Current Status and Future of Anti-fibrotic Drugs: From Approved Drugs to Clinical Trials

Introduction: The Dawn of Fibrosis Therapeutics

Fibrosis was once considered "irreversible," with almost no effective treatments available. However, the approval of Pirfenidone and Nintedanib as treatments for Idiopathic Pulmonary Fibrosis (IPF) in 2014 changed the landscape completely. These became the first anti-fibrotic drugs to slow the decline in lung function, marking the beginning of a new era where "fibrosis is treatable." This article summarizes the latest findings on the mechanisms of currently approved anti-fibrotic drugs and promising candidate compounds in Phase 2/3 clinical trials.

1. Approved Anti-fibrotic Drugs

Pirfenidone: The "Origin" with Pleiotropic Effects

Approved Indications

Idiopathic Pulmonary Fibrosis (IPF) (Approved by FDA in 2014)
Slows the rate of FVC (Forced Vital Capacity) decline in IPF patients by approximately 50%.

Mechanism of Action

Although the exact mechanism of Pirfenidone is not fully elucidated, the following pleiotropic effects have been reported (American Journal of Respiratory Cell and Molecular Biology):

Anti-fibrotic Action
- Suppression of TGF-β1: Reduces TGF-β1 mRNA expression and protein production, suppressing Smad3 signaling.
- Inhibition of Fibroblast Proliferation: Inhibits differentiation into myofibroblasts and reduces collagen synthesis.
- Inhibition of mTOR/p70S6K Pathway: Suppresses Collagen I production.
Anti-inflammatory Action
- Suppresses production of pro-inflammatory cytokines like TNF-α and IL-1β.
- Also targets the inflammasome pathway.
Antioxidant Action
- Neutralizes Reactive Oxygen Species (ROS) and reduces oxidative stress.

Clinical Results

CAPACITY Trial, ASCEND Trial: Significantly suppressed FVC decline in IPF patients.
Side Effects: Gastrointestinal symptoms (nausea, anorexia), photosensitivity.

Nintedanib: Multi-Kinase Inhibitor

Approved Indications

Idiopathic Pulmonary Fibrosis (IPF) (Approved by FDA in 2014)
Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype (PF-ILD) (Approved in 2020)
Systemic Sclerosis-Associated Interstitial Lung Disease (SSc-ILD)

Mechanism of Action

Nintedanib is a Triple Angiokinase Inhibitor that simultaneously inhibits multiple Receptor Tyrosine Kinases (RTKs):

PDGFR (α/β): Suppresses fibroblast proliferation and migration.
FGFR (1/2/3): Suppresses fibroblast activation and angiogenesis.
VEGFR (1/2/3): Suppresses angiogenesis and vascular permeability.
Also inhibits non-receptor tyrosine kinases like Src and Lck.

By blocking these pathways, it comprehensively suppresses fibroblast activation, ECM deposition, and angiogenesis.

Clinical Results

INPULSIS-1/2 Trials: Suppressed the annual rate of FVC decline in IPF patients by approximately 50% (compared to placebo).
SENSCIS Trial: Delayed lung function decline in SSc-ILD patients.
Side Effects: Diarrhea is the most frequent adverse event.

Resmetirom: First MASH Treatment (Approved in 2024)

Approved Indications

MASH (Metabolic Dysfunction-Associated Steatohepatitis) (Approved by FDA in 2024)

Mechanism of Action

Thyroid Hormone Receptor β (THR-β) Selective Agonist.
Improves lipid metabolism in the liver and reduces inflammation and fibrosis.

Significance

It is the first approved drug for liver fibrosis, opening a new era in MASH treatment.

2. Promising Candidates in Phase 2/3 Clinical Trials

Idiopathic Pulmonary Fibrosis (IPF)

PDE4 Inhibitors

Nerandomilast (Boehringer Ingelheim)
- Achieved endpoints in Phase 3 trial (2024).
- Suppresses cAMP degradation, exerting anti-inflammatory and anti-fibrotic effects.

LPA (Lysophosphatidic Acid) Antagonists

LPA is a lipid mediator promoting fibroblast migration and proliferation.
LPA receptor antagonists suggested suppression of FVC decline in Phase 2 trials.

Integrin αvβ6/αvβ1 Dual Inhibitors

Integrins are mechanistic receptors that activate latent TGF-β.
Simultaneous inhibition of αvβ6/αvβ1 fundamentally suppresses TGF-β activation.
Promising results in Phase 2 trials.

Prostacyclin Agonist: Treprostinil

Suggested anti-fibrotic effects in addition to vasodilation and anti-platelet effects.
Inhaled formulation is being tested in IPF.

Liver Fibrosis

SGLT2 Inhibitors (Empagliflozin), GLP-1 Receptor Agonists (Liraglutide)

Approved as diabetes treatments, but efficacy for liver fibrosis is also being verified (Phase 3).

Obeticholic Acid

Farnesoid X Receptor (FXR) Agonist.
Expected to improve liver fibrosis, but side effects (pruritus) are a challenge.

3. Challenges and Prospects in Anti-fibrotic Drug Development

High Failure Rate

Success rate from Phase 2 to Phase 3 is about 17% (Failure rate 83%).
Fibrosis is a complex pathology spanning multiple organs, so single targets have limited efficacy.

Lack of Biomarkers

Lack of biomarkers capable of evaluating early intervention effects other than FVC and tissue biopsy.
Serum markers (KL-6, SP-D, Hyaluronic Acid, etc.) are supportive but limited for determining therapeutic efficacy.

Pan-fibrotic Approach

Strategy targeting fibrosis mechanisms common across organs (TGF-β, Wnt, YAP/TAZ, NF-κB, etc.).
Simultaneous inhibition of multiple pathways and combination therapies are gaining attention.

Tissue-Specific Delivery

Organ-specific delivery using nanoparticles or antibody drugs is being developed to avoid side effects from systemic administration.

Conclusion

The success of Pirfenidone and Nintedanib proved that fibrosis is a "treatable disease." However, these only slow disease progression and have not achieved regression or complete cure of fibrosis. Next-generation anti-fibrotic drugs aim for "regression" of fibrosis by targeting upstream targets (TGF-β activation, mechanotransduction) and employing combination therapies and organ-specific approaches.

Our fibrosis models support every stage of anti-fibrotic drug development, from verifying the mechanisms of existing drugs like Pirfenidone/Nintedanib to judging Phase 2 transition for novel compounds.

References

Richeldi L, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082.
King TE Jr, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-2092.
Lambrecht BN, et al. The emerging role of ADAM metalloproteinases in immunity. Nat Rev Immunol. 2018;18(12):745-758.