Pivekimab sunirine (pivekimab sunirine-pvzy; DECNUPAZ™) is first-in-class CD123-directed antibody-drug conjugate (ADC) developed by ImmunoGen for the treatment of haematological malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN) and acute myeloid leukaemia (AML). CD123 is an attractive therapeutic target because it is highly expressed on malignant cells and leukaemic stem cells, but has limited expression on normal haematopoietic stem cells. On 27 May 2026, pivekimab sunirine received its first approval in the USA for the treatment of adult patients with BPDCN. This article summarizes the milestones in the development of pivekimab sunirine leading to this first approval.
The MYC family oncoproteins, including MYC, MYCN, and MYCL, are potent drivers of tumorigenesis across a broad range of human cancers, frequently linked to aggressive tumor behavior, poor prognosis, and therapy resistance. They function as master transcriptional regulators that orchestrate gene expression programs governing nearly all aspects of tumor development. Despite their pivotal oncogenic role, they have long been considered “undruggable” due to their intrinsically disordered structure, lack of enzymatic activity, and the difficulty of targeting their protein–DNA and protein–protein interactions with conventional small-molecule approaches. Recent advances are beginning to overcome these challenges through innovative molecular strategies that either directly inhibit MYC activity or exploit MYC regulatory networks. Importantly, the first direct MYC inhibitor evaluated in humans, OMO-103, recently demonstrated promising antitumor activity in phase I clinical trials. Indirect approaches have focused on suppressing MYC transcription, translation, or stability by targeting upstream signaling pathways, as well as by exploiting MYC-associated cofactor interactions and synthetic lethal vulnerabilities to improve therapeutic specificity. In this review, we highlight the multifaceted roles of MYC in different cancer types and provide a comprehensive overview of current therapeutic strategies targeting MYC with a particular focus on epigenetic modifiers and metabolic vulnerabilities.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with few treatment options, especially for APOE4/4 homozygotes who carry high genetic risk. Valiltramiprosate/ALZ-801 is an oral small-molecule inhibitor of amyloid-beta oligomer formation in late-stage development as a disease-modifying therapy for AD. A recent Phase 3 trial did not meet its primary clinical endpoint in the overall population, but demonstrated significant benefits in cognition, function, and brain volumetric MRI (vMRI) in the prespecified subgroup with mild cognitive impairment (MCI). Here, we report plasma p-tau217, p-tau217/Aβ42, and neurofilament light chain (NfL) results from the Phase 3 trial, along with 4-year fluid biomarker data from the Phase 2 study in APOE4 carriers with early AD. The 78-week, APOLLOE4 Phase 3 trial randomized APOE4/4 homozygotes to placebo (n = 162) or valiltramiprosate 265 mg BID (n = 163). The Phase 2 trial was an open-label biomarker study in APOE4 carriers with early AD who received valiltramiprosate 265 mg BID (N = 84) for 104 weeks, followed by a 2-year extension on the same regimen. Plasma p-tau217 and p-tau217/Aβ42 were measured every 6 months in both trials using FDA-approved Fujirebio Lumipulse G assay. Plasma NfL was measured in the Phase 3 trial using the Simoa assay. Associations between plasma biomarkers and clinical or vMRI outcomes were assessed using Spearman’s correlation. Data are reported separately by study. Baseline plasma p-tau217/Aβ42 confirmed amyloid positivity in 94
Vepdegestrant (VEPPANU; formerly ARV 471) is a novel PROteolysis TArgeting Chimera (PROTAC) that is able to simultaneously bind the estrogen receptor (ER) and an E3 ubiquitin ligase complex, resulting in polyubiquitination of the ER and its subsequent degradation via a proteasome. It is being developed by Arvinas and Pfizer primarily as a treatment for ER+, HER2− breast cancer. In May 2026, vepdegestrant received its first global approval in the USA for adults with ER+, HER2−, ESR1-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy. This article summarizes the milestones in the development of vepdegestrant leading to its first approval in this indication.
Acute anterior uveitis (AAU) is the most common extra-musculoskeletal manifestation of radiographic axial spondyloarthritis (r-axSpA) and is an important consideration when selecting biological therapy. Although adalimumab (ADA) and infliximab are commonly used in patients with r-axSpA and AAU, direct comparative evidence, particularly between ADA and subcutaneous infliximab (IFX-SC), remains limited. The objective of this study was to compare the risk of AAU flare between ADA and IFX-SC in patients with r-axSpA and a history of AAU. This multicenter, head-to-head, randomized, open-label trial enrolled patients with r-axSpA and a documented AAU event within the preceding 2 years. Participants were randomly assigned (1:1) to receive ADA (40 mg every 2 weeks) or IFX-SC (intravenous 5 mg/kg induction followed by subcutaneous 120 mg every 2 weeks) and were followed for 48 weeks. The primary endpoint was AAU flare occurrence. Hazard ratios (HRs) were estimated using Cox proportional hazards models. Secondary endpoints included changes in best-corrected visual acuity (BCVA), r-axSpA disease activity and functional indices, and safety outcomes. Fifty-six patients were randomized (ADA, n = 28; IFX-SC, n = 28). During follow-up, one AAU flare episode occurred in each group. The adjusted HR of IFX-SC (vs ADA) for an AAU flare was 0.496 (95
Baxdrostat (BAXFENDY™) is a first-in-class, highly selective and potent aldosterone synthase inhibitor being developed by AstraZeneca for the treatment of hypertension, chronic kidney disease (CKD) and primary aldosteronism, and for the prevention of heart failure. On 15 May 2026, baxdrostat received its first approval in the USA for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure (BP) in adults who are not adequately controlled on other agents. This article summarizes the milestones in the development of baxdrostat leading to this first approval for hypertension.
Despite two decades of therapeutic clinical trials in metabolic dysfunction-associated steatotic liver disease (MASLD), only two drugs have been approved so far for those with metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis but not cirrhosis. Treatment responses are variable and difficult to predict, reflecting the complexity of disease pathophysiology as well as the current inability to capture disease heterogeneity, all precluding making informed individualized choices that potentially might improve treatment results. Liver biopsy for diagnosis and efficacy assessment is to date a prerequisite in late-stage trials, which limits large-scale trials and translation to routine clinical practice, and also fails to capture that heterogeneity. Several non-invasive tests (NITs) have been developed as a diagnostic surrogate to reflect disease severity, mostly addressing fibrosis, which is the strongest predictor of liver-related outcomes. This article highlights the dissonance between drug development for 'at-risk' MASH that targets both active disease and fibrosis relying on strict histological criteria, and current NITs that have been proposed for patient selection for pharmacotherapy and monitoring in clinical practice but largely reflect fibrosis. Although increasing evidence suggests their usefulness in diagnosis and follow-up, their ability to capture disease heterogeneity and select the right patients for the right treatments seems limited. Emerging NITs are derived from disease pathophysiological mechanisms and integrate lipidomic and proteomic analysis with existing biomarkers, as well as with other parameters such as the genetic background, the liver microenvironment, or the gut microbiome. Utilizing novel NITs therefore has the potential to identify appropriate candidates for therapy and also monitor responses, allowing in the future for true personalized medicine. Furthermore, understanding the complex pathophysiological mechanisms can potentially unravel not only novel diagnostics but also innovative therapeutic targets. This could lead to (personalized) choices of drugs and drug combinations that engage multiple pathways to improve efficacy, not only in terms of liver disease, but also in relation to the cardiometabolic risk profile. Moving towards precision medicine in MASLD, information provided non-invasively via circulating biomarkers (liquid liver biopsy) may hence guide risk stratification and therapeutic decisions in the near future.
Autoimmune diseases remain a major cause of chronic morbidity despite substantial advances in targeted immunomodulatory therapies. In many autoantibody-mediated conditions, disease refractoriness and relapse are driven by long-lived plasma cells, which are largely resistant to conventional immunosuppression and upstream B cell–directed strategies. CD38, a surface molecule highly expressed on plasmablasts and plasma cells and functionally involved in immunometabolic regulation, has emerged as a promising therapeutic target to overcome this limitation. Clinical interest in anti-CD38 therapy has been catalyzed by experience in plasma cell dyscrasias, where anti-CD38 monoclonal antibodies induce rapid and profound depletion of antibody-secreting cells. Over recent years, accumulating reports and early-phase studies have explored the repurposing of CD38-directed therapies in severe, treatment-refractory autoimmune diseases. The most compelling evidence has emerged in lupus nephritis and immune thrombocytopenia, with additional proof-of-concept data in autoimmune cytopenias and plasma cell–driven renal disorders such as immunoglobulin light chain (AL) amyloidosis. These experiences suggest that targeting CD38 can lead to meaningful clinical and immunological improvement, often accompanied by rapid reductions in pathogenic autoantibody production. However, the current evidence base remains heterogeneous and largely derived from small cohorts, case series, and early-phase trials, and important questions remain regarding durability of response, optimal treatment strategies, and long-term safety, particularly with respect to hypogammaglobulinemia and infection risk. We summarize the biological rationale for CD38 targeting in autoimmunity and plasma cell–driven immune-mediated diseases, critically appraise the emerging clinical evidence across disease settings, and discuss key challenges and future directions for integrating plasma cell–directed therapies into immunological disease management.
Lenacapavir [YEZTUGO® (USA); YEYTUO® (EU)] is the first twice‑yearly long‑acting injectable option to be approved for HIV pre‑exposure prophylaxis (PrEP). As a potent HIV capsid inhibitor, lenacapavir disrupts multiple stages of the viral replication cycle. Its slow absorption and long half‑life permit administration as a subcutaneous (SC) injection once every 6 months. Lenacapavir is indicated for PrEP to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents weighing ≥ 35 kg who are at risk for HIV-1 acquisition. In two large phase III clinical trials, lenacapavir demonstrated efficacy in preventing HIV acquisition across diverse populations, including cisgender women, cisgender gay, bisexual, and other men, transgender women, transgender men, and gender-nonbinary persons who have sex with partners assigned male at birth. HIV incidence with lenacapavir was significantly lower than the background HIV incidence and the HIV incidence with daily oral PrEP (emtricitabine/tenofovir disoproxil fumarate). Adherence to lenacapavir was consistently high across both trials. Lenacapavir was generally well tolerated, with mostly mild or moderate injection‑site reactions (ISRs) that declined in frequency over time. With its convenient twice‑yearly dosing schedule and SC route of administration, lenacapavir represents a valuable addition to the current portfolio of HIV PrEP options. Pre‑exposure prophylaxis (PrEP) requires people who do not have HIV to take a pill every day to protect them from acquiring the infection. Daily oral PrEP with emtricitabine combined with tenofovir disoproxil fumarate or tenofovir alafenamide is highly effective for preventing HIV infection, but its impact is limited by poor adherence. Long‑acting injectable options with less frequent dosing schedules were developed to help address this challenge. Lenacapavir [YEZTUGO® (USA); YEYTUO® (EU)] is a first-in-class HIV capsid inhibitor that is designed for slow drug release and can be administered by SC injection twice a year. It is approved for PrEP in adults and adolescents at risk of acquiring HIV infection. In clinical trials, lenacapavir was effective for preventing HIV infection across diverse populations. Adherence to twice‑yearly injections was high. Lenacapavir was generally well tolerated. The most common adverse events were ISRs, which were mostly mild or moderate in severity. Twice-yearly lenacapavir offers practical advantages over existing PrEP options and represents a valuable addition to the HIV prevention portfolio.
Small-cell lung cancer (SCLC) is widely considered one of the most aggressive human malignancies, characterized by development of rapid metastases and eventual resistance to platinum chemotherapy and immunotherapy. For decades, despite rigorous scientific investigation and well-established mouse models providing a basis for mechanistic understanding, there were limited therapeutic advances for SCLC. The past decade has seen reinvigoration of drug development for SCLC as well as US Food and Drug Administration (FDA) approval of tarlatamab, a bispecific T-cell engager with unprecedented survival advantage in this recalcitrant disease. Multiple other promising clinical trials in the first and later-line settings are underway that seek to challenge standards of first-line chemoimmunotherapy, investigate combination treatments in the later line, and introduce T-cell engagers earlier in treatment. This review provides a comprehensive primer on the biology and molecular landscape of SCLC, in the context of how both shape ongoing investigational strategies. A broad overview of established multidisciplinary management of both limited-stage and extensive-stage SCLC is discussed to provide understanding of how the next decade is likely to bring significant clinical gains as emerging therapeutics seek to redefine the management of SCLC and build upon novel advances.
Healthcare systems face immense economic pressures, workforce challenges, and increased demand for services, culminating in high occupational burnout among physicians. Here, we evaluate how one department tried to navigate these evolving challenges while simultaneously supporting the occupational well-being and work environment characteristics that influence well-being among pathologists. Existing electronic health records data from the Stanford Medicine Department of Pathology and de-identified data collected from the Stanford Doctor Survey™ were used to evaluate caseload sign-out patterns and trends in occupational well-being. Changes over time were modeled using linear regression/linear mixed models. Department caseload and cases signed out after hours increased between 2020 and 2024, and significantly higher on average following the adoption of a new laboratory information system (LIS) (total: b = 1861.0 [95% CI 1567.0, 2155.0] p < 0.0001; after-hours: b = 1165.4 [95% CI 1042.7, 1288.1] p < 0.0001). There was no significant change in the number of cases per pathologist/year, although per-person case complexity increased significantly (b = 670.6 [95% CI 491.5, 849.7] p = 0.004) and the percentage of cases signed out after hours increased by 10%. Despite these increases, measures of occupational well-being improved, including professional fulfillment (2020 vs. 2024: b = 0.78 [0.10-1.47] p < 0.026; 2022 vs. 2024: b = 1.08 [0.39-1.77] p = 0.002) and burnout (2022 vs. 2024: b = -0.77 [-1.38,-0.16] p = 0.013). These improvements appear related to simultaneous improvements in efficiency of clinical practice, supportive leadership behaviors, teamwork climate, helpfulness of electronic health records, self-valuation, and personal-organizational values alignment. Collectively, these data illustrate how a large pathology department simultaneously increased productivity and physician well-being through improvements in these core elements of a supportive work environment.
Lunsotogene parvec (lunsotogene parvec-cwha; OTARMENI™) is a dual adeno-associated virus (AAV) gene transfer therapy developed by Regeneron Pharmaceuticals for the treatment of profound, congenital hearing loss caused by OTOF variants. Delivery of the OTOF transgene to the inner hair cells facilitates production of functional otoferlin protein to restore synaptic transmission to the auditory nerve. Lunsotogene parvec received its first approval on 23 April 2026 in the USA for the treatment of paediatric and adult patients with severe-to-profound and profound sensorineural hearing loss (any frequency > 90 dB HL) associated with molecularly confirmed biallelic variants in the OTOF gene, preserved outer hair cell function and no prior cochlear implant in the same ear. This article summarises the milestones in the development of lunsotogene parvec leading to this first approval for OTOF-associated sensorineural hearing loss.
Continuous biologic therapy achieves psoriasis control but may be limited by cost, adherence burden, safety concerns, and patient preference. Evidence on outcomes after early, patient-driven discontinuation of secukinumab in routine practice is limited. The aim of this study was to describe clinical outcomes after voluntary secukinumab discontinuation among patients achieving predefined week-12 response targets and to explore factors associated with relapse. This prospective single-center cohort enrolled 172 adults with moderate-to-severe plaque psoriasis initiating secukinumab during 2022–2024. At week 12, patients achieving target response achievement 1 (TRA1: Psoriasis Area and Severity Index [PASI]75, Physician’s Global Assessment [PGA] 0/1, or body surface area [BSA] <3
