Potential of phosphodiesterase 4B inhibition in the treatment of progressive pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is often regarded as the archetypal progressive fibrosing interstitial lung disease (ILD). The term “progressive pulmonary fibrosis” (PPF) generally describes progressive lung fibrosis in an individual with an ILD other than IPF. Both IPF and PPF are associated with loss of lung function, worsening dyspnea and quality of life, and premature death. Current treatments slow the decline in lung function but have side effects that may deter the initiation or continuation of treatment. There remains a high unmet need for additional therapies that can be used alone or in combination with current therapies to preserve lung function in patients with IPF and PPF. Phosphodiesterase-4 (PDE4) is an enzyme involved in the regulation of inflammatory processes. Pre-clinical studies have shown that preferential inhibition of PDE4B has anti-inflammatory and antifibrotic effects and a lower potential for gastrointestinal adverse events than pan-PDE4 inhibition. The preferential PDE4B inhibitor nerandomilast demonstrated efficacy in preserving lung function in a phase II trial in patients with IPF and is under investigation in phase III trials as a treatment for IPF and PPF.

Plain language summary

Potential of phosphodiesterase 4B inhibition in the treatment of progressive pulmonary fibrosis

Progressive (worsening) lung fibrosis leads to loss of lung function and premature death. The drugs currently used to treat progressive lung fibrosis slow down loss of lung function, but lung function continues to worsen. In addition, these drugs have side-effects such as diarrhoea, which mean that some patients are unable to keep taking them.

Phosphodiesterase-4B (PDE4B) is an enzyme that is involved in pathways that lead to inflammation and fibrosis (scarring) of the lungs. Reducing the activity of PDE4B is being investigated as a way to slow down the progression of lung fibrosis.

Nerandomilast is a drug that reduces the activity of PDE4B. Clinical trials are comparing changes in lung function over a year in patients with progressive lung fibrosis who are given nerandomilast or a placebo (dummy). The results of these trials will be announced in the first half of 2025.

Introduction

Interstitial lung diseases (ILDs) comprise a diverse group of diseases characterized by inflammation and/or fibrosis of the lung parenchyma. Some ILDs are idiopathic, while others have a known cause, such as an autoimmune disease or environmental exposure. ¹ The pathophysiology of lung fibrosis is thought to involve an aberrant response to epithelial injury in the lungs. Immune cells such as neutrophils and macrophages migrate to the site of injury. The release of pro-inflammatory and pro-fibrotic mediators promotes the proliferation of fibroblasts and their differentiation into myofibroblasts, which deposit excess extracellular matrix in the alveolar space.^2,3 Progression of lung fibrosis shows commonalities in pathogenic processes irrespective of the initial injury and becomes self-sustaining.^4,5 The term “progressive pulmonary fibrosis” or “PPF” generally describes progressive lung fibrosis in individuals with an ILD other than idiopathic pulmonary fibrosis (IPF), which is often regarded as the archetypal progressive fibrosing ILD. ⁶

While PPF has been defined in various ways,^{6 –9} IPF and PPF are known to be associated with worsening of radiological abnormalities, decline in lung function, worsening of health-related quality of life, and premature death.^{10 –13} Decline in lung function in patients with PPF may be as rapid as in patients with IPF (Figure 1). ¹⁴ Therapies are available that slow the loss of lung function in patients with IPF/PPF, but these do not stop the progression of lung fibrosis and are associated with adverse events that deter initiation or continuation of treatment.^7,15,16 New treatments are needed that preserve, or ideally improve, lung function and provide better outcomes for patients with IPF/PPF. A promising therapeutic target under investigation is phosphodiesterase (PDE) 4B inhibition. In this article, we review the potential of PDE4B inhibition in the treatment of PPF.

Figure 1.

Observed change in FVC over 52 weeks in the placebo groups of the INPULSIS trials in patients with IPF and the INBUILD trial in patients with PPF. ¹⁴

The burden of pulmonary fibrosis

The rate and pattern of lung function decline in patients with IPF and PPF are variable.^{11,17 –20} Decline in forced vital capacity (FVC) has been identified as an independent predictor of mortality in patients with several ILDs.^17,18,21 Although several risk factors for the progression of fibrotic ILD have been identified, including male sex, lower FVC, and a greater extent of fibrosis on high-resolution computed tomography (HRCT),^{10,22 –25} the course of disease progression for an individual remains difficult to predict. The presence of a usual interstitial pneumonia pattern on HRCT or histology has been associated with progressive disease and worse outcomes; however, other fibrotic patterns, such as hypersensitivity pneumonitis (HP) and nonspecific interstitial pneumonia may also develop PPF.^{11,25 –28}

IPF and PPF are frequently associated with symptoms such as cough, dyspnea, and fatigue, which impair physical activity, deter social participation, and have a negative impact on patients’ health-related quality of life and emotional well-being.^{29 –32} Work productivity may also be affected: among 148 employed patients with fibrotic ILD in a Canadian registry, productivity loss was reported by 55% of patients. ³³ Use of supplemental oxygen can improve symptoms, but limits physical and social activities and is associated with marked impairment in quality of life.^29,34

IPF and PPF are associated with high mortality^{12,35 –37} (Figure 2). Recent data suggest that median survival following a diagnosis of IPF is approximately 4–5 years.^{38 –40} Sudden acute deteriorations in lung function, known as acute exacerbations, occur in some patients with IPF/PPF and are a major cause of morbidity and mortality, particularly in patients with IPF.^37,41,42 In a Japanese study of 462 patients with IPF, the estimated 90-day mortality after an acute exacerbation was 47%. ⁴² In the INBUILD trial in patients with PPF, the estimated risk of death in the 180 days after an acute exacerbation was 37%. ⁴³

Figure 2.

Transplant-free survival in patients with PPF according to criteria used to define PPF in Austin Health ILD Registry and Canadian Registry for Pulmonary Fibrosis. ¹²

IPF and PPF place a considerable burden on healthcare resources,^{44 –46} largely due to high rates of hospitalization.^47,48 Among 1001 patients with IPF enrolled in the IPF-PRO Registry, 56.7% had at least one hospitalization over a median follow-up of 23.7 months. ⁴⁷ A study of US claims data showed that over 12 months of follow-up, 40.7% of patients with progressive fibrosing ILDs had an inpatient visit. ⁴⁵ Healthcare resource use and costs are markedly higher in patients with progressive disease than in patients with fibrosing ILD that has not yet become progressive.^45,46

Unmet needs in the management of fibrotic ILDs

The antifibrotic drugs nintedanib and pirfenidone are licensed for the treatment of IPF in many countries^49,50 and are regarded as the standard of care. ⁵¹ However, many patients with IPF remain untreated^{52 –54} or discontinue antifibrotic therapy due to adverse events, most frequently diarrhea.^15,16,55,56 Lung function and quality of life continue to decline even in patients receiving approved therapies.^57,58

Most patients with ILD associated with autoimmune disease receive immunosuppressive therapy, which may slow the progression of ILD.^{59 –63} Nintedanib has been demonstrated to slow the progression of ILD associated with systemic sclerosis ⁶⁴ and progressive fibrosing ILDs associated with autoimmune disease ⁶⁵ and is licensed for these indications. Tocilizumab, an antibody of the interleukin-6 receptor, has been approved by the FDA for slowing the decline in lung function in patients with ILD associated with systemic sclerosis. ⁶⁶ While recommendations for the treatment of ILD associated with autoimmune disease have been issued by the American College of Rheumatology and American Thoracic Society,^67,68 these did not provide treatment algorithms and there is no consensus on when treatment should be initiated, or on which therapies should be used.

Patients with HP also commonly receive immunosuppressants, but the evidence supporting the benefit of immunosuppression is weak.^{69 –72} Close monitoring without treatment may be appropriate for patients with non-fibrotic HP if the inciting antigen has been removed. ⁷³ If fibrosis is present, immunosuppressive or antifibrotic therapy should be considered. Nintedanib is licensed for the treatment of chronic fibrosing ILDs with a progressive phenotype, including fibrosing HP.

Lung transplantation can improve the quality of life and survival in patients with IPF and PPF.^74,75 However, lung transplantation is only a viable option for a minority of patients with IPF/PPF. Factors such as age, comorbidities, overall health, and psychosocial factors may mean that a transplant is not appropriate for an individual. ⁸⁰ Socioeconomic and geographic factors may also impact the likelihood of receiving a lung transplant.^76,77

There remains a high unmet need for additional therapies that can be used alone or in combination with current treatments to preserve lung function, improve health-related quality of life, and extend life in patients with IPF or PPF, with a side-effect profile that does not deter treatment.

PDE4 inhibition

PDEs regulate intracellular signaling by mediating the breakdown of cyclic nucleotides such as cyclic adenosine monophosphate (cAMP). ⁷⁸ PDE4 is a cAMP-specific PDE with four subtypes (A to D) that is involved in the regulation of inflammatory progress.^79,80 As such, PDE4 inhibitors are utilized in the treatment of inflammatory diseases: roflumilast for reducing exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis ⁸¹ and for plaque psoriasis and atopic dermatitis ⁸² ; apremilast for psoriatic arthritis, plaque psoriasis and oral ulcers associated with Behçet’s disease ⁸³ ; and crisaborole for atopic dermatitis. ⁸⁴

Nerandomilast

The PDE4B subtype is widely distributed, including in immune cells and in lung tissue. ⁸⁵ Interest in preferential inhibitors of the PDE4B subtype in the treatment of pulmonary fibrosis was generated by pre-clinical data showing that PDE4B inhibitors have anti-inflammatory and antifibrotic effects (Figure 3) and a lower potential for gastrointestinal adverse events such as emesis than pan-PDE4 inhibitors. ⁸⁶

Figure 3.

Mechanism of action of phosphodiesterase 4B inhibition in the treatment of IPF and PPF.

Nerandomilast (formerly known as BI 1015550) is an orally administered preferential PDE4B inhibitor.^85,86 Nerandomilast has shown both anti-inflammatory and antifibrotic effects in models of lung fibrosis. In a mouse model, nerandomilast inhibited lipopolysaccharide-induced release of tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, while in the Suncus murinus (shrew) model, nerandomilast inhibited lipopolysaccharide-induced influx of neutrophils into bronchoalveolar lavage fluid. ⁸⁶ Nerandomilast has also been shown to inhibit the proliferation of primary lung fibroblasts from patients with IPF, the transformation of fibroblasts into myofibroblasts when stimulated by transforming growth factor-β1, and the expression of genes encoding extracellular matrix proteins. ⁸⁶ In a rat model of pulmonary fibrosis, nerandomilast increased lung volume and reduced lung tissue density. ⁸⁷

Phase I studies showed a dose-proportional increase in exposure to nerandomilast. After five administrations of 18 mg twice daily, 95% of the steady-state concentration was reached. ⁸⁸ The efficacy and safety of nerandomilast 18 mg bid were investigated in a 12-week, placebo-controlled phase II trial in patients with IPF. ⁸⁹ The results showed that nerandomilast stabilized lung function, both in patients who were and were not receiving background antifibrotic therapy (nintedanib or pirfenidone) (Figure 4). ⁸⁹ A post hoc analysis of this trial suggested that there was an additive effect of nerandomilast plus nintedanib, as the adjusted mean change in FVC at week 12 in patients who received nerandomilast was 6.1 mL in patients not taking background antifibrotic therapy versus 23.4 mL in patients taking background nintedanib. ⁹⁰ The most frequent adverse event was diarrhea, which was reported in 31% of patients receiving nerandomilast and 16% of patients receiving placebo in the subgroup taking background antifibrotic therapy, and in 17% of patients receiving nerandomilast and 8% of patients receiving placebo in the subgroup without background antifibrotic therapy. ⁸⁹

Figure 4.

Change in FVC (mL) over 12 weeks in the phase II trial of nerandomilast in patients with IPF. ⁸⁹

The phase III FIBRONEER-IPF trial ⁹¹ investigated 9 and 18 mg bid doses of nerandomilast versus placebo in 1177 patients with IPF. The primary endpoint was the change from baseline in FVC (mL) at week 52. In September 2024, it was announced that this trial was positive and the publication of the results is eagerly awaited. The results of the phase III FIBRONEER-ILD trial ⁹² conducted in 1178 patients with PPF will also report results in the first half of 2025.

Conclusion

IPF and PPF are associated with loss of lung function, worsening of symptoms and quality of life, and premature death. There remains a need for more efficacious and better-tolerated treatments that can be used alone or in combination with existing drugs to preserve lung function and improve outcomes for patients with IPF/PPF. Inhibition of PDE4B has anti-inflammatory and antifibrotic effects and has the potential to slow the progression of IPF/PPF with better tolerability than existing therapies. The preferential PDE4B inhibitor nerandomilast is under investigation in phase III trials.