Experimental autotaxin inhibitors for the treatment of idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible, and fatal lung disease with unmet medical needs. Autotaxin (ATX) is an extracellular enzyme involved in the generation of lysophosphatidic acid (LPA). Preclinical and clinical data have suggested the ATX-LPAR signaling axis plays an important role in the pathogenesis and the progression of IPF. AREAS COVERED: The aim of this review is to provide an update on the available evidence on autotaxin inhibitors in IPF and further details on the ongoing clinical studies involving these molecules. EXPERT OPINION: The development of autotaxin inhibitors as a potential therapy for idiopathic pulmonary fibrosis has gained attention due to evidence of their involvement in the disease. Preclinical and early-phase clinical studies have explored these inhibitors' efficacy and safety, offering a novel approach in treating this disease. Combining autotaxin inhibitors with existing anti-fibrotic agents is considered for enhanced therapeutic effects. Large phase III trials assessed Ziritaxestat but yielded disappointing results, highlighting the importance of long-term observation and clinical outcomes in clinical research. Patient stratification and personalized medicine are crucial, as pulmonary fibrosis is a heterogeneous disease. Ongoing research and collaboration are essential for this advancement.

An up-to-date review of approved and emerging antibody therapies for idiopathic pulmonary fibrosis.

INTRODUCTION: The use of pirfenidone and nintedanib in treating Idiopathic Pulmonary Fibrosis (IPF) has shown significant slowing down of the progressive functional decline in these patients. In recent times, antibody-based therapies with precise molecular targets have also been explored as alternative treatments to IPF. AREAS COVERED: This review aims to summarize the available updates regarding monoclonal antibodies that have been tested in IPF. The drugs describedare developed to antagonize inflammation,immunity pathways and fibrogenesis. Currently, the anti-CTGF pamrevlumab has demonstrated a significant reduction in functional decline as compared to placebo and is undergoing the last stages of phase 3 trial. EXPERT OPINION: Although antibody-based therapies for IPF have had unsatisfactory results in most trials in the last few years, the pursuit of therapeutic development in this field should continue to deliver a more personalized treatment approach in the future, which is currently not available with existing treatment options. However, several molecules are still under study and some have shown encouraging results in the early phases of clinical trials. Future investigations need to be more carefully designed and valid predictive markers of response to treatment should be used to enhance the effectiveness of future trials.

BI 1015550: an investigational phosphodiesterase 4B (PDE4B) inhibitor for lung function decline in idiopathic pulmonary fibrosis (IPF).

INTRODUCTION: The two available therapies for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, slow down but do not halt IPF progression. Therefore, several agents with specific molecular targets have been recently investigated to find a cure for IPF. Phosphodiesterase 4 (PDE4) inhibition is known for its anti-inflammatory and antifibrotic properties. BI 1015550, an oral preferential inhibitor of the isoform PDE4B, could express complementary activity to current therapies in IPF and other forms of progressive pulmonary fibrosis. AREAS COVERED: In this review, we first provide an overview toof the current IPF treatment market, followed by the description of pharmacokinetics and pharmacodynamics of BI 1015550. The main preclinical and early clinical evidence on BI 1015550 is then described, as well as its potential as an IPF treatment. EXPERT OPINION: Oral treatment with BI 1015550 was shown to stabilize lung function as compared to placebo over 12 weeks, both among patients with and without background antifibrotic use, with an acceptable safety profile in a phase 2 trial, and a phase 3 trial has been initiated. To date, this represents to date the largest effect size for an IPF investigational drug tested in a phase 2 trial with the shortest duration.

When one plus one means more than two: the blockade of both IL-4 and IL-13 inflammatory pathways with dupilumab in a case of severe refractory T2-high asthma.

Novel approach of asthma includes personalised therapy involving specific immune pathways. We describe here a case of T2-high asthma in a 66-year-old woman treated with maximal inhaled therapy and inappropriate usage of oral corticosteroids showing poor symptoms control. Both anti-IgE and (omalizumab) and anti-interleukin (IL)-5 (mepolizumab) monoclonal antibodies treatments were prescribed without significant benefit. Add-on subcutaneous dupilumab, a monoclonal antibody directed against the IL-4 receptor subunit alpha, inhibiting signalling from both IL-4 and IL-13, proved to be an effective and safe medication to obtain rapid asthma control. Considering the previous lack of response to both anti-IgE and anti-eosinophilic strategies, we hypothesise that dupilumab upstream activity could exert different and more relevant effects than the simple inhibition of the two single downstream pathways. The current case highlights the need for a deeper analysis of biomolecular interactions in the framework of different asthma endotypes, to identify peculiar profiles associated with specific treatment responses.

Ventilatory Support in Patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the novel coronavirus disease 2019 (COVID-19) pandemic, which spread throughout the world. Acute hypoxemic respiratory failure is the most dangerous complication of COVID-19 pneumonia. To date, no specific therapeutic drugs or vaccines have been proven efficacious. Ventilatory support is still a significant challenge for physicians facing COVID-19. The mechanisms underlying hypoxemia in those patients are not fully understood, but a new physiopathology model has been proposed. Oxygen therapy should be delivered to patients with mild to moderate hypoxemia. More severe patients could benefit from other treatments (high-flow nasal cannula, noninvasive ventilation or intubation, and invasive ventilation). Given the rapid evolution of COVID-19, there has been a paucity of the high-quality data that typically inform clinical practice guidelines from professional societies, and a worldwide consensus is still lacking. This chapter aims to illustrate the potentials of ventilatory support as therapeutic options for adult and pediatric patients affected by COVID-19 pneumonia.

Obstructive sleep apnea in sarcoidosis and impact of cpap treatment on fatigue.

RATIONALE: An increased incidence of Obstructive Sleep Apnea (OSA) in sarcoidosis has been described in small sample size studies. Fatigue is common in sarcoidosis and OSA could be a relevant, treatable comorbidity. To date, the effect of Continuous Positive Airway Pressure (CPAP) on fatigue has never been assessed. OBJECTIVES: To investigate the prevalence of OSA in sarcoidosis, fatigue status and daytime sleepiness in patients of our center. To explore the effect of CPAP in fatigue and daytime sleepiness after 3 months using validated questionnaires. METHOD: Single group, one center, open-label prospective cohort study. MEASUREMENTS AND MAIN RESULT: We enrolled 68 patients and OSA was diagnosed in 60 (88.2%): 25 (36.8%) were mild while 35 (51.5%) were moderate-to-severe. 38 (55.9%) patients received CPAP but only 20 (30.9%) were compliant at 3-month evaluation. Questionnaires demonstrated fatigue in 34 (50%) and daytime sleepiness in 21 (30.9%). In multivariate regression analysis, Scadding stage and FAS behave as predictors of Apnea-Hypopnea Index (AHI) severity while sleepiness and steroids weren't associated. FAS score (ΔFAS = 6.3; p = 0.001) and ESS score (ΔESS = 2.8; p = 0.005) improved after three months of CPAP. CONCLUSIONS: OSA is highly prevalent in patients affected by sarcoidosis. ESS questionnaire is not reliable for OSA screening and other pre-test probability tool should be evaluated in further studies. CPAP leads to a significative reduction of fatigue and daytime sleepiness at three-month. Further studies are needed to confirm the high prevalence of OSA in sarcoidosis and the positive role of CPAP in fatigue. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 169-178).

Pamrevlumab for the treatment of idiopathic pulmonary fibrosis.

INTRODUCTION: The two available therapies for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, slow down but do not halt IPF progression. As such, in the last few years several agents with specific molecular targets have been investigated to find a cure forIPF. Pamrevlumab, a recombinant human antibody that binds to connective tissue growth factor (CTGF) has emerged as a potential therapy for IPF and has advanced to phase 3 clinical trials. AREAS COVERED: The authors offer a backdrop to the current IPF treatment market and describe the chemistry, pharmacokinetics and pharmacodynamics of pamrevlumab. They summarize the preclinical and early clinical evidence on pamrevlumab and propose ways of progressing this agent further as a potential IPF treatment. EXPERT OPINION: Pamrevlumab was effective and safe in patients in a placebo-controlled phase 2 trial, demonstrating its potential to become an alternative therapeutic option for IPF; however, the feasibility of intravenous administration in clinical practice may be a hurdle to its use as a first-line treatment. Further studies are necessary to assess its effects when administered with pirfenidone or nintedanib and this could open up a new era of combined therapeutic approaches for IPF.