CHMP issues positive opinion for JASCAYD® (nerandomilast), bringing a new IPF and PPF therapy closer to patients in the EU

CHMP Recommends JASCAYD® for IPF and PPF in EU

Boehringer Ingelheim's JASCAYD® (nerandomilast) has received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency for marketing authorization in the European Union. This recommendation is for the treatment of adults with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). The positive opinion is supported by results from the Phase III FIBRONEER™ program, which demonstrated that nerandomilast slowed lung function decline, measured by absolute change in forced vital capacity (FVC) from baseline to week 52, compared to placebo. The drug also exhibited a favorable safety and tolerability profile, with no requirement for liver monitoring and discontinuation rates similar to placebo, marking a crucial step towards a new IPF treatment in Europe.

• The Phase III FIBRONEER™ program, encompassing FIBRONEER™-IPF and FIBRONEER™-ILD trials, successfully met its primary endpoint, showing that nerandomilast slowed the decline in lung function, as measured by absolute change in forced vital capacity (FVC) from baseline to week 52. Although key secondary endpoints were not met, a numerical reduction in mortality was observed across both trials, achieving nominal significance in FIBRONEER™-ILD.
• JASCAYD® (nerandomilast) is poised to become the first new treatment option for IPF in Europe in over a decade, addressing a significant unmet medical need. It is also the first and only oral, preferential PDE4B inhibitor authorized for use in IPF and PPF in the U.S., China, the UAE, and Japan, offering a new mechanism of action and a well-tolerated profile for these life-threatening lung conditions.
• IPF and PPF are progressive conditions affecting over 500,000 people in the EU, characterized by irreversible lung scarring and a prognosis worse than many cancers. Current treatments often have limitations due to side effects, leading to delayed or discontinued therapy. Nerandomilast's favorable safety and tolerability, combined with its efficacy in slowing lung function decline, offer hope for sustained treatment and improved quality of life for patients.

Addressing the High Unmet Need in IPF and PPF

Current treatment approaches for IPF and PPF face substantial limitations that leave patients with significant unmet medical needs. Only two antifibrotic medications are approved for IPF treatment, and these primarily slow disease progression rather than provide curative benefit. The complex and incompletely understood pathogenesis of pulmonary fibrosis further complicates therapeutic development efforts.

• Limited therapeutic arsenal - Only two approved medications exist (nintedanib and pirfenidone) with significant side effects, high costs, and the need for careful patient monitoring, while lung transplantation remains the only curative option

• Ineffective traditional therapies - Conventional approaches including corticosteroids and immunomodulatory drugs are often ineffective and associated with notable adverse effects, with IPF showing no response to immunosuppressive therapies

• Delayed diagnosis and treatment initiation - Patients experience diagnostic delays ranging from 0.8 to 2.0 years after symptom onset, undergo 7-10 clinical tests before diagnosis, and face additional delays before treatment initiation

• Poor disease progression outcomes - Despite available antifibrotic therapies, IPF remains a progressive disease with median survival of 3-5 years from diagnosis and 12-month hospitalization rates ranging from 24% to 64% across different countries

• Inadequate treatment satisfaction - Only 50% of patients with moderate to severe IPF report satisfaction with their current treatment, despite antifibrotic use increasing from 57% to 69% between 2016 and 2019

• Significant quality of life burden - Patients report low quality of life scores (mean EQ-5D visual analogue scale: 61.7/100) and experience considerable stress, symptom burden, and inadequate preparedness for end-of-life care planning

• Knowledge and care gaps - Limited attention has been paid to patient experiences, unmet needs, and quality of life considerations, while patients and caregivers lack adequate knowledge about disease management and self-care strategies

FIBRONEER™ Program: Efficacy and Safety of Nerandomilast

Recent clinical studies in IPF and PPF have demonstrated varied therapeutic approaches with distinct safety and efficacy profiles. The evidence spans comparative analyses of established antifibrotics, novel PDE4 inhibitors, and emerging biomarker-guided therapies across different patient populations.

Nerandomilast's Potential to Reshape IPF/PPF Treatment

Current standard-of-care antifibrotic treatments, pirfenidone and nintedanib, represent significant advances in IPF management but demonstrate important limitations that drive continued therapeutic development. Both FDA-approved agents effectively slow disease progression by reducing forced vital capacity (FVC) decline and decreasing the risk of ≥10% FVC deterioration over 12 months. Nintedanib demonstrates superior protection against acute exacerbations and shows better preservation of diffusion capacity for carbon monoxide compared to pirfenidone. However, neither agent reverses fibrosis or provides substantial survival benefits, with antifibrotic treatment yielding a pooled relative risk for all-cause mortality of 0.55. Treatment response varies significantly among patients, and adverse effects frequently necessitate discontinuation in clinical practice, highlighting the need for more effective therapeutic alternatives.

Investigational therapies currently under development target diverse pathophysiological mechanisms beyond the antifibrotic pathways addressed by current treatments. Thirty experimental agents with unique mechanisms of action are being evaluated, including approaches that inhibit nuclear factor κ-B transcription, reduce metalloproteinase 7 expression, block transforming growth factor β effects, and decrease reactive oxygen species. Notable candidates include GDC-3280, an orally available small molecule designed to improve upon pirfenidone's activity, which demonstrated acceptable safety and pharmacokinetic profiles in phase 1 trials. Additionally, novel molecular targets identified through genome-wide association studies, including semaphorin 7A, connective tissue growth factor, integrin αvβ6, and calcium-activated potassium channels, offer promising therapeutic avenues for modulating IPF pathophysiology.

The therapeutic landscape suggests a fundamental shift from the current paradigm of slowing fibrotic progression toward potentially arresting or reversing the disease process. Investigational agents are anticipated to provide more favorable adverse effect profiles compared to current treatments, which commonly cause gastrointestinal and skin-related side effects that limit tolerability. Experimental compounds such as the STAT3 inhibitor 10K have demonstrated efficacy comparable to nintedanib in preclinical models while targeting epithelial-mesenchymal transition pathways. These developments, combined with novel drug delivery approaches including nanoparticle formulations that enhance pulmonary targeting and reduce systemic toxicity, represent the next generation of IPF therapeutics designed to address the substantial unmet medical need in this devastating disease.

Expanding the Potential of Nerandomilast Beyond IPF/PPF

Nerandomilast is being investigated for systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD), representing an expansion beyond its core IPF and PPF development programs. SARD-ILD comprises a heterogeneous group of fibrosing lung disorders frequently complicated by progressive pulmonary fibrosis and associated with accelerated lung function decline and increased mortality.

• Primary indication beyond IPF/PPF: Systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD), where nerandomilast represents a promising investigational strategy bridging antifibrotic and immunomodulatory mechanisms

• Evidence basis: Subgroup analyses from progressive pulmonary fibrosis populations have suggested potential benefit in autoimmune-related diseases, although evidence remains limited and warrants further dedicated studies in SARD-ILD

• Safety considerations: The safety profile appears mainly characterized by gastrointestinal adverse events, with ongoing evaluation of neuropsychiatric safety and drug interactions in complex autoimmune populations

• Intervention model limitations: No specific intervention models for autoimmune ILD trials are explicitly described in the available literature, indicating that formal clinical trial designs for these indications may still be in development stages

A New Era for Fibrotic Lung Disease Treatment

The European Medicines Agency's CHMP positive opinion for nerandomilast marks a significant moment for patients battling idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). These conditions, characterized by relentless lung function decline and a poor prognosis, have long presented a substantial unmet medical need. While existing antifibrotic therapies like pirfenidone and nintedanib have offered some benefit by slowing disease progression, they often come with tolerability challenges that can impact patient adherence and quality of life.

Nerandomilast, a preferential phosphodiesterase 4B (PDE4B) inhibitor, introduces a novel therapeutic approach. Its mechanism of action, which involves elevating intracellular cyclic adenosine monophosphate (cAMP), allows it to exert both anti-inflammatory and antifibrotic effects. This dual action is crucial, as it addresses multiple facets of these complex diseases, including fibroblast activation, inflammatory signaling, and vascular dysfunction. Clinical data from the FIBRONEER™ program demonstrated a significant reduction in the rate of FVC decline, a critical measure of lung function, with a safety profile that appears more favorable than some current options, notably without requiring liver monitoring and with low discontinuation rates.

However, the journey ahead is not without considerations. While FVC decline was significantly slowed, the FIBRONEER-IPF trial did not show a statistically significant impact on composite endpoints like acute exacerbations, hospitalizations, or death, although a numerically lower risk of death was observed with the higher dose. Furthermore, the market is already served by established therapies, and shifting prescribing patterns, which can be influenced by various factors, will be a key challenge. Diarrhea, a common adverse event, while generally mild, will require careful management to ensure patient adherence.

Ultimately, nerandomilast represents a pivotal step towards a new generation of antifibrotic therapies. Its unique mechanism and improved tolerability profile offer a promising new option, potentially enabling more patients to receive and remain on effective treatment. This development also underscores a broader shift towards a precision medicine approach in interstitial lung diseases, where targeting specific pathways like PDE4B inhibition can lead to more tailored and effective patient care.