From Slowing to Stopping IPF progression: Where Are We Now?

Fibrosis is what happens when the body’s repair system gets stuck in the “on” position.

Normally, when tissue is injured, the body sends in repair cells, inflammation settles down, and healing eventually stops. But in fibrotic disease, that healing process fails to switch off. Fibroblasts continue producing scar-like tissue, organs become stiff, and over time they lose their ability to function.

This is especially devastating in idiopathic pulmonary fibrosis, or IPF, a progressive lung disease where scarring builds up in the lungs without a clearly identifiable cause.

For years, IPF treatment has largely focused on slowing decline. That alone has been meaningful, because IPF is a serious and progressive disease. But the field is now aiming higher: not just delaying lung function loss, but stopping the scarring process at its roots — and possibly, in some cases, reversing active fibrotic biology.

The fibrosis space is moving away from broad, blunt anti-fibrotic approaches and toward precision mechanisms that target the specific signals keeping scar formation alive.

The central challenge: efficacy without toxicity

Fibrosis has always presented a difficult therapeutic trade-off.

One of the most important pathways in fibrosis is TGF-beta, often described as a “master regulator” of scar formation. The logic of targeting it is clear: if TGF-beta helps drive fibrosis, blocking it should slow scarring.

The problem is that biology is rarely that simple.

TGF-beta also plays important roles in immune regulation, inflammation resolution, and normal tissue repair. Blocking it too broadly can interfere with healthy biology and create serious safety concerns. That is why early anti-fibrotic strategies often struggled to find a workable therapeutic window.

Current IPF therapies can slow the annual decline in lung function, but they do not fully stop disease progression. Many also come with tolerability challenges, especially gastrointestinal side effects, which can make long-term treatment difficult for patients.

That leaves two major unmet needs:

Therapies that can arrest disease progression, rather than simply slow the rate of decline
Drugs that patients can stay on for years — tolerable enough for chronic use, and safe enough to combine with other therapies

IPF is not one simple disease category

Pulmonary fibrosis is often discussed as if it were one condition, but clinically it includes multiple diseases and drivers.

IPF is the largest and best-defined category. It is “idiopathic,” meaning the trigger is unknown. Its course is often progressive and relatively predictable compared with other forms of fibrotic lung disease.

Progressive pulmonary fibrosis, or PPF, includes non-IPF fibrotic lung diseases that continue to worsen over time. These cases may be linked to autoimmune disease, environmental exposures, or other underlying causes. Because the triggers vary, the patient population is more heterogeneous, and clinical trials can be more complicated.

This matters because drug development depends heavily on selecting the right patients, measuring the right signals, and reducing noise in trial outcomes.

The diagnostic hurdle: still too few biomarkers

One of the biggest challenges in IPF is the lack of simple blood-based biomarkers that can reliably diagnose the disease or predict how quickly a patient’s forced vital capacity, or FVC, will decline.

FVC remains one of the most important clinical endpoints in IPF trials because it measures how much air a person can forcibly exhale after taking a deep breath. In simple terms, it is a practical way to track whether lung capacity is being preserved or lost.

But FVC changes slowly, and IPF itself can be variable. That makes trials long, expensive, and highly dependent on careful patient selection.

This is where high-resolution CT imaging is becoming increasingly important. HRCT scans, especially when paired with advanced image analysis, can help researchers see how fibrosis is evolving inside the lung over time. Imaging is not replacing FVC, but it is becoming a powerful companion tool for understanding whether a therapy is changing disease biology.

The pipeline is expanding across multiple mechanistic fronts

Idiopathic pulmonary fibrosis (IPF) drug development is shifting from a narrow focus on broad antifibrotics toward a diversified pipeline that targets specific nodes in fibrotic signaling, epithelial injury, and tissue remodeling. Recent reviews and pipeline analyses now describe dozens of clinical candidates grouped across intracellular signaling, cell-surface activation mechanisms, targeted biologics, epithelial repair, and local delivery technologies. This reflects a deliberate move away from “one big hammer” strategies toward a toolbox of agents that can potentially be sequenced or combined based on underlying disease biology. pulmonaryfibrosis, pmc.ncbi.nlm.nih

1. Intracellular signaling and enzyme inhibitors

One of the clearest advances is in intracellular signaling modulators, particularly phosphodiesterase and cytokine-linked pathways. Nerandomilast (Jascayd, BI 1015550), a preferential PDE4B inhibitor from Boehringer Ingelheim, has shown antifibrotic activity in preclinical models and clinical studies, where it reduced or stabilized the rate of forced vital capacity (FVC) decline compared with placebo. Experimental work suggests that selective PDE4B inhibition elevates intracellular cAMP and dampens pro-inflammatory and pro-fibrotic signaling in lung tissue, providing a more targeted alternative to non-selective PDE4 inhibition. Nerandomilast subsequently became the first PDE4 inhibitor approved for IPF in the United States, adding a new mechanism alongside nintedanib and pirfenidone. bpspubs.onlinelibrary.wiley

Beyond PDE4B, several companies are pursuing kinase and cytokine-linked targets that sit upstream of fibrotic gene expression. TNIK inhibition, as exemplified by rentosertib (INS018_055), is being evaluated on the premise that TNIK participates in Wnt and cytoskeletal pathways that drive aberrant extracellular matrix deposition and myofibroblast activation. In parallel, Boehringer has advanced BI 765423, a monoclonal antibody that neutralizes interleukin-11 (IL-11), into phase 2a trials in IPF after preclinical studies implicated IL-11 as a central driver of fibrosis and barrier dysfunction in multiple organs. Early-phase data in healthy volunteers showed an acceptable safety profile, and the ongoing trial will test whether IL-11 blockade can slow lung function decline or even partially restore tissue integrity in patients. sciencedirect

Hedgehog-pathway modulation, including small molecules such as taladegib, remains an area of interest given the pathway’s role in mesenchymal activation and tissue remodeling, although clinical evidence in IPF is still early and less mature than for PDE4B and IL-11 inhibition. Collectively, these programs illustrate a trend toward precise intracellular intervention rather than broad kinase blockade. synapse.patsnap

2. Cell surface receptors and local fibrosis activation

A second major pillar focuses on cell surface receptors and local activation of profibrotic cascades. Lysophosphatidic acid receptor 1 (LPA1) is a leading example: LPA1 signaling has been shown to promote fibroblast recruitment, vascular leak, and matrix deposition after lung injury. Bristol Myers Squibb’s LPA1 antagonist admilparant (BMS-986278) has completed phase 2 testing in IPF and progressive pulmonary fibrosis, with data supporting progression into phase 3 evaluation. This builds on earlier proof-of-concept work with LPA1 antagonists indicating that modulating this lipid signaling axis can reduce fibrosis-related endpoints in interstitial lung disease. semanticscholar

Integrins are another intensively studied class of tissue-localized activators. Epithelial αvβ6 and stromal αvβ1 integrins can convert latent TGF-β into its active form directly at sites of injury, thereby amplifying local fibrosis while sparing distant tissues. Clinical and translational studies have shown that excessive αvβ6-mediated TGF-β activation contributes to uncontrolled fibrotic remodeling, and several oral small-molecule inhibitors, such as dual αvβ6/αvβ1 antagonists (for example PLN-74809), are being developed to selectively blunt this activation without systemic TGF-β blockade. Newer efforts from companies like Haisco and Pliant have also identified additional αvβ1, αvβ6, and αvβ8 integrin antagonists that may further refine this strategy. linkedin

These receptor-directed approaches underscore how fibrosis drug development is high-risk: strong mechanistic and animal data do not guarantee late-stage success, as illustrated by the failure of the anti-CTGF antibody pamrevlumab in phase 3 IPF trials despite promising earlier-phase results. However, they also highlight a clear shift toward hitting key “on switches” for fibrosis as close to the diseased tissue as possible. pmc.ncbi.nlm.nih

3. Targeted biologics and RNA therapeutics

Biologics and nucleic acid therapies are opening an additional frontier focused on selective modulation of fibrotic signaling networks. Several groups are developing antibodies or fusion proteins against matricellular and secreted factors that amplify TGF-β and inflammatory loops. Pentraxin-2 (PRM-151, recombinant human pentraxin-2) is a prototype in this space: long-term phase 2 studies showed that PRM-151 was generally well tolerated and associated with slower FVC decline and preservation of 6-minute walk distance in IPF, consistent with a role in redirecting wound-healing responses away from scarring. Other programs, including antibodies against WISP1 (also called CCN4) and related CCN family members, seek to disrupt feed-forward fibrotic loops that are particularly active in inflamed lung tissue but less critical in healthy adult organs. pubmed.ncbi.nlm.nih

At the same time, RNA-based therapeutics, including small interfering RNA (siRNA) and antisense oligonucleotides, are being used to downregulate genes associated with epithelial injury and matrix remodeling. Candidates such as ARO-MMP7, which targets MMP7, illustrate this gene-silencing approach in IPF, even though they are still in earlier stages compared with more advanced small molecules and antibodies. More broadly, RNAi is now an established modality in other diseases and is being repurposed for lung fibrosis, buoyed by precedent from approved RNAi drugs and by better delivery systems. These efforts aim to combine the specificity of biologics with the flexibility of gene-level intervention. oligotherapeutics

4. Epithelial protection and tissue repair

A key conceptual shift in IPF biology is the recognition that disease progression reflects both persistent fibroblast activation and repeated epithelial injury with failed repair. This has fueled a new generation of therapies that aim to stabilize or restore alveolar epithelial cell function, often alongside antifibrotic effects. Experimental agents designed to modulate pathways such as Caveolin-1 signaling, AT2 receptor agonism, and epithelial stress responses seek to protect the vulnerable epithelium from ongoing micro-injury while rebalancing the local immune milieu. For example, recombinant pentraxin-2 not only influences fibrocyte differentiation but also appears to shift wound-healing toward resolution rather than chronic scarring, indirectly supporting epithelial integrity. bio-integration

Emerging reviews emphasize that epithelial-directed strategies may be particularly important for reversing or remodeling disease, not just slowing decline. Preclinical data with IL-11 blockade and other epithelial-mesenchymal crosstalk targets suggest potential for partial restoration of barrier function and improved lung mechanics, though this still needs confirmation in adequately powered phase 2 and 3 studies. As a result, major pharma and biotech programs increasingly incorporate epithelial injury biomarkers and imaging endpoints to capture these repair-oriented effects. allsci

5. Localized delivery and inhaled formulations

Finally, route of administration has become a strategic lever in IPF. Conventional oral agents expose the entire body to drug, which can limit dosing and increase adverse events, whereas inhaled and lung-targeted systems offer the prospect of higher local concentrations with reduced systemic exposure. Inhaled treprostinil is a leading example: recent phase 3 data in IPF demonstrated a smaller decline in FVC and fewer clinical-worsening events compared with placebo, supporting the idea that lung-directed prostacyclin analog therapy can meaningfully influence disease trajectories. Reviews of pulmonary fibrosis drug delivery now highlight liposomal, nanoparticle, and dry-powder platforms as promising ways to further concentrate drugs in the distal lung while minimizing off-target effects. pubmed.ncbi.nlm.nih

Multiple companies are also exploring inhaled versions of mechanistically targeted agents, including LPA1 antagonists and other small molecules, to align drug exposure more tightly with regions of active fibrosis. These innovations in formulation are increasingly viewed as part of the mechanism story: local delivery is not just about convenience, but about enabling mechanisms that would be too toxic or inefficient if delivered systemically. As these technologies mature, they are likely to become central components of combination strategies that pair systemic and inhaled agents. bio-integration

Beyond IPF: the pan-fibrotic opportunity

What makes fibrosis such a compelling area is that many organs appear to share common scarring pathways.

The lung, kidney, liver, skin, and heart are obviously very different organs. But once fibrosis is underway, many of the same biological themes appear again and again: fibroblast activation, inflammatory signaling, extracellular matrix deposition, epithelial or endothelial injury, and mechanical tissue stiffening.

That is why IPF is often viewed as a gateway indication.

If a drug can show meaningful anti-fibrotic activity in IPF, it may have potential in other fibrotic diseases, including kidney fibrosis, liver fibrosis, systemic sclerosis, and broader progressive fibrotic conditions.

This is especially important because fibrosis is not a niche problem. It is a common endpoint of many chronic diseases, and it contributes significantly to organ failure across medicine.

The bigger picture

The IPF field is entering a new phase.

The goal is no longer simply to make scarring progress more slowly. The ambition is to understand the disease deeply enough to interrupt the signals that keep fibrosis alive.

That means targeting earlier alarm signals such as S100A4.

It means disrupting tissue-specific pro-fibrotic loops such as CCN proteins and WISP1.

It means blocking intracellular remodeling nodes such as PDE4B, TNIK, STAT3, and Hedgehog signaling.

It means silencing harmful proteins through RNA interference.

It means protecting epithelial cells before downstream scarring becomes irreversible.

And it means delivering therapies directly to the lung when local treatment can improve the safety profile.

There is still a long way to go. IPF remains a difficult disease, and the history of fibrosis drug development is full of programs that looked promising but failed to translate.

But the field is clearly moving in the right direction: from broad suppression to precision modulation, from systemic toxicity to localized delivery, and from slowing decline to disease modification.

For patients, that shift matters enormously.

Because in fibrosis, the real breakthrough will not be a drug that merely delays the next step down.

It will be a therapy — or a combination of therapies — that helps the body finally stop scarring.