Treatment Possibilities in Fibrotic Diseases

Session Focus

Bonventre opened by noting the panel had far less time than the subject warranted, and dispensed with individual introductions so panelists could introduce themselves while answering.

His framing: fibrosis is estimated to account for or contribute to 45 percent of all deaths in the developed world, involving kidney, lung, liver, skin, heart and retina. Therapeutics have historically been very difficult to develop, but the field now sits at an inflection point where technology and varied approaches justify considerably more optimism.

Fibrosis as Continuum, Not End Stage

Frank Waldron-Lynch MD, PhD offered the reframing that anchored much of the discussion. He sees fibrosis less as an end stage and more as a continuum of inflammation.

The practical consequence is decisive. Treating fibrosis as an end stage makes it very difficult to treat. The productive questions concern the primary drivers of fibrosis and how to affect them.

His explanation for why this is an inflection point: the field finally has advanced therapeutics capable of addressing tissue-level immunity and clearing out the immune system. What follows is determining what residual disease remains in fibrotic tissue, what it looks like there, and how meaningful that is for patients. He expects this to dramatically change the trajectory of most fibrosis patients.

He overlaid Bonventre’s 45 percent figure with another: immune-mediated diseases account for roughly 50 percent of all disease. What the field is largely seeing is immune-mediated disease arriving at end stage. The questions become how to intervene earlier, how to treat with deeper immune therapeutics, and how to read out in patients to raise probability of success.

The Pulmonary Fibrosis Landscape

Sydney Montesi MD described rapid development since 2014, moving from the first demonstrated efficacy to a present in which multiple investigational therapeutics are entering early phase trials with a phase three readout coming soon.

She was precise about current limits. Three FDA-approved treatments exist for idiopathic pulmonary fibrosis, all shown to slow decline in forced vital capacity. None stops disease progression and none reverses it. The field is slowing the rate at which disease worsens.

That makes tolerability the main differentiator. Choosing among the three comes down to patient preference based on side effect profiles, which in some cases are significant, alongside dosing frequency, interactions and effects on comorbidity.

Bonventre, speaking as a nephrologist, said he has always envied pulmonologists for having a good biomarker.

Montesi explained why FVC decline works. Multiple longitudinal cohort studies associate it with morbidity, mortality and patient-reported outcomes, making it a surrogate tied to how patients feel, function and survive. Focusing on it rather than the composite endpoints used in the pre-antifibrotic era, covering acute exacerbation, categorical FVC decline, mortality or hospitalization, advanced the field. It also provides context for comparing new phase two results against placebo arm declines.

Organ-Specific or Pan-Fibrotic

Bonventre asked whether drug development should pursue agents working across organs given the conserved nature of fibrosis, or remain organ-specific.

Rahul Ballal PhD described the organizing principle for his company, which was born out of Mass General Brigham: pick registrational endpoints in proof of concept studies that justify moving to large-scale trials.

In practice that means FVC in the IPF study partnered with Lilly, now in phase two, and mRSS, a measure of skin thickening, in the systemic sclerosis phase two. Both are registrational endpoints.

Kidney is where he described the rubber meeting the road. Important surrogate endpoints exist, including biomarkers of kidney injury such as KIM-1 and NGAL, which Bonventre pioneered, and outcome-based surrogates including urine albumin-creatinine ratio. The difficulty is that outcome surrogates take a long time.

His summary of the challenge facing first-in-class therapies: how do you convince investors on the basis of a hundred-patient study that a 48-week registrational trial in 300 patients is worthwhile. Pick the registrational endpoints you can, and be inventive elsewhere.

Is Fibrosis Reversible

Montesi addressed when fibrosis becomes irreversible and when intervention is optimal.

Theoretically, earlier treatment should work better. The problem is that FVC can remain normal for a very long time in early disease, which raises both a scientific question about the optimal point in the continuum and a practical one, since an early trial requires a large sample size and longer follow-up.

On reversibility she described work with colleagues developing a type 1 collagen PET probe, used in a phase 2a study of a dual integrin inhibitor. After twelve weeks of treatment, lung uptake of collagen was numerically reduced, suggesting potential for favorable lung remodeling.

Her broader argument was for pairing a registrational endpoint like FVC with novel molecular assessments, because the collagen finding would have been invisible otherwise. Visual evidence of pharmacodynamic effect provides additional grounds for belief.

Ballal was direct that his company is trying to change the dogma that fibrosis is not reversible, building on Mass General Brigham investigators who believe targeting the myofibroblast, the key pathogenic cell laying down aberrant collagen extracellular matrix, can halt and possibly reverse progressive disease.

His supporting logic is that target levels rise as fibrosis progresses. WISP-1 is elevated in late-stage pulmonary fibrosis. Ephrin B2 is elevated in later-stage systemic sclerosis. SMOC2, with the highest clarity, is elevated in late-stage kidney disease where fibrosis is rampant. If the target is present and can be blocked, there is at least a shot at undermining the dogma.

AI and the Validation Bottleneck

Meredith Fisher PhD, a partner at Mass General Brigham Ventures and an investor in Mediar, identified the constraint as existing independently of AI.

The underlying challenge in fibrosis at scale is the fundamental biology, which depends on highly curated and extensive patient datasets. AI cannot resolve a target validation problem that rests on data the field does not yet have in adequate form.

Key Takeaways

1. Fibrosis contributes to an estimated 45 percent of deaths in the developed world, across at least six organ systems.

2. Treating fibrosis as end stage makes it intractable. Framing it as a continuum of inflammation locates treatable drivers earlier.

3. Immune-mediated disease accounts for roughly 50 percent of all disease, much of it arriving at fibrotic end stage.

4. Three approved IPF therapies slow FVC decline; none halts or reverses progression, so tolerability differentiates them.

5. A good surrogate endpoint advanced the lung field, which is what kidney fibrosis still lacks for practical trial design.

6. A collagen PET probe showed reduced lung uptake at twelve weeks, the first visual evidence of possible remodeling.

7. Target levels rise as fibrosis progresses, which is the basis for challenging the dogma that fibrosis is irreversible.