Pulmonary fibrosis, or chronic scarring of the lungs, is a cohort of lifelong debilitating diseases that affects approximately three million people around the world. Patients with this condition have difficulty breathing due to a gradual decline in lung function. Although a variety of risk factors have been identified, the cause of fibrosis remains unknown in most cases. These are classified as idiopathic pulmonary fibrosis (IPF) and affect over 100,000 individuals in the United States alone. IPF is a devastating diagnosis: there is currently no cure and a life expectancy of less than five years if left untreated. Therefore, IPF presents a major unmet need in the critical research area of therapeutics.
Current treatment regime for idiopathic pulmonary fibrosis:
Early treatments for IPF involved anti-inflammatory drugs such as corticosteroids. The triple therapy of prednisolone plus azathioprine and N-acetylcysteine became the standard of care by the early 2000s, but in 2011 the NIH announced it was harmful and discontinued this option. Following a series of disappointing clinical trials investigating alternative treatment regimes, an antifibrotic option comprising Roche’s pirfenidone (Esbriet) and Boehringer Ingelheim’s nintedanib (Ofev) was approved by the US FDA in 2014. However, although pirfenidone and nintedanib can improve survival rates by slowing down deterioration of fibrotic lung function, they may entail severe side effects and have not been shown to improve patients’ quality of life. A lung transplant is the last resort for IPF patients, but life expectancy after transplant is still only 4.5 years, few patients qualify for the procedure, and there is a shortage of donors.
Hence, there is a need for exploration of new therapies with a higher tolerability profile as well as better management of the disease. Development of improved IPF therapeutics has been hindered by the complexity of disease pathogenesis and mechanisms. Although characterization of the specific causes behind IPF remains an area of active research, the last decade has seen great improvements in our understanding of IPF biology. In this article, we will review recent clinical advances and survey the long-term outlook for IPF therapeutics.
Drug regimes: Targeting key signaling pathways
Since idiopathic pulmonary fibrosis presents with activation of several signaling pathways, combination therapy with repurposed or novel drugs is an area of high interest. A recombinant version of pentraxin (PTX-2), a protein that can reduce fibrosis-promoting cell types, was developed by Promedior and acquired by Roche in 2019. It has received breakthrough therapy designation from the FDA and is slated to start a phase III clinical trial. FibroGen’s pamrevlumab (FG-3019), a fully human recombinant monoclonal antibody targeting profibrotic growth factor CTGF, has received orphan drug and fast track designations, with two phase III studies recently announced. MediciNova’s tipelukast (MN-001), a leukotriene B4 antagonist, is currently in phase II trials and has received FDA orphan drug designation.
Protein kinase inhibitors are another attractive class of drugs, with phase II clinical trials currently underway for Kadmon Corporation’s ROCK2 inhibitor belumosudil (KD025) as well as Celgene’s JNK inhibitor tanzisertib (CC-930). Finally, Pfizer’s sirolimus (Rapamune), already approved as an immunosuppressive drug, is being examined in the context of IPF in a pilot study by University of Virginia researchers.
However, not all news is as promising. Liminal Biosciences’ fezagepras (PBI-4050) showed positive outcomes in early clinical studies, but clinical development was stopped based on interim pharmacological data from a phase II trial. The autotaxin inhibitor ziritaxestat (GLPG1690), an oral drug developed by Galapagos and Gilead Sciences, gave positive results in phase II studies, but the planned phase III clinical studies were halted due to toxicity concerns.
Alternative approaches: Microbiome, stem cells, senolytics, and senomorphics
The respiratory tract is colonized by microbes, and altered lung microbiota can precede lung injury, exacerbating inflammation and initiating the excessive repair that contribute to fibrosis. Thus, targeting the lung microbiome could be an attractive strategy to slow fibrosis. Antibiotic therapy with a combination of co-trimoxazole or doxycycline is currently under investigation by a cross-university collaboration in a phase II study sponsored by Weill Medical College.
Mesenchymal stem cells (MSCs) have the capability to differentiate into various cell types and have shown antifibrotic effects in preclinical studies. A phase I clinical trial headed by University of Miami researchers administered MSCs to early IPF patients and reported improved lung function. However, other reports suggest that MSCs may not perform well within a fibrotic environment. Thus, further research is needed to characterize the true potential of this approach.
A growing number of studies have identified increased senescent cells as contributors to IPF pathogenesis, leading to interest in senolytics (which induce apoptosis in senescent cells) and senomorphics (which change the phenotype of senescent cells). Preclinical results with the tyrosine kinase inhibitor dasatinib (Sprycel) and the flavonol quercetin in combination (DQ) are promising, but there has been only one human pilot study examining DQ efficacy in IPF patients, and concerns remain about potential negative consequences due to disruption of the lung’s stem cell reservoir. Hence, targeted senolysis is being explored by University of Alabama researchers in a phase II study with the dual NOX1/4 inhibitor GKT13783. Further approaches targeting senescence-associated secretory phenotype (SASP) proteins have been proposed but are still in infancy and require more proof-of-concept studies before human clinical trials can be carried out.
Future approaches: Gene therapy and personalized medicine
Gene therapy, which modulates the targets in cells by introducing genetic material, has shown promise in many diseases and is now being explored for IPF. The concept is to modulate the expression of dysregulated genes and proteins driving the disease, thus affecting targets that have until now been considered undruggable. Promising approaches include mRNA therapeutics, which can produce a protein of interest for a short duration, or gene editing via CRISPR, which could be used to permanently silence or regulate the expression of dysfunctional protein. However, this area is still in the nascent stages for IPF and has not progressed beyond proof-of-concept animal studies.
Beyond developing drugs and novel therapeutic approaches, it is becoming glaringly evident that IPF therapies will have to be tailored to patients presenting specific signaling pathway dysregulations. An approach toward such personalized therapeutics could be guided by biomarkers to identify patient cohorts that might benefit from therapies already in use or under development. Predictive genetic biomarkers are being explored in this area, with promising candidates identified as potential mediators of patient response to therapy. Recent advances in sequencing technologies suggest that a personalized approach combined with gene therapy could be the future of IPF treatment.
Conclusions:
Despite our evolved understanding of the pathobiology of idiopathic pulmonary fibrosis, there is no cure for this disabling disease. The current treatments and those under investigation have only been able to slow the disease progression, at best. Further efforts are required to better understand the mechanisms to find key targets and develop novel therapies that can halt or reverse — and possibly cure — the disease. Promising targeted drug treatments are already in clinical trials, with alternatives such as targeting the lung microbiome and delivering stem cells being pursued. Although at even earlier stages of development, gene therapies are very promising.
A major requirement to emphasize is biomarker development, to better identify the appropriate patients for a given therapy and predict outcomes. An all-encompassing approach tying in personalized medicine could help in speeding the development and delivery of the right therapies and bring us a step closer to finding a cure.
