Disease indication · a manifestation of systemic sclerosis
Fourteen approved drugs and one dedicated trial, run in 2000. These patients were a subgroup in everyone else's pivotal, they respond less well than the population those trials were designed around, and what actually improved their survival was a screening algorithm.
Disease-modifying: Delay hospitalisation, clinical deterioration, transplantation and death, judged on an adjudicated composite that accumulates over years rather than a walk test at sixteen weeks. This became the standard in 2013, and it is the reason modern pulmonary hypertension therapy is defensible as more than symptom relief. Patients with this disease were in every one of those trials as a minority subgroup, and did less well in all of them.
Epoprostenol in the scleroderma spectrum, published in 2000 — a drug requiring a permanent indwelling central line and continuous infusion. Every approval since has come from trials in which these patients were a minority subgroup of a broader pulmonary arterial hypertension population.
Consistently worse across registries on the same treatment. The right ventricle in this disease adapts poorly to a given afterload, and myocardial fibrosis is present in many patients before pulmonary pressures ever rise — so the limiting organ may be the heart rather than the lung vasculature.
Strongly associated with anticentromere antibodies and limited cutaneous disease — the serological group least likely to develop lung fibrosis. The two lethal organ manifestations of this disease tend to occur in different patients.
In lupus and mixed connective tissue disease, pulmonary hypertension frequently responds to immunosuppression. In this disease it does not — a hard negative result that separates a superficially similar group of diseases and constrains what the mechanism here can be.
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.
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.
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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.
The only page here where the endpoint problem is solved and the disease is still not. There is an accepted functional endpoint, an accepted event-driven endpoint, and an accepted haemodynamic surrogate. What is missing is a trial that enrolled these patients on their own.
| Endpoint | Type | Read at | Standing |
|---|---|---|---|
| Time to clinical worsening | Composite | 2–3 years | Accepted |
| Pulmonary vascular resistance | Laboratory | 16–24 weeks | Surrogate |
| NT-proBNP | Laboratory | 12–24 weeks | Surrogate |
| DETECT screening algorithm | Trial design | Annual, indefinitely | Accepted |
An unusual matrix for this site: the models are poor descriptions of the human lesion and have nonetheless supported fourteen approvals. What they capture well is vasoconstriction, which is what the approved drugs relieve. What they miss is the obliterative remodelling that kills people — and no drug addressed that until 2024.
| Model | FaceDoes it look like the disease? | ConstructDoes it arise the same way? | PredictivePrevent worsening and death |
|---|---|---|---|
The moment the field grew up is visible in the year column. From 2013 trials stopped reading walk distance and started counting hospitalisations and deaths — and the drugs kept working, which is the strongest validation of a mechanism anywhere on this site.
| Intervention | Rested on | Primary endpoint | Reached | Outcome |
|---|---|---|---|---|
Sotatercept Acceleron / Merck · Activin signalling inhibitor, rebalancing the BMPR2 and activin pathways to reverse vascular remodelling rather than dilate vessels | SuHxMonocrotalinePatient PASMC/PAEC | Change in pulmonary vascular resistance at 24 weeks | Approved STELLAR · 2024 | Approved |
Selexipag Actelion · Oral selective prostacyclin receptor agonist, chemically distinct from prostacyclin itself | MonocrotalineSuHx | Time to first morbidity or mortality event | Approved GRIPHON · 2015 | Approved |
Ambrisentan plus tadalafil, as initial combination Gilead / GSK · Simultaneous endothelin receptor blockade and PDE5 inhibition from the start of treatment, rather than adding a second drug on failure of the first | MonocrotalineSuHx | Time to first clinical failure event | Approved AMBITION · 2015 | Approved |
DETECT screening algorithm Actelion / academic consortium · Not a therapy. A two-step decision rule identifying which patients to catheterise before symptoms develop | Sensitivity for detecting pulmonary arterial hypertension against right heart catheterisation in every participant | Prospective cohort (n=466) DETECT · 2014 | Benefit, no approval | |
Macitentan Actelion · Dual endothelin receptor antagonist with improved tissue penetration over bosentan | MonocrotalineSuHx | Time to first morbidity or mortality event, over a median of two years | Approved SERAPHIN · 2013 | Approved |
Cyclophosphamide with glucocorticoids Academic (French PH network) · Broad immunosuppression, on the hypothesis that the vasculopathy is autoimmune in origin and therefore reversible | Fra-2 | Change in haemodynamics and functional class after induction immunosuppression | Observational cohort French PH network series · 2008 | Failed |
How long a patient goes before dying, being hospitalised for their pulmonary hypertension, or deteriorating in a pre-specified way
The endpoint the Parkinson's page wishes existed and the Crohn's stricture page cannot construct. It is worth noting what made it possible — events here are unambiguous, and a hospitalisation needs no instrument to detect.
The cheapest per success of the three scleroderma pages, because a programme in pulmonary arterial hypertension is among the likelier ones in medicine to reach approval. That figure describes the parent indication. It has never been earned in this subgroup specifically.
Two years, counting hospitalisations and deaths. The standard since 2013, and the reason a modern programme here costs several times what the walk-distance era cost — the trial has to run long enough for events to happen.
918 patient-years against 231 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 Longer than the symptomatic path, because antiremodelling agents are typically biologics with immunogenicity and long-half-life questions rather than small-molecule vasodilators. Conventional first-in-human design for a biologicmoderate confidence | 50 | 9 mo | 38 | $1.4M–$2.2M |
| Phase 2 | Dose-ranging with invasive haemodynamics on background therapy Reads: Change in pulmonary vascular resistance at 24 weeks, on top of established therapy Placebo-controlled add-on rather than monotherapy, because withholding effective treatment is no longer acceptable. That raises the bar: a new agent must beat a regimen rather than nothing. PULSAR (Humbert et al., NEJM 2021); STELLAR programme designhigh confidence | 180 | 1 yr | 180 | $5.8M–$9.5M |
| Phase 3 | One event-driven pivotal, median two years on study, blinded adjudication Reads: Time to first morbidity or mortality event Modelled smaller than SERAPHIN and GRIPHON, both of which enrolled 700 to 1,150 across the whole pulmonary arterial hypertension population. A trial restricted to this subgroup would be a fraction of that size — and no sponsor has ever run one, which is the point the page makes. Pulido et al., NEJM 2013 (SERAPHIN); Sitbon et al., NEJM 2015 (GRIPHON)moderate confidence | 350 | 2 yr | 700 | $18M–$31M |
| Total | 3.8 yr of clinical development, treating phases as sequential | 918 | $25M–$43M |
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 $4.8M–$7.6M, against published pivotal trial costs of $12–33M (median $19M) across all indications. The event-driven pivotal is the expensive part: two years on study rather than four months, which is what separates the post-2013 programmes from the walk-distance approvals that preceded them. Even so a single pivotal lands below the published all-indication median, because enrolment is modest and much of the cost is per-patient rather than per-patient-year. Moore et al., JAMA Internal Medicine 2018.
Programme cost divided by a 15% likelihood of approval from Phase 1 in pulmonary arterial hypertension — what one success costs once the failures are paid for. BIO / Informa / QLS, Clinical Development Success Rates — cardiovascular sits mid-table, and pulmonary arterial hypertension sits well above it on a record of fourteen approvals across four mechanistic classes.
Read this one carefully: The most heavily caveated number on this site, because it belongs to the parent indication rather than to this page. Programmes in pulmonary arterial hypertension succeed unusually often: the endpoints are accepted, the haemodynamics are measurable, and events accumulate fast enough to power a trial. None of that has ever been demonstrated in this population on its own, where treatment effects are consistently smaller. Read 15% as the odds of approval for a drug these patients will end up taking, not the odds of a drug proven in them.
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.
A first drug aimed at the remodelling rather than the tone, a screening algorithm that did more than any drug, and a trial nobody has run.
Every drug approved here before 2024 relieves vasoconstriction; the vessels keep closing regardless, which is why patients decline on full triple therapy. The activin inhibitor approved in 2024 is the first agent selected against obliterative remodelling in a model that produces obliterative lesions, and the first to show reversal of that remodelling in patients. Whether it does the same in this disease is unknown for the usual reason: this population was 15% of the trial. The relevant question for the next decade is whether a remodelling agent can help a right ventricle that was already fibrotic before the pressures rose.
Hoeper et al., NEJM 2023 (STELLAR); Humbert et al., NEJM 2021 (PULSAR)
Survival in this manifestation improved substantially over two decades, and the timing tracks the adoption of systematic annual screening at least as well as it tracks any individual approval. Patients found before symptoms start in a better functional class, and functional class at diagnosis is among the strongest predictors of how long they live. That result is uncomfortable for the way this site's other pages are usually read: the highest-return intervention in this disease required no new molecule and no new endpoint, only the decision to look.
Coghlan et al., Ann Rheum Dis 2014 (DETECT); registry survival trend analyses
There has been one dedicated randomised trial in this population, in 2000. The obstacles are real: eight to twelve percent of a rare disease is a very small population, and placebo control is now unethical because effective background therapy exists — any new trial must be an add-on. But subgroup analyses have shown a consistent shortfall for twenty years without anyone establishing whether the cause is the pulmonary vessels, coexisting lung fibrosis, or a heart that fails early because it is already fibrotic. Those three answers imply entirely different drugs, and the evidence to choose between them has never been generated.
Badesch et al., Ann Intern Med 2000; subgroup analyses across PAH pivotal trials