The study — a double-blind, multicenter, randomized, placebo-controlled trial — will enroll 300 adults aged 18 to 70 with serologically confirmed, actively hyperthyroid Graves’ disease. Participants cannot have prior radioactive iodine (RAI) treatment or thyroid surgery, making this a first-line biologics test in treatment-naïve patients (NCT07661056).

The mechanism

BHV-1300 is a MoDE (Modular Degradation Engine) small-molecule IgG degrader — a mechanistic class Biohaven explicitly distinguishes from FcRn inhibitors. Rather than blocking the neonatal Fc receptor that recycles IgG antibodies, BHV-1300 routes IgG toward degradation through a separate pathway, without interacting with FcRn. By depleting IgG, the drug reduces all IgG subclasses — including TSH receptor antibodies (TRAb), the autoantibodies that drive hyperthyroidism in Graves’ disease. The hypothesis: deplete TRAb fast enough and the thyroid quiets down without lifelong drug dependence.

What the trial is measuring

The primary endpoint is the number of participants who are off antithyroid drugs (ATD) with normal Total T3, free T4, and TSH at Week 26 — a composite euthyroidism-off-treatment bar. Pre-specified secondary endpoints include: TRAb (TBII) change from baseline at Weeks 6 and 26; total IgG change at Weeks 6 and 26; proportion off ATD with normal Total T3 and free T4 at Week 26; time to normal thyroid hormones off ATD; time to euthyroidism off ATD; TRAb seronegativity at Week 26; and the composite of euthyroid, off ATD, and TRAb seronegative at Week 26. Safety secondaries track serious adverse events, Grade 3/4 lab abnormalities, and discontinuations.

Standard options — ATDs, RAI, thyroidectomy — carry well-known trade-offs: high ATD relapse rates, permanent hypothyroidism after ablation, and surgical risk. An IgG-depleting strategy that eliminates the causative autoantibody could offer durable remission without those consequences, though that claim remains unproven at this scale.

The trial is slated to begin enrolling in June 2026, with primary completion estimated in January 2028. BHV-1300 is investigational and not approved for any indication.

Correction — June 23, 2026: Two critical errors have been corrected in this article. (1) The headline and body originally described BHV-1300 as an “FcRn Blocker” and “FcRn inhibitor.” BHV-1300 is a MoDE (Modular Degradation Engine) small-molecule IgG degrader that, per Biohaven, does not interact with FcRn; the mechanism section has been rewritten accordingly. (2) The original text stated this was “the first Phase 3 trial of an FcRn inhibitor specifically designed to treat Graves’ hyperthyroidism.” This claim was wrong on two counts: BHV-1300 is not an FcRn inhibitor, and prior FcRn inhibitor trials for Graves’ disease exist (including a batoclimab Phase 2 proof-of-concept study and an IMVT-1402 extension study). The article now accurately describes BHV-1300 as the first Phase 3 trial of a MoDE IgG degrader for Graves’ hyperthyroidism.

The trial (NCT02364557), sponsored by NRG Oncology and funded by the National Cancer Institute, enrolled 129 women across more than 160 U.S. and international sites. Patients had newly oligometastatic breast cancer — up to four extracranial metastatic lesions, each no larger than 5 cm, with a controlled primary — and were on first-line standard systemic therapy for no more than 12 months at registration. They were randomized 1:1 to standard-of-care (SOC) systemic therapy alone or SOC plus stereotactic body radiotherapy (SBRT) and/or surgical resection of all known metastases.

The Phase II primary endpoint was a progression-free survival signal sufficient to justify proceeding to a fully powered Phase III overall survival analysis. That signal did not materialize. Median PFS was 23 months in the SOC-alone arm versus 19.5 months in the ablation arm. Two-year PFS rates were nearly identical — 45.7% versus 46.8% — and three-year rates were 32.8% versus 38.1%, differences that were neither statistically nor clinically meaningful. Median overall survival was not reached in either arm; 36-month OS was 71.8% in the SOC arm and 68.9% in the ablation arm (log-rank p = 0.54).

One secondary finding was biologically instructive: ablation did suppress in-field recurrence — only 6.7% of ablation-arm patients developed new metastases inside the treated area, versus 29.2% in the SOC arm. Yet new metastases outside the treated field emerged at equal rates in both groups (approximately 40%). The implication is stark: eradicating the visible disease does not address the systemic seeding already underway.

Safety was not the limiting factor. There were no grade 5 treatment-related events. Grade 3 adverse events occurred in 9.7% of SOC-alone patients and 5.3% of the ablation group — low rates that confirm modern SBRT is deliverable safely in this setting.

The consequence is decisive: NRG-BR002 will not advance to the Phase III component. The Phase III arm was designed to detect an OS benefit; absent a Phase II PFS signal, accrual to that larger, longer study was not warranted.

Trial Card — NCT02364557

• Phase: II/III (Phase III did not proceed)
• Sponsor: NRG Oncology | Collaborator: NCI
• Enrollment: 129 | Final completion: September 4, 2025
• Registry: NCT02364557

The results join a pattern emerging across tumor types: local ablation controls the treated site but does not rewrite the metastatic program. Whether better patient selection — guided by ctDNA kinetics or receptor subtype — could identify a subset who benefit remains an active research question. For now, outside a clinical trial, the evidence does not support adding SBRT or surgery to systemic therapy in the first-line oligometastatic breast cancer setting.

Correction, 2026-06-22: An earlier version of this article described NRG-BR002 as “the largest randomized test” of ablative therapy in oligometastatic breast cancer. Primary sources consistently describe it as the first breast cancer-specific randomized trial of this question, not the largest; with 129 patients it is a Phase IIR signal-detection study, not a definitive Phase III. The article’s headline has also been updated to remove the word “Definitive,” which overstated the conclusiveness of a Phase IIR screening trial powered at α=0.15. The core finding — that the Phase II signal criterion was not met and Phase III will not proceed — is unchanged.

The Trials

ISLEND-1 (NCT06630286) and ISLEND-2 (NCT06630299) are double-blind, double-dummy randomized controlled trials enrolling adults whose HIV-1 is virologically suppressed on a stable daily antiretroviral regimen. Participants were randomized to once-weekly islatravir/lenacapavir or to continue their existing daily therapy — primarily bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or equivalent. The primary endpoint in both trials is the proportion of participants with HIV-1 RNA at or above 50 copies/mL at Week 48 (the virologic failure rate per the FDA Snapshot algorithm); non-inferiority is demonstrated when this failure rate is no worse in the experimental arm.

Both Gilead and Merck announced that preliminary Week 48 results met the pre-specified non-inferiority margin. The announcement is consistent with Phase 2 data (PMC11777299), which showed 94.2% virologic suppression with once-weekly islatravir/lenacapavir versus 92.3% with daily B/F/TAF — though Phase 2 sample sizes are smaller and enrollment criteria differ.

What Remains Undisclosed

The sponsor announcements did not include actual Week 48 suppression rates, confidence interval widths, the number of virologic failures in each arm, resistance emergence data, or detailed safety findings. Full data are expected to be presented at an upcoming scientific conference; no conference or regulatory submission timeline has been specified.

A once-weekly oral pill would meaningfully reduce the daily treatment burden for many people living with HIV. Daily therapy is highly effective for adherent patients, but real-world adherence is imperfect. A weekly schedule also offers an alternative to the injectable long-acting regimens that require clinic visits for administration.

Why This Combination

Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI); lenacapavir is a capsid inhibitor. The two drugs target distinct steps in the HIV replication cycle with complementary mechanisms and non-overlapping resistance profiles. Lenacapavir is already approved as a twice-yearly injectable (Sunlenca) for heavily treatment-experienced patients.

Gilead Sciences and Merck ISLEND-1/2 topline announcements, June 2026. NCT06630286, NCT06630299 (ClinicalTrials.gov). PMC11777299 (Phase 2 reference data).

Correction (June 21, 2026): An earlier version of this article stated the primary non-inferiority endpoint was “HIV-1 RNA <50 copies/mL at Week 48.” Per Gilead and Merck topline announcements and ClinicalTrials.gov records, the primary efficacy endpoint in both ISLEND-1 and ISLEND-2 was the proportion of participants with HIV-1 RNA ≥50 copies/mL at Week 48 per the FDA Snapshot algorithm — the virologic failure rate, not the virologic success rate. The front-matter claim and body text have been corrected.

The Scientific Rationale

Factor XI inhibition represents a mechanistically distinct anticoagulation strategy. Factor XI sits one step upstream from the factor Xa target of apixaban and rivaroxaban, and unlike factor Xa, it plays a relatively limited role in primary hemostasis — the platelet-driven process that forms the initial clot at a wound site. The theoretical appeal is a narrower therapeutic window between anticoagulation and bleeding, particularly relevant in cancer patients who carry both high thrombotic risk and elevated bleeding risk due to malignancy, cancer-directed therapy, and procedures.

ASTER was designed to test that hypothesis specifically in a population with cancer-associated VTE, where apixaban is a guideline-recommended standard based on the ADAM-VTE and SELECT-D trials. Demonstrating non-inferiority or superiority to apixaban with a better bleeding profile would have been a significant clinical finding.

What Is and Is Not Known

The public registry shows ASTER’s status as terminated. The most common reasons for Phase 3 trial termination in the absence of a public safety signal are futility (failure to demonstrate anticipated benefit at an interim analysis), resource constraints, or a strategic program reassessment — but none of these can be confirmed from the registry record alone.

A trial termination without results is a data gap, not a negative result in the conventional sense. It removes one anticipated data source from the Factor XI inhibitor field in cancer-associated VTE — a population counting on the trial to clarify whether the mechanistic promise of Factor XI inhibition holds in this high-risk group.

Abelacimab continues in other trials, including AZALEA-TIMI 71 (NCT04755283) in atrial fibrillation, suggesting the broader program has not been abandoned. The cancer-associated VTE indication appears to have been discontinued.

NCT05171049 (ASTER, terminated). Anthos Therapeutics and Novartis abelacimab program. NCT04755283 (AZALEA-TIMI 71, active).

Trial Design and Enrollment

SNAP (Staphylococcal Bacteremia Antibiotic Treatment Platform) enrolled 1,303 adults with confirmed methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia at centers across the United States, Canada, and Australia, using an adaptive Bayesian platform design that allowed continuous learning and pre-specified interim decisions. Participants were randomized to cefazolin 2 g intravenously every eight hours or to an ASP — nafcillin, oxacillin, or flucloxacillin at investigator’s choice — for a minimum of 14 days, with duration adjusted for source and clinical response.

The primary endpoint was 90-day all-cause mortality. A key secondary endpoint was acute kidney injury (AKI) within 14 days, defined by KDIGO criteria.

What the Data Showed

Ninety-day mortality was 15.0% with cefazolin versus 17.0% with ASP. The adjusted odds ratio of 0.81 (95% credible interval 0.59–1.12) satisfied the pre-specified Bayesian noninferiority criterion; the posterior probability that cefazolin was noninferior exceeded the trial’s threshold.

The kidney signal was not subtle. AKI at 14 days occurred in 13.9% of cefazolin recipients versus 19.6% in the ASP group (aOR 0.67, 95% CrI 0.50–0.89) — a 32% relative reduction in early nephrotoxicity.

The AKI advantage is clinically meaningful because bacteremia patients frequently accumulate concurrent nephrotoxic exposures: empiric vancomycin while cultures are pending, iodinated contrast for source-control imaging, and vasopressors in septic shock. Replacing the antistaphylococcal penicillin with cefazolin removes one layer of that stacked renal hazard.

Caveats and Scope

SNAP was not designed as a superiority trial. The mortality credible interval includes values modestly favoring ASP, and noninferiority does not establish that cefazolin is better on survival — only that it is not meaningfully worse. The trial enrolled predominantly catheter-related bacteremia; patients with endocarditis, particularly prosthetic-valve or device-associated infection, were managed with individualized therapy and are incompletely represented in the randomized cohort. Whether the survival equivalence extends to CNS seeding or complicated left-sided endocarditis requires further study.

Notwithstanding those limits, SNAP represents the largest randomized comparison of cefazolin versus ASP in MSSA bacteremia by a substantial margin. The platform design’s Bayesian framework also sets a precedent: future arms can be added without starting a new trial, enabling the research community to build cumulative evidence for additional management questions in this common and lethal infection.

SNAP Investigators. Cefazolin versus antistaphylococcal penicillins for MSSA bacteremia. N Engl J Med. 2026;394:2329–2339. DOI: 10.1056/NEJMoa2602847.

The trial design

The SNAP (Staphylococcal Non-Antistaphylococcal Penicillin) trial was a multicentre randomised controlled trial comparing benzylpenicillin (penicillin G) with flucloxacillin in adults hospitalised with confirmed PSSA bacteraemia — organisms known to be fully susceptible to penicillinase-stable and narrow-spectrum penicillins. Standard-of-care in most of Europe and Australia for MSSA bacteraemia is flucloxacillin; benzylpenicillin is narrower-spectrum and has superior pharmacodynamic properties for susceptible organisms.

The primary endpoint was 90-day all-cause mortality, analysed as a non-inferiority test with a margin pre-specified in the protocol. The Bayesian posterior probability of non-inferiority reached 96.1%, which the investigators noted as providing strong evidence in favour of equivalence. However, the trial did not formally meet its pre-specified non-inferiority criterion: the primary Bayesian analysis found the upper bound of the 95% credible interval for the adjusted odds ratio (1.28) exceeded the pre-specified non-inferiority margin of OR < 1.20, so the primary endpoint was technically not met. The SNAP trial used a Bayesian — not frequentist — primary analysis throughout.

AKI reduced by half

The secondary endpoint of acute kidney injury told a different story. Patients in the benzylpenicillin arm experienced significantly fewer AKI events — approximately half the rate observed in the flucloxacillin or cloxacillin arm (cloxacillin was used in Canada, Israel, Singapore, and South Africa). This difference is biologically plausible: flucloxacillin carries a recognised nephrotoxicity risk, particularly with high-dose prolonged courses such as those used in deep-seated bacteraemia, whereas benzylpenicillin does not share this toxicity profile.

AKI in bacteraemia is not a soft endpoint. It prolongs hospital stay, worsens prognosis in patients already critically ill, and contributes to long-term renal decline. A halving of AKI events is a clinically meaningful secondary finding.

Implications for practice

The SNAP result puts antimicrobial stewardship in tension with clinical conservatism. Flucloxacillin has been the unchallenged first-line agent for MSSA bacteraemia in the UK and much of Europe for decades. A trial showing comparable 90-day mortality and substantially lower nephrotoxicity with the narrower-spectrum benzylpenicillin will prompt revision of clinical guidelines, though regulatory bodies and societies typically wait for formal non-inferiority confirmation before updating standards of care.

The 96.1% Bayesian posterior probability of non-inferiority is, to Bayesian practitioners, a strong statement. Whether that is sufficient for guideline change will be a matter for infectious disease societies; the trial provides the evidence base for that conversation.

The Lancet. 2026. DOI: 10.1016/S0140-6736(26)00761-0. PMID: 42309115.

Correction (2026-06-19): Three errors corrected by post-publication fact-check. (1) The trial used a Bayesian — not frequentist — primary analysis; the non-inferiority criterion (OR < 1.20) was not met because the upper 95% credible interval (1.28) exceeded the margin, not because a frequentist p-value threshold was missed. (2) The comparator arm was “flucloxacillin or cloxacillin” (cloxacillin was used in Canada, Israel, Singapore, and South Africa), not flucloxacillin alone; the article has been updated throughout. (3) The NCT identifier “NCT-SNAP” is not a valid registry number; the correct ClinicalTrials.gov identifier is NCT05137119.

The international, multicenter, randomized, double-blind, placebo-controlled Phase 4 trial enrolled 2,401 patients admitted for acute heart failure (AHF) across multiple countries. Sponsored by the TIMI Study Group with AstraZeneca as collaborator and funder, the study randomized patients who had been stabilized during their hospitalization — no earlier than 24 hours and up to 14 days after presentation — to dapagliflozin 10 mg once daily versus placebo, continuing blinded treatment for two months. Patients were enrolled regardless of left ventricular ejection fraction, type 2 diabetes status, or whether the presentation was de novo or worsening chronic heart failure.

Primary endpoint: neutral

The primary endpoint — time to first occurrence of cardiovascular death or worsening heart failure (defined as worsening HF during the index admission, rehospitalization for worsening HF, or an urgent HF visit) at 2 months — was not significantly reduced by dapagliflozin. Berg et al. report a hazard ratio of 0.86 (95% CI, 0.68–1.08; p = 0.20), consistent with a clinically plausible but statistically non-significant 14% reduction that the trial was not powered to confirm at this magnitude.

All-cause mortality: a signal that doesn’t cross

A notable secondary finding was all-cause mortality, for which dapagliflozin produced a hazard ratio of 0.66 (95% CI, 0.43–1.00). The upper confidence limit reaches exactly 1.00 and no p-value for this endpoint was reported in the primary publication’s abstract, making directional characterization inappropriate; the result is borderline and the trial was not powered for mortality as a primary endpoint.

Context: why EMPULSE and SOLOIST-WHF showed benefit

EMPULSE (empagliflozin, in-hospital initiation) and SOLOIST-WHF (sotagliflozin, peri-discharge) both demonstrated benefit on composite hierarchical or event-rate endpoints. DAPA ACT HF-TIMI 68 is the largest of these trials by enrollment and the first powered specifically for cardiovascular death or worsening HF as a time-to-event primary endpoint. Its neutral result raises three unresolved questions: whether benefit with other SGLT2 inhibitors is drug-specific; whether endpoint construction (hierarchical vs. time-to-first-event) drives the apparent discrepancy; or whether a two-month window is simply too short to capture a mortality signal in a broadly enrolled AHF population that includes patients unlikely to respond to contractility-independent mechanisms.

Key safety endpoints pre-specified in the protocol — symptomatic hypotension and worsening renal function — did not show significant differences between arms in the Berg et al. report.

The design rationale was published in JACC Heart Failure in May 2025 (Berg DD et al., DOI: 10.1016/j.jchf.2025.03.014).

Correction — June 18, 2026: An earlier version of this article described the all-cause mortality result (HR 0.66, 95% CI 0.43–1.00) as “trending toward benefit but not statistically significant.” The CI upper bound reaches exactly 1.00 and no p-value for this secondary endpoint was reported in the primary abstract; the article has been corrected to remove the directional “trending toward benefit” characterization, which overstated the strength of a borderline result. Identified by The Vital Record’s post-publication fact-check.

SUCCESSOR-2 (NCT05552976) enrolled 479 patients with relapsed or refractory multiple myeloma who had received at least two prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody—a population that has historically had median progression-free survival of less than 9 months. Patients were randomly assigned 3:2 to MeziKD (n=288) or Kd (n=191).

The primary endpoint was reached decisively. Median progression-free survival was 18.0 months with MeziKD versus 8.3 months with Kd (hazard ratio 0.48 [95% CI 0.36–0.63]; p<0.0001), representing a 52% reduction in the relative risk of progression or death. Responses were deeper and more frequent in the MeziKD arm: overall response rate 67.7% versus 43.7%, with very good partial responses or better in 53.5% versus 27.2%.

Mezigdomide is a next-generation cereblon E3 ligase modulator (CELMoD agent) that degrades Ikaros family zinc fingers 1 and 3 (IKZF1/IKZF3) more potently than lenalidomide or pomalidomide and retains activity in patients who have become resistant to both. Pairing it with carfilzomib—a second-generation proteasome inhibitor that irreversibly blocks the 20S proteasome and depletes anti-apoptotic proteins in myeloma cells—and dexamethasone exploits complementary cytotoxic mechanisms, adding CELMoD-driven immune restoration to proteasome-inhibitor-driven cell death in a population already exposed to lenalidomide but not necessarily to carfilzomib.

The safety profile was consistent with known risks. Grade 3 or 4 adverse events occurred in 84% of MeziKD patients and 56% of Kd patients; the most common serious events in the MeziKD arm were neutropenia (61%) and infections (34%). No unexpected safety signals emerged beyond those established in earlier mezigdomide dose-finding work.

Bristol-Myers Squibb is now preparing regulatory submissions in multiple jurisdictions. The data position MeziKD as a likely standard of care for the triple-class-exposed population ahead of CAR-T eligibility—a gap the current myeloma armamentarium has not adequately filled.

Correction, 2026-06-16: An earlier version of this article incorrectly named the experimental regimen as mezigdomide + elotuzumab + dexamethasone (MEd). SUCCESSOR-2 evaluates mezigdomide + carfilzomib + dexamethasone (MeziKD) vs carfilzomib + dexamethasone (Kd). Grade 3/4 adverse event rates have also been corrected (MeziKD 84%, Kd 56%; neutropenia 61%, infections 34%), reflecting the published Lancet abstract.

NAAVIGATE (NCT07592273) is a phase 2b/3 randomized, sham-controlled trial enrolling 576 patients with moderately severe or severe nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) across sites in the United States and Puerto Rico. Participants receive either a single suprachoroidal injection of surabgene lomparvovec (ABBV-RGX-314) or a sham procedure. The gene therapy delivers an AAV8 vector encoding a soluble anti-VEGF protein designed to provide sustained expression in the retinal pigment epithelium, with the goal of preventing progression to vision-threatening events including proliferative DR.

Surabgene lomparvovec emerged from AbbVie’s collaboration with RegenxBio, which developed the proprietary AAV8 vector and suprachoroidal delivery system. Earlier phase 2 data in wet age-related macular degeneration, a related anti-VEGF indication, showed sustained biologic expression at 36 months following suprachoroidal delivery.

NAAVIGATE is the pivotal read that will determine whether the gene therapy platform can prevent vision-threatening events in a larger, younger, and more heterogeneous patient population than AMD. The trial’s 576-patient size reflects the statistical power needed to detect a meaningful disease-course benefit in earlier-stage DR.

Enrollment has opened at investigational sites with anticipated primary completion in June 2028. The primary endpoint is a 2-step or greater improvement from baseline in the Diabetic Retinopathy Severity Scale (DRSS) at week 52. Key secondary endpoints include prevention of vision-threatening events (VTEs) and progression to proliferative DR.

Correction, 2026-06-16: An earlier version of this article described NAAVIGATE as a trial for proliferative diabetic retinopathy. The trial (NCT07592273) enrolls patients with nonproliferative DR (NPDR) without CI-DME. The described geographic scope (US, Europe, Asia-Pacific) was also wrong; sites are in the United States and Puerto Rico only. The primary endpoint has been corrected from BCVA change at 24 months to ≥2-step DRSS improvement at week 52.

C-PRE was designed to enroll 420 patients at NCI-affiliated sites and randomly assign them to perioperative cemiplimab plus surgery versus surgery alone, with recurrence-free survival as the primary endpoint. Cemiplimab has an established role in unresectable CSCC, but perioperative immunotherapy in the resectable setting had not previously been evaluated in a phase 3 trial. The study opened in February 2025 and had been accruing for approximately 16 months before the suspension took effect.

The ClinicalTrials.gov record notes a safety monitoring board review as the impetus for the pause, but no further information has been made public. The NCI issued no statement as of Sunday evening, and the patient community organization Skin Cancer Foundation could not be reached for comment.

The suspension puts C-PRE in a pattern that has become increasingly visible: NCI-sponsored immunotherapy trials have been placed on clinical hold or paused in recent months with minimal public disclosure. A second NCI-sponsored immunotherapy study, in an unrelated indication, was also suspended in the same calendar window, according to the registry.

Dermatologic oncologists say the clinical impact on patients is limited for now—cemiplimab retains its current standing in unresectable disease, and patients in the resectable setting who were not yet enrolled can pursue surgery on standard timelines. But the scientific community is watching closely: if C-PRE does not resume, the perioperative immunotherapy question in resectable CSCC may not be answerable without a new sponsor.

The Vital Record has contacted the NCI Office of Communications for comment and will update this story when a response is received.

The termination decision

On November 19, 2023, Bayer announced that the IDMC had recommended stopping the Phase 3 trial based on interim surveillance showing inferior efficacy of asundexian versus the apixaban control arm. At the time of termination, 14,830 of a planned 18,000 patients had been randomised across 1,069 sites.

Trial design

OCEANIC-AF (NCT05643573) was a double-blind, double-dummy, Phase 3 trial enrolling patients with atrial fibrillation at elevated stroke risk. It launched December 5, 2022, and carried three co-primary endpoints: (1) the composite of stroke or systemic embolism (efficacy), (2) ISTH major bleeding (safety), and (3) the composite of stroke, systemic embolism, or ISTH major bleeding. ISTH major bleeding was defined as fatal bleeding, bleeding into a critical organ, a haemoglobin drop of ≥2 g/dL, or transfusion of ≥2 units of packed red blood cells.

Results

Full results were presented at the European Society of Cardiology (ESC) Annual Congress on September 1, 2024, and simultaneously published in the New England Journal of Medicine (DOI: 10.1056/NEJMoa2407105). Patients on asundexian experienced significantly more strokes and systemic embolic events than those on apixaban (1.3% vs. 0.4%; hazard ratio 3.79). Asundexian did, however, produce fewer major bleeding events than apixaban during the observation period.

What this means for FXIa inhibition

The genetic rationale for FXIa inhibition — derived from observations that individuals with congenital factor XI deficiency have lower rates of stroke without a commensurate increase in bleeding — had generated substantial excitement. OCEANIC-AF demonstrated that pharmacological FXIa inhibition at the dose tested is insufficient to prevent cardioembolic stroke in atrial fibrillation, even as it reduces bleeding. Whether higher degrees of FXIa inhibition, different patient populations, or alternative FXIa inhibitors can thread that needle remains an open research question. Thirteen pre-specified secondary endpoints — including ischemic stroke, all-cause mortality, cardiovascular death, and intracranial haemorrhage — should be interpreted in the context of the early termination.

Primary endpoint — not met: Among 6,522 patients randomised to empagliflozin (n=3,260) or placebo (n=3,262), a first HF hospitalization or death from any cause occurred in 8.2% of the empagliflozin group versus 9.1% in the placebo group (hazard ratio 0.90; 95% CI 0.76–1.06; P=0.21). This difference was not statistically significant.

Trial design: EMPACT-MI (NCT04509674), sponsored by Boehringer Ingelheim and Eli Lilly and Company, enrolled patients hospitalised for STEMI or NSTEMI at elevated risk for heart failure, defined as newly reduced left ventricular ejection fraction (LVEF <45%) or signs/symptoms of congestion requiring treatment, plus at least one additional high-risk feature (age >65, prior MI, eGFR <60, atrial fibrillation, type 2 diabetes, or elevated natriuretic peptides). Randomisation occurred within 14 days. Median follow-up was 17.9 months.

Secondary HF analyses (prespecified, from Circulation): A prespecified secondary analysis published simultaneously in Circulation (DOI 10.1161/CIRCULATIONAHA.124.069217) found that empagliflozin was associated with a significant reduction in first HF hospitalization alone (3.6% vs 4.7%; HR 0.77; 95% CI 0.60–0.98; P=0.031) — approximately 23% relative reduction — and in total HF hospitalizations (148 vs 207 events; rate ratio 0.67; 95% CI 0.51–0.89; P=0.006) — approximately 33% relative reduction.

Critical framing: These secondary findings are hypothesis-generating and do not override the primary result. Patients should not interpret these results as establishing empagliflozin as indicated post-MI; regulatory determination of that question requires further review.

Correction — June 15, 2026: The trial design section previously omitted sponsor disclosure. EMPACT-MI was sponsored by Boehringer Ingelheim and Eli Lilly and Company (confirmed: NEJM PMID 38587237 and ClinicalTrials.gov NCT04509674). The sponsorship has been added to the trial design paragraph above.

The study, known as ZENITH (NCT07181109), is sponsored by Alnylam Pharmaceuticals in collaboration with Hoffmann-La Roche and will enroll 11,000 participants across 856 sites worldwide — making it one of the largest cardiovascular outcomes trials currently underway.

What Is Zilebesiran?

Zilebesiran is an investigational small interfering RNA (siRNA) designed to silence the hepatic gene that produces angiotensinogen — the protein at the very top of the renin-angiotensin-aldosterone system (RAAS), the pathway that regulates blood pressure. By blocking angiotensinogen production in the liver, the drug aims to suppress the entire RAAS cascade at its source, a fundamentally different approach from existing antihypertensives such as ACE inhibitors or ARBs, which act further downstream.

Trial Design

ZENITH is a global, randomized, double-blind, placebo-controlled Phase 3 trial. Participants must be adults with established cardiovascular disease (age 18 or older) or high cardiovascular risk (age 55 or older), already taking at least two standard antihypertensive medications including a diuretic, yet still inadequately controlled. The study is event-driven, with follow-up of up to approximately five years.

The trial’s primary endpoint is the time to first occurrence of a composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, or a heart failure event (defined as hospitalization for heart failure or an urgent heart failure visit).

The trial began recruiting in September 2025, with an estimated completion date of September 2030. No efficacy or safety results have been posted to the registry.

Zilebesiran is an investigational drug that has not been approved by any regulatory authority. This article reports trial design only; no results are available.

The D1AMOND study (NCT05615220), sponsored by Emalex Biosciences, enrolled 216 participants aged 6 years and older. All participants entered a 12-week open-label period in which ecopipam was titrated to a target dose of 1.8 mg/kg/day. Those achieving at least a 25% improvement from baseline on the Yale Global Tic Severity Scale–Total Tic Score (YGTSS-TTS) were then randomized 1:1 to continue ecopipam or switch to placebo for a further 12 weeks. Relapse was defined as loss of ≥50% of the YGTSS-TTS improvement gained during the open-label period, combined with rescue medication use or hospitalization.

Primary endpoint — pediatric cohort (ages 6 to <18): Relapse occurred in 41.9% of ecopipam-treated patients versus 68.1% of placebo-treated patients (HR 0.5; 95% CI 0.3–0.8; P = .0084).

Key secondary endpoint — full randomized cohort: The relapse rate was 41.2% with ecopipam versus 67.9% with placebo (HR 0.5; 95% CI 0.3–0.8; P = .0050).

Adults — exploratory only: A prespecified adult subgroup analysis (n = 14) was directionally similar but did not reach statistical significance (HR 0.51; 95% CI 0.11–2.30; P = .37). Ecopipam’s development program targets pediatric Tourette’s disorder; the pooled significance is driven by the pediatric majority (90 of 104 randomized).

Ecopipam’s mechanism sets it apart from the three drugs with FDA approval specifically for Tourette’s disorder — haloperidol (1978), pimozide (1984), and aripiprazole (2014) — which act at D2 receptors and carry known risks of weight gain, metabolic changes, and drug-induced movement disorders. In D1AMOND, no clinically meaningful changes in weight, metabolic parameters, or extrapyramidal movement disorders were observed. Across the open-label and double-blind periods, the most common adverse events with ecopipam were somnolence (11.1%), anxiety (9.7%), headache (9.7%), insomnia (8.8%), worsening of tics (7.9%), and fatigue (6.5%).

Emalex Biosciences has indicated it plans to meet with the FDA to discuss an NDA submission. If approved, ecopipam would represent the first new mechanistic class for Tourette’s disorder in over five decades.

Correction — June 13, 2026: Two errors corrected in this article. (1) The original version stated ecopipam “sets it apart from the two FDA-approved tic treatments, aripiprazole and haloperidol.” Three drugs carry FDA approval specifically for Tourette’s disorder: haloperidol (1978), pimozide (1984), and aripiprazole (2014); pimozide was omitted. (2) The original version described the 25% YGTSS-TTS improvement threshold for randomization entry without disclosing how relapse was defined in the withdrawal phase; the relapse definition (loss of ≥50% of open-label YGTSS-TTS improvement plus rescue medication use or hospitalization) has been added for clinical context. Both corrections are consistent with NCT05615220 and JAMA Neurology.

INTEGRATE IIb enrolled 462 patients across multiple countries who had progressed on at least two prior lines of therapy for gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Participants were randomised to regorafenib plus nivolumab or active chemotherapy. The primary endpoint was overall survival. Results presented at ESMO 2025 (LBA80) showed a hazard ratio of 0.88 (95% CI 0.71–1.09; p=0.23) — a numerical trend favouring the combination that did not meet statistical significance.

The objective response rate was 7.4% for RegoNivo versus 2.6% for the control arm. A higher response rate that does not translate into survival benefit is a pattern seen before in this tumour type, and it does not justify the combination as a new standard of care. The OS primary endpoint is the clinically decisive finding.

The result is a significant setback for a regimen that generated substantial interest after a Phase 1b study (REGONIVO) published in the Journal of Clinical Oncology in 2020 reported a 44% objective response rate — a figure that, in retrospect, reflects the optimism-selection bias endemic to small, open-label, single-arm dose-escalation studies. The Phase 3 trial enrolled a more representative patient population with an active comparator, conditions that routinely reveal smaller effects than early-phase data predict.

Gastro-oesophageal adenocarcinoma remains one of the most therapeutically challenged malignancies. Refractory-line options are limited to regorafenib, trifluridine/tipiracil, and — in select PD-L1-positive or MSI-H populations — pembrolizumab. The INTEGRATE IIb result adds nothing to that list, leaving the field to look toward emerging options including claudin 18.2-targeting agents and bispecific antibodies now in Phase 2 development.

The trial (NCT06267001) enrolled patients with completely resected stage IB–IIIA PD-L1-positive NSCLC and randomized them to receive tiragolumab, an investigational anti-TIGIT monoclonal antibody, in combination with atezolizumab (Tecentriq, an approved anti-PD-L1 antibody) or placebo plus atezolizumab as post-surgical adjuvant therapy. The trial enrolled just 56 participants — a fraction of its originally projected enrollment — before Roche suspended efficacy analysis and reclassified the study’s primary objective to safety follow-up only, as reflected in a ClinicalTrials.gov status update this week.

A pattern of failure

SKYSCRAPER-15 is the fourth successive Phase 3 setback for tiragolumab:

• SKYSCRAPER-01 (first-line metastatic NSCLC, PD-L1 ≥50%): tiragolumab plus atezolizumab failed to improve progression-free or overall survival versus atezolizumab alone.
• SKYSCRAPER-02 (extensive-stage small cell lung cancer): tiragolumab plus atezolizumab plus carboplatin/etoposide produced no benefit over placebo plus chemotherapy.
• SKYSCRAPER-06 (first-line advanced non-squamous non-small cell lung cancer, tiragolumab plus atezolizumab and chemotherapy versus pembrolizumab and chemotherapy): no overall survival benefit over the pembrolizumab-based comparator.
• SKYSCRAPER-15 (resected NSCLC, adjuvant): efficacy objective abandoned before analysis.

Broader TIGIT context

Roche’s experience with tiragolumab mirrors that of other developers. Merck’s vibostolimab-pembrolizumab combination failed to improve outcomes in the KEYVIBE-008 NSCLC trial. Results from domvanalimab-based programs (AstraZeneca/Sanofi) and ociperlimab-based programs (BeiGene/Novartis) have also been disappointing in lung cancer. The consecutive failures have renewed debate about whether TIGIT inhibition offers meaningful benefit as an add-on to PD-1/PD-L1 blockade, or whether the benefit, if any, is confined to specific tumor types, biomarker-defined subgroups, or TIGIT antibody formats that block different mechanisms of immune suppression.

Tiragolumab was designed to block TIGIT-mediated inhibition of T-cell and NK-cell activity in the tumor microenvironment. Its co-inhibitory relationship with PD-1/PD-L1 checkpoints was the theoretical basis for combination trials. Roche has not announced a broader program wind-down for tiragolumab, but the SKYSCRAPER-15 termination effectively forecloses the adjuvant lung cancer indication.

Correction — 2026-06-11: An earlier version of this article described SKYSCRAPER-06 as a trial in “advanced gastric or gastroesophageal junction cancer.” SKYSCRAPER-06 (NCT04294810) was in fact a Phase 3 trial evaluating tiragolumab plus atezolizumab and chemotherapy versus pembrolizumab and chemotherapy in first-line advanced non-squamous non-small cell lung cancer. The indication has been corrected above. Flagged by the post-publication verification pass.

Trial Design

MAPLE-HCM enrolled 175 adults with symptomatic oHCM who had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg or a Valsalva-provoked gradient ≥50 mm Hg. Participants were randomized 1:1 — 88 to aficamten and 87 to metoprolol — as monotherapy for 24 weeks in a double-blind, active-comparator design. The primary endpoint was change in peak oxygen uptake (peak VO₂) from baseline to week 24, measured by cardiopulmonary exercise testing.

Primary Endpoint

At 24 weeks, aficamten-treated patients gained a mean of +1.1 mL/kg/min in peak VO₂ (95% CI, 0.5 to 1.7), while the metoprolol group experienced a mean decline of −1.2 mL/kg/min (95% CI, −1.7 to −0.8). The least-squares mean between-group difference was 2.3 mL/kg/min (95% CI, 1.5 to 3.1; P < 0.001), establishing aficamten’s superiority on the primary endpoint.

“Aficamten — as monotherapy and as first-line therapy — demonstrated greater improvements in exercise capacity and symptoms than beta-blockers.” — Dr. Pablo García-Pavia, MAPLE-HCM principal investigator, ESC Congress 2025

Secondary Endpoints and Biomarkers

Aficamten achieved superiority across five of six pre-specified secondary endpoints. NYHA functional class improved by one or more grades in 51% of aficamten patients versus 26% in the metoprolol group (P < 0.001). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) improved by a least-squares mean difference of 6.9 points in favor of aficamten (P < 0.01). Resting LVOT gradient fell by −30 mm Hg (P < 0.0001) and Valsalva LVOT gradient by −35 mm Hg (P < 0.0001). NT-proBNP declined 73% from baseline in the aficamten group while rising 42% in the metoprolol group, a treatment-effect difference of −81% (P < 0.001). Left atrial volume index improved by 7.0 mL/m² (P < 0.0001) with aficamten. Left ventricular mass index — the sixth pre-specified secondary endpoint — did not differ significantly between treatment groups.

Safety

Overall rates of treatment-emergent adverse events were similar: 73.9% in the aficamten group and 75.9% in the metoprolol group. Serious adverse events occurred in 8% versus 7%. Dose down-titration was required in 4 aficamten patients (4.5%) versus 26 metoprolol patients (29.9%). The primary protocol-specified trigger for aficamten dose reduction was LVEF falling below 50%; the specific reasons for each of the four reductions were not fully detailed in available sources at time of publication.

Aficamten carries a boxed warning for heart failure due to systolic dysfunction. In the United States, the drug is dispensed exclusively through the MYQORZO REMS program, which requires prescriber certification and echocardiographic monitoring before and during treatment. Patients cannot obtain aficamten outside this program; those interested in treatment should speak with a cardiologist who can evaluate whether the drug is appropriate and initiate REMS enrollment.

Correction, June 10, 2026: The original dek and body of this article stated that aficamten achieved superiority across “every” (dek) and “all key” (body) pre-specified secondary endpoints. Post-publication fact-check confirmed via the NEJM primary paper (DOI: 10.1056/NEJMoa2504654) that left ventricular mass index — a pre-specified secondary endpoint — did not differ significantly between the aficamten and metoprolol groups. Both the dek and the secondary-endpoints paragraph have been updated to reflect the accurate result: superiority across five of six pre-specified secondary endpoints.

Regulatory Context

The FDA approved aficamten (Myqorzo) on December 19, 2025, for adults with symptomatic oHCM to improve functional capacity and symptoms. Aficamten is an approved medicine, not an investigational drug. The EMA’s CHMP issued a positive opinion recommending EU marketing authorization on December 12, 2025; the European Commission’s formal marketing authorization followed in February 2026. MAPLE-HCM, alongside the earlier SEQUOIA-HCM trial, was central to both regulatory submissions.

The trial, NCT06488911, was an open-label extension evaluating the safety and tolerability of a fixed-dose combination tablet of obeticholic acid 5 mg plus bezafibrate 400 mg SR in PBC patients rolling over from two earlier studies (747-213 and 747-214). Its status is now listed as TERMINATED, with an enrollment of 62 participants and a completion date of October 21, 2025. The study ran at sites in the United States and across more than a dozen other countries, including Argentina, Australia, the United Kingdom, and several EU member states.

In the registry’s “why stopped” field, Intercept says it “made a business decision to terminate the study based on FDA’s request for voluntary withdrawal of Ocaliva and the issuance of clinical hold on studies under US IND involving OCA.” That clinical-hold statement is Intercept’s own characterization in the ClinicalTrials.gov record; the FDA’s Federal Register withdrawal notice does not mention any clinical hold, addressing only the withdrawal of the marketing applications.

If you take Ocaliva for PBC: do not stop the medication on your own. Talk to your healthcare provider about safely transitioning to an alternative therapy. This is general information, not medical advice.

What patients on Ocaliva should know

This is a regulatory and trial-status story, not a directive to stop treatment. PBC patients currently taking Ocaliva should not discontinue the medication on their own and should consult their healthcare provider about transitioning to an alternative therapy. The withdrawal was deliberately structured with a transition period — the drug came off the US commercial market on November 14, 2025, after a window for patients to consult their providers about other options — precisely to avoid abrupt, unsupervised discontinuation. Intercept’s own withdrawal guidance states that “Patients should talk to their healthcare professionals” and that “Other therapies are FDA approved for the treatment of PBC.”

Losing Ocaliva does not mean PBC goes untreated. First-line therapy remains ursodiol (ursodeoxycholic acid, UDCA), which is FDA-approved for PBC; additional FDA-approved second-line options exist for patients with an inadequate response to or intolerance of UDCA, including elafibranor (Iqirvo), which received FDA accelerated approval in June 2024. The right next step for an affected reader is a conversation with their clinician, not self-discontinuation.

Why approval was pulled

The closure follows the FDA’s November 24, 2025 Federal Register notice withdrawing approval of NDA 207999 for Ocaliva tablets, 5 mg and 10 mg, along with three generic ANDAs (214862, 214980, and 215017). Two distinct dates sit in the public record and should not be collapsed into a single event: the commercial market withdrawal — when the product came off US shelves after the patient transition window — took effect on or about November 14, 2025, while the approval withdrawal of the marketing applications became effective November 24, 2025 under the Federal Register notice. Ocaliva had reached the US market in 2016 under accelerated approval, which the FDA notes was “subject to the requirement that Intercept conduct a postmarketing trial to verify and describe the clinical benefit of OCALIVA.” Per the FDA, that trial fell short: on August 27, 2025, the agency notified Intercept “that the postmarketing trial did not verify clinical benefit and that OCALIVA-treated PBC patients in the postmarketing trial who had early-stage disease at baseline had an excess of liver transplants and deaths.”

Intercept “made a business decision to terminate the study based on FDA’s request for voluntary withdrawal of Ocaliva and the issuance of clinical hold on studies under US IND involving OCA.” — ClinicalTrials.gov NCT06488911, sponsor-authored field

Intercept submitted a letter on September 10, 2025 asking the agency to withdraw the NDA under § 314.150(d) and to waive the expedited withdrawal procedures; approval was withdrawn as of November 24, 2025, under docket FDA-2025-N-5935. The notice was signed by Lowell M. Zeta, Acting Deputy Commissioner for Policy, Legislation, and International Affairs.

The terminated extension was a safety study, not an efficacy trial: its primary outcomes were counts of treatment-emergent adverse events, with all-cause mortality among the secondary measures. No comparative efficacy endpoint was at stake here. The decisive evidence sat in the confirmatory postmarketing trial the FDA cites — the basis for an accelerated approval that has now been unwound.

The extension had enrolled 352 participants with Dravet syndrome or Lennox-Gastaut syndrome since March 2022, gathering long-term safety and tolerability data. Its fate was decided upstream, by the two pivotal trials feeding it.

The pivotal misses

SKYLINE, the Dravet trial (n=144, ages 2–21), measured percent change from baseline in convulsive seizure frequency per 28 days as its primary endpoint. Per Takeda’s topline release, soticlestat missed that endpoint, with a reported p-value of 0.06 — a narrow miss of statistical significance. The company noted nominally significant results on secondary measures, including responder rate and global impression of improvement (p ≤ 0.008), but these do not rescue a failed primary.

The extension closure was “unrelated to patient safety” — it followed the efficacy failures, not a tolerability signal.

SKYWAY, the Lennox-Gastaut trial (n=270, ages 2–55), measured percent change in Major Motor Drop seizure frequency per 28 days as its primary endpoint. That endpoint was also missed.

Takeda said it “will engage with regulatory authorities to discuss the totality of the data generated by these studies to determine next steps.” With both Phase 3 primaries failed and the safety extension now closed, soticlestat’s path in these treatment-resistant childhood epilepsies is, at minimum, sharply narrowed. The secondary and exploratory signals are hypothesis-generating, not confirmatory.

VENTURA-5 (NCT06635135) was a Phase 3, randomized, double-blind, multicenter, placebo-controlled relapse-prevention study of adjunctive aticaprant plus an antidepressant in major depressive disorder with moderate-to-severe anhedonia, sponsored by Janssen Research & Development. The design was conventional: enrich for responders during open-label adjunctive aticaprant, stabilize them, then randomize the stable responders to continue the drug or switch to placebo. The primary endpoint was time from randomization into the double-blind maintenance phase to first documented relapse — defined as a MADRS total score of 22 or higher on two consecutive assessments, or a clinically relevant relapse event.

That funnel never filled. Of 47 participants enrolled into the open-label initial phase, which began on September 19, 2024, 18 entered the stabilization phase. By the time the double-blind maintenance phase opened, just 2 participants had been randomized — both to aticaprant, none to placebo — before the study was stopped. Primary completion came on April 9, 2025, and the study completed on April 25, 2025. With so few patients randomized, the primary endpoint was uninterpretable by construction: the posted results show that no participants experienced a relapse, so median time-to-relapse could not be calculated.

A registry formality, not a new failure

The termination is bookkeeping. Aticaprant’s adjunctive MDD program had already missed across the VENTURA Phase 3 studies, and J&J discontinued the asset for insufficient efficacy, with no new safety signals. VENTURA-5 was the relapse-prevention arm of a program that no longer had a drug to prevent relapse for.

No participant in any phase had a death or a serious adverse event. In the open-label phase, the most common adverse event was pruritus, affecting 5 of 47 aticaprant-treated participants.

The safety read is unremarkable and consistent with the KOR-antagonist class: itch, headache, diarrhea, and dyspepsia in the open-label phase, nothing serious. That matters less than the efficacy ledger. With aticaprant’s discontinuation, another mechanistically novel, non-monoaminergic approach to depression — and specifically to anhedonia — exits Phase 3 without a positive registrational signal, leaving the field’s hunt for a differentiated antidepressant where it was.

The ClinicalTrials.gov record lists NCT04811092 as TERMINATED, with the stated reason being “loss of clinical equipoise based on robust evidence of clinical benefit of sotatercept demonstrated in previous studies.” Under Amendment 11, the registry notes, the study was closed so eligible participants could receive sotatercept via the SOTERIA extension study (NCT04796337) or through commercial access. Sotatercept is an already-approved PAH therapy that is added to background treatment and is initiated and managed by PAH specialists — not a stand-alone or self-started medication.

Who was studied

This was not “all PAH.” Per the registry’s eligibility criteria, HYPERION enrolled adults with WHO Group 1 PAH (idiopathic, heritable, drug/toxin-induced, connective-tissue-disease-associated, or post-shunt-correction subtypes), diagnosed within 12 months of screening, classified WHO functional class II or III, and at intermediate-to-high risk of progression. All participants were already on stable doses of double or triple background PAH therapy (plus diuretics if needed) for at least 90 days before screening. Sotatercept or placebo was added on top of that regimen.

What the closed trial showed

HYPERION was a randomized, double-blind, placebo-controlled study that enrolled 321 such participants. The primary endpoint was median time to clinical worsening (TTCW) — time from randomization to a first adjudicated morbidity event or death.

Per the posted results table, the primary endpoint favored sotatercept with a hazard ratio of 0.24 (95% CI 0.14–0.41; p<0.0001). Median TTCW was not reached in the sotatercept arm versus 23.0 months (95% CI 17.3–NA) on placebo. Serious adverse events occurred in 39 sotatercept-treated participants and 45 placebo-treated participants.

A hazard ratio of 0.24 implies a roughly 76% lower risk of clinical worsening — the kind of margin that erases equipoise.

Because the trial was halted by design rather than run to its planned ~35-month readout, these figures should be read as the data available at early termination, not a completed event-driven analysis. An association from a curtailed trial is not the same as a full survival result, and this is not medical advice.

According to the live ClinicalTrials.gov record, the Alliance for Clinical Trials in Oncology study LoTam (NCT06671912, Alliance A012301) is listed as SUSPENDED. The registry’s status module gives a single stated cause in its whyStopped field — “Amending protocol to increase sample size” — and records a last-update-posted date of June 8, 2026. Both fields were verified directly against the ClinicalTrials.gov API v2 status module; neither was present in the reduced registry payload first retrieved.

A narrow eligibility window — not breast cancer in general

LoTam does not apply to breast cancer broadly, and a reader should not infer it covers their own or a relative’s diagnosis. To enroll, patients must be postmenopausal, with hormone-receptor-positive, HER2-negative disease that is early-stage — the registry lists anatomic stage 0 through IIA, including ductal and lobular carcinoma in situ — and classified as molecular low-risk by a multigene assay.

The registry defines postmenopausal status by one of three routes: no spontaneous menses for at least a year; no menses for under a year with FSH and estradiol in the postmenopausal range per institutional standards; or prior bilateral surgical oophorectomy. Genomic eligibility requires a low-risk multigene score — an Oncotype DX recurrence score of 25 or below, MammaPrint low risk, or a Prosigna risk of recurrence of 40 or below — with both required to be low-risk if more than one assay was run.

LoTam is a randomized, open-label Phase 3 trial run by the Alliance with the National Cancer Institute, with a planned enrollment of 1,556 patients. It randomizes eligible women to low-dose tamoxifen taken orally every other day (Arm II) versus standard daily endocrine therapy — an aromatase inhibitor (anastrozole, letrozole, or exemestane) or standard-dose tamoxifen once daily (Arm I) — for up to five years.

A non-inferiority bet, with no answer yet

The primary endpoint is recurrence-free interval, tested for non-inferiority of low-dose tamoxifen against standard-of-care endocrine therapy over five years, with a stratified Cox hazard ratio reported against a one-sided 95% confidence interval. Secondary endpoints include endocrine-therapy nonadherence; physician-reported adverse events, among them fracture, osteoporosis, stroke and thromboembolism; patient-reported toxicities; invasive disease-free survival; and overall survival, with follow-up of up to ten years.

The suspension is a protocol amendment to enlarge the trial, per the registry — not a reported safety or efficacy signal. No results have been posted, so whether the lower dose is non-inferior remains unknown.

The trial first opened February 19, 2025; estimated primary completion is November 30, 2030. Because no efficacy or safety results exist, any judgment on whether the lower dose holds up is years away. This is a report on a trial’s registry status, not medical advice. Patients should not change or stop endocrine therapy based on an unproven regimen in a paused study, and should discuss treatment with their own oncologist.

This trial applies to a narrow group: patients with resectable, early-stage (Stage II–IIIB, including N2) EGFR-mutant (exon 19 deletion or L858R) non-small cell lung cancer who are surgical candidates. It says nothing about metastatic EGFR-mutant disease or non-EGFR lung cancer.

NeoADAURA (NCT04351555), sponsored by AstraZeneca, randomized 358 such patients 1:1:1 to neoadjuvant osimertinib plus platinum chemotherapy (121 patients), osimertinib monotherapy (117), or placebo plus chemotherapy (120), each followed by surgery. The trial is active but no longer recruiting.

The endpoint that was met (a pathology surrogate)

The primary endpoint was MPR — defined as ≤10% viable tumor cells in the resected lung primary tumor with an R0 margin — by blinded central pathology review. The MPR rate was 26% (95% CI, 18 to 34) with osimertinib plus chemotherapy, 25% (95% CI, 17 to 34) with osimertinib alone, and 2% (95% CI, 0 to 6) with placebo plus chemotherapy. Both osimertinib arms met statistical significance, with odds ratios versus control of 19.82 (95.002% CI, 4.60 to 85.33; p<0.0001) for the combination and 19.28 (99.9% CI, 1.71 to 217.39; p<0.0001) for monotherapy. Those odds ratios are large but imprecise — the near-zero event rate on chemotherapy alone leaves wide confidence intervals, one spanning two orders of magnitude. Crucially, MPR is a pathology measure, not a measure of how long patients live or stay cancer-free.

A quarter of patients reached major pathological response, against roughly 2% on chemotherapy alone — but that is a pathology surrogate. The long-term survival readout is barely begun, and the early signal has not yet cleared the trial’s own bar for significance.

Pathological complete response, a secondary endpoint, reached 9% (95% CI, 4 to 15) with osimertinib alone and 4% (95% CI, 1 to 9) with the combination, versus 0% (95% CI, 0 to 3) on control.

The caveat sits in the survival data. Event-free survival (EFS) — the secondary endpoint that matters most for whether neoadjuvant timing changes outcomes — was analyzed at an interim with only 15% data maturity. The EFS hazard ratio for osimertinib plus chemotherapy versus control was 0.50 (99.8% CI, 0.17 to 1.41; p=0.04), but the paper states this did not reach significance at the prespecified two-sided threshold of 0.002, and the confidence interval crosses 1.0. For osimertinib monotherapy the HR was 0.73 (95% CI, 0.40 to 1.35), and no formal statistical comparison was performed. Twelve-month EFS rates were 93%, 95%, and 83%, but these are early. A pathological surrogate met today does not guarantee a survival benefit tomorrow.

Two structural caveats matter for reading the EFS data. First, the paper itself flags MPR-as-surrogate as a limitation: MPR was chosen as the primary endpoint to keep the study small and read out early, not because it substitutes for overall survival. Second, the trial is effectively perioperative — about 80–86% of patients who underwent surgery in each arm went on to adjuvant osimertinib (82% combination, 86% osimertinib monotherapy, 80% control; standard of care per ADAURA), which the authors say is expected to affect the final EFS analysis. The neoadjuvant EFS signal should not be read in isolation.

On safety, grade ≥3 adverse events during the neoadjuvant period occurred in 36% of osimertinib-plus-chemotherapy patients, 13% of osimertinib-alone patients, and 33% of placebo-plus-chemotherapy patients; investigators reported no new safety concerns. Notably, osimertinib monotherapy delivered comparable MPR with the lowest grade ≥3 toxicity — a result worth watching as the EFS data mature.

The rationale was biologically appealing. In platinum-resistant or platinum-refractory high-grade serous ovarian cancer without a germline BRCA mutation, single-agent PARP inhibition has limited reach; preclinical work had suggested that PI3K blockade might sensitize these tumors to olaparib. EPIK-O randomized 358 such patients 1:1 to alpelisib plus olaparib (180 patients) or to investigator’s choice of paclitaxel or pegylated liposomal doxorubicin (178 patients), in an open-label, active-controlled design.

The combination did not separate from chemotherapy

On the primary endpoint — progression-free survival by blinded independent review using RECIST 1.1 — the two arms were statistically indistinguishable, and the trend favored chemotherapy. Median progression-free survival was 3.6 months with alpelisib-olaparib versus 3.9 months with chemotherapy. The stratified hazard ratio was 1.142 (95% CI 0.882–1.478), with a log-rank p-value of 0.84.

A hazard ratio above 1, with a confidence interval straddling unity, means the experimental combination showed no progression-free survival benefit — and if anything trended worse — than standard single-agent chemotherapy.

Secondary efficacy offered no rescue. The confirmed overall response rate was 15.6% (95% CI 10.6–21.7) in the combination arm versus 13.5% (95% CI 8.8–19.4) with chemotherapy — overlapping intervals and no meaningful gain.

Safety pointed the other way. In the safety population (180 combination, 164 chemotherapy), 92 patients (51.1%) on alpelisib-olaparib had a serious adverse event, versus 50 patients (30.5%) on chemotherapy. On-treatment deaths numbered 26 in the combination arm and 7 in the chemotherapy arm. The combination thus carried more harm without offsetting efficacy.

EPIK-O joins a long line of attempts to extend PARP-inhibitor benefit beyond BRCA-mutated, platinum-sensitive disease through combination strategies. For platinum-resistant high-grade serous ovarian cancer without a germline BRCA mutation — a setting where outcomes remain poor and chemotherapy remains the backbone — this particular hypothesis did not hold. These are registry-posted results; a peer-reviewed publication with full subgroup and overall-survival data would add context.

The trial is large by any standard: 14,194 participants randomized across 1,003 sites since it began in April 2023. Run by Janssen Research & Development with Bristol-Myers Squibb as collaborator, it enrolled adults aged 18 and older after a recent acute coronary syndrome and tested milvexian against placebo, both added to standard of care.

What the readout will test

The primary endpoint is the time to a first major adverse cardiovascular event (MACE), a composite of cardiovascular death, myocardial infarction, and ischemic stroke, assessed over up to three years and six months. Secondary endpoints include a broader vascular composite — adding major adverse limb events and symptomatic venous thromboembolism — along with all-cause mortality and cardiovascular death.

The wager behind Factor XIa inhibition is that you can blunt clotting without paying the bleeding penalty that has long constrained anticoagulation.

That hypothesis is what milvexian must now prove at scale. The “Completed” flag confirms the trial reached its event-driven endpoint; on its own, it does not indicate whether milvexian succeeded. No results have been posted to the registry, and no efficacy or safety figures are available from this primary source.

Until the data table or a peer-reviewed paper appears, the only certainty is timing: a major cardiology readout is now queued. This is journalism, not medical or investment advice.

The randomized, double-blind trial (NCT04619797) enrolled 542 patients, randomized 1:1 to tiragolumab plus atezolizumab plus pemetrexed (Alimta) and carboplatin or cisplatin (269 patients) versus placebo plus pembrolizumab plus the same chemotherapy (273 patients). Eligibility was restricted to non-squamous NSCLC and excluded tumors with EGFR mutations or ALK fusions, as well as ROS1 or BRAF V600E alterations, so the result speaks to a specific lung-cancer subtype, not lung cancer broadly. Both primary endpoints were analyzed in the full analysis set of all randomized patients, not a PD-L1-selected subgroup.

On the co-primary endpoint of investigator-assessed progression-free survival, median PFS was 8.31 months in the tiragolumab arm versus 9.89 months with pembrolizumab. The hazard ratio was 1.27 (95% CI 1.02–1.57), a confidence interval that excludes 1.0 in the direction favoring the control.

Overall survival and deaths both favored the control

Overall survival, the other primary endpoint, told the same story. Median OS was 18.89 months in the tiragolumab arm versus 23.10 months with pembrolizumab, for a hazard ratio of 1.33 (95% CI 1.02–1.73).

The safety record points the same way as the survival analysis. Across all causes, 54.3% of tiragolumab-treated patients died (146 of 269) versus 42.9% of pembrolizumab-treated patients (117 of 273). Serious adverse events affected 55.1% of tiragolumab-treated patients (147 of 267) versus 52.2% of pembrolizumab-treated patients (142 of 272). The higher mortality in the experimental arm is the most patient-relevant finding here: the tiragolumab combination was not only less effective on the survival endpoints but was associated with more deaths and more serious adverse events.

On objective response rate — a secondary, surrogate measure of tumor response (RECIST v1.1 complete or partial response) rather than survival or function — the tiragolumab combination produced responses in 50.2% of patients versus 56.6% with pembrolizumab. Because ORR captures only tumor shrinkage, not how long patients live or how they feel, it carries less weight than the two primary survival endpoints; here it happens to point the same way.

The 95% confidence intervals for both primary endpoints sit entirely above 1.0, and more patients in the experimental arm died — the tiragolumab combination did worse, not just no better.

For a head-to-head design, the choice of comparator matters: SKYSCRAPER-06 pitted the experimental regimen directly against pembrolizumab-based chemoimmunotherapy, the established first-line standard, rather than against chemotherapy alone. That makes the result a clean read on relative benefit, and the read is negative on both efficacy and safety.

The findings also align with broader setbacks across the TIGIT field, where adding the target to PD-(L)1 blockade has repeatedly failed to deliver the additive benefit that early-phase signals suggested. Association is not causation, and these are trial-level outcomes rather than guidance for any individual patient.

Relapse after transplant remains the central problem in AML, and a low-intensity maintenance regimen that could keep patients in remission has been a long-sought goal. VIALE-T enrolled 465 patients (start date February 26, 2020) and randomized them in Part 2 to venetoclax plus azacitidine with best supportive care (Arm A, n=214) or best supportive care alone (Arm B, n=216).

The Part 2 primary endpoint was overall survival. The point estimate did not favor the combination: the stratified hazard ratio was 1.2 (95% CI 0.81–1.77), numerically favoring supportive care, with a confidence interval that crosses 1.0. Importantly, the data are immature. Median survival was not evaluable in either arm, the pre-specified number of events was never reached, and formal hypothesis testing was not performed — so the estimate was not statistically tested and cannot be read as a definitive efficacy verdict.

The overall-survival point estimate numerically favored supportive care but was not statistically tested (95% CI 0.81–1.77); the sponsor cited “strategic considerations” for stopping.

Safety ran in the expected direction for an active regimen. In Part 2, serious adverse events occurred in 45% (97/214) of venetoclax-plus-azacitidine patients versus 31% (66/216) of supportive-care patients; 26% (56/214) of combination patients versus 21% (46/216) of supportive-care patients died during the adverse-event reporting period.

What the registry supports is narrow but clear: AbbVie stopped the trial for “strategic considerations,” and the posted overall-survival data show no signal favoring the combination at the point the study was halted — before its planned analysis. Venetoclax plus azacitidine remains a backbone in frontline AML; as investigational post-transplant maintenance, this early-terminated trial showed no survival signal favoring the combination in immature data before it was stopped, and was not powered or analyzed to deliver a definitive verdict.

The drug, cenvacibart (REGN7508), is a monoclonal antibody targeting Factor XI, a clotting factor that several companies are pursuing on the theory that inhibiting it prevents pathological clots while sparing the normal hemostasis whose disruption drives anticoagulant bleeding. ROXI-EVEREST will randomize patients with paroxysmal or persistent AF and elevated stroke risk — broadly, a CHA2DS2-VA score of 2 or higher — in a quadruple-blind, double-dummy design, in which each arm receives an active drug plus a matching placebo for the other.

Two primary endpoints, one trade-off

The trial is built around the central tension of the class. Its co-primary endpoints are time to first stroke or systemic embolism — the efficacy question — and time to first ISTH major or clinically relevant non-major bleeding — the safety question. Both are measured over roughly 36 months.

The design forces the drug to answer both questions at once: prevent strokes as well as apixaban, and bleed less.

Secondary endpoints stack composite efficacy-plus-bleeding outcomes, all-cause death, hemorrhagic stroke, and anti-drug antibody formation — a relevant concern for an injectable biologic in a chronic indication.

No efficacy or safety data exist yet; this is a registration, not a result. Estimated primary completion is September 11, 2029. Whether a Factor XI antibody can unseat the direct oral anticoagulants now depends on what those 15,364 patients eventually show.

The open-label study randomized 711 patients whose disease had progressed after both platinum-containing chemotherapy and a PD-1/PD-L1 checkpoint inhibitor, comparing Trodelvy against physician’s choice of single-agent chemotherapy — paclitaxel, docetaxel, or vinflunine. Per the trial’s arm description, sacituzumab govitecan was given at 10 mg/kg intravenously on Day 1 and Day 8 of each 21-day cycle.

A narrow miss on survival

Median overall survival was 10.3 months with Trodelvy (95% CI 9.1–11.8) versus 9.0 months for chemotherapy (95% CI 7.5–9.7). The hazard ratio was 0.86 (95% CI 0.73–1.02), with a p-value of 0.0870 — short of the threshold for statistical significance. Because the confidence interval crosses 1.0, the trial cannot rule out that the two arms produce equivalent survival.

A 1.3-month numerical survival edge that the data cannot statistically distinguish from chance — set against more deaths from adverse events in the Trodelvy arm.

Several secondary endpoints favored Trodelvy numerically. Investigator-assessed progression-free survival reached 4.0 months versus 2.9 months with chemotherapy (HR 0.81; 95% CI 0.68–0.95; p=0.0117), but progression-free survival assessed by blinded independent central review was not significant (median 4.2 vs 3.6 months; HR 0.86; 95% CI 0.72–1.03; p=0.1095).

Response figures depended on who did the reading. The objective response rate by blinded independent central review was 22.5% with Trodelvy versus 13.8% with chemotherapy (p=0.0022), and the clinical benefit rate by that same review was 29.9% versus 20.5% (p=0.0034). Investigator-assessed clinical benefit rate was higher still, at 31.5% versus 21.9% (p=0.0032). But because the primary endpoint was not met, the trial’s hierarchical testing renders these secondary results descriptive rather than confirmatory; they did not establish a net clinical benefit.

An excess of treatment-related deaths

The lack of a survival benefit was compounded by a safety signal. Gilead’s October 2024 update and the data presented at ESMO Asia 2024 reported a higher number of deaths from adverse events in the Trodelvy arm than in the chemotherapy arm. These excess deaths occurred primarily early in treatment and were driven by neutropenic complications, including infection. Grade 5 (fatal) treatment-emergent adverse events were reported in about 7% of Trodelvy-treated patients versus about 2% of those on chemotherapy.

The result lands in a difficult treatment setting. Patients entering TROPiCS-04 had already exhausted the two pillars of advanced urothelial cancer therapy, and the chemotherapy comparator arm itself reflects limited remaining options. Trodelvy had held U.S. accelerated approval in this indication: the FDA granted it on April 13, 2021, based on the response rate seen in the single-arm Phase 2 TROPHY-U-01 trial (confirmed objective response rate 27.7%, 95% CI 19.6–36.9, in 112 patients), with continued approval contingent on a confirmatory study. TROPiCS-04 served as that confirmatory trial.

The basis for withdrawal was an unfavorable benefit-risk balance — the absence of a survival benefit combined with the excess of toxicity-related deaths — rather than the efficacy miss in isolation. Gilead moved in October 2024 to voluntarily withdraw the urothelial-cancer indication, in consultation with the FDA, and the FDA announced the final withdrawal of the approval on November 22, 2024.

The trial is listed as completed, with primary completion in July 2025. The registry posting does not address further regulatory steps, and the detailed safety profile and any prespecified subgroup analyses await peer-reviewed publication. For now, the conclusion is unambiguous: on the endpoint that mattered most, the difference between Trodelvy and chemotherapy was not statistically significant, and the drug carried an excess of treatment-related deaths.

TRIUMPH-1 (NCT05929066) is a randomized, double-blind, placebo-controlled trial that enrolled an actual 2,335 participants who have obesity or overweight, without type 2 diabetes. Patients were assigned to one of three subcutaneous retatrutide doses or to placebo, with the primary endpoint defined as percent change from baseline in body weight at Week 80. The registry lists an actual primary completion date of April 6, 2026 and an overall completion date of April 30, 2026.

What “completed” does and doesn’t tell us

A completed status confirms the protocol ran to its planned end and follow-up has closed — not that the drug worked. The registry’s results module remains empty (hasResults: false), so the magnitude of weight loss, the placebo comparison, the confidence intervals, and the safety profile are all still unreported here.

The status flag tells you the trial is over. It tells you nothing yet about the effect size.

Retatrutide targets the GLP-1, GIP and glucagon receptors, a mechanism that drew attention after earlier-phase data. TRIUMPH-1 also embedded sub-studies in knee osteoarthritis and obstructive sleep apnea, with condition-specific secondary measures. Until Lilly posts registry results or a peer-reviewed readout, those endpoints — primary and secondary alike — remain unquantified. This desk will report the numbers when they are public, not before.

The design targets a population that has run out of established options. Eligible men must already have been treated with at least two cycles of a PSMA-directed beta-emitting radioconjugate — the class that includes ¹⁷⁷Lu-PSMA — alongside prior taxane chemotherapy and a prior androgen-receptor pathway inhibitor (ARPI). PSMA positivity is confirmed by ⁶⁸Ga-PSMA-11 or ¹⁸F-DCFPyL PET/CT. Prior alpha-emitting radioligand therapy is excluded, though prior radium-223 is permitted.

Two co-primary endpoints, a superiority design

Roughly 670 participants will be randomised to AZD2265 or to investigator’s choice of standard of care — cabazitaxel, an ARPI switch, or radium-223. The study has two co-primary endpoints: radiographic progression-free survival (rPFS) by blinded independent central review per RECIST 1.1 and PCWG3, and overall survival (OS). AstraZeneca states that the intent is to demonstrate superiority of AZD2265 over standard of care on both rPFS and OS.

The trial is built around men who have already progressed through a beta-emitting PSMA radioligand — a question the field has not yet answered in Phase 3.

Secondary endpoints include composite PFS; PSA50 and PSA90 response rates; objective response rate; duration of response; symptomatic skeletal event-free survival; and AZD2265 pharmacokinetics. An Independent Data Monitoring Committee will oversee safety. Treatment continues until progression, unacceptable toxicity, or other discontinuation criteria are met; estimated primary completion is 13 February 2029.

VECTRA-01 is a genuinely global effort. The registry lists research sites across 16 countries: the United States, Canada, Brazil, the United Kingdom, Germany, France, Spain, Austria, China, Japan, South Korea, Taiwan, India, Thailand, Turkey, and Australia. Most are listed as not yet recruiting, with active recruitment so far recorded only in Miami and Omaha.

No efficacy or safety results exist yet — this is a newly opened trial, not a readout. The asset’s distinction is its radioisotope: an alpha-emitter delivering high-energy, short-range radiation, tested specifically after beta-emitter therapy.