Disease indication · a manifestation of systemic sclerosis
Two approvals in three years, in the same patients whose skin has none — and mostly out of the same trials. The difference is not the biology. It is that a spirometer settles arguments a clinician's fingers cannot.
Disease-modifying: Slow the loss of lung function, judged on forced vital capacity — an objective spirometric measure that cannot be moved by how a patient reports feeling. Two drugs have cleared that bar since 2019, one an antifibrotic borrowed from idiopathic pulmonary fibrosis and one an anti-inflammatory that missed its own skin primary in the trial that approved it.
Nintedanib in 2019 and tocilizumab in 2021, both in the United States, both naming this disease specifically. Rituximab was additionally approved in Japan in 2021. Against zero for the skin manifestation, in the same patients and largely from the same trials.
Clinically significant, progressive disease affects roughly a quarter to a third. The gap between the imaging figure and the clinical figure is why trials screen with HRCT and enrol on physiology, and why an enrichment strategy matters so much here.
The leading single cause of death in this disease since renal crisis became treatable in the 1980s. Pulmonary hypertension is second.
Nintedanib reduced the annual rate of FVC decline from 93 mL/year to 52 mL/year. That is a real effect, and it is a slower decline rather than a halt or a recovery. Nothing on this page has stopped the disease.
Systemic sclerosis is four therapeutic problems that happen to occur in the same patient, and holding them side by side explains more about this disease than any single page can. Same autoimmunity, same fibroblasts, same person — and one manifestation was solved with a borrowed blood pressure pill, one has fourteen drugs it can borrow, one has two of its own, and one has nothing at all.
Progressive thickening and tethering of the skin, and the feature the disease is named and classified by. Rarely the direct cause of death, and the best single predictor of who dies of everything else.
Progressive interstitial fibrosis, present on imaging in most patients and clinically significant in roughly a third. The only manifestation to have produced a drug approval naming this disease.
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Obliterative narrowing of the small pulmonary arteries, raising pressures until the right ventricle fails. Fourteen drugs are available to these patients and were licensed for a category rather than for them.
Abrupt malignant hypertension with acute kidney failure, once the most feared complication of this disease and almost uniformly fatal within months. It is now largely survivable, and it was solved by accident.
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These may be nearer to separate diseases than the shared name implies, and the autoantibody is the clearest evidence for that. Anti-topoisomerase I predicts lung fibrosis, anti-RNA polymerase III predicts renal crisis and rapid skin thickening, and anticentromere predicts pulmonary hypertension with limited skin involvement. The two manifestations that decide survival largely occur in different patients, and a trial enrolling on the diagnosis mixes them all.
Everything on this page rests on the first row. Forced vital capacity is objective, instrument-measured, accepted by every regulator, and the reason this organ has drugs while the skin does not. It is also insensitive, effort-dependent, and a poor description of what patients experience.
| Endpoint | Type | Read at | Standing |
|---|---|---|---|
| Forced vital capacity (FVC) decline | Performance | 52 weeks | Accepted |
| Categorical FVC response | Performance | 52 weeks | Accepted |
| Quantitative ILD extent on HRCT | Imaging | 12–24 months | Exploratory |
| Diffusing capacity for carbon monoxide (DLCO) | Performance | 52 weeks | Contested |
| K-BILD and SGRQ breathlessness scores | Self-reported | 12–52 weeks | Contested |
| Time to progression or death | Trial design | 2–3 years | Accepted |
The models here are the ones from the skin page with the injection redirected into the airway, and they carry the same defect: fibrosis that resolves on its own. Two drugs were nonetheless approved out of them. Compare against the RA-ILD page, where the identical model produced no approval — the model is not what separates these two diseases.
| Model | FaceDoes it look like the disease? | ConstructDoes it arise the same way? | PredictiveSlow lung decline |
|---|---|---|---|
The shortest ledger on the site with two approvals in it. Note how many entries improved lung function without producing a licence: generic drugs, absent sponsors, and one trial that had no placebo arm to prove anything against.
| Intervention | Rested on | Primary endpoint | Reached | Outcome |
|---|---|---|---|---|
Rituximab versus cyclophosphamide Academic (UK, NIHR) · B-cell depletion compared head-to-head against broad alkylating immunosuppression | sclGVHD | Change in forced vital capacity at 24 weeks | Phase 2b RECITAL · 2023 | Missed primary |
Pirfenidone Genentech / academic · Antifibrotic of incompletely defined mechanism, reducing TGF-β-driven fibroblast activity | Bleomycin lung | Tolerability and dose-titration (LOTUSS); change in FVC added to background mycophenolate (SLS III) | Phase 2 LOTUSS; Scleroderma Lung Study III · 2023 | Ongoing |
Tocilizumab Roche / Genentech · Monoclonal antibody blocking the interleukin-6 receptor | sclGVHDBleomycin lung | Change from baseline in modified Rodnan skin score at 48 weeks | Approved focuSSced · 2021 | Approved |
Rituximab Zenyaku Kogyo / academic (Japan) · Monoclonal antibody depleting CD20-positive B cells | sclGVHD | Change from baseline in modified Rodnan skin score at 24 weeks | Approved (Japan) DESIRES · 2021 | Approved |
Nintedanib Boehringer Ingelheim · Intracellular inhibition of multiple tyrosine kinases, including PDGF, FGF and VEGF receptors, reducing fibroblast proliferation | Bleomycin lungFra-2 | Annual rate of decline in forced vital capacity, in millilitres per year, over 52 weeks | Approved SENSCIS · 2019 | Approved |
Autologous haematopoietic stem-cell transplantation Academic consortia (EBMT/EULAR; NIAID) · Ablation of the autoreactive immune repertoire followed by autologous reconstitution | sclGVHD | Event-free survival, with lung function among the adjudicated components | Phase 3 (randomised, two trials) ASTIS; SCOT · 2018 | Benefit, no approval |
Mycophenolate mofetil Academic (NHLBI) · Inhibition of inosine monophosphate dehydrogenase, selectively suppressing lymphocyte proliferation | sclGVHD | Course of percent-predicted forced vital capacity over 24 months | Phase 3 Scleroderma Lung Study II · 2016 | Benefit, no approval |
Imatinib Investigator-initiated · Tyrosine kinase inhibitor blocking PDGF receptor and c-Abl, downstream of TGF-β | Bleomycin lungAdTGF-β1 | Change in percent-predicted forced vital capacity at 12 months | Phase 2 Small open-label and randomised studies · 2011 | Failed |
Bosentan Actelion · Dual endothelin receptor antagonist | Fra-2 | Change in six-minute walk distance at 12 months | Phase 3 BUILD-2 · 2010 | Failed |
Oral cyclophosphamide Academic (NHLBI) · Alkylating agent producing broad, non-selective immunosuppression | sclGVHDBleomycin lung | Percent-predicted forced vital capacity at 12 months | Phase 3 Scleroderma Lung Study I · 2006 | Benefit, no approval |
The volume of air a patient can forcibly exhale after a maximal breath in, tracked over time
The entire reason this page differs from the skin page. Identical patients, frequently the identical trial — and the organ with an instrument-measured endpoint has two drugs while the organ with an examiner-rated one has none.
The cheapest per success of the three scleroderma pages, and the reason is entirely the endpoint. An accepted objective measure raises the odds a programme survives, and the odds are what dominate cost per approved drug.
Fifty-two weeks of serial spirometry to fit a rate of decline. A single large pivotal rather than two, because that is what actually happened twice — and the reason one sufficed is that the endpoint is objective, instrument-measured and already accepted from another disease.
738 patient-years against 250 for a symptomatic programme. Cost grows more slowly than exposure because the fixed enrolment cost of each participant — screening, baseline imaging — is paid once however long they are then followed. The goal, not the molecule, still sets the budget.
Citedenrolment, duration and study counts, from named trials.Assumptionthe two cost parameters below.Computedeverything else.
| Phase | Design | N × studies | Duration | Patient-years | Modelled cost |
|---|---|---|---|---|---|
| Phase 1 | SAD / MAD, healthy volunteers Reads: Safety, tolerability and pharmacokinetics Antifibrotics carry gastrointestinal and hepatic tolerability questions that shape later dosing, so first-in-human work is not abbreviated. Conventional first-in-human designmoderate confidence | 50 | 9 mo | 38 | $1.4M–$2.2M |
| Phase 2 | Dose-ranging on rate of FVC decline, on background immunosuppression Reads: Annual rate of FVC decline, with quantitative HRCT extent as a supporting read A full year even at Phase 2, because the endpoint is a rate of change rather than a level. Increasingly run as an addition to background mycophenolate rather than against placebo, which raises the bar and the required size. Antifibrotic Phase 2 designs in fibrotic ILD; SLS III protocolmoderate confidence | 150 | 1 yr | 150 | $4.8M–$8.0M |
| Phase 3 | One large pivotal, 52 weeks, serial spirometry, background therapy permitted Reads: Annual rate of decline in FVC in millilitres per year, over 52 weeks Sized after SENSCIS, which enrolled 576 and carried an approval on its own. Both approvals in this disease came from a single trial each — the practical value of an endpoint every regulator already accepts. Distler et al., NEJM 2019 (SENSCIS); Khanna et al., Lancet Respir Med 2020 (focuSSced)high confidence | 550 | 1 yr | 550 | $18M–$29M |
| Total | 2.8 yr of clinical development, treating phases as sequential | 738 | $24M–$39M |
Model assumptions, not citations — the only free parameters here. The fixed component covers screening, baseline imaging and randomisation, incurred once per participant; the running component covers visits, monitoring and site fees for each year on study. Splitting them matters: a single rate per patient-year would price short symptomatic trials far below what pivotal trials actually cost.
Calibration: priced this way a single pivotal trial in this programme comes to $4.4M–$7.1M, against published pivotal trial costs of $12–33M (median $19M) across all indications. A single 52-week pivotal here approaches the lower quartile of the published all-indication range, because the trials are larger than most rare-disease programmes — the registrational trial enrolled 576 — even though the disease is rare. The endpoint is what allows a single pivotal to carry an approval, and that is what keeps the programme total down. Moore et al., JAMA Internal Medicine 2018.
Programme cost divided by a 11% likelihood of approval from Phase 1 in fibrotic interstitial lung disease with an accepted physiological endpoint — what one success costs once the failures are paid for. BIO / Informa / QLS, Clinical Development Success Rates — respiratory sits mid-table, fibrotic lung disease well below it, adjusted upward here for two completed approvals.
Read this one carefully: Above the RA-ILD figure on this site and for one reason only: two drugs have actually cleared this bar since 2019, where the other disease has one category approval that does not name it. The preclinical models are the same and just as unreliable, the biology is arguably harder, and the difference is a well-populated regulatory precedent. Treat 11% as an estimate anchored on two successes, which is a thin base.
These are portfolio figures spanning all of R&D and already carry the cost of failure, so they are not comparable with the per-programme clinical costs above — they are the order of magnitude those costs roll up into.
The field is moving from asking which drug to asking how many at once, and from enrolling by diagnosis to enrolling by behaviour.
Nintedanib's registrational trial permitted background mycophenolate, and roughly half the participants took it — the antifibrotic effect held on top of the immunosuppressant. That result quietly reframed the field from choosing between an immune drug and an antifibrotic to giving both, and current trials increasingly test additions to background therapy rather than against placebo. It also raises the cost of every future programme, because a drug now has to beat an active regimen rather than nothing.
Distler et al., NEJM 2019 (SENSCIS background therapy subgroup); Highland et al., Lancet Respir Med 2021
The progressive pulmonary fibrosis construct groups lungs that are actively scarring regardless of what started them, and it has already produced a licence spanning many causes at once. For this disease that cuts both ways: it opens a second route to a label, and it means a sponsor can reach these patients without ever running a scleroderma trial. The countervailing move is enrichment — anti-topoisomerase I antibody, extent of disease on CT, and recent rate of decline all identify who is going to progress, and using them makes a trial smaller and much harder to fill.
Raghu et al., Am J Respir Crit Care Med 2022 (progressive pulmonary fibrosis criteria); Flaherty et al., NEJM 2019 (INBUILD)
The MUC5B promoter variant is the dominant common-variant risk factor for idiopathic pulmonary fibrosis and is a strong risk factor for lung fibrosis in rheumatoid arthritis — and it is not associated with lung fibrosis in this disease. Two fibrotic ILDs treated with the same drug on the same endpoint, arriving there by different genetic routes. It is an argument for caution in borrowing further from idiopathic pulmonary fibrosis, and the sharpest available reason to think this organ's disease is autoimmune in origin rather than a variant of age-related lung scarring.
Juge et al., NEJM 2018 (MUC5B in RA-ILD); Peljto et al. and subsequent MUC5B association studies in systemic sclerosis