Respiratory & fibrosis
12 articles
Windward Bio files for Nasdaq IPO to fund China-derived assets and in-house R&D
- Basel-based Windward Bio filed an F-1 to list shares on the Nasdaq Global Market under the symbol WWB; pricing terms are not yet set.
- Its pipeline draws on ex-China rights licensed from Chinese companies including Kelun-Biotech, Harbour BioMed and Qyuns Therapeutics.
- The company closed a $165 million crossover round led by OrbiMed in May 2026.
A $165M crossover in May followed by an F-1 five months later is the classic window-testing playbook, and Windward is betting investors will pay for China-sourced ex-China rights without the discount once attached to them. Sourcing from Kelun-Biotech, Harbour BioMed and Qyuns gives it a cheap, fast pipeline, but little proprietary edge beyond execution; the in-house R&D pitch is how it tries to change that.
Windward Bio files for Nasdaq IPO to fund China-derived assets and in-house R&D ↗
Silicon-containing tubastatin A analogs yield selective HDAC3 inhibitor for liver fibrosis
- Tubastatin A was redesigned by changing both the cap group and the zinc-binding motif, introducing silicon-containing alkyl hydrazides to steer selectivity toward HDAC3.
- Lead compound 6b inhibited HDAC3 at low-nanomolar potency with clear selectivity over HDAC5, HDAC6 and HDAC8, and docking supported the binding mode. It showed antifibrotic effects in TGF-β-stimulated stellate and sinusoidal endothelial cell models, with favorable ADMET properties.
- In a CCl4 mouse liver fibrosis model, 6b lowered liver enzymes and fibrosis markers and improved histology, outperforming tubastatin A and nintedanib; it appeared to act by dampening TGF-β/Smad signaling via altered histone acetylation.
Changing both cap and zinc binder on an HDAC6-leaning scaffold and ending up HDAC3-selective is a clever pivot, and a silicon alkyl hydrazide is a chemotype I would happily add to my own collection. Still, I doubt docking alone proves the selectivity, and hydrazides raise metabolic and safety questions under chronic dosing. Beating nintedanib in a single CCl4 model encourages without settling anything.
Antibody blocking the ZIP12 zinc importer curbs pulmonary artery cell remodeling and shows early clinical tolerability
- ZIP12 is a zinc importer elevated in remodeled pulmonary arterioles in PAH; raising it in human smooth muscle cells increased free intracellular zinc and drove proliferation, while knockdown eased disease in rodents.
- The humanized antibody APL-9796 restored zinc levels and dampened proliferation, cytoskeletal change and contractility in patient-derived fibroblasts, smooth muscle cells and engineered artery tissue.
- In humanized Slc39a12 rats it improved cardiopulmonary readouts in a dose-dependent way, and it was well tolerated in phase 1 studies; transcriptomics implicated AMPK, PPAR and PI3K-Akt pathways.
Upregulation in human tissue and rodent knockdown support ZIP12, but without human loss-of-function genetics the validity case stays correlative. The humanized rat is also a convenient fit for the antibody, and the readouts do not show how much ZIP12 is engaged in remodeled arterioles. Phase 1 tolerability is not efficacy, so the translational gap in PAH remains wide open.
Targeting ZIP12-mediated Zn2+ signaling as a treatment for pulmonary hypertension ↗
Inhaled-by-design pyrrolopyrimidine DDR1/2 inhibitors target pulmonary fibrosis
- Structure-based design delivered two 5:6 heterocyclic series with strong DDR1/DDR2 affinity and a promising kinome selectivity profile.
- An inhaled-by-design strategy then tuned potency, physicochemical and in vitro ADME properties toward lung-restricted compounds.
- Compound 25 combined antifibrotic activity in a TGF-β-induced in vitro fibrosis model with a favorable pharmacokinetic profile for local delivery.
Inhaled kinase inhibitors live or die on lung retention versus systemic clearance, and designing for that from the start is the right call rather than retrofitting a systemic compound. The pitfalls I'd watch are lysosomal trapping and mucociliary clearance, which in vitro ADME rarely captures. DDR biology is compelling in fibrosis, but it's still a target waiting for clinical validation.
Lung-Tailored Pyrrolo-pyrimidine DDR Inhibitors Designed for Optimized Local Delivery ↗
YKS-34: a PDE4B inhibitor with >1000-fold isoform selectivity for pulmonary fibrosis
- The authors set out to improve on the only approved PDE4B-preferential drug, nerandomilast, which is only about 9-fold selective over PDE4D.
- YKS-34 is a potent PDE4B inhibitor with more than 1000-fold selectivity over PDE4A, PDE4C and PDE4D.
- It suppressed TGF-β-driven fibroblast activation and LPS-induced TNF-α release in vitro, and showed favorable PK with accumulation in lung tissue.
PDE4D inhibition is what drives nausea and vomiting, so going from 9-fold to over 1000-fold is the right kind of optimization to chase. The pocket differences between B and D are tiny, which makes me curious what the binding mode looks like. I'd want to see this in a bleomycin model with a therapeutic dosing regimen before getting too excited.
Lactam bridge replaces oxidation-prone thioether in an IL-11 antagonist peptide
- The oxidation-sensitive thioether in an IL-11-binding peptide was replaced with a lactam bridge, with linker length screened systematically.
- The optimized analog 4L6–16 bound IL-11 with good affinity and antagonized it more strongly than the starting peptide.
- It showed renoprotective effects in both cell and animal models of renal fibrosis.
Swapping a thioether for a lactam is a textbook peptide-stability fix, and it's encouraging that it also improved antagonism rather than just shelf life. Binding in the mid-nanomolar range leaves room to tighten, and proteolytic stability in plasma is the next number I'd ask for.
Development of a Lactam-Bridged Peptide as Interleukin-11 Antagonist for Renal Fibrosis Treatment ↗
DNMT1 PROTAC B7 blocks catalytic and scaffolding roles in liver fibrosis
- DNMT1 drives fibrogenesis through both catalytic and non-catalytic mechanisms, so the team built PROTAC degraders starting from DC-517 to hit both at once.
- Lead compound B7 mediates ubiquitin-proteasome degradation of DNMT1, lowers global DNA methylation and suppresses profibrotic responses in vitro.
- In vivo, B7 reduced DNMT1 levels and attenuated liver fibrosis, with less collagen deposition and better hepatic function.
DNMT1 is a textbook case for degrading rather than inhibiting, because an active-site inhibitor leaves the scaffolding role untouched. My worry is selectivity for liver and what removing an essential maintenance methyltransferase does in dividing tissue; fibrosis models are forgiving on both counts.
Property-driven design yields inhaled sGC stimulator frespaciguat for PH-COPD
- Oral sGC stimulators can cause systemic hypotension and worsen ventilation-perfusion mismatch in PH-COPD, motivating a lung-restricted design.
- SAR and PK work identified high systemic clearance and low permeability as the key drivers of pulmonary selectivity.
- Compound 15 (frespaciguat, MK-5475) is a very potent stimulator with long target residence time and more than 200-fold unbound lung-to-plasma exposure after inhalation, with efficacy in a rat chronic hypoxia model.
Designing for high clearance and low permeability on purpose is the opposite of oral-drug instinct, which is exactly why this paper is useful for inhaled programs. Residence time plus lung retention is the combination I'd want to see replicated before believing the therapeutic window in humans.
CSL pays $355M upfront to co-develop Alentis' anti-Claudin-1 antibody lixudebart
- CSL will pay $355 million upfront, plus up to $1.2 billion in commercial milestones, to co-develop and co-commercialize the anti-Claudin-1 antibody lixudebart.
- Profits split 55% CSL and 45% Alentis; CSL funds the ongoing phase 2 in ANCA-associated vasculitis with rapidly progressive glomerulonephritis and a phase 3.
- Phase 2 studies in focal segmental glomerulosclerosis and primary sclerosing cholangitis are also planned.
A 55/45 profit split with a $355M upfront is unusually rich for a phase 2 asset, and it tells me CSL wants a nephrology franchise on real terms. Alentis keeps a meaningful economic stake instead of a royalty. The multi-indication plan across kidney and liver is the bet: one Claudin-1 mechanism, several fibrotic diseases.
CSL pays $355M to co-develop Alentis' phase 2-stage fibrosis drug ↗
FDA Widens Winrevair's Reach to Newly Diagnosed PAH Patients
- The FDA approved an updated label for Merck's Winrevair (sotatercept-csrk) incorporating Phase 3 HYPERION trial data in adults recently diagnosed with pulmonary arterial hypertension.
- The trial found that adding Winrevair to background therapy substantially lowered the risk of clinical worsening events versus placebo.
- The update supports earlier use of Winrevair in the PAH treatment journey, marking the drug's third positive Phase 3 study.
Earlier-line positioning is what actually moves Winrevair's addressable market: shifting from a background-therapy add-on to newly diagnosed patients sets up a genuine first-line challenge to United Therapeutics' oral PAH franchise, and a third consecutive positive Phase 3 makes this look like a durable platform rather than a one-hit trial.
Merck nabs updated FDA label for soon-to-be-blockbuster Winrevair ↗
Sionna Therapeutics Cuts 46% of Staff After Cystic Fibrosis Add-On Drug Fails Trial
- Sionna Therapeutics is cutting approximately 46% of its workforce as part of a broader strategic restructuring.
- The move follows the failure of a clinical trial testing SION-719, an NBD1 stabilizer, as an add-on cystic fibrosis (CF) therapy.
- SION-719 was tested alongside Vertex Pharmaceuticals' Trikafta in CF patients homozygous for the F508del mutation.
- The trial did not produce a statistically significant reduction in sweat chloride, a standard biomarker used to gauge CFTR modulator efficacy in CF.
- Sionna's program had aimed to build on and improve outcomes beyond the market-leading Trikafta regimen.
- The layoffs and pipeline reprioritization mark a strategic shift for the company following this clinical setback.
Trikafta's add-on moat just claimed another name. SION-719 joins a growing list of CF programs that have failed to clear the sweat-chloride bar once layered on top of triple-combo therapy — a pattern that says less about any one company's execution and more about how close to a ceiling Trikafta already sits. That's the more interesting read for the mechanism itself: NBD1 stabilization is scientifically rational (Vertex runs its own NBD1 programs internally), yet delivering a clean, statistically significant delta on top of an already-near-maximal correction is proving brutally hard across the class, not just for Sionna. A 46% headcount cut is not routine trimming — it's a company betting its remaining cash runway on a sharply narrowed, likely earlier-stage pipeline rather than continuing broad-front development. Net effect for the competitive landscape: one fewer credible Trikafta challenger, which further entrenches Vertex's CF monopoly and eases pressure on both its pricing power and its own pipeline urgency.
Sionna lays off 46% of workforce in strategic shift after cystic fibrosis trial fail ↗
Tozorakimab Notches Third Phase III Win in COPD
- AstraZeneca reported full results from two Phase III trials, OBERON and TITANIA, testing tozorakimab, an anti-IL-33 monoclonal antibody, added to standard inhaled therapy for chronic obstructive pulmonary disease (COPD).
- Across both trials, tozorakimab substantially cut moderate-to-severe exacerbation rates versus placebo in former smokers, with meaningful reductions also seen in a broader population including current smokers.
- The antibody is engineered to engage two separate IL-33 signaling pathways at once, a mechanism AstraZeneca positions as differentiating it from earlier single-pathway IL-33 drugs.
- This marks tozorakimab's third positive Phase III readout; results were presented at the European Respiratory Society Congress in Barcelona and published simultaneously in the New England Journal of Medicine.
- AstraZeneca is targeting US regulatory approval, expected in early 2027.
Three-for-three in Phase III is the real headline here — a track record like that de-risks tozorakimab in a way single-pathway IL-33 rivals (think itepekimab, astegolimab) can't yet match, strengthening AstraZeneca's hand with regulators and payers alike. The dual-pathway engineering pitch is the commercial wedge: as COPD biologics get crowded, "we hit both arms of IL-33 signaling" is a differentiation story sales teams can actually use. Strategically, this is AstraZeneca building a respiratory biologics franchise in a market that's long been underserved beyond inhalers — COPD's patient pool dwarfs severe asthma's. And running NEJM publication simultaneously with the ERS presentation isn't routine; it's a credibility move, front-loading peer-reviewed validation well ahead of the 2027 filing to pre-empt scrutiny.
AstraZeneca's faith in IL-33 inhibitor continues to pay off with latest phase 3 COPD win ↗