Verve Therapeutics (United States)

Abstract Description MSLN is highly expressed in solid tumors but weakly in few normal tissues, making it a promising target for CAR T cell therapy. Early MSLN CAR T trials using the SS1 anti-MSLN binder with 41BB-CD3z showed clinical safety, but lacked efficacy. A recent report describing patient lung toxicity with a MSLN CAR T using a different binder underscores the urgent need for safer CAR T with enhanced tumor specificity. We previously developed a KIR-CAR, SynKIR-110 comprised of a split-chain design: a SS1 MSLN binding domain, and DAP12 T cell activation domain. This design mimics natural multichain immunoreceptors and demonstrates greater potency vs CD3z-based CAR T in vivo. To investigate SynKIR-110 tumor specificity we compared it to the clinically tested SS1-41BBz. T cells were stimulated with MSLN-positive (MSLN+) or negative (MSLN-) targets. T cell growth, phenotype, co-culture cytokines, and longitudinal tumor lysis were assessed. SynKIR-110 showed 4-fold higher growth, 4-fold lower CAR MFI expression and 6-fold lower 41BB+% vs SS1-41BBz at baseline. Both eliminated MSLN+ targets similarly. However, SS1-41BBz also showed higher basal killing and secreted higher cytokine levels upon MSLN- target co-culture, while SynKIR-110 did not. Overall SynKIR-110 demonstrates improved tumor specificity without the constitutive activation seen in SS1-41BBz. Further studies will explore the molecular pathways linked to enhanced tumor specificity, potency and exhaustion resistance of SynKIR-110. Funding Sources Verismo Therapeutics Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Disclosure: K.B. Kaylan: None. T. Nargis: None. K. Figatner: None. J.E. Wang: None. S. Pratuangtham: None. A. Chakraborty: None. I. Casimiro: None. J.L. Nadler: None. M.B. Boxer: MBB is a Veralox Therapeutics employee. D.J. Maloney: DJM is a Veralox Therapeutics employee. R.M. Anderson: None. R.G. Mirmira: RGM received an investigator-initiated award from Veralox Therapeutics. RGM serves on the Scientific Advisory Board for Veralox Therapeutics. S.A. Tersey: SAT received an investigator-initiated award from Veralox Therapeutics.Individuals with obesity can develop peripheral insulin resistance and hyperinsulinism even without impaired glucose tolerance or type 2 diabetes (T2D). Obesity is also associated with macrophage infiltration in peripheral tissues, further contributing to insulin resistance and progression to T2D. The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and is known to promote the migration of macrophages, yet its role in T2D and obesity-associated inflammation remains incompletely understood. Here, we used a human gene replacement mouse model in which endogenous mouse Alox15 is replaced by the human ALOX12 (B6.hALOX12). As a human-relevant model of obesity and T2D, we treated male B6.hALOX12 mice at 8 weeks of age with high-fat diet (HFD, 60% total calories from fat) and vehicle or VLX-1005, a potent and selective inhibitor of 12-LOX, given by oral gavage at 30 mg/kg/day for 10 weeks. B6.hALOX12 mice treated with VLX-1005 showed improved random-fed blood glucose levels and glucose tolerance testing with non-statistically significant improvements in insulin tolerance testing, glucose-stimulated insulin secretion, and homeostasis model assessment of insulin resistance values. In these mice, we additionally observed no changes in β cell mass, decreased β cell dedifferentiation, and decreased macrophage infiltration in islets and adipose tissue. Western blot analysis of adipose tissue immediately after insulin injection (3 units/kg) showed improved biochemical insulin sensitivity by phosphorylated AKT with VLX-1005 treatment. Isolation of the stromal vascular fraction from adipose tissue showed decreases in CD11b+ myeloid cells and Tnfα expression with VLX-1005 treatment. In a complementary transgenic zebrafish model in which macrophages are labelled by GFP, Tg(mpeg:eGFP)gI22, we observed decreased macrophage infiltration in pancreatic islets with VLX-1005 treatment after a HFD treatment (5% egg yolk). Last, to answer whether LOX enzyme expression has cell type-specific effects, we generated a conditional knockout of Alox15 in myeloid cells (B6.Alox15Δmyel). In B6.Alox15Δmyel mice, we observed unchanged glucose homeostasis and β cell mass, decreased β cell dedifferentiation, and decreased macrophage infiltration in both islets and adipose tissue. In summary, inhibition of 12-LOX with VLX-1005 in B6.hALOX12 mice results in improvement in glucose homeostasis and decreased macrophage infiltration in islets and adipose tissue. Our mouse model provides a platform by which to investigate the pathophysiological role of 12-LOX in other metabolic diseases, such as atherosclerosis and metabolic-dysfunction associated steatotic liver disease. These findings also suggest that 12-LOX inhibition could serve as a therapeutic strategy for obesity and T2D.Presentation: Monday, July 14, 2025

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with up to 50% of patients progressing to ESKD or death within 20 years. The cytokines B-cell Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) play key roles in IgAN pathophysiology by binding to the TACI receptor on B cells and fueling production of galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies. Gd-IgA1 is recognized as an autoantigen by anti-Gd-IgA1 autoantibodies, forming the immune complexes which drive kidney pathology and clinical disease. Atacicept is a fully humanized TACI-Fc fusion protein that inhibits both BAFF and APRIL with nanomolar binding affinity, interrupting the immunopathogenesis of IgAN. Atacicept is self-administered at home by subcutaneous injection once weekly (QW). The ORIGIN 2b study evaluated the safety and efficacy of atacicept in IgAN and met the primary endpoint with a statistically significant and clinically meaningful UPCR reduction at 24 wk, with deepening efficacy through 36 wk as compared to placebo. In the open-label extension (OLE), atacicept demonstrated further Gd-IgA1 reductions, hematuria improvements, and UPCR reductions with eGFR stabilization at a rate of decline similar to the general population without kidney disease through 96 wk, suggesting atacicept offers a potentially safe, long-term, disease-modifying treatment for IgAN. Herein, we report the changes in Gd-IgA1 and eGFR during the 26-wk follow-up period after atacicept discontinuation. Method The randomized, double-blind, placebo-controlled Phase 2b ORIGIN study included 116 participants with biopsy-proven IgAN, 24 h urine protein >0.75 g/day or UPCR >0.75 g/g, and eGFR ≥30 mL/min/1.73 m2 despite optimized renin–angiotensin system blockade. Participants were randomized to atacicept or placebo QW for up to 36 wk. The double-blind, randomized treatment period was followed by an OLE in which participants received atacicept 150 mg QW for up to 60 wk, for a total of up to 96 wk of treatment. Participants were subsequently followed for a 26-wk follow-up period after completing atacicept treatment, with evaluations at 12 and 26 wk post-treatment. During this follow-up period, routine hematology, chemistry, and Gd-IgA1 levels were collected and analyzed; no urine samples were collected. This analysis includes participants treated with atacicept who had a last on-treatment Gd-IgA1 or eGFR value in the study wk 96 analysis window and ≥1 measure in the follow-up period, with the study wk 96 values reset as the new baseline and analyzed along with the follow-up 12 and 26 wk data. Gd-IgA1 and eGFR changes were analyzed using a MMRM model. Results There were 103 participants who received ≥1 atacicept dose for ≥60 wk and remained in the follow-up study period. Following completion of atacicept treatment, increases in serum Gd-IgA1 were observed at wk 12 and 26 of +90% and +117% respectively. In addition, changes in eGFR at wk 12 and 26 were −1.6 and −3.9 ml/min/1.73 m2, respectively. (Fig. 1) Conclusion IgAN is a chronic and progressive disease of B-cell origin, in which cytokines BAFF and APRIL are sustaining factors in its pathophysiology. Treatment with atacicept, a precision B-cell modulator inhibiting both BAFF and APRIL, demonstrated significant and sustained reductions in Gd-IgA1, improvements in hematuria, and reductions in UPCR, along with stabilization of eGFR over 96 wk. Following discontinuation of atacicept, an increase in Gd-IgA1 and decline in eGFR were observed, consistent with the typical clinical progression of IgAN in high-risk patients despite standard-of-care treatments. In light of these findings, participants may enroll in a new OLE study (ORIGIN Extend), which will provide insights into the effects of atacicept treatment reinitiation. The rapid impact on key markers of kidney function decline and disease progression after atacicept discontinuation underscores the potential therapeutic benefit of atacicept and supports the paradigm of sustained treatment with atacicept in IgAN patients.

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with up to 50% of patients progressing to end-stage kidney disease or death within 20 years [1, 2]. B-cell Activating Factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) bind to the TACI receptor on B cells and play key roles in IgAN pathophysiology by fueling B cells to produce both galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies. Gd-IgA1 is recognized as an autoantigen by anti-Gd-IgA1 autoantibodies, forming the immune complexes which drive kidney pathology and clinical disease. Atacicept is a fully humanized TACI-Fc fusion protein that binds BAFF and APRIL with nanomolar binding affinity to modulate the activity of dysregulated B cells and has been shown to reduce circulating levels of Gd-IgA1, anti-Gd-IgA1, and immune complexes. The ORIGIN 2b study evaluated the safety and efficacy of atacicept in patients with biopsy-proven IgAN and met the primary endpoint with a statistically significant and clinically meaningful UPCR reduction at 24 weeks, with deepening efficacy through 36 weeks as compared to placebo. In the open-label extension, atacicept demonstrated further Gd-IgA1 reductions, hematuria improvement, and UPCR reduction with eGFR stabilization at a rate of decline similar to the general population without kidney disease through 96 weeks, suggesting atacicept offers a potentially safe, long-term, disease-modifying treatment for IgAN [3]. Method ORIGIN 3 is a global, randomized, double-blind, placebo-controlled Phase 3 study evaluating safety and efficacy of atacicept 150 mg for treatment of IgAN (Fig. 1). Eligible patients are adults with biopsy-proven IgAN and persistent proteinuria despite stable and maximum-tolerated RASi regimen for ≥12 weeks (see Fig. 1 for key entry criteria). 376 patients globally will be randomized 1:1 to at-home self-administered weekly subcutaneous atacicept 150 mg or placebo for a 104-week double-blind treatment period, followed by a 52-week open-label extension. Results The primary endpoint is UPCR % change from baseline at 36 weeks analyzed using a mixed-effects model with repeated measurement. The key secondary endpoint is eGFR annualized rate of change through 104 weeks. Conclusion This pivotal Phase 3 study has a consistent design, patient population and atacicept dose and subcutaneous formulation with that of the completed ORIGIN Phase 2b study, which demonstrated the efficacy of atacicept in reducing Gd-IgA1, improving hematuria, reducing proteinuria, and stabilizing eGFR. This Phase 3 study will further evaluate atacicept's disease-modifying potential as a treatment for IgAN.

Abstract Background and Aims IgA nephropathy (IgAN) is a B-cell mediated kidney disease that is predominantly diagnosed in young adults. At least 50% of patients with IgAN develop kidney failure within 10–20 years of diagnosis. B-cell Activating Factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) bind to the TACI receptor on B cells and have a crucial role in their maturation, differentiation, and effector function. BAFF and APRIL play key roles in IgAN pathophysiology by fueling B cells to produce both galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies. Gd-IgA1 is recognized as an autoantigen by anti-Gd-IgA1 autoantibodies, forming the immune complexes which drive kidney pathology and clinical disease. Atacicept is a fully humanized TACI-Fc fusion protein that binds BAFF and APRIL with nanomolar binding affinity to modulate the activity of dysregulated B cells and has been shown to reduce circulating levels of Gd-IgA1, anti-Gd-IgA1, and immune complexes. The ORIGIN 2b study evaluated the safety and efficacy of atacicept in patients with biopsy-proven IgAN and met the primary endpoint with a statistically significant and clinically meaningful UPCR reduction at 24 weeks, with deepening efficacy through 36 weeks as compared to placebo. In the open-label extension, atacicept demonstrated further Gd-IgA1 reductions, hematuria improvement, and UPCR reduction with eGFR stabilization at a rate of decline similar to the general population without kidney disease through 96 weeks, suggesting atacicept offers a potentially safe, long-term, disease-modifying treatment for IgAN [1]. ORIGIN 3 is an ongoing global, randomized, double-blind, placebo-controlled Phase 3 study of atacicept 150 mg or placebo for 104 weeks followed by a 52 week open-label extension. The ORIGIN 3 study design, patient population and atacicept dose and subcutaneous formulation is consistent with the completed ORIGIN 2b study. Here we describe an open label extension trial developed to ensure continued access to atacicept for study participants. Method ORIGIN Extend is a global multicenter Phase 2 study to evaluate long-term safety, tolerability, and efficacy of atacicept 150 mg for treatment of IgAN. Eligible participants must have completed the protocol-defined treatment period in the ORIGIN 2b or ORIGIN 3 clinical trials. Participants will receive atacicept 150 mg self-administered at home via subcutaneous weekly injection for up to 3 years or until atacicept is commercially available in their region. Results Key efficacy and safety endpoints include changes in serum Gd-IgA1 levels, hematuria, proteinuria, and eGFR. Conclusion The ORIGIN Extend study will provide patients with extended access to atacicept prior to commercial availability in their country or region, capture longer-term data for research purposes, and generate data from reinitiation of atacicept treatment following an off-treatment period.

Pan-genomics and genome-editing technologies are revolutionizing breeding of global crops1,2. A transformative opportunity lies in exchanging genotype-to-phenotype knowledge between major crops (that is, those cultivated globally) and indigenous crops (that is, those locally cultivated within a circumscribed area)3, 4–5 to enhance our food system. However, species-specific genetic variants and their interactions with desirable natural or engineered mutations pose barriers to achieving predictable phenotypic effects, even between related crops6,7. Here, by establishing a pan-genome of the crop-rich genus Solanum8 and integrating functional genomics and pan-genetics, we show that gene duplication and subsequent paralogue diversification are major obstacles to genotype-to-phenotype predictability. Despite broad conservation of gene macrosynteny among chromosome-scale references for 22 species, including 13 indigenous crops, thousands of gene duplications, particularly within key domestication gene families, exhibited dynamic trajectories in sequence, expression and function. By augmenting our pan-genome with African eggplant cultivars9 and applying quantitative genetics and genome editing, we dissected an intricate history of paralogue evolution affecting fruit size. The loss of a redundant paralogue of the classical fruit size regulator CLAVATA3 (CLV3)10,11 was compensated by a lineage-specific tandem duplication. Subsequent pseudogenization of the derived copy, followed by a large cultivar-specific deletion, created a single fused CLV3 allele that modulates fruit organ number alongside an enzymatic gene controlling the same trait. Our findings demonstrate that paralogue diversifications over short timescales are underexplored contingencies in trait evolvability. Exposing and navigating these contingencies is crucial for translating genotype-to-phenotype relationships across species.

Familial partial lipodystrophy (FPLD) is a heterogenous group of syndromes associated with a high prevalence of cardiometabolic diseases. Prior work has proposed DEXA-derived fat mass ratio (FMR) - defined as trunk fat percentage (trunk fat %) divided by leg fat percentage (leg fat %) - as a biomarker of FPLD, but this metric has not previously been characterized in large cohort studies. We set out to (1) understand the cardiometabolic burden of individuals with high FMR in up to 40,796 participants in the UK Biobank and 9,408 participants in the Fenland study, (2) characterize the common variant genetic underpinnings of FMR, and (3) build and test a polygenic predictor for FMR. Participants with high FMR were at higher risk for type 2 diabetes (OR = 2.30, p = 3.5 × 10-41) and MASLD/MASH (OR = 2.55, p = 4.9 × 10-7) in UK Biobank, and had higher fasting insulin (difference = +19.8 pmol/L, p = 5.7 × 10-36) and fasting triglycerides (difference = +36.1 mg/dL, p = 2.5 × 10-28) in the Fenland Study. Across FMR and its component traits, 61 conditionally independent variant-trait pairs were discovered, including 13 newly-identified pairs. A polygenic score for FMR was associated with increased risk of cardiometabolic diseases. This work establishes the cardiometabolic significance of high FMR - a biomarker for FPLD - in two large cohort studies and may prove useful in increasing diagnosis rates of patients with metabolically unhealthy fat distribution to enable treatment or a preventive therapy.