Lixar (lixivaptan) / Centessa - LARVOL DELTA

Radiosynthesis and Evaluation of a 18F-labeled PET ligand for Imaging the Peripheral Vasopressin 1A Receptor (SNMMI 2025) - "The signal intensities significantly reduced upon co-incubation with V1A antagonists PF184563, balovaptan and SRX246, while vasopressin 2 receptor antagonist Lixivaptan and the V1B receptor antagonist TASP325 led to minimal signal reduction, confirming high specific binding of [18F]8 with V1A receptor (Figure 1C-D). Compound 8 was synthesized in a yield of 19% over five steps and compound 10 was prepared in 8% yield over five steps (Figure 1A–B). The LogD value of compound 8 was measured as 1.89. Compound 8 demonstrated nanomolar potency and high affinity for the hV1A receptor (IC50 = 6.22 nM and Ki = 1.23 nM)."

Autism Spectrum Disorder • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Mood Disorders • Nephrology • Psychiatry • Renal Disease

Radiosynthesis and Evaluation of a 18F-labeled PET ligand for Imaging the Peripheral Vasopressin 1A Receptor (SNMMI 2025) - "The signal intensities significantly reduced upon co-incubation with V1A antagonists PF184563, balovaptan and SRX246, while vasopressin 2 receptor antagonist Lixivaptan and the V1B receptor antagonist TASP325 led to minimal signal reduction, confirming high specific binding of [18F]8 with V1A receptor (Figure 1C-D). Compound 8 was synthesized in a yield of 19% over five steps and compound 10 was prepared in 8% yield over five steps (Figure 1A–B). The LogD value of compound 8 was measured as 1.89. Compound 8 demonstrated nanomolar potency and high affinity for the hV1A receptor (IC50 = 6.22 nM and Ki = 1.23 nM)."

Autism Spectrum Disorder • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Mood Disorders • Nephrology • Psychiatry • Renal Disease

CARACTERIZACIÓN CLÍNICA Y EPIDEMIOLÓGICA DE LA ENFERMEDAD RENAL POLIQUÍSTICA EN PACIENTES ATENDIDOS EN UN CENTRO DE REFERENCIA DE CUARTO NIVEL DEL CARIBE COLOMBIANO DURANTE EL PERIODO 2008-2022 (ISN-WCN 2024) - "Los pacientes que presentan una progresión rápida de esta patología se benefician del antagonista del receptor V2 de la vasopresina Tolvaptan, único aprobado hasta el momento por la FDA (34)(35). Se encuentran en investigación moléculas como lixivaptan, venglustat, bardoxolona, tesevatinib, RGLS4326 (oligonucleótido inhibidor de microARN miR-17), GLPG2737 (corrector regulador de conductancia transmembrana de fibrosis quística), los cuales han venido demostrando efectos benéficos potenciales (36)(37)(38)(39). Otros medicamentos como everolimus ha evitado la progresión del volumen renal, pero no evitó la progresión de la enfermedad (40)... La ERP es una patología sistémica de relevancia importante debido al gran impacto que puede producir al deteriorar la salud de la persona comprometida, puede cursar desde estados asintomáticos a casos donde la función renal esta severamente deteriorada y por..."

Fibrosis • Gastroenterology • Gastrointestinal Disorder • Immunology • Oncology • MIR17 • PKD1 • PRKD1

Autosomal Dominant Polycystic Kidney Disease Therapies on the Horizon. (PubMed, Adv Kidney Dis Health) - "This review discusses the potential strategies to improve the tolerability of tolvaptan, the progress on the use of an alternative vasopressin 2 receptor antagonist lixivaptan, and somatostatin analogs. Recent advances in understanding the pathophysiology of PKD have led to new approaches of treatment via targeting different signaling pathways. We review the new pharmacotherapies and dietary interventions of ADPKD that are promising in the preclinical studies and investigated in clinical trials."

Journal • Review • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Optical-Controlled Kinetic Switch: Fine-Tuning of the Residence Time of an Antagonist Binding to the Vasopressin V Receptor in In Vitro, Ex Vivo, and In Vivo Models of ADPKD. (PubMed, J Med Chem) - "We adapted the photoswitching trait of azobenzene to the parent VR antagonist lixivaptan (LP) to generate azobenzene lixivaptan derivatives (aLPs)...Furthermore, conversion of the cis/trans isomer of aLPs-5g resulted in different efficacies of inhibiting renal cystogenesis ex vivo and in vivo. Overall, aLPs-5g represents a photoswitch for precise control of ligand-receptor residence time and, consequently, the pharmacological activity."

Journal • Preclinical • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Activation of tolvaptan-responsive T-cell clones with the structurally-related mozavaptan. (PubMed, Toxicol Lett) - "Herein, we addressed this question through the exposure of tolvaptan-responsive T-cell clones to similar pharmaceutical agents. Whilst lixivaptan and conivaptan did not activate tolvaptan-responsive T-cells, mozavaptan evoked proliferative responses comparable with tolvaptan itself, indicating that there may be collateral immunological intolerance to this compound as a product of sensitization to tolvaptan."

Journal • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Hepatology • Immunology • Liver Failure • Nephrology • Polycystic Kidney Disease • Renal Disease

Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P3 | N=7 | Terminated | Sponsor: Palladio Biosciences | N=50 ➔ 7 | Active, not recruiting ➔ Terminated; Commercial reassessment of compound

Enrollment change • Trial termination • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Roll-over Study to Assess Safety of Lixivaptan in Participants With ADPKD Who Completed Study PA-ADPKD-303 (clinicaltrials.gov) - P3 | N=1 | Terminated | Sponsor: Palladio Biosciences | N=12 ➔ 1 | Active, not recruiting ➔ Terminated; The decision is based on a thorough reassessment of the commercial potential of lixivaptan as a potential best-in-class therapy for patients with ADPKD.

Enrollment change • Trial termination • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

ACTION: Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P3 | N=12 | Terminated | Sponsor: Palladio Biosciences | N=1350 ➔ 12 | Trial completion date: Apr 2026 ➔ Aug 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Feb 2025 ➔ Aug 2022; The decision is based on a thorough reassessment of the commercial potential of lixivaptan as a potential best-in-class therapy for patients with ADPKD.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P3 | N=50 | Active, not recruiting | Sponsor: Palladio Biosciences | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2024 ➔ Oct 2022 | Trial primary completion date: Dec 2023 ➔ Sep 2022

Enrollment closed • Trial completion date • Trial primary completion date • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Roll-over Study to Assess Safety of Lixivaptan in Participants With ADPKD Who Completed Study PA-ADPKD-303 (clinicaltrials.gov) - P3 | N=12 | Active, not recruiting | Sponsor: Palladio Biosciences | Enrolling by invitation ➔ Active, not recruiting | Trial completion date: Jul 2026 ➔ Oct 2022 | Trial primary completion date: Jul 2026 ➔ Sep 2022

Enrollment closed • Trial completion date • Trial primary completion date • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

ACTION: Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P3 | N=1350 | Active, not recruiting | Sponsor: Palladio Biosciences | Recruiting ➔ Active, not recruiting

Enrollment closed • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

"$CNTA Centessa Pharmaceuticals Makes Strategic Decision to Discontinue Clinical Development of Lixivaptan for Autosomal Dominant Polycystic Kidney Disease (ADPKD) https://t.co/9GYEZNjHXv" (@stock_titan)

Clinical • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Safety of Lixivaptan in Subjects Previously Treated With Tolvaptan for Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P3 | N=50 | Recruiting | Sponsor: Palladio Biosciences | Trial completion date: Nov 2022 ➔ Jan 2024 | Trial primary completion date: Oct 2022 ➔ Dec 2023

Trial completion date • Trial primary completion date • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Roll-over Study to Assess Safety of Lixivaptan in Participants With ADPKD Who Completed Study PA-ADPKD-303 (clinicaltrials.gov) - P3 | N=12 | Enrolling by invitation | Sponsor: Palladio Biosciences | Not yet recruiting ➔ Enrolling by invitation

Enrollment open • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Open-label, Roll-over Study to Assess Safety of Lixivaptan in Participants With ADPKD Who Completed Study PA-ADPKD-303 (clinicaltrials.gov) - P3; N=12; Not yet recruiting; Sponsor: Palladio Biosciences

New P3 trial • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

A clinical trial to look at how safe and how effective Lixivaptan is in patients with kidney disease compared to a placebo treatment. (clinicaltrialsregister.eu) - P3; N=1200; Ongoing; Sponsor: Palladio Biosciences Inc.,

Clinical • New P3 trial • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • MRI

Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P3; N=1200; Recruiting; Sponsor: Palladio Biosciences; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • MRI

Lixivaptan in a Single Subject With Intractable Pain Due to Polycystic Kidney Disease (clinicaltrials.gov) - P=N/A; N=N/A; No Longer Available; Sponsor: Palladio Biosciences; Phase classification: P2 ➔ P=N/A

Clinical • Phase classification • Genetic Disorders • Nephrology • Pain • Polycystic Kidney Disease • Renal Disease • MRI

Pre-clinical evaluation of dual targeting of the GPCRs CaSR and V2R as therapeutic strategy for autosomal dominant polycystic kidney disease. (PubMed, FASEB J) - "Lixivaptan is expected to have a safer liver profile compared to tolvaptan, the only drug approved to delay PKD progression, based on computational model results and initial clinical evidence. These data point to an intriguing new application for two existing drugs in PKD treatment. The potential for synergy between these two compounds suggested in these animal studies, if confirmed in appropriate clinical investigations, would represent a welcome advancement in the treatment of ADPKD."

Journal • Preclinical • Autosomal Dominant Polycystic Kidney Disease • Fibrosis • Genetic Disorders • Immunology • Nephrology • Polycystic Kidney Disease • Renal Disease • PRKD1

Enantioenriched α-Vinyl 1,4-Benzodiazepines and 1,4-Benzoxazepines via Enantioselective Rhodium-Catalyzed Hydrofunctionalizations of Alkynes and Allenes. (PubMed, J Org Chem) - "The asymmetric hydroamination of (aminomethyl)anilines gave rise to 3-vinyl-1,4-BZDs with excellent enantioselectivities. Orthogonal N-deprotection of 1,4-BZDs allowed an easy entry to an advanced pyrrolobenzodiazepine metabolite of the V-receptor antagonist Lixivaptan."

Journal

Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P3; N=1200; Not yet recruiting; Sponsor: Palladio Biosciences; Trial completion date: Dec 2025 ➔ Apr 2026

Clinical • Trial completion date • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Lixivaptan in a Single Subject With Intractable Pain Due to Polycystic Kidney Disease (clinicaltrials.gov) - P2; N=1; Terminated; Sponsor: Palladio Biosciences; Active, not recruiting ➔ Terminated; Subject withdrew consent to participate

Clinical • Trial termination • Genetic Disorders • Nephrology • Pain • Polycystic Kidney Disease • Renal Disease

Efficacy and Safety of Lixivaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease (clinicaltrials.gov) - P3; N=1200; Not yet recruiting; Sponsor: Palladio Biosciences; Trial completion date: Dec 2024 ➔ Dec 2025; Trial primary completion date: Jul 2024 ➔ Dec 2024

Clinical • Trial completion date • Trial primary completion date • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Lixivaptan in a Single Subject With Intractable Pain Due to Polycystic Kidney Disease (clinicaltrials.gov) - P2; N=1; Active, not recruiting; Sponsor: Palladio Biosciences; Enrolling by invitation ➔ Active, not recruiting

Clinical • Enrollment closed • Genetic Disorders • Nephrology • Pain • Polycystic Kidney Disease • Renal Disease