CFDB - Cystic Fibrosis DataBase

Anti-inflammatory therapy

Non-steroidal anti-inflammatory therapy

Background

Prevention of lung deterioration is one of the most important goals in CF therapy. Persistent pulmonary infection causes a hyperactive inflammatory response and inflammation mediators give an important contribution to airway damage. The inflammation of the CF lung is dominated by neutrophils, that release oxidants and proteases, particularly elastase, in the CF airway secretions. As affirmed (Cantin AM, 2015), several defective inflammatory responses have been linked to CFTR deficiency including innate and acquired immunity dysregulation, cell membrane lipid abnormalities, various transcription factor signaling defects, as well as altered kinase and toll-like receptor responses. Recently (Patergnani S, 2020)  it has been suggested that a decline in mithocondrial function endorses the development of hyperinflammation in CF and that new therapeutic avenues, that aim to target the mito-inflammation, can improve CF patient’s inflammatory state.

Up to date, in addition to systemic corticosteroids and azithromycin, between non-steroidal anti-inflammatory drugs (NSAIDs) only ibuprofen at high doses (serum concentration higher than 50 micrograms per millilitre), has been recommended to prevent the loss of lung function.

International Guidelines (Flume PA, 2007), had suggested that ibuprofen had to be prescribed in individuals with FEV1 greater than 60% predicted, even if, more recently, an international committee (Mogayzel PJ, 2013) has narrowed the previous recommendation to include only children 6–17 years of age, because of the insufficient information about adult population and has stressed the necessity to maintain the ibuprofen serum concentration of 50–100 mg/m, because of neutrophil migration increases, rather than decreases, at lower serum levels.

In 2018 (Konstan MW,2018) an association was observed between high-dose ibuprofen use and both slower lung function decline and improved long-term survival, in a study about 775 high-dose ibuprofen users and 3,665 non-users CF children. In the same year (Shah PN, 2018) it has been demonstrated that, in vitro, ibuprofen is effctive  in reducing the growth rate and bacterial burden of P.a. and B.cepacia.

The necessity to study efficacy and safety of  antinflammatory new drugs has been, far back, discussed (Banner KH, 2009), revised three years later (Rowe SM, 2012) and in 2015 (Cantin A, 2015), (Sagel SD, 2015). In particular, on the basis of the results about the LTB4 receptor antagonist use in CF (Konstan MW, 2014), it has been speculated that the administration of potent anti-inflammatory compounds to individuals with chronic infections, may increase the risk of infection-related adverse events, because of the potential to significantly suppress the inflammatory response.

Recently, ( Consalvi S, 2021)  a review has discussed the rational for further studies of COX-2 inhibitors -NO releaser hybrids ( NO-Coxibus), already studied compounds for the tratment of arthitis.   for the treatment of airway inflammation in CF.

The Cystic Fibrosis Foundation, in early 2014, established a working group to address antiinflammatory drug development in CF. It has been suggested that, before bringing new antiinflammatory drugs to clinical trial, preclinical safety studies must be conducted in disease-relevant models, to assuage safety concerns and that pharmacokinetic-pharmacodynamic studies and early-phase safety studies have to be performed before proceeding to larger studies of longer duration (Torphy TJ, 2015).

In the 2021   CFF drug development Pipeline, besides Ibuprofene, three compounds are taken into consideration regarding anti-inflammatory therapy:

  • 1 in phase two: a form of the retinoid fenretinide (LAU-7b).
  • 2 in phase one: a compound designed to block the function of neutrophil elastase (POL 6014) and CB-280 an oral drug designed to increase in the lung, the amount of arginina for the production of nitric oxide (NO), that is a important factor to reduce inflammation.

Issues

  • NSAIDs efficacy in preventing pulmonary deterioration, evaluated in terms of lung function evolution, lung infection exacerbation frequency, quality of life and survival.
  • Short-term and long-term NSAIDs therapy-associated adverse events (above all increase of pulmonary infective exacerbations, haemorrhagic episodes, gastrointestinal symptoms, allergic reactions, fluid retention, kidney and liver problems).
  • Useful markers of inflammatory status.

What is known

 

One CDSR  (Lands LC, 2016), updated 2019 (Lands LC, 2019) included four trials and 287 participants aged five to 39 years and maximum follow up four years: three trials compared ibuprofen to placebo and one trial assessed piroxicam versus placebo. Combined data from the two largest ibuprofen trials showed a significantly lower annual rate of decline for lung function in the ibuprofen group in younger children. In one trial, long-term use of high-dose ibuprofen was associated with reduced intravenous antibiotic use, improved nutritional and radiological pulmonary status. No major adverse effects were reported. In the trial comparing piroxicam to placebo, no data were available to show difference between the groups.

One RCT published in 2012 (Elborn S,2012) evaluated the safety and the efficacy of the neutrophil elastase inhibitor AZD9668 on clinical outcomes, inflammation biomarkers and tissue damage. In the AZD9668 group, there was a trend towards reduction in sputum inflammatory biomarkers (interleukin-6, RANTES, and urinary desmosine).

One phase II RCT published in 2013 (Nahrlich L, 2013) studied the sphingomyelinase inhibitor acid Amitriptyline, which showed, to be safe and to be able to increases FEV1 and reduces ceramide in lung cells

In 2016 ( Adams C, 2016) an RCT showed that Amitriptyline significantly increases FEV1, reduces ceramide in lung cells and increases weight in patients treated with 25mg amitriptyline twice daily and observed after one, two and three years after continuous use of the drug.

In 2015 (Chmiel JF, 2015) it has been published an open-label, controlled trial to assess IL-6, IL-8, TNF-α, IL-1-β, free neutrophil elastase, and white cell counts, in patients randomized to high dose of ibuprofen or to routine care. IL-6 was the only biomarker with significant within-group change among ibuprofen-treated subjects and no change in the control group.

In 2016 (Gaggar A,2016)  a RCT has studied the safety of therapy with Inhaled alpha1-proteinase inhibitor prescribed once daily for 3 weeks in 30 CF adults and has showed that it is safe and well tolerated.

One RCT published in 2018 (Jain R, 2018) showed that KB001-A, an anti-PcrV PEGylated monoclonal antibody fragment to the Type III secretion system of P.aeruginosa, is  safe,  well-tolerated and associated with a modest FEV1 benefit and reduction in select sputum inflammatory markers.

 

In 2021 (Elborn, S, 2021) A phase 2 RCT of leukotriene A4 hydrolase inhibitor (Acebilustat) in adult subjects with CF (Empire -CF study) showed that Acebilustat did not improve lung function, even if a trend towards reduced pulmonary exacerbations in subjects with an earlier stage of lung disease suggests a potential effect in this population.

 

UNRESOLVED QUESTIONS

  • Efficacy and safety of the new antinfiammatory drugs.
  • Efficacy and safety of ibuprofen therapy for a prolonged period of time, mainly in children, also in pre-symptomatic ones.

Several RCT are ongoing:

A Phase 2 RCT to evaluate the efficacy, safety, and tolerability of CTX-4430 (ACEBILUSTAT), an oral anti-inflammatory drug that reduces production of Leukotriene B4 (LTB4), administered orally once-daily for 48 weeks in Adults. (NCT02443688)

A Phase 2, Muticenter RCT to evaluate efficacy and safety of Lenabasum 5 mg vs placebo CF patients older than 12 years of age (NCT03451045)

A Phase 2 RCT Study about  Efficacy and Safety of LAU-7b in the Treatment of Cystic Fibrosis in Adults -  (NCT03265288)

A Phase IIa, RCT to evaluate safety and efficacy of subcutaneous administration of Anakinra in Patients With Cystic Fibrosis who are ≥ 12 years of age  (NCT03925194)

An open label study to investigate if Losartan as anti-infiammatory therapy is able to  augment CFTR rescue in CF Patients (NCT03435939)

An retrospective observational study to evaluate Anti-IL5 and Other Biotherapies efficacy in French CF Centers (NCT04256772)

A Phase Ib, Randomised, Double-blind, Placebo-controlled study to Investigate the safety, tolerability and pharmacokinetics of inhaled CHF 6333 (NCT04010799)

A Phase 3 RCT about prednisone in CF pulmonary exacerbations (NCT03070522)

Unresolved questions

  • Efficacy and safety of the new antinfiammatory drugs.
  • Efficacy and safety of ibuprofen therapy for a prolonged period of time, mainly in children, also in pre-symptomatic ones.

Several RCT are ongoing:

A Phase 2 RCT to evaluate the efficacy, safety, and tolerability of CTX-4430 (ACEBILUSTAT), an oral anti-inflammatory drug that reduces production of Leukotriene B4 (LTB4), administered orally once-daily for 48 weeks in Adults. (NCT02443688)

A Phase 2, Muticenter RCT to evaluate efficacy and safety of Lenabasum 5 mg vs placebo CF patients older than 12 years of age (NCT03451045)

A Phase 2 RCT Study about  Efficacy and Safety of LAU-7b in the Treatment of Cystic Fibrosis in Adults -  (NCT03265288)

A Phase IIa, RCT to evaluate safety and efficacy of subcutaneous administration of Anakinra in Patients With Cystic Fibrosis who are ≥ 12 years of age  (NCT03925194)

An open label study to investigate if Losartan as anti-infiammatory therapy is able to  augment CFTR rescue in CF Patients (NCT03435939)

An retrospective observational study to evaluate Anti-IL5 and Other Biotherapies efficacy in French CF Centers (NCT04256772)

A Phase Ib, Randomised, Double-blind, Placebo-controlled study to Investigate the safety, tolerability and pharmacokinetics of inhaled CHF 6333 (NCT04010799)

A Phase 3 RCT about prednisone in CF pulmonary exacerbations (NCT03070522)

 

 

Keywords: Anti-Inflammatory Agents; Leukotriene antagonists;