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Idiopathic pulmonary fibrosis is scarring of the lungs with no identified cause. For decades it was treated with steroids and drugs that suppress the immune system — until a trial showed that combination was actively harmful. Two medicines are now licensed that slow the scarring. Neither reverses it. This page explains how the treatments developed, what is being tested now, and why exercise and rehabilitation matter more here, not less.
From "nothing can be done" to two antifibrotics
In IPF, lung tissue is progressively replaced by scar. The lungs become stiff and small, oxygen transfer falls, and breathlessness on exertion builds over months to years. It behaves differently from most lung disease: it is not primarily about inflammation, mucus or airway narrowing, and treatments that work elsewhere often do not work here.
That distinction was learned the hard way. Because the lungs looked inflamed, standard practice for years was prednisolone with azathioprine, often with N-acetylcysteine. A large trial designed to confirm the benefit instead had to be stopped early because people receiving the combination were dying and being hospitalised more often than those on placebo. It was a genuinely important negative result, and it changed the field.
What antifibrotics do
Two medicines are licensed in Australia for IPF. Both act on the scarring process rather than on inflammation:
- Pirfenidone — a tablet with anti-fibrotic and anti-inflammatory actions. Common problems are nausea, appetite loss, and marked sun sensitivity, so sun protection matters.
- Nintedanib — a capsule that blocks several growth-factor pathways driving fibrosis. The main problem is diarrhoea, which is usually manageable but often needs active planning.
Both slow the rate at which lung function declines by roughly half, on average, across a treated population. That is worth having, and it is not the same as stopping or reversing the disease. Being clear about this from the outset tends to help rather than harm — it allows people to make decisions while they are well.
Figure 3. Adjusted annual rate of change in forced vital capacity, nintedanib versus placebo, in the two identical INPULSIS trials.1 Two points are worth seeing at once. The treated slope is roughly half the placebo slope — and it still falls: antifibrotic therapy slows decline, it does not arrest or reverse it. And the two nintedanib lines sit almost on top of each other across independent trials, which is what replication looks like.
- 1. Source. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370(22):2071–2082. INPULSIS-1: nintedanib −114.7 vs placebo −239.9 mL/year, difference 125.3 (95% CI 77.7 to 172.8). INPULSIS-2: −113.6 vs −207.3 mL/year, difference 93.7 (95% CI 44.8 to 142.7).
- 2. Endpoint. The primary endpoint was the annual rate of decline in FVC in mL over 52 weeks, estimated by random-coefficient regression. Lines are drawn from baseline to that adjusted annual rate; they are a representation of the rate, not observed mean values at each visit.
- 3. Why pirfenidone is not plotted. ASCEND’s primary endpoint was the proportion of patients with a 10 per cent or greater decline in predicted FVC or death, in a differently selected population. The effect is of comparable magnitude, but placing it on this axis would imply a like-for-like comparison that the trial designs do not support.
- 4. Population. Trial cohorts were selected by physiology and diagnosis; an individual’s trajectory may differ substantially from a cohort mean, in either direction.
What to expect on treatment
Treatment is started and monitored by a respiratory specialist, usually after the diagnosis has been agreed at a multidisciplinary meeting that includes a radiologist and often a pathologist. You would expect regular lung-function testing, blood tests for liver function, and a discussion about oxygen if your levels drop when you move.
Because side-effects are common and dose adjustment is normal, it is worth reporting problems early rather than stopping on your own — most are manageable with timing, food, dose changes or supportive medicines.
What is being tested now
- A new class of tablet targeting an enzyme called PDE4B has completed large phase 3 trials with positive results on lung function, in IPF and in other progressive fibrosing lung diseases. This is the first genuinely new mechanism to succeed at scale since the antifibrotics.
- Inhaled treatments, including inhaled prostacyclin analogues, aiming to act on the lung directly with fewer whole-body side-effects.
- Drugs blocking the signals that activate scar-forming cells — several are in phase 2 and 3.
- A number of promising candidates have failed in phase 3 in recent years. That is normal in this field and a reason to be cautious about early results.
Why exercise and rehabilitation matter
People are often told that because the disease is progressive, exercise cannot help. That is wrong. Pulmonary rehabilitation improves walking distance, symptoms and quality of life in fibrotic lung disease. The benefit does fade after the programme ends, which is an argument for ongoing maintenance rather than against doing it.
IPF has one feature that changes how exercise must be prescribed: oxygen levels often fall steeply and early with exertion, sometimes without much warning. Exercise should be prescribed with saturation monitoring and, where needed, supplemental oxygen — not avoided because desaturation occurs.
We assess exercise capacity with saturation monitoring, prescribe and progress rehabilitation for fibrotic lung disease specifically, advise on ambulatory oxygen alongside your respiratory team, and work on breathlessness management and pacing.
A clinician-level synthesis of how IPF therapeutics arrived at antifibrosis, the pivotal randomised trials, the shift from disease-specific to behaviour-specific treatment, what is in phase 2 and 3 now, Australian access, and the implications for physiotherapy. Prepared July 2026. A reference summary, not a prescribing protocol — verify current TGA approvals and PBS criteria before clinical use.
1 · The arc: from presumed inflammation to fibrogenesis
IPF was long conceptualised as chronic inflammation progressing to fibrosis, which made corticosteroids and cytotoxic immunosuppression the logical treatment. The reconceptualisation of usual interstitial pneumonia as an epithelial-driven, aberrant wound-healing disorder — fibroblast foci, myofibroblast persistence, extracellular matrix deposition with relatively little inflammatory infiltrate — reframed the therapeutic target from inflammation to fibrogenesis itself.1 Every subsequent success has followed that reframing, and the principal failures have come from ignoring it.
Figure 2. The fibrogenesis sequence in usual interstitial pneumonia. The driver is aberrant epithelial repair rather than inflammatory infiltrate — the reframing that made antifibrosis the rational target, and that explains both why prednisone with azathioprine caused harm in PANTHER-IPF and why every drug in the panel below acts on stages 2 to 4 rather than on inflammation.
- 1. A schematic of the dominant mechanism, not a complete pathway: alveolar epithelial senescence, telomere biology, aberrant basaloid cells and the immune contribution are all omitted for clarity.
- 2. Stage assignments for drug action are indicative of the principal target. Both licensed antifibrotics are pleiotropic and act at more than one point.
- 3. Admilparant (LPA1 antagonism) is investigational; nerandomilast is recently phase-3 positive. Verify current TGA and PBS status before clinical use.
2 · PANTHER-IPF: the turning point, and a lesson in equipoise
PANTHER-IPF randomised prednisone plus azathioprine plus N-acetylcysteine against NAC alone and placebo. The combination arm was terminated early for increased mortality and hospitalisation, with 11 deaths versus 1 in the placebo arm at interim analysis.2 Triple therapy had been widespread standard practice on pathophysiological reasoning alone. The trial is worth citing to trainees not only for its result but because it demonstrates that plausible mechanism plus consensus practice can be actively lethal, and that this is discoverable only by randomisation.
The corollary is that IPF is not a secretion-retention or inflammatory airway disease. Routine chest physiotherapy techniques directed at clearance have no role in the absence of a specific indication, and the same reasoning error — treating a fibrotic lung as though it were an obstructed one — is a recognisable failure mode in acute practice.
3 · Pirfenidone
The CAPACITY programme produced discordant results across its two parallel trials, one meeting and one missing its primary endpoint, which delayed regulatory acceptance.3 ASCEND was designed to resolve it and did: pirfenidone reduced the proportion of patients with a 10 per cent or greater decline in FVC or death at 52 weeks by 47.9 per cent relative to placebo, with a reduction in six-minute-walk decline.4 Pooled analyses across the programme subsequently showed a mortality signal that individual trials were underpowered to detect.
4 · Nintedanib
TOMORROW established the dose and signal; INPULSIS-1 and INPULSIS-2 then showed a reduction in the annual rate of FVC decline of approximately 110 mL per year versus placebo, consistent across both trials.5,6 Diarrhoea occurred in roughly two-thirds of patients and is the principal limitation on adherence, usually manageable with dose reduction and loperamide rather than discontinuation.
Neither agent improves lung function. Both approximately halve the rate of decline. Framing this accurately at initiation is a clinical skill: patients who expect improvement and experience side-effects without symptomatic gain discontinue treatment.
5 · From disease label to disease behaviour — INBUILD and the PPF construct
INBUILD randomised patients with fibrosing ILD other than IPF who had progressed despite management, and showed nintedanib reduced FVC decline irrespective of the underlying diagnosis and of the radiological pattern.7 SENSCIS showed the same in systemic-sclerosis-associated ILD.8 Together these established progressive pulmonary fibrosis as a treatable behaviour rather than a diagnosis — now embedded in the 2022 ATS/ERS/JRS/ALAT guidance.9
The practical consequence for physiotherapy is that the population presenting with fibrotic physiology, exertional desaturation and rehabilitation needs is considerably larger than the IPF cohort, and is defined by trajectory rather than label.
6 · The pipeline now
PDE4B inhibition — the first new mechanism to succeed at scale. Nerandomilast, a preferential phosphodiesterase 4B inhibitor with antifibrotic and anti-inflammatory activity, met its primary endpoint in phase 3 in IPF (FIBRONEER-IPF) and in progressive pulmonary fibrosis other than IPF (FIBRONEER-ILD), with attenuation of FVC decline at 52 weeks on a background of permitted antifibrotic therapy.10,11 The design point matters: benefit was demonstrated in addition to existing antifibrotics, which makes combination therapy a realistic prospect for the first time. Regulatory and reimbursement status differs by jurisdiction and should be verified locally.
Inhaled treprostinil. INCREASE established benefit in pulmonary hypertension associated with ILD, with an improvement in six-minute-walk distance; the TETON programme extended inhaled treprostinil into IPF itself on the hypothesis of a direct antifibrotic effect.12 An inhaled route with predominantly local action is attractive in a population poorly tolerant of systemic adverse effects.
Lysophosphatidic acid pathway. LPA1 antagonism (admilparant) produced encouraging phase 2 results in both IPF and PPF and has progressed to phase 3.13
Notable phase 3 failures. Pamrevlumab (anti-CTGF) did not meet its primary endpoint in ZEPHYRUS-1 despite a positive phase 2. Ziritaxestat (autotaxin inhibitor) was terminated for futility in the ISABELA programme. Several integrin and other candidates have been discontinued.14 The attrition rate is high and phase 2 signals in IPF have repeatedly failed to replicate — relevant when patients ask about trial participation or about agents reported in the media.
Earlier-stage targets include anti-IL-11, senolytics, LTBP and autophagy modulation, and cell-based approaches. None is close to practice.
7 · Symptom-directed pharmacology and what has been abandoned
- Antacid therapy for presumed reflux-driven microaspiration is no longer recommended routinely for IPF; guidance moved from conditional support to a recommendation against treating asymptomatic reflux for pulmonary outcomes.9
- Cough is often the dominant symptom and is poorly served. Low-dose opioids have trial support for cough and breathlessness; P2X3 antagonists have shown promise in chronic cough generally with emerging data in IPF-related cough.
- Ambulatory oxygen improved quality of life in a randomised crossover trial in ILD with exertional desaturation — directly relevant to exercise prescription.15
- Anticoagulation and sildenafil as disease-modifying strategies have not shown benefit in IPF and should not be used for that indication.
8 · Australian access
Pirfenidone and nintedanib are PBS-subsidised for IPF under authority criteria that have historically required multidisciplinary-meeting diagnosis and lung function within a specified range, with continuation dependent on demonstrated absence of rapid decline. Criteria change; verify current PBS listings and the position for progressive pulmonary fibrosis other than IPF, which has followed behind the IPF indication. Practical implications are that diagnosis needs to reach an ILD MDM to unlock treatment, and that referral should not wait for severe impairment.
9 · Implications for physiotherapy
- Pulmonary rehabilitation works in fibrotic ILD. The Cochrane review shows improvement in six-minute-walk distance, dyspnoea and quality of life, with attenuation of benefit after programme completion — an argument for maintenance strategies, not for withholding rehabilitation.16
- Exertional desaturation is the defining prescription problem. It is steeper, earlier and less symptomatic than in COPD. Prescribe with continuous saturation monitoring, use interval formats and supplemental oxygen to sustain training load, and do not treat desaturation itself as a stop signal in isolation.
- Assess with a field test that exposes the physiology. A six-minute walk with saturation and Borg, repeated over time, tracks the trajectory that matters and informs the oxygen conversation.
- Clearance techniques have no routine role — see section 2. Breathlessness management, pacing, positioning and inspiratory muscle work are the relevant skill set.
- Timing is a therapeutic variable. Rehabilitation, transplant referral and advance-care discussions all benefit from happening earlier than instinct suggests in a disease with an unpredictable step-wise decline and a real risk of acute exacerbation.
- Acute exacerbation of IPF carries very high mortality and is not a secretion problem; recognising it and escalating rather than treating it as a chest infection is the physiotherapy contribution.
10 · Principal evidence gaps
- Whether combination antifibrotic therapy delivers additive clinical benefit at acceptable tolerability, now that add-on efficacy has been demonstrated.10
- Optimal rehabilitation dose, format and maintenance strategy in fibrotic ILD, and how to sustain gains after programme completion.16
- Whether oxygen during training alters outcomes beyond enabling training load.15
- Treatment of the IPF cough, which remains the least well served major symptom.
- Prediction of acute exacerbation, and any effective treatment for it.
- Whether earlier treatment in mild or subclinical interstitial abnormality changes trajectory — and whether screening is justified.
References & evidence base
- Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134(2):136–151.
- Idiopathic Pulmonary Fibrosis Clinical Research Network; Raghu G, Anstrom KJ, King TE, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012;366(21):1968–1977.
- Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377(9779):1760–1769.
- King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis (ASCEND). N Engl J Med 2014;370(22):2083–2092.
- Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis (TOMORROW). N Engl J Med 2011;365(12):1079–1087.
- Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis (INPULSIS). N Engl J Med 2014;370(22):2071–2082.
- Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases (INBUILD). N Engl J Med 2019;381(18):1718–1727.
- Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease (SENSCIS). N Engl J Med 2019;380(26):2518–2528.
- Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2022;205(9):e18–e47.
- Richeldi L, Azuma A, Cottin V, et al. Nerandomilast in patients with idiopathic pulmonary fibrosis (FIBRONEER-IPF). N Engl J Med 2025. [Verify current TGA and PBS status before clinical use.]
- Maher TM, Assassi S, Azuma A, et al. Nerandomilast in patients with progressive pulmonary fibrosis (FIBRONEER-ILD). N Engl J Med 2025. [Verify current TGA and PBS status before clinical use.]
- Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease (INCREASE). N Engl J Med 2021;384(4):325–334.
- Corte TJ, Lancaster L, Swigris JJ, et al. Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 antagonist, in patients with idiopathic or progressive pulmonary fibrosis. BMJ Open Respir Res 2021;8(1):e001026.
- Richeldi L, Fernandez Perez ER, Costabel U, et al. Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis: lessons from phase 2 and phase 3 evaluation. Lancet Respir Med 2020;8(1):25–33.
- Visca D, Mori L, Tsipouri V, et al. Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial. Lancet Respir Med 2018;6(10):759–770.
- Dowman L, Hill CJ, May A, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev 2021;(2):CD006322.
References are numbered in citation order (Vancouver/BMJ style) and were current at the time of writing. Guidelines are living documents — verify against the latest version before clinical use. Drug approvals in idiopathic pulmonary fibrosis are moving quickly — verify current Australian PBS and TGA status before clinical use.
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