Therapeutic targets and early stage clinical trials for pulmonary fibrosis

ABSTRACT

Introduction: Idiopathic pulmonary fibrosis (IPF) is an age-associated, progressive, and irreversible fatal interstitial lung disease. Although many drugs have failed in clinical trials, these failures improved the understanding of the pathogenesis of IPF. Currently, there are two drugs approved for IPF that slow the progression of the disease. However, the prognosis for patients with IPF remains poor and the search continues for drugs that inhibit the pathogenic pathways active in IPF to further reduce or even halt the progression of the disease.

Areas covered: We highlight the recent information on the therapeutic targets currently explored in early stage clinical trials and discuss the potential for new therapy and the limitation of basic research in the treatment of IPF.

Expert opinion: A key challenge in the coming years will lie in deciding which compounds to combine and how to evaluate combination therapies in clinical trials. The drugs most likely to provide additive efficacy when used in combination with one of the approved therapies are those with alternative, complementary, or synergistic mechanisms of action.

Trial registration: ClinicalTrials.gov identifier: NCT02257177.

Trial registration: ClinicalTrials.gov identifier: NCT02738801.

Trial registration: ClinicalTrials.gov identifier: NCT02538536.

Trial registration: ClinicalTrials.gov identifier: NCT02503657.

Trial registration: ClinicalTrials.gov identifier: NCT01371305.

Trial registration: ClinicalTrials.gov identifier: NCT02550873.

Trial registration: ClinicalTrials.gov identifier: NCT02688647.

Trial registration: ClinicalTrials.gov identifier: NCT01872689.

Trial registration: ClinicalTrials.gov identifier: NCT01529853.

Trial registration: ClinicalTrials.gov identifier: NCT02345070.

Trial registration: ClinicalTrials.gov identifier: NCT01629667.

Trial registration: ClinicalTrials.gov identifier: NCT01890265.

Trial registration: ClinicalTrials.gov identifier: NCT01262001.

Trial registration: ClinicalTrials.gov identifier: NCT03142191.

Trial registration: ClinicalTrials.gov identifier: NCT02036970.

Trial registration: ClinicalTrials.gov identifier: NCT00463983.

Trial registration: Japan Primary Registries Network identifier: JapicCTI-183898.

KEYWORDS:

• Idiopathic pulmonary fibrosis
• drug targets
• clinical trial
• Phase II

Article highlights

• The pathogenesis of IPF is extremely complicated because of the large number of pathways and target molecules involved.

• The fact that multiple cell types are involved in pulmonary fibrosis, and some of them playing opposing roles in the fibrotic process, complicates the development of efficient therapies.

• Novel therapies currently target many of the mediators and signaling pathways involved in the pathogenesis of pulmonary fibrosis.

• Several potential therapies that have shown activity in pre-clinical models are currently under investigation in Phase II trials.

• Ultimately, combination therapy is the best approach to provide the most effective treatment.

• Novel drugs with putative direct activity on EMT, FMT, ECM deposition, resolution of fibrosis, fibroblast apoptosis, stimulation of re-epithelialization, or oxidative stress might become suitable combination partners for the approved drugs.

This box summarizes key points contained in the article.

Declaration of interest

T. Yanagihara has received personal fees from ProMetic. M Kolb has received grants and personal fees from Boehringer Ingelheim and Roche, personal fees from GlaxoSmithKline, Gilead, AstraZeneca, ProMetic and Genoa and grants from Actelion, Respivert, the Canadian Institutes of Health Research (MOP-136950) and the Canadian Pulmonary Fibrosis Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.