Insmed (Nasdaq: INSM) announced that it will discontinue development of brensocatib — an oral inhibitor of dipeptidyl peptidase 1 (DPP1) — in hidradenitis suppurativa (HS), after the Phase IIb CEDAR study failed to meet its primary or secondary efficacy endpoints at either tested dose. CEDAR does not support brensocatib as an effective therapy for HS, though the negative result does not by itself resolve whether DPP1 is irrelevant to the disease biology or whether the pathway was insufficiently modulated in this setting.
Trial specifics
CEDAR was a randomized, double-blind, placebo-controlled trial enrolling 214 adults with moderate to severe HS across 72 sites globally. Participants were assigned 1:1:1 to brensocatib 10 mg once daily, brensocatib 40 mg once daily, or placebo for 16 weeks, after which placebo recipients were re-randomized to one of the active arms. The primary endpoint was percent change from baseline in total abscess and inflammatory nodule count at Week 16. Safety and secondary efficacy measures were co-objectives of the proof-of-concept design.
The efficacy data were unambiguous in their direction. At Week 16, patients in the 10 mg arm showed a 45.5% reduction in abscess and inflammatory nodule count from baseline, and those in the 40 mg arm showed a 40.3% reduction — compared with a 57.1% reduction in the placebo group. Neither active arm met the primary endpoint, and Insmed said no secondary endpoints were met in either treatment group. The company said the study was designed as a proof-of-concept evaluation, and the results prompt a full exit from the HS program.
The placebo response magnitude warrants attention. A 57.1% reduction in the primary lesion count among placebo recipients is a figure that would represent a clinically meaningful outcome in its own right, and it substantially exceeded the active arms. The phenomenon is not without precedent in HS trials: the disease lacks validated preclinical models, as Insmed's chief medical officer Martina Flammer noted in the company statement, and the subjective and variable nature of lesion counting in a condition with fluctuating severity can amplify placebo effects. Whether the high placebo response reflects regression to the mean, assessment variability, or a genuine psychobiological response to trial participation cannot be determined from topline data alone. Full results are expected to be presented at a future medical congress, the company said.
The safety profile did not contribute to the discontinuation. Treatment-emergent adverse events occurred in 55.4% of patients in the 10 mg group, 42.9% in the 40 mg group, and 45.7% in the placebo group. Severe adverse events were reported in 1.4% of patients in the 10 mg arm and none in the 40 mg or placebo arms. Serious adverse events occurred in 4.1%, 1.4%, and 1.4% respectively. Insmed said the safety data were consistent with findings from prior brensocatib studies and that no new signals were identified, including at 40 mg — the highest dose the company has studied to date. The clean tolerability profile means the CEDAR outcome does not create safety overhang for brensocatib's use in other indications.
DPP1 in HS
Brensocatib works by inhibiting DPP1, a lysosomal cysteine protease that activates neutrophil serine proteases — including neutrophil elastase, proteinase 3, and cathepsin G — during granulocyte maturation in the bone marrow. By blocking this upstream activation step, the molecule was intended to reduce the protease burden carried by circulating neutrophils, dampening protease-mediated tissue injury and downstream inflammatory amplification. The rationale for testing this mechanism in HS was grounded in the disease's prominent neutrophilic infiltration: lesions in HS feature abscess formation and tissue destruction that neutrophil granule proteases could, in principle, sustain. The CEDAR data suggest that either DPP1-mediated protease activation is not a controlling driver of lesion activity as measured by AN count, or that the degree of pathway suppression achieved was insufficient to produce a detectable clinical signal against the backdrop of a large placebo response.
The HS program was always positioned as exploratory within Insmed's portfolio. The company's primary focus is brensocatib in non-cystic fibrosis bronchiectasis, where it received FDA approval in 2025 under the trade name Brinsupri as the first approved therapy for that indication and the first-in-class DPP1 inhibitor to reach the market. That approval, combined with Insmed's broader pipeline in pulmonary and inflammatory conditions, means the CEDAR failure carries limited strategic consequence for the company's near-term commercial trajectory. The HS program's discontinuation is consistent with a post-approval resource allocation strategy that concentrates investment on validated indications.
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