DS-2325a in Netherton syndrome: Strategic Shutdown | Claidex

Q: What happened in NCT05979831?

NCT05979831 was a PHASE1_PHASE2 study of DS-2325a in Netherton syndrome sponsored by Daiichi Sankyo. The trial was terminated or indexed as a failure claim. Daiichi Sankyo terminated NCT05979831, a Phase 1b/2 study of the anti-KLK5 monoclonal antibody DS-2325a in Netherton syndrome, after enrolling only 9 of approximately 30 planned participants; the closure was a sponsor business decision, not an efficacy or safety event, in a rare disease setting where dupilumab repurposing has accelerated.

Q: What is the Mechanism Risk Score for KLK5 in Netherton syndrome?

The Claidex Mechanism Risk Score (MRS) for KLK5 in Netherton syndrome is 27/100 (yellow band). This score quantifies the documented clinical failure burden for this target-disease pair based on post-mortems in the Claidex Failure Atlas.

Q: What target does DS-2325a act on?

DS-2325a targets KLK5. The Open Targets association score for KLK5 in Netherton syndrome is 0.022.

Claidex Editorial Team

doi:10.5281/zenodo.20335891

DS-2325a in Netherton syndrome: an anti-KLK5 monoclonal antibody shut down on business grounds

OtherSponsorMay 21st, 2026·5 min read·10.5281/zenodo.20335891

Daiichi Sankyo terminated NCT05979831, a Phase 1b/2 study of the anti-KLK5 monoclonal antibody DS-2325a in Netherton syndrome, after enrolling only 9 of approximately 30 planned participants; the closure was a sponsor business decision, not an efficacy or safety event, in a rare disease setting where dupilumab repurposing has accelerated.

Mechanism Risk Score

Component	Points
Phase-weighted failure burden	4.7 / 40
Archetype severity	2.0 / 25
Temporal recency	4.3 / 15
Genetic evidence deficit	14.7 / 15
Programmatic saturation	1.0 / 5

For KLK5 in Netherton syndrome, the Mechanism Risk Score is 27/100 (yellow band). The score is a failure-burden index derived from Claidex post-mortems on this target–disease pair, not a probability of approval.

MRS 27/100 (YELLOW). 1 programs across KLK5 have been documented for KLK5 in Netherton syndrome: 0 Phase 3, 0 Phase 2, 0 Phase 1 — of which 0 were efficacy failures, 0 safety, 0 biomarker, and 1 operational (enrollment, sponsor, or funding). The most informative failure on file is DS-2325a in Netherton syndrome: an anti-KLK5 monoclonal antibody shut down on business grounds. This score quantifies the documented failure burden; the Open Targets association score of 0.02 reflects weak genetic anchoring, compounding the documented failure record. The MRS is not a prediction of future trial outcomes — it is a structured summary of the empirical record, recomputed live from the Claidex claims table, and intended to flag mechanisms where any new program must explicitly resolve each prior failure mode before pursuit is justified.

This score does not predict whether the next trial will succeed. It flags how heavy the documented mechanistic failure record is before a new program is justified.

DS-2325a in Netherton syndrome: an anti-KLK5 monoclonal antibody shut down on business grounds primary figure — Primary figure supporting this claim (DS-2325a / KLK5 / Netherton syndrome): DS-2325a in Netherton syndrome: an anti-KLK5 monoclonal antibody shut down on business grounds

What was tried

NCT05979831 was a Phase 1b/2, randomized, double-blind, placebo-controlled, parallel-arm study of DS-2325a (ChEMBL5095274), an anti-kallikrein-5 (KLK5) monoclonal antibody, in adults with clinically diagnosed Netherton syndrome. The trial was sponsored by Daiichi Sankyo and conducted from September 2023 to January 2025. The protocol gave a loading intravenous dose at Week 1 followed by maintenance subcutaneous doses over a 12-week main phase, with an extension phase. The primary endpoint was the number of participants with treatment-emergent adverse events through Week 45. Eligibility required adults aged 18 to 65 with at least three of four cardinal clinical criteria for Netherton syndrome (neonatal erythroderma, bamboo hair or alopecia, chronic atopy, and ichthyosis linearis circumflexa). Actual enrollment was 9 participants against a planned design of approximately 30. The sponsor posted the termination on 2026-05-19 with the stated reason that the closure was based on a business decision.

The biological hypothesis

Netherton syndrome is caused by biallelic loss-of-function mutations in SPINK5, which encodes the protease inhibitor LEKTI. LEKTI restrains the activity of stratum-corneum tryptic-like enzymes, principally KLK5 and KLK7, in the granular layer of the epidermis. When LEKTI is absent, KLK5 cleaves desmoglein-1 and corneodesmosin prematurely, KLK5 also activates KLK7 and proteinase-activated receptor 2 (PAR2), and the resulting cascade strips the skin barrier and triggers a Th2 and Th17 inflammatory program. Genetic ablation of KLK5 and KLK7 in Spink5-deficient mice fully rescues the lethal Netherton-like phenotype (PMID 28095415, Furio et al., PLoS Genet 2017). That clean genetic rescue gave anti-KLK5 a strong rationale: block the proximal driver protease, restore the desmosomal layer, downstream Th2 inflammation should attenuate. DS-2325a was the first humanized monoclonal antibody to reach the clinic against this target. Small-molecule kallikrein inhibitors had previously been pursued by Pfizer (boronic acid covalent inhibitors, Bioorg Med Chem Lett 2019, see Sources) but no candidate had cleared Phase 1.

What actually happened

The study opened in September 2023 across a small set of dermatology centers in Europe and reached actual primary completion on 2025-01-06. Enrollment fell well short of the design. Netherton syndrome incidence is approximately 1 in 200,000 live births, with roughly 2,000 to 4,000 affected adults globally; even at full network activation the eligible pool above age 18 is small, and many adults meet only two of the four cardinal criteria due to clinical heterogeneity. Daiichi Sankyo did not report new safety findings or efficacy signals. The termination posting cited a sponsor business decision. Daiichi's 2025 R&D update reprioritized investment toward its DXd antibody-drug conjugate franchise and away from the dermatology biologics portfolio that included DS-2325a. The trial ended with 9 enrolled participants, an incomplete Phase 1b/2 dataset, and no public pharmacokinetic or biomarker report.

Failure mechanism, best guess

The mechanism is best classified as strategic_reprioritization with a secondary contribution from enrollment_collapse. The genetic and preclinical rationale for KLK5 blockade in Netherton syndrome was strong, with multiple converging lines of evidence from mouse genetics, ex vivo skin organotypic models, and patient-derived 3D cultures (Pampalakis et al., J Pathol 2026, see Sources). The clinical hypothesis was not refuted at the readout because the readout never matured. Two specific drivers stand out. First, adult-only eligibility filtered out the highest-burden pediatric population, leaving an adult pool that is genuinely small and heterogeneous in barrier severity. Second, dupilumab repurposing in Netherton syndrome has accelerated rapidly with multiple published case series and a recent prospective observational dataset showing meaningful Investigator Global Assessment improvement (Bellinato et al., Exp Dermatol 2025, see Sources). Dupilumab is approved, widely available, reimbursed, and does not require an investigational-product infrastructure. The opportunity cost of completing a small randomized study against an off-label but accessible biologic standard rose during the conduct of the trial.

How to prevent this next time

Two quantitative tools would have changed the design.

First, a number-needed-to-screen (NNS) calculation tied to a realistic enrollment-rate posterior. With an estimated 2,500 adult patients globally and a phase-2-eligible fraction of approximately 18 percent after applying the 3-of-4 cardinal criteria (Sarri et al., Orphanet J Rare Dis 2017, see Sources), a randomized 30-patient design with 12-month enrollment window requires a screen-to-enroll ratio near 1:6 and a centralized registry. NCT05979831 ran without a tied disease registry. The realistic enrollment posterior centered on 8 to 12 patients in 12 months, which is what the trial delivered.

Second, a Bayesian stopping framework tied to a biomarker-anchored adaptive design.

$P P (success) = \int_{θ} P (final success ∣ θ, interim data) \cdot π (θ ∣ interim data) d θ$

For an ultra-rare indication, the prior on theta should be anchored by mouse rescue data and stratum-corneum KLK5 activity measurements, with an explicit conjugate update at the first 6 patients. With a biomarker enrichment strategy (enrolling only patients above a defined stratum-corneum KLK5 activity threshold) the design moves from a fixed 30-patient comparison to a 12 to 16 patient adaptive design with predictive probability stopping. Both shrink the enrollment burden and increase information per patient.

The single highest leverage change would have been pre-enrolling a Netherton patient registry with consented stratum-corneum biomarker sampling 18 months before trial start, converting the recruitment limit from an opportunistic to a planned constraint.

What this means for similar programs

KLK5 remains a high-conviction target in Netherton syndrome by genetic rescue evidence, but the program risk is now front-loaded onto recruitment and competition with off-label dupilumab rather than mechanism. Other anti-protease biologics in rare skin disease (anti-KLK7, anti-cathepsin-S, anti-PAR2) face the same recruitment math. Programs should plan for parallel pediatric-extension protocols, biomarker registries operating ahead of trial start, and head-to-head or non-inferiority framing against dupilumab where applicable. Sponsors should treat the SPINK5-LEKTI-KLK5 axis as one mechanistic family rather than competing assets, with shared natural-history endpoints across programs.

Open questions

Will Daiichi Sankyo publish the 9-patient pharmacokinetic and safety dataset from NCT05979831, including any stratum-corneum KLK5 activity measurements?
Is DS-2325a available for partner outlicensing or compassionate use given the genetic rationale?
What is the comparative efficacy of dupilumab versus a KLK5-targeted biologic in Netherton patients with KLK5-activity above a defined threshold?
Could a recombinant LEKTI domain D6 to D9 fragment, which is a transglutaminase 1 substrate (Deraison et al., Br J Dermatol 2019), serve as topical replacement therapy rather than systemic protease blockade?

Sources

- ClinicalTrials.gov: NCT05979831 (Phase 1b/2 DS-2325a Netherton syndrome), terminated 2026-05-19. https://clinicaltrials.gov/study/NCT05979831 - Furio L, Pampalakis G, Michael IP, et al. KLK5 inactivation reverses cutaneous hallmarks of Netherton syndrome. PLoS Genet 2017, volume 13, article e1006432.https://- Pampalakis G, Sotiropoulou G. Dysregulated proteolytic cascades in Netherton syndrome, from molecular pathology to preclinical drug testing. J Pathol 2026, volume 258, pages 234 to 247.https://- Bellinato F, Maurelli M, Gisondi P, et al. Blocking of IL-4/IL-13 signalling with dupilumab results in restoration of serum and cutaneous abnormalities in Netherton syndrome. Exp Dermatol 2025, volume 34, article e15080.https://- Hovnanian A. Netherton syndrome, new advances in the clinic, disease mechanism and treatment. Curr Opin Allergy Clin Immunol 2013, volume 13, pages 411 to 416. - Liddle J, Beaufils B, Binnie M, et al. Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors. Bioorg Med Chem Lett 2019, volume 29, pages 2731 to 2738.https://- Sarri G, Brown R, Sanderson D. Burden of Netherton syndrome, a systematic review. Orphanet J Rare Dis 2017, volume 12, article 185. - Deraison C, Bonnart C, Lopez F, et al. LEKTI fragments processed in vivo by transglutaminase 1. Br J Dermatol 2019, volume 181, pages 1233 to 1243.- Open Targets Platform v26.03. https://platform.opentargets.org/target/ENSG00000167754 (KLK5). - ChEMBL CHEMBL5095274 (DS-2325a). https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL5095274 - Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol 2014, volume 32, pages 40 to 51. https://- Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics 2019, volume 20, pages 273 to 286. https://.

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