BARCELONA, Spain — For more than a decade, the standard clinical management of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis relied almost exclusively on two antifibrotic medications: pirfenidone and nintedanib. These antifibrotic therapies slow disease progression, but don’t stop it.

Now, with a wave of novel therapeutic agents targeting distinct biological pathways entering phase 3 clinical trials, respiratory clinicians discuss whether to initiate combination antifibrotic therapy upfront at diagnosis or adopt a cautious, stepwise add-on approach at the European Respiratory Society (ERS) 2026 International Congress.

Defending the pro stance, Vincent Cottin, MD, PhD, professor of medicine at the University of Lyon in Lyon, France, argued that waiting for a patient to show irreversible decline in lung function before intensifying therapy is a flaw in current care. “Antifibrotics slow down disease; they do not halt the progression of the disease,” Cottin said. “So we need to do better, and combination is a way to do better.”

On the other hand, Claudia Valenzuela, MD, PhD, an interstitial lung disease specialist at the Hospital Universitario de la Princesa in Madrid, Spain, urged caution: “Combination therapy and upfront combination makes sense, of course, and is considered the most promising approach. But [it] is not yet validated. I don’t think we can use it in clinical practice so fast.”

The Argument for Early, Aggressive Intervention

Cottin said that early therapeutic intervention consistently yields superior long-term clinical outcomes. Observational data from 207 patients with IPF show that initiating antifibrotic treatment within 6 months of diagnosis, rather than deferring therapy between 6 and 12 months, significantly reduced the risk for overall disease worsening and respiratory-related hospitalizations.

To support multi-pathway targeting, Cottin drew parallels to other complex fields of medicine. “In many domains in respiratory disease, but also outside of respiratory disease, combination is better,” he said. “That’s the case in lung cancer, in [chronic obstructive pulmonary disease], in asthma, and pulmonary arterial hypertension, for example.” In pulmonary arterial hypertension, for instance, the AMBITION trial established upfront dual therapy (tadalafil plus ambrisentan) as the standard of care after demonstrating a 50% reduction in primary clinical failure events compared with monotherapy.

While historical attempts to combine the first-generation antifibrotics nintedanib and pirfenidone, such as in the 12-week INJOURNEY trial, were hampered by high treatment discontinuation rates, Cottin emphasized that a new era of antifibrotics has arrived.

Novel candidates target entirely distinct molecular cascades. Agents such as nerandomilast, a preferential phosphodiesterase 4B inhibitor, and inhaled treprostinil, a prostacyclin receptor agonist, elevate intracellular cyclic adenosine monophosphate across multiple lung cell types. This mechanism acts downstream to suppress fibroblast proliferation, myofibroblast differentiation, and collagen synthesis, while simultaneously dampening the release of inflammatory cytokines from macrophages.

Phase 3 clinical trials, including FIBRONEER-IPF, FIBRONEER-ILD, TETON-1, and TETON-2, have shown that adding these next-generation agents to background nintedanib or pirfenidone yields robust, consistent reductions in the rate of decline in forced vital capacity. Also safety profiles remained manageable. In FIBRONEER-IPF, for example, the 52-week study drug discontinuation rate for nerandomilast 18 mg twice daily was almost identical to placebo (12.9% vs 12.6%).

Cottin acknowledged that pure data evaluating upfront combination therapy in completely treatment-naive patients remains limited. However, he urged the field to move away from the traditional wait-to-fail approach.

“I believe it is time to treat stronger, harder pulmonary fibrosis, including upfront combination therapy, so that we can hit harder and earlier, especially in patients with a high risk of progression,” Cottin said.

The Case for Caution and Validation 

Taking the stage to defend the con position, Valenzuela agreed that multi-pathway targeting makes theoretical sense but insisted that clinical practice is not ready for routine upfront adoption.

Valenzuela distinguished between sequential add-on therapy, intensifying treatment as a patient shows signs of progression, and true upfront combination in a drug-naive patient. “An [upfront] combination is not yet validated,” Valenzuela argued.

While acknowledging the impressive results of the FIBRONEER and TETON phase 3 trials, Valenzuela pointed out a major methodological caveat. None of these trials were designed to test upfront combination therapy. Instead, the vast majority of trial participants were already established on background antifibrotic monotherapy (up to 78% in FIBRONEER-IPF and 75% in the TETON program).

“What is telling us this result? It’s telling us that nerandomilast works alone, or works on top of the treatment they were receiving,” Valenzuela explained. “But it doesn’t tell us that there is a synergistic effect of pirfenidone and nintedanib when combined with nerandomilast. Not directly. And they also don’t tell us if combination therapy between nerandomilast and any of them is better than monotherapy.”

Valenzuela outlined several major clinical concerns that must be addressed before upfront dual therapy can be embraced:

• Safety and tolerability: Combining active agents carries an inherent risk for additive or overlapping adverse events, particularly gastrointestinal toxicity.
• Treatment burden: Managing multiple complex dosing schedules can negatively affect patient adherence and daily quality of life and may require intensive clinical monitoring.
• Drug-drug interactions: Pharmacokinetic interactions between novel and established antifibrotics, such as those observed between pirfenidone and nerandomilast, require thorough evaluation.
• Economic factors: Polypharmacy drastically increases direct drug costs, threatening to widen healthcare access disparities across different healthcare systems and regions.

Valenzuela urged clinicians not to rush into unproven strategies, stressing that sequential escalation remains a highly effective, controlled approach while dedicated upfront trial evidence is gathered.

The Audience Verdict

The compelling arguments delivered by both speakers prompted a shift in the audience’s opinion. In an initial pre-debate poll, 56% of the audience favored upfront combination therapy, while 43% opposed it. Following the presentations and panel discussion, a re-vote revealed that the con position had won over the room with 63% of votes against upfront combination therapy.

Cottin reported receiving consultation fees from AbbVie, AstraZeneca, Avalyn, Boehringer Ingelheim, Bristol Myers Squibb, CSL (Behring Vifor), Ferrer/United Therapeutics, Gossamer, GlaxoSmithKline, Liquida, MSD, Pliant, Pulmovant, PureTech, Roche, Sanofi. Valenzuela reported receiving consultation fees from Boehringer Ingelheim, International GmbH (BI), Pliant, Ferrer, MSD, AbbVie, Avalyn.

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.