Zaltenibart in C3 glomerulopathy: a MASP-3 proof of concept ended by the asset sale

What was tried

Omeros opened NCT06209736 in March 2024 as an open-label, single-group Phase 2 proof-of-concept study of OMS906 (zaltenibart) in C3 glomerulopathy and idiopathic immune complex-mediated glomerulonephritis. Dosing was 5 mg/kg intravenously at four-week intervals. Entry required biopsy-confirmed C3G, including dense deposit disease, or ICGN within 36 months of screening, two 24-hour urine protein-creatinine ratios of at least 0.8 g/g collected 14 to 28 days apart, estimated GFR of at least 45 mL/min per 1.73 m2, subnormal screening serum C3, and 90 days on stable maximally tolerated RAAS blockade. The primary endpoint was adverse event counts over 48 weeks. Secondary endpoints were changes in proteinuria by 24-hour UPCR, protein excretion, albumin excretion and albumin-creatinine ratio. Actual enrollment was three participants. Primary completion is recorded as 14 April 2026, and the study was terminated with the stated reason that it was stopped for strategic reasons related to the molecule's recent acquisition.

The biological hypothesis

Zaltenibart (ChEMBL6068191) is an antibody against MASP-3, the serine protease encoded by MASP1 (ENSG00000127241). MASP-3 converts pro-factor D to mature factor D, and in resting human blood it is the only activator that does so (doi:10.1038/srep31877, doi:10.4049/jimmunol.1900605). Factor D is the rate-limiting protease of the alternative complement pathway amplification loop (doi:10.1111/imr.13155). Blocking MASP-3 therefore lowers the supply of active factor D and damps alternative pathway amplification at a node upstream of the C3 convertase, while leaving classical and lectin routes to C3b intact.

C3 glomerulopathy is defined by alternative pathway overactivation in the fluid phase and in the glomerular microenvironment, with prominent C3 deposition on biopsy (Open Targets disease description for MONDO_0018013). On that logic the target is well chosen. The genetic evidence, however, sits elsewhere. Open Targets returns no association record at all between MASP1 and MONDO_0018013, while the complement regulators and components score highly: CFH at 0.817, CFHR5 at 0.731, C3 at 0.647, CFHR1 at 0.585, CFB at 0.547 and CFI at 0.534. MASP1 is not flagged as an essential gene and sits in a loss-of-function tolerant constraint bin. Open Targets lists no clinical candidates against MASP1, so this was the only program of its kind in the platform's view.

What actually happened

There is no efficacy or safety readout. The study enrolled three participants across roughly 25 months and posted no results. The termination reason points outside the data.

Novo Nordisk announced on 15 October 2025 an asset purchase and license agreement giving it exclusive worldwide rights to zaltenibart in all indications, with up to 340 million dollars in upfront and near-term milestones, up to 2.1 billion dollars in total, and tiered royalties. That release states that Novo Nordisk aims to initiate a global Phase 3 programme for zaltenibart in paroxysmal nocturnal haemoglobinuria after closing, and that it will explore further development in a range of other rare blood and kidney disorders. It does not name C3 glomerulopathy as a committed indication. Omeros retained its unrelated preclinical MASP-3 programmes, including small-molecule inhibitors.

The molecule survived the transaction. This indication did not.

Failure mechanism, best guess

The archetype is a sponsor decision, and the proximate cause is documented in the registry text. Two pressures converged.

The first is portfolio consolidation after a change of control. Zaltenibart had completed Phase 1 and Phase 2 studies in PNH and had a Phase 3 path described by the acquirer. A single-arm, 48-week proof-of-concept study in an ultra-rare nephrology indication is the natural item to drop when an asset moves to an owner that has already said where it will run registrational work.

The second is that the competitive ground shifted while the study was open. Iptacopan, an oral factor B inhibitor acting at the same amplification loop, was tested in C3 glomerulopathy in APPEAR-C3G, a randomised, double-blind, placebo-controlled Phase 3 study with relative reduction in proteinuria at six months as the primary endpoint, reported in late 2025 (doi:10.1016/S0140-6736(25)01148-1). An intravenous antibody dosed every four weeks, acting one node further upstream, entered a market conversation that an oral agent had already reframed.

Enrollment deserves separate mention. Three participants in 25 months would have constrained this study regardless of the acquisition. The registry attributes the stop to the transaction, and that attribution should be taken at face value, but the enrollment figure means the study was not positioned to deliver an interpretable proteinuria signal either way.

How to prevent this next time

No endpoint data exist here, so the applicable levers are structural rather than statistical. A Bayesian update on three participants and no posted outcomes would manufacture precision the record does not contain.

Sequence indications by evidence density rather than by mechanistic elegance. PNH offered a direct pharmacodynamic readout, prior clinical experience and a defined regulatory path. C3G required a long proteinuria study in a biopsy-confirmed, ultra-rare population. Running both at once from a small balance sheet made the nephrology study the obvious casualty of any portfolio event.

Treat eligibility stacking as a quantitative feasibility risk before first patient in. The five entry filters here are each defensible. Stacked, in a disease with few eligible patients per centre, they produce an enrollment rate that can be estimated in advance from registry and biopsy-series data.

Separate target genetics from pathway genetics in the program thesis, and say so explicitly. The case for complement in C3G is strong and the case for MASP1 specifically is absent from Open Targets. That does not make MASP-3 the wrong node, but the burden of proof falls on pharmacodynamics, such as depth and duration of factor D suppression and serum C3 normalisation, which should be read out before a 48-week clinical endpoint is committed.

Finally, write indication continuity into partnering terms, including which studies survive a change of control.

The single highest leverage change would have been to gate the C3G study on a prespecified enrollment feasibility milestone and an interim factor D and C3 pharmacodynamic readout, rather than committing to a 48-week proteinuria design while the asset was in an active partnering process.

What this means for similar programs

The Claidex mechanism risk score for MASP1 after this entry is 32 of 100, band yellow: phase burden 8.05, archetype 2.0, recency 4.25, genetic deficit 15.0 and saturation 2.72. The shape is informative. The genetic-deficit term is at its ceiling because the platform records no MASP1 to C3G association, and the saturation term is near its floor because this is the only clinical program against the target. That is the profile of an undervalidated target rather than an exhausted one.

Terminations of this kind cost the field more than efficacy failures do. An efficacy failure retires a hypothesis. This one leaves the MASP-3 node in C3G untested, with no public data from the three dosed participants, while the pathway immediately downstream now has a Phase 3 readout.

Open questions

Will the new owner pursue C3 glomerulopathy, and under what design? Does MASP-3 inhibition suppress factor D enough to normalise serum C3 in C3G, and how does that compare with factor B inhibition? Will any data from the three dosed participants be reported? Does ICGN respond to proximal alternative pathway inhibition in the same way as C3G, given that the two were pooled in one arm here?

Sources

1. • ClinicalTrials.gov record for NCT06209736, Omeros Corporation, accessed 2026-11-08. https://clinicaltrials.gov/study/NCT06209736 - Open Targets Platform GraphQL API v4, target ENSG00000127241 (MASP1), disease MONDO_0018013 associated targets and disease description, accessed 2026-11-08. - ChEMBL molecule record CHEMBL6068191 (zaltenibart), accessed 2026-11-08. - Novo Nordisk and Omeros announce asset purchase and license agreement for Omeros' clinical-stage MASP-3 inhibitor zaltenibart (OMS906), 15 October 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916434 - Dobo J, et al. MASP-3 is the exclusive pro-factor D activator in resting blood. Sci Rep 2016.- Role of MASP-3 in the physiological activation of factor D of the alternative complement pathway. J Immunol 2019.- Factor D. Immunol Rev 2023.- Kavanagh D, et al. Oral iptacopan therapy in patients with C3 glomerulopathy: a randomised, double-blind, parallel group, multicentre, placebo-controlled, phase 3 study (APPEAR-C3G). Lancet 2025;406:1587-1598.- C3 glomerulopathy: consensus report. Kidney Int 2013.- openFDA FAERS queried for zaltenibart on 2026-11-08: no matching reports returned.