 1996 and June 2017 at a care center in Virginia, nine (almost 1%) were dental workers, a proportion 23 times greater than that of dentists in the overall American population (0.04%). The only dentist in the cluster who spoke to researchers said he used compounds with known or potential respiratory toxicity — namely silica, alginate, polyvinyl siloxane, among others — to perform his daily tasks. While the scientists speculated that such respiratory contaminants may have contributed to developing IPF, they also cautioned that additional studies are needed.

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No. 9 — “Planned Phase 3 Trial of PBI-4050 in IPF Patients Among Top Priorities, Prometic Says”

After a Phase 2 trial (NCT02538536) in IPF patients showed that a 12-week treatment with PBI-4050 stabilized lung function both as a stand-alone therapy and in combination with Ofev (nintedanib, marketed by Boehringer Ingelheim), PBI-4050’s developer, Prometic Life Sciences, announced that a Phase 3 trial in this patient population would be a top priority in 2018. The international study would be open to all patients with mild to moderate IPF and intends to test the effectiveness and safety of PBI-4050 with or without Ofev.

No. 8 — “Esbriet and Ofev Show Significant Benefits in Real-Life Clinical Setting”

In line with data from Phase 3 trials (discussed here and here), a study conducted at the Florence ILD Referral Centre in Italy, found that treatment with Genentech’s Esbriet or Ofev slowed IPF progression. A total of 82 patients (66 men, mean age of 78.3 years) were included in the study, 52 on Esbriet and 30 on Ofev. The two therapies showed the same efficacy at six months across all analyzed parameters. Data at 12 months were only available for Esbriet — because Ofev had been recently approved in Italy — and indicated a stable benefit in lung function.

No. 7 — “#ATS2018 — Pamrevlumab Slows Fibrosis Progression, Improves Lung Function in IPF, Phase 2 Trial Shows”

Results of the Phase 2b PRAISE trial (NCT01890265) presented at the American Thoracic Society 2018 meeting showed that investigational treatment pamrevlumab (30 mg/kg) halted the progression of lung fibrosis (scarring) and improved the lung function of IPF patients over 48 weeks. No safety risks were found. The FibroGen therapy, which targets a molecule called connective tissue growth factor (CTGF), had shown superior effectiveness in lowering lung density over Ofev and Esbriet in preclinical studies in mice, which suggests reduced lung fibrosis and remodeling.

No. 6 — “FDA Puts FibroGen’s Pamrevlumab on Fast Track as IPF Treatment”

Our sixth most-read article of 2018 also covered pamrevlumab, with the U.S. Food and Drug Administration granting the therapy fast track designation in September for the treatment of IPF. This designation is intended to accelerate the development and review of potential medications for serious conditions with an unmet medical need. It also enables more frequent communication with the FDA throughout clinical development. FibroGen is planning to start Phase 3 studies of pamrevlumab early this year.

No. 5 — “Common Diabetes Medication Reverses Pulmonary Fibrosis in Mouse Model of Disease”

Metformin, a common oral medication for type 2 diabetes, quickly reversed PF in a mouse model and lessened lung fibrosis in PF patients, as shown in a study from The University of Alabama at Birmingham. The effects of metformin were mediated via the activation of an enzyme known as AMPK, a sensor of cellular energy and a metabolic regulator. The team found that the activity of AMPK was lower than usual in fibrotic regions of the lung in IPF patients, particularly in myofibroblasts — cells that release collagen during the development of fibrosis. Through its AMPK activation, metformin eased fibrosis and increased the production of mitochondria (the cellular power plants) in myofibroblasts. In the mouse model, metformin led to AMPK-dependent faster resolution of fibrosis.

No. 4 — “Chemical in Vegetables Displays Anti-Fibrotic Activity in Lung Tissue, Study Reports”

Sulphoraphane — a compound found in broccoli, cauliflower, Brussels sprouts, kale, cabbage, and bok choy — showed anti-fibrotic properties in preclinical experiments in cells and in a mouse model. The team from South Korea reported that the chemical reversed fibrosis-related alterations in cells, as indicated by an increased level of a marker of normal epithelial cells called E-cadherin. Lung epithelial cells transition into key fibrosis cells called fibroblasts and myofibroblasts through a process known as epithelial-mesenchymal transition (EMT). Sulphoraphane also lowered the amount of proteins associated with fibrosis, such as fibronectin, collagen I, collagen IV, and alpha-SMA. In mice, sulphoraphane reduced lung fibrosis by decreasing the levels of fibronectin, collagen I, and TGF-beta1, also a driver of fibrosis. EMT prevention may explain the anti-fibrosis benefit of sulphoraphane, the scientists suggested.

No. 3 — “LOXL2 Inhibitor PXS-5382A Shows Potential to Treat IPF, Other Fibrotic Diseases in Phase 1 Trial”

A Phase 1 trial (ACTRN12617001564347) in 48 healthy volunteers found that a 100 mg dose of Pharmaxis’ PXS-5382A, a small molecule inhibitor of the fibrosis promoter LOXL2 enzyme, was stable upon administration, achieving more than 85% inhibition of the enzyme over 24 hours. Treatment with PXS-5382A was well-tolerated and had no reported significant adverse events. The findings are in line with prior preclinical studies and suggest that the investigational therapy holds potential to treat fibrotic diseases, the researchers said.

No. 2 — “Phase 3 Trial Planned for PBI-4050, Potential Treatment for Mild-to-Moderate IPF Patients”

Our second most-read article of 2018 reported the planned Phase 3 trial of PBI-4050, referred to in No. 9 of this list. The study will evaluate oral PBI-4050 as a stand-alone therapy and as an add-on treatment to Ofev for its ability to slow lung function decline. Patients on Esbriet (pirfenidone) will be excluded as a drug-to-drug interaction between Esbriet and PBI-4050 has been reported. Final trial design resulted from recommendations by the FDA. Participants will receive either PBI-4050 (800 mg or 1,200 mg) or a placebo for up to 52 weeks. The study will take place at sites across the U.S., Canada, Australia, and Europe.

No. 1 — “Enzyme Can Start Process That Leads to Tissue Scarring Being Reversed, Study Shows”

The most-read PF article of 2018 described a study from the U.S. and Wales that focused on a cell surface protein called CD44. Faulty versions of CD44, a receptor for a molecule called hyaluronan, had been linked to fibrotic disorders. One of the processes through which CD44 exerts its effects is called alternative splicing — creating different messenger RNA molecules from the same gene in protein production. The team found that hyaluronidase 2, an enzyme that breaks down hyaluronan, regulates CD44 gene splicing in myofibroblasts. This leads to a CD44 variant — CD44v7/8— that prevents and reverses the differentiation of these cells. These results suggest that this approach may be used to stop myofibroblasts from producing scar tissue, according to Soma Meran, the study’s senior author. “This opens up exciting new research avenues in the study of fibrosis,” she said.

At Pulmonary Fibrosis News, we hope that these articles, along our reporting throughout 2019, help inform and improve the lives of everyone dealing with PF.

We wish all our readers a happy 2019.