Pulmonary fibrosis remains a disease with a high unmet medical need despite modern antifibrotic drugs.

The approved standard therapies nintedanib and pirfenidone can slow the loss of lung function, but they generally cannot stop fibrosis or structurally reverse it.

At the ANOVA Institute for Regenerative Medicine in Offenbach/Main, a novel, experimental combined therapy approach is now being pursued. As Germany’s first institution with a manufacturing authorization for mesenchymal stem cell secretome, ANOVA has a unique starting position: a cell-free, biologically active regenerative approach can be combined with established antifibrotic and senolytic mechanisms. The intended goal is not only to slow fibrosis progression, but to biologically reprogram the fibrotic environment of the lung.

The proposed approach combines three complementary mechanisms of action:

Nintedanib, pirfenidone — and, prospectively, nerandomilast — address central pro-fibrotic signaling pathways and reduce the annual loss of FVC. Nerandomilast, a selective PDE4B inhibitor, was approved in the United States in 2025 for IPF; according to the FDA, this was the first new IPF therapy in more than ten years.

The inhaled aerosol potentially delivers bioactive factors, extracellular vesicles, miRNAs, and immunomodulatory signals directly to the site of pathology: the alveolar epithelium, interstitial fibroblasts, macrophages, and the disrupted epithelial-mesenchymal niche. Early external experimental clinical data from small studies using nebulized hUCMSC-EVs in pulmonary fibrosis indicate safety and possible efficacy, but remain exploratory.

Senescent cells are considered drivers of chronic inflammation, SASP signaling, fibroblast activation, and impaired tissue repair. The combination of dasatinib and quercetin has already been investigated in IPF in a phase I pilot study; it was feasible and provided early signals, but is not approved as an IPF therapy.

The hypothesis: the antifibrotic drug stops the progression of pulmonary fibrosis, senolytics remove pathological signaling drivers, and the mesenchymal stem cell secretome supports repair and immunomodulation. The inhaled application of the secretome is strategically attractive in particular: high local exposure, direct access to lung tissue, a small compartment with a high dose, and avoidance of degradation in the blood.

The preferred development path would be an add-on design based on approved standard therapy, such as nintedanib or pirfenidone, with a sequential or cyclic senolytic regimen and accompanying inhaled secretome administration.

To rule out side effects, the therapy is performed during a short inpatient stay. During this time, liver toxicity, bleeding risk, pleural effusions, pulmonary hypertension, susceptibility to infection, and pharmacokinetic interactions are monitored. Dasatinib is an oncological tyrosine kinase inhibitor with relevant risks, while nintedanib also carries liver and bleeding risks.

The clinical vision is a multimodal, locally enhanced, biologically rational combination approach for patients with IPF or progressive pulmonary fibrosis: standard of care plus targeted senescence elimination plus inhaled regenerative secretome — with the ambition to move from merely slowing progression toward disease modification.

At the ANOVA Institute for Regenerative Medicine, we have relied for many years on progress through experimental translational medicine. We are among the pioneers of stem cell therapy in Europe and pursue a wide range of regenerative medicine approaches. For us, innovative therapeutic approaches are not a threat — but a fascinating world of new possibilities for our patients.

If you suffer from pulmonary fibrosis and are seeking access to an advanced, personalized therapy, talk to us. It is a small step that could change your life.

Pulmonary fibrosis is rare, but devastating. Idiopathic pulmonary fibrosis alone is estimated to affect around 3 million people worldwide; in the United States, more than 250,000 people live with pulmonary fibrosis or interstitial lung disease. For Germany, insurance data on IPF show a point prevalence of approximately 24 per 100,000 inhabitants, corresponding roughly to around 20,000 IPF patients — in addition to other forms of progressive pulmonary fibrosis.

Pulmonary fibrosis is rare, but devastating. Idiopathic pulmonary fibrosis alone is estimated to affect around 3 million people worldwide; in the United States, more than 250,000 people live with pulmonary fibrosis or interstitial lung disease. For Germany, insurance data on IPF show a point prevalence of approximately 24 per 100,000 inhabitants, corresponding roughly to around 20,000 IPF patients — in addition to other forms of progressive pulmonary fibrosis.

The disease has also become known to a broader public since Crown Princess Mette-Marit of Norway was diagnosed with chronic pulmonary fibrosis in 2018. According to reports citing the Norwegian royal family, her condition has deteriorated; a lung transplant is, or was, being prepared.

For patients in the end stage, lung transplantation often remains the only life-prolonging option. Interstitial lung diseases, including pulmonary fibrosis, are among the most important indications for lung transplantation worldwide. Nevertheless, only a small proportion of patients are eligible because age, comorbidities, organ shortage, and disease dynamics greatly limit patient selection. A German analysis reported that after the introduction of the Lung Allocation Score, IPF accounted for a significantly larger share of the transplanted high-urgency group — approximately 27% in category D.

Transplantation can be lifesaving, but it is highly risky: it is a major procedure involving lifelong immunosuppression, infection risk, rejection reactions, chronic graft dysfunction, and a limited long-term prognosis. Recent reviews cite an overall median survival of around 6.2 years for lung transplant recipients, and approximately 5.2 years for interstitial lung diseases. This is precisely why there is an urgent need for therapies that intervene earlier, slow progression, protect tissue, and help delay or ideally avoid transplantation.

Idiopathic pulmonary fibrosis and other progressive fibrosing interstitial lung diseases are characterized by a misguided repair response of lung tissue. Repeated microscopic injuries to the alveolar epithelium lead to epithelial dysfunction, activation of fibroblasts and myofibroblasts, excessive extracellular matrix deposition, loss of architecture, and increasing impairment of gas exchange. Clinically, this results in progressive dyspnea, cough, exercise intolerance, exacerbations, and reduced survival.

Current guidelines for IPF and progressive pulmonary fibrosis are based on antifibrotic therapies. The 2022 ATS/ERS/JRS/ALAT guideline addresses IPF and PPF together and gives a conditional recommendation for nintedanib in PPF; for pirfenidone in PPF, further research was recommended. In Europe, Ofev/nintedanib is approved for adults with IPF and for other chronic fibrosing ILDs with a progressive phenotype; Esbriet/pirfenidone is approved for adult patients with IPF.

Despite these advances, the therapeutic effect remains limited: antifibrotics slow FVC decline, but typically do not lead to robust regeneration of destroyed alveolar structures. A modern development approach should therefore not merely inhibit a single pro-fibrotic signaling pathway, but address multiple pathobiological levels: fibroblast activation, senescent cell populations, inflammatory dysregulation, epithelial repair, and the local tissue microenvironment.

The proposed combination is biologically plausible because the three components address different but complementary levels of fibrosis.

Nintedanib inhibits several tyrosine kinases, including signaling axes mediated by VEGF, FGF, and PDGF receptors, which are involved in fibroblast proliferation, migration, myofibroblast differentiation, and matrix production. It is therefore particularly suitable as a basic therapy in IPF and progressive fibrosing ILD. The EMA product information lists 150 mg twice daily as the recommended dose, with 100 mg twice daily as an option in cases of intolerance.
Pirfenidone has antifibrotic and anti-inflammatory effects, including through modulation of TGF-β-associated mechanisms, collagen synthesis, and oxidative stress. It is approved in Europe for adult patients with IPF.
Nerandomilast is the most recent relevant development. The selective PDE4B inhibitor showed a smaller decline in FVC compared with placebo in phase III data and was approved by the FDA in October 2025 for adult patients with IPF; the FDA approval lists 18 mg twice daily. For a German or European concept, however, the regulatory status must be carefully checked. The EMA orphan designation for nerandomilast in IPF was withdrawn from the EU register in 2025 at the sponsor’s request, which is not equivalent to EU approval.
For a German development program that can be implemented in the short term, nintedanib would therefore be the most robust combination anchor, especially in progressive fibrosing ILDs. Pirfenidone would be an alternative in IPF. Nerandomilast is scientifically highly interesting, but for an EU/Germany concept it should currently be regarded more as a prospective option or international reference.

In many preclinical models, mesenchymal stromal/stem cells appear to act less through permanent cell integration and more through paracrine signaling. The therapeutically relevant principle lies in the secretome: soluble growth factors, cytokines, chemokines, lipids, proteins, mRNA/miRNA, and extracellular vesicles. A cell-free secretome could theoretically offer several advantages over living cells: better standardization, lower risk of uncontrolled cell persistence, better storability, measurable biological activity, and improved regulatory characterization.

For pulmonary fibrosis, inhaled administration is particularly attractive. While systemic cell or vesicle therapies depend on biodistribution, pulmonary first-pass effects, and immunological clearance, an aerosol allows direct deposition in the target organ. Pathophysiologically relevant target structures include type I/II alveolar epithelium, activated interstitial fibroblasts, alveolar macrophages, endothelial cells, and the extracellular matrix niche. The central hypothesis is that local secretome can modulate the inflammatory and pro-fibrotic microenvironment, reduce epithelial stress, influence macrophage polarization, and promote repair programs.

A clinical study published in 2025 on nebulized human umbilical cord MSC-EVs reported early indications of safety and possible clinical activity in pulmonary fibrosis; two patients with advanced post-inflammatory fibrosis showed clinically relevant regression in serial CT examinations. These data are promising but exploratory and not sufficient to regard efficacy as proven. Reviews on MSC-EVs continue to emphasize preclinical support, but also major open questions regarding dosing, potency assays, long-term safety, manufacturability, and clinical translation.

For ANOVA, the manufacturing authorization is a strategic advantage because the translation of such biological products depends substantially on GMP-related process control: cell source, culture conditions, secretome harvesting, purification, concentration, sterility, endotoxin levels, particle characterization, proteome/miRNA profile, release criteria, and bioactivity assays must be reproducibly defined. For an inhaled product, additional factors include aerosol physics, particle size distribution, nebulizer compatibility, stability after nebulization, and deposition in the distal lung compartment.

Senescent cells are metabolically active, unable to divide, and secrete a pro-inflammatory, matrix-modulating profile known as the SASP — senescence-associated secretory phenotype. In pulmonary fibrosis, senescent epithelial cells, fibroblasts, and immune cells can maintain chronic tissue dysfunction. Senescent cells produce, among other things, inflammatory cytokines, growth factors, and matrix-remodeling enzymes that can intensify fibroblast activation, epithelial stress, and immune dysregulation.

The combination of dasatinib and quercetin is one of the best-known experimental senolytic regimens. Dasatinib is an approved oncological tyrosine kinase inhibitor, used among other things against BCR-ABL and Src-family kinases; quercetin is a flavonoid that affects anti-apoptotic and metabolic signaling pathways. In IPF, D+Q has already been tested in a randomized phase I pilot study that examined feasibility and tolerability; however, the evidence remains early-phase and is not sufficient for an approved IPF indication.

The combination with secretome is conceptually interesting: senolytics could reduce pathological, pro-fibrotic signal sources, while the secretome could then support a reparative, immunomodulatory environment. One possible sequence would therefore not necessarily be simultaneous, but cyclic or sequential: first stabilization with an antifibrotic drug, then short senolytic pulses to reduce senescent cell burden, accompanied or followed by inhaled secretome to support regenerative programs.

For a translational program in Germany, nintedanib appears to be the preferred combination partner for four reasons:

First, nintedanib is established in Europe both for IPF and for other chronic fibrosing ILDs with a progressive phenotype. Second, it addresses growth-factor-driven fibroblast activation and thereby complements the immunomodulatory and regenerative logic of the secretome. Third, clinical experience in progressive fibrosing diseases is broad. Fourth, an add-on study design based on nintedanib is easier to justify from a regulatory perspective than a complete departure from the standard of care.

Pirfenidone remains a sensible alternative, especially in classic IPF and in patients who do not tolerate nintedanib. Nerandomilast is scientifically attractive, particularly because it has been studied both as monotherapy and as an add-on to existing antifibrotic therapy; however, for a German development narrative, it should be classified as a future option until clear EU availability exists.

A combination approach involving nintedanib, dasatinib/quercetin, and inhaled secretome is biologically plausible, but demanding from a safety perspective.

Nintedanib is associated with gastrointestinal side effects, elevations in liver enzymes, and bleeding risks. The EMA product information also points to P-gp-mediated interactions; strong P-gp inducers can reduce nintedanib exposure, while inhibitors can increase exposure.

Dasatinib has a significantly different risk profile than classical pulmonary medications. The EMA product information describes its use as oncological therapy; known risks include myelosuppression, infections, bleeding, pleural effusions, and pulmonary arterial hypertension. This is particularly relevant in pulmonary fibrosis because pleural effusions, dyspnea, and pulmonary vascular complications can clinically overlap with the underlying disease.

Quercetin can influence CYP3A4 and P-gp activity; dasatinib is relevant to CYP3A4 and transporters, which means pharmacokinetic interactions are not trivial.

This leads to the conclusion that the combination should not be conceived as a permanent triple long-term therapy, but as a controlled, short, closely monitored senolytic window within a stable antifibrotic basic therapy. Monitoring should include blood count, liver values, coagulation/bleeding events, ECG/QT risk, echocardiography if pulmonary hypertension is suspected, pleural effusions, infections, oxygen requirement, exacerbations, and HRCT progression.

Pulmonary fibrosis is more than excessive collagen deposition; it is a chronically misguided repair program. A single antifibrotic drug can slow this program, but rarely reverse it. The combination of modern antifibrotic basic therapy, senolytic reset, and inhaled mesenchymal stem cell secretome opens a rational path to systematically bring together progression control and tissue repair for the first time. For patients suffering from pulmonary fibrosis, the particular opportunity lies in the possibility that combination therapy may shift the treatment of pulmonary fibrosis from “slowing progression” toward direct disease modification, in the hope of avoiding a lung transplant or at least delaying it.