Cardiovascular & renal
15 articles
Ferulic acid-based PROTAC degrades TLR4 to protect endothelial cells
- Six PROTACs built on ferulic acid, a weakly active natural product, were tested for TLR4 degradation and migration in HUVECs.
- The lead, FP-4, degraded TLR4 and dampened TLR4/MyD88–NF-κB signaling plus TNF-α, ICAM-1 and VCAM-1 expression.
- Protection was also seen in zebrafish, extending PROTAC use beyond oncology.
Using a PROTAC to rescue a weak natural-product binder is clever, but TLR4 is a membrane receptor and the evidence here is thin on which E3 ligase is engaged and on ternary-complex dependence. I'd ask for rescue experiments with ligase and proteasome inhibitors before believing the mechanism.
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 ↗
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 ↗
Novo bets up to $1.4B on Orbis's oral macrocycle platform
- Orbis Medicines signed a multi-target discovery and license deal with Novo Nordisk worth up to $1.4B in upfront and milestone payments plus tiered royalties.
- Novo also takes a strategic equity stake in the private Copenhagen company; this is Orbis's first pharma partnership.
- The work uses Orbis's AI-enabled nGen platform to make macrocycles aimed at turning injectable cardiometabolic therapies into orals.
- Orbis reported preclinical oral bioavailability up to 18%; targets and disease areas beyond cardiometabolic were not disclosed.
This is Novo hedging its oral strategy beyond small-molecule GLP-1s and oral semaglutide: macrocycles are the bet that peptide-like potency can survive the gut. The headline number is mostly milestones, so the real signal is the equity stake and a multi-target structure that lets Novo test the platform cheaply. Lilly is also an Orbis backer, which tells you both obesity leaders want the same oral-peptide option.
Lilly-backed Orbis does up to $1.4B macrocycle deal with Novo ↗
Sefaxersen Hits Primary Endpoint in Phase 3 IgA Nephropathy Trial, Opening Path to Accelerated Approval
- Sefaxersen, Ionis's antisense oligonucleotide suppressing liver complement factor B, met the primary endpoint of Roche's Phase 3 IMAgINATION trial in high-risk primary IgA nephropathy.
- A prespecified interim analysis of 459 patients (1:1 randomized) showed statistically significant, clinically meaningful proteinuria reduction (24-hour UPCR) vs. placebo at week 37.
- The once-monthly, self-administered subcutaneous drug could support accelerated approval in a crowded IgAN market that already includes sparsentan.
Complement factor B suppression becomes a third distinct mechanism validated in IgA nephropathy, joining sparsentan's endothelin/AT1 blockade and the B-cell/APRIL plays from atacicept and sibeprenlimab; convergent proteinuria data across mechanisms suggests the market fragments by dosing convenience, not efficacy. Once-monthly self-injection undercuts daily oral and infused rivals on adherence, while Ionis banks another platform-licensing win validating its originate-and-out-license model.
Roche kidney drug's Phase 3 win sets up path to accelerated approval ↗
Vertex's Inaxaplin Hits Phase 2b Marks in Broader APOL1 Kidney Disease Populations
- Vertex's oral APOL1 inhibitor inaxaplin met Phase 2b AMPLIFIED goals in two new AMKD populations beyond the original cohort.
- Among 41 patients, Week 13 UACR fell 42.7% with modest proteinuria (n=23) and 17.3% with AMKD plus type 2 diabetes (n=18).
- This broadens inaxaplin's market as pivotal AMPLITUDE trial enrollment completes, with interim data due early 2027.
APOL1-mediated kidney disease has essentially no targeted competition — a genetically defined, high-unmet-need population overwhelmingly of African ancestry that mainstream nephrology has largely ignored — and Vertex is quietly building the second pillar of its post-CF story there. Widening efficacy into milder-proteinuria and diabetic AMKD subgroups ahead of AMPLITUDE's 2027 readout meaningfully expands the addressable market and de-risks the label.
Vertex's midstage data amplify kidney disease market opportunity ↗
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 ↗
Roche Opens New Innovation Center in Boston Focused on Cardiovascular, Renal and Metabolic Research
- Roche and Genentech held the grand opening of the Roche Genentech Innovation Center Boston, located at Harvard's Enterprise Research Campus in Allston, Massachusetts.
- The 95,000-square-foot facility is leased for 10 years and can accommodate up to 500 employees.
- It will serve as Roche's hub for Cardiovascular, Renal and Metabolic (CVRM) disease research, spanning discovery research, clinical development, and AI/data science.
- The center is designed to provide an end-to-end R&D presence in CVRM, from early discovery through late-stage clinical development.
- The opening forms part of Roche and Genentech's broader $50 billion commitment to U.S. manufacturing and R&D investment, alongside recent expansions in Holly Springs, North Carolina, and Hillsboro, Oregon.
Roche is planting 500 seats squarely in cardiometabolic territory that Novo Nordisk and Eli Lilly currently own by revenue, valuation, and narrative — that's the real story here, not the ribbon-cutting. Roche's own GLP-1/amylin assets (CT-388, petrelintide) are still early and have yet to prove they can compete on efficacy or tolerability — a shiny 95,000-square-foot building doesn't change that math. Read the CVRM bet as portfolio triage as much as ambition: consolidating discovery-through-clinical talent in one hub is what you do when you need faster kill/advance decisions, not just more capacity. And the timing — loud US R&D investment amid tariff and reshoring pressure — reads as much like government-relations optics tied to the $50B pledge as it does science strategy. The signal worth tracking is a phase 2/3 readout from this hub, not the lease signing itself.
Roche expands its Boston footprint with new research center ↗
Longeveron's Stem Cell Therapy Fails Pediatric Heart Trial, Triggers Cost Cuts
- Longeveron's Phase 2b ELPIS II trial tested laromestrocel, a mesenchymal stem cell therapy, as an add-on to Stage 2 palliative surgery in 40 infants with hypoplastic left heart syndrome (HLHS), a rare, severe congenital heart defect.
- The trial missed its primary endpoint: at 12 months, right ventricular ejection fraction did not improve meaningfully in treated infants versus controls.
- No new safety signals emerged; treated infants had numerically fewer deaths than controls over 12 months — reassuring, but not a substitute for the missed efficacy signal.
- Following the miss, Longeveron said it will cut costs, is "exploring all options" for the program and company strategy, and plans further FDA discussions.
- Shares fell sharply in premarket trading after the announcement.
This is another entry in cell therapy's uneven ledger: mesenchymal stem cell candidates have repeatedly stumbled in small, underpowered pediatric and rare-disease trials, and a 40-patient study was never going to generate a statistically bulletproof efficacy case either way. The "numerically fewer deaths" framing is a familiar move — a directionally encouraging but non-significant number, worth reading as reassurance on safety, not as a rescue for the missed primary endpoint. More telling is the language around cost cuts and "exploring all options": for a small-cap with a thin, concentrated pipeline built largely around laromestrocel, that's the standard prelude to a strategic pivot — partnering out remaining assets, a reverse merger, or a slow wind-down — rather than business as usual. Investors should expect the MSC therapy category's credibility gap with capital markets to widen further on this news.
Longeveron's phase 2b stem cell flop spurs cost cutting, exploration of 'all options' ↗
Vera's Trutakna Hits All Endpoints in Final Phase 3 IgA Nephropathy Trial
- Vera Therapeutics announced that TRUTAKNA (atacicept-vymj) met all prespecified endpoints in the final efficacy analysis of the Phase 3 ORIGIN 3 trial in adults with primary IgA nephropathy at risk of disease progression.
- Over 52 weeks, TRUTAKNA stabilized kidney function (eGFR), while patients on placebo continued to decline.
- Through 104 weeks, the drug substantially reduced composite kidney disease progression events, including dialysis, transplant, and death, compared with placebo.
- Secondary measures also improved, including proteinuria, galactose-deficient IgA1, and hematuria, with a safety profile comparable to placebo.
- TRUTAKNA already holds accelerated FDA approval for IgA nephropathy, and Vera plans to file a supplemental BLA in the fourth quarter of 2026 seeking full approval, alongside early positive commercial uptake since launch.
Confirmatory data this clean removes the single biggest overhang on TRUTAKNA's commercial story: accelerated approvals routinely get pulled or delayed when post-marketing trials disappoint, and Vera now walks into its Q4 sBLA filing with full-approval leverage rather than hope. That matters in a field crowding fast — Travere's Filspari, Calliditas/Otsuka's Tarpeyo, Novartis's Fabhalta, and Otsuka's sibeprenlimab are all fighting for the same nephrologists. Atacicept's dual APRIL/BAFF mechanism gives Vera a real differentiation story on upstream disease modification, not just symptom control, which should support pricing and payer positioning as uptake scales. For a company Vera's size, a de-risked full approval also reshapes M&A calculus — this is now a cleaner acquisition target for a larger nephrology or immunology player looking to buy share rather than build it.
Vera kidney drug Trutakna shows strong final results in Phase 3 trial ↗
Vera's TRUTAKNA Meets All Endpoints in Final ORIGIN 3 Kidney Disease Trial
- Vera Therapeutics reported that TRUTAKNA (atacicept) met all prespecified endpoints in the final, two-year efficacy analysis of the Phase 3 ORIGIN 3 trial in adults with primary IgA nephropathy (IgAN), a chronic autoimmune kidney disease.
- Atacicept is a BAFF/APRIL-targeting fusion protein; treatment stabilized kidney function and reduced the risk of kidney-related death and other disease complications.
- Statistically significant, hierarchically tested reductions were achieved across proteinuria, galactose-deficient IgA1 (Gd-IgA1) levels, and hematuria.
- eGFR trends aligned with the KDIGO clinical treatment goal of slowing kidney-function decline toward the normal physiologic rate.
- TRUTAKNA already holds FDA accelerated approval for IgAN, granted July 2026; these final two-year data are intended to support Vera's case for full, non-accelerated approval.
Full, hierarchically-tested endpoint clearance across proteinuria, Gd-IgA1, and hematuria is exactly the kind of data package payers and prescribers weight most heavily when a drug's approval is still accelerated and provisional — this reads as Vera's strongest case yet for converting TRUTAKNA to full approval and retiring the confirmatory-trial overhang that's been sitting on the stock. That matters disproportionately for a single-asset company: Vera has no second program to fall back on if ORIGIN 3 had disappointed, so a clean conversion is existential, not incremental. It also sharpens the IgAN scramble — Travere's sparsentan (Filspari), Novartis's atrasentan (Vanrafia), and Otsuka's entrants are all fighting for first-line real estate in a field that's gone from orphan afterthought to genuinely contested in under two years. Durable, un-caveated data is now the differentiator, not novelty of mechanism alone.
Vera kidney drug Trutakna shows strong final results in Phase 3 trial ↗
Novo Nordisk halts two more ziltivekimab heart trials on futility finding
- Novo Nordisk is stopping two Phase 3 trials, HERMES and ATHENA, of ziltivekimab early after a data monitoring committee flagged futility.
- Ziltivekimab is an antibody that targets interleukin-6 (IL-6), an inflammatory cytokine, and the trials were testing it in heart failure patients with inflammation.
- The committee concluded neither trial was likely to produce a different result from the earlier Phase 3 ZEUS trial, which missed its cardiovascular endpoint in July.
- HERMES tracked time to cardiovascular death or heart failure-related hospitalization/urgent visits; ATHENA measured broader heart failure outcomes including quality of life.
- Novo Nordisk is continuing a separate Phase 3 trial, ARTEMIS, testing ziltivekimab as an acute post-heart-attack treatment, with a readout expected in the first half of 2027.
- The repeated failures raise doubts about IL-6 inhibition as a viable cardiovascular treatment strategy.
Three strikes on cardiovascular endpoints now — ZEUS in July, HERMES and ATHENA today — and Novo isn't spinning this as a design problem anymore; the DMC futility call is about as clear a kill signal as you get. Sunk cost here isn't trivial: ziltivekimab was Novo's flagship diversification bet outside GLP-1s, and this guts the broader inflammation-in-CV thesis that Novartis also struggled to validate with canakinumab post-CANTOS. IL-6 as a druggable node for heart failure now looks structurally shaky, not just underpowered. ARTEMIS surviving to 2027 reads less like conviction and more like sunk-cost inertia — acute post-MI biology differs, but a quiet wind-down before readout wouldn't surprise me if enrollment softens. Zoom out and this underscores just how thin Novo's non-GLP-1 pipeline really is, right as obesity/diabetes competition intensifies.
Updated: Novo Nordisk cans two more trials of IL-6 heart drug for futility ↗
Novartis' Lp(a)-lowering drug pelacarsen fails cardiovascular outcomes trial
- Novartis' pelacarsen missed the primary endpoint in the Phase 3 Lp(a)HORIZON cardiovascular outcomes trial, which enrolled 8,323 patients with elevated lipoprotein(a) and established cardiovascular disease.
- Pelacarsen is an antisense oligonucleotide, licensed from Ionis Pharmaceuticals, designed to suppress hepatic production of Lp(a), a lipid-protein particle linked to elevated cardiovascular risk.
- The drug achieved substantial lowering of Lp(a) levels in treated patients, but this biomarker reduction did not translate into a statistically significant drop in cardiovascular death, heart attack, stroke, or urgent revascularization versus placebo.
- The result is the first major late-stage setback for the emerging Lp(a)-lowering drug class, raising questions for rival programs from Amgen and Eli Lilly that use different modalities but showed larger Lp(a) reductions in earlier-stage studies.
- Novartis and Ionis had held global rights under a licensing and collaboration deal, with Ionis having discovered and advanced pelacarsen through early development before Novartis took it into Phase 3.
Pelacarsen just became the class's first hard-outcomes readout — and it missed, despite deep Lp(a) lowering. That's the uncomfortable part: this was the cleanest test yet of the Lp(a) causal hypothesis, and it didn't confirm it. Olpasiran (Amgen) and lepodisiran (Lilly) post larger percentage reductions in early studies, but bigger knockdown of the same biomarker doesn't guarantee outcomes benefit — their own outcomes trials now carry real doubt, not just execution risk. For Novartis, this was a marquee asset licensed from Ionis to anchor its cardiovascular pipeline; the miss removes a near-term blockbuster case and puts pressure on how the Ionis partnership economics get valued going forward. Biggest read-through: Lp(a) may need rethinking as a validated drug target, not just a biomarker to chase.
Novartis' experimental cardiovascular drug fails a pivotal study ↗
Alnylam Defends ATTR-CM Franchise After Rival's Wainua Trial Stumbles
- Full Phase 3 CARDIO-TTRansform results, presented at ESC Munich, showed AstraZeneca/Ionis's TTR silencer eplontersen (Wainua) failed to significantly cut cardiovascular death/events in ATTR-CM over roughly 140 weeks (rate ratio 0.89, p=0.277).
- Critically, patients already on a stabilizer (Pfizer's Vyndaqel, BridgeBio's Attruby) saw no added benefit from Wainua; only silencer-monotherapy patients showed a nominal gain.
- That subgroup split is uncomfortable for Alnylam, whose Amvuttra and pipeline candidate nucresiran are the same drug class and increasingly used alongside stabilizers.
- Alnylam shares fell nearly 5%.
- Executives countered that Amvuttra achieves deeper TTR knockdown than eplontersen and that nucresiran's larger TRITON-CM trial should avoid Wainua's pitfalls.
The subgroup data is the real story: if silencers add nothing once patients are already stabilized, the industry's drift toward stabilizer-plus-silencer combos loses its evidence base, and AZ/Ionis must reposition Wainua as monotherapy — a much smaller, harder-to-sell market. That's a strategic problem, not just a trial miss, and it makes Intellia's one-and-done knockdown pitch relatively more attractive. Alnylam's rebuttal (deeper knockdown, a bigger trial) is the self-interested defense you'd expect from a company facing guilt-by-association, resting on cross-trial comparisons Alnylam itself is asserting, not independent data — treat "deeper knockdown" as a hypothesis until TRITON-CM reads out. Nucresiran's margin for error just got narrower. Watch prescriber messaging: whoever wins the "silencer as add-on vs. backbone" argument sets ATTR-CM's standard of care.
Alnylam defends heart disease drugs after failure of AstraZeneca's Wainua ↗