Disease indication · a behaviour of Crohn’s disease
The endoscope that solved luminal Crohn's cannot see this. Every approved drug targets inflammation; the scarring it leaves behind still sends patients to surgery.
Disease-modifying: Prevent, halt or reverse the collagen deposition that thickens and narrows the bowel wall. Nothing has ever been approved to do this in the intestine — not because nobody has tried a mechanism, but because there is no accepted way to demonstrate that a mechanism worked.
None anywhere in the world. The lung has two approved antifibrotics; the intestine has none, despite fibrosis being the dominant reason Crohn's patients reach an operating theatre.
There is no validated, regulator-accepted measure of intestinal fibrosis or its reversal. This — not the absence of candidate mechanisms — is what the field itself now identifies as the bottleneck.
Roughly half of Crohn's patients undergo surgery within ten years of diagnosis, and stricturing disease is the leading reason — a rate that modern biologics have reduced but not eliminated.
Under the Montreal classification most patients begin as non-stricturing, non-penetrating disease; about half convert to stricturing or penetrating behaviour over two decades. The disease's own taxonomy treats this as a distinct behaviour, not a complication.
Crohn's is classified by behaviour, not just by site — the Montreal system types it as inflammatory, stricturing or penetrating — and about half of patients who start with inflammation alone convert to one of the other two within twenty years. The three respond very differently to the drugs on this site, and the numbers on any one of these pages describe only its own column.
Mucosal and transmural inflammation of the bowel wall. Five approved mechanisms, and the behaviour every current drug was developed against.
Fibrotic narrowing of the bowel. The leading reason Crohn's patients reach an operating theatre, and the behaviour no drug has ever been approved to treat.
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Fistulas tunnelling through the bowel wall to other organs or the skin. Anti-TNF genuinely helps, and a locally injected cell therapy was approved in Europe and then withdrawn when its confirmatory trial failed.
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The split is the field's own, not an editorial one. It matters here because every approved Crohn's mechanism was developed and measured against the first column: the endoscope that made luminal disease tractable reaches the mucosa, which is exactly where the other two behaviours are not.
Nothing here is accepted, and the reason is mechanical rather than statistical. Parkinson's cannot separate a disease-modifying effect from symptom relief. This disease has a blunter problem: on every available instrument, inflamed bowel and scarred bowel look substantially alike — and the fibrosis is transmural, so the endoscope that solved the luminal disease cannot reach it.
No endpoint is accepted as establishing disease-modifying benefit in Fibrostenotic Crohn's Disease. Every measure below is either contested or exploratory. A trial can therefore succeed on its own terms and still not support the claim.
| Endpoint | Type | Read at | Standing |
|---|---|---|---|
| Fibrosis reversal or stabilisation | Composite | 52+ weeks | None accepted |
| MR / CT enterography stricture morphology | Imaging | 26–52 weeks | Exploratory |
| Intestinal ultrasound | Imaging | 8–52 weeks | Exploratory |
| Surgery-free and obstruction-free survival | Clinician-rated | 1–5+ years | Contested |
Two models here reproduce genuine intestinal fibrosis, and neither has ever carried a drug to a readout — because there is nothing to carry one to. When no endpoint exists, model validity stops being the binding constraint, and this matrix should be read as untested rather than as failed.
| Model | FaceDoes it look like the disease? | ConstructDoes it arise the same way? | PredictiveReverse fibrosis |
|---|---|---|---|
The shortest ledger on this site, and the emptiness is the finding. No antifibrotic has ever been approved for the gut, and the entries below are mostly things that treat the inflammation alongside the fibrosis without touching the fibrosis itself.
| Intervention | Rested on | Primary endpoint | Reached | Outcome |
|---|---|---|---|---|
Antifibrotic repurposing from other organs Various · Agents targeting TGF-β signalling, ROCK, LOXL2 and related fibrogenic pathways | Chronic DSSHuman myofibroblasts | No agent has reached a controlled trial with a fibrosis endpoint in this disease | Preclinical / exploratory 2024 | Ongoing |
Early combined immunosuppression strategy Investigator-led · Treating to a target of mucosal healing early, before fibrosis accumulates | Mucosal healing and clinical remission; stricture and surgery rates as longer-term secondary outcomes | Phase 3 strategy trials REACT and related treat-to-target programmes · 2015 | Benefit, no approval | |
TNF inhibitors Multiple · Neutralisation of tumour necrosis factor | Chronic TNBSChronic DSS | No trial has used a fibrosis endpoint; evidence comes from stricture-related surgical rates as secondary or observational outcomes | Observational for this indication 2010 | Benefit, no approval |
Whether the collagen deposition narrowing the bowel has been halted or reduced
The reason this page exists. Every mechanism below was tested against inflammation because inflammation is what the field could measure.
Every figure here is hypothetical, because you cannot size a pivotal trial against an endpoint that does not exist. What the model can show honestly is the shape of the problem: a long trial, an imaging endpoint nobody has validated, and a likelihood of approval with no precedent to anchor it.
Entirely hypothetical — no antifibrotic has ever run a controlled trial with a fibrosis endpoint in this disease. What the model can show is the shape such a trial would need: large, and long enough to outlast the years over which strictures actually form. That duration, not the headcount, is what makes it the second most expensive disease-modifying programme on this site.
1,618 patient-years against 225 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 The one phase here that is not hypothetical in design, because it does not depend on being able to measure fibrosis. Conventional first-in-human designmoderate confidence | 50 | 9 mo | 38 | $1.4M–$2.2M |
| Phase 2 | Dose-ranging against an imaging endpoint Reads: Change in stricture morphology on cross-sectional imaging or ultrasound elastography A full year, because fibrosis does not move on the timescale inflammation does — and read against an endpoint nobody has validated, which is the reason no sponsor has run this trial. Hypothetical; no antifibrotic Phase 2 has been run in this diseaselow confidence | 180 | 1 yr | 180 | $5.8M–$9.5M |
| Phase 3 | Two pivotals, two years, imaging plus surgery-free survival Reads: Stricture morphology on imaging, with obstruction-free and surgery-free survival Two years is the floor for a structural claim in a disease whose strictures form over years, and it is what makes this programme cost more than any other on this site except Parkinson's disease modification. The endpoint it would read does not yet exist. Hypothetical; sized by analogy with antifibrotic programmes in other organslow confidence | 350 × 2 | 2 yr | 1,400 | $36M–$62M |
| Total | 3.8 yr of clinical development, treating phases as sequential | 1,618 | $44M–$73M |
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 $4.0M–$6.4M, against published pivotal trial costs of $12–33M (median $19M) across all indications. The symptomatic column here is procedural — dilation and surgical series rather than drug trials — so it lands far below the published range, which is set by pharmaceutical programmes. The disease-modifying column is hypothetical throughout: no trial of this shape has ever been run in this disease. Moore et al., JAMA Internal Medicine 2018.
Programme cost divided by a 5% likelihood of approval from Phase 1 in intestinal fibrosis (no observed programme history) — what one success costs once the failures are paid for. Not a published figure. No antifibrotic has ever run a registrational programme in the intestine, so there is no denominator from which a rate could be computed.
Read this one carefully: The most speculative number on this site, and stated as an assumption rather than a citation. It is set below every observed rate here on the reasoning that a field with no accepted endpoint cannot reliably demonstrate success even with a working drug — the constraint this whole page is about. Treat the resulting risk-adjusted figures as an illustration of what an absent endpoint costs, not as a forecast.
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 has worked out that the endpoint is the bottleneck, and is building one — which is roughly where ulcerative colitis stood in the 1980s and where DM1 stands now.
Dedicated consortium work is now attempting what this disease has never had: an agreed definition of a stricture, an agreed way to measure it, and an outcome regulators would accept. Getting that right is the precondition for everything else, and it puts this disease roughly where ulcerative colitis stood before the Mayo score and where DM1 stands with its splicing surrogate today.
Consortium initiatives on stricture definition and outcome measurement in Crohn's disease
Shear-wave elastography measures tissue stiffness directly rather than inferring it from thickness, which is the one thing every current instrument fails at. If it can reliably distinguish a fibrotic stricture from an inflamed one at the bedside, the measurement problem that defines this page becomes tractable — with the same operator-variability hurdle that central blinded reading had to solve for the endoscope.
Shear-wave elastography validation studies in Crohn's strictures
Fibrosis is being treated successfully in the lung and pursued hard in the liver and kidney, drawing on largely shared pathways. The intestine is the conspicuous gap, and the reason is not that intestinal fibrosis is more mysterious — it is that the other organs have measurable endpoints. Lung fibrosis has spirometry; liver fibrosis has biopsy and increasingly elastography. The bowel has neither.
Cross-organ antifibrotic development literature