Vortosiran for VTE Prevention

Key Inclusion Criteria: Cohort A 1. Adult male and female participants (≥18 years) meeting the specified below criteria for Cohort A. 2. Postmenopausal women are eligible without additional contraceptive measures. Postmenopausal status is defined as: * Age ≥55 years with ≥12 months of spontaneous amenorrhoea, or * Age \<55 years with ≥12 months of spontaneous amenorrhoea and follicle-stimulating hormone in the postmenopausal range, or surgical menopause (bilateral oophorectomy, with or without hysterectomy) documented in the medical history. 3. Women of childbearing potential must agree to use highly effective contraception for the duration of trial treatment and for the specified post-treatment period. 4. Able and willing to provide written informed consent and to comply with trial procedures and follow-up. 5. Objectively confirmed symptomatic index of the lower limbs at the popliteal vein or more proximal, and/or symptomatic PE, documented by objective imaging modalities (eg. DVT: compression ultrasonography/duplex ultrasound; computed tomography/magnetic resonance venography; or contrast venography. PE: computed tomography pulmonary angiography; high probability ventilation/perfusion scan; or pulmonary angiography). 6. Completed 3 to 12 months of standard therapeutic anticoagulant therapy for the index VTE episode (vitamin K antagonists, DOACs, low molecular weight heparin, or fondaparinux at therapeutic dose) at least 2 weeks before randomization. Cohort B 1. Adult male and female participants (≥18 years) meeting the specified below criteria for Cohort B. 2. Postmenopausal women are eligible without additional contraceptive measures. Postmenopausal status is defined as: * Age ≥55 years with ≥12 months of spontaneous amenorrhoea, or * Age \<55 years with ≥12 months of spontaneous amenorrhoea and follicle-stimulating hormone in the postmenopausal range, or surgical menopause (bilateral oophorectomy, with or without hysterectomy) documented in the medical history. 3. Women of childbearing potential must agree to use highly effective contraception for the duration of trial treatment and for the specified post-treatment period. 4. Able and willing to provide written informed consent and to comply with trial procedures and follow-up. 5. Eastern Cooperative Oncology Group performance status 0-2 during screening 6. Newly diagnosed cancer site or progression of malignant disease, with: * No recent chemotherapy or radiotherapy (≤3 months), and * No recent surgery (≤2 weeks). * Histologically or cytologically confirmed active malignancy (solid tumor or lymphoma) requiring initiation of a new systemic cytotoxic chemotherapy course; newly diagnosed disease or documented progression/recurrence qualifies. Key Exclusion Criteria: Cohort A 1. Women who are pregnant, currently breastfeeding, or planning pregnancy during the trial or within the defined post-treatment period are not eligible. 2. Evidence of active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection at Screening, defined as any of the following: * Positive hepatitis B surface antigen (HBsAg), or positive total hepatitis B core antibody (anti-HBc) with detectable HBV DNA; * Positive hepatitis C virus antibody (anti-HCV) with detectable HCV RNA; or * Reactive HIV-1/2 antigen/antibody test confirmed by a positive confirmatory test. Participants who are total anti-HBc-positive must undergo HBV DNA testing, and participants who are anti-HCV-positive must undergo HCV RNA testing. Participants with undetectable HBV DNA or HCV RNA may be eligible provided there is no clinical or laboratory evidence of active liver disease. 3. Planned surgery that may change VTE/bleeding risk during the trial period and no recent surgery (≤2 weeks prior screening). 4. Any serious medical, psychiatric, or social condition that, in the investigator's opinion, would interfere with trial participation, compliance, or interpretation of trial results. 5. eGFR \<30 mL/min (calculated per CKD-EPI 2021, expected to be reported in mL/min per 1.73 m2) 6. Clear indication for indefinite/extended anticoagulation for any reason, including but not limited to: * Atrial fibrillation or flutter requiring anticoagulation. * Mechanical heart valve or moderate/severe rheumatic mitral stenosis. * Recent or ongoing VTE requiring therapeutic anticoagulation (symptomatic or incidental). * Known antiphospholipid syndrome with a high-risk profile, defined as the presence of lupus anticoagulant. * Active cancer requiring anticoagulant prophylaxis or treatment. * Strong thrombophilia (eg, homozygous factor V Leiden, homozygous prothrombin mutation, combined thrombophilias, antithrombin deficiency) where guidelines favor extended anticoagulation. Cohort B 1. Women who are pregnant, currently breastfeeding, or planning pregnancy during the trial or within the defined post treatment period are not eligible. 2. Evidence of active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection at Screening, defined as any of the following: * Positive hepatitis B surface antigen (HBsAg), or positive total hepatitis B core antibody (anti-HBc) with detectable HBV DNA; * Positive hepatitis C virus antibody (anti-HCV) with detectable HCV RNA; or * Reactive HIV-1/2 antigen/antibody test confirmed by a positive confirmatory test. Participants who are total anti-HBc-positive must undergo HBV DNA testing, and participants who are anti-HCV-positive must undergo HCV RNA testing. Participants with undetectable HBV DNA or HCV RNA may be eligible provided there is no clinical or laboratory evidence of active liver disease. 3. Planned surgery that may change VTE/bleeding risk during the trial period and no recent surgery (≤2 weeks prior screening). 4. Any serious medical, psychiatric, or social condition that, in the investigator's opinion, would interfere with trial participation, compliance, or interpretation of trial results. 5. eGFR \<30 mL/min (calculated per CKD-EPI 2021, expected to be reported in mL/min per 1.73 m2) 6. High bleeding risk, defined as any of the following: * Any condition that, in the investigator's judgment, confers an increased risk of clinically significant bleeding. * Known intracranial malignancy at high hemorrhage risk, defined as known primary brain tumor, or known intracranial metastases with prior intracranial hemorrhage, known hemorrhagic metastases, or other intracranial lesion judged high risk by the investigator (no protocol-mandated screening imaging). * Active or untreated high risk gastrointestinal or GU lesions, including but not limited to active peptic ulcer disease, untreated/high risk esophageal or gastric varices, or GU lesions/tumors associated with active bleeding (eg, macroscopic hematuria from bladder/urinary tract tumor), unless adequately treated and clinically stabilized. * Clinically overt bleeding (eg, gastrointestinal bleeding, macroscopic hematuria, epistaxis requiring medical attention, or any bleeding requiring an acute care visit) within 4 weeks prior to screening. * Unexplained decrease in hemoglobin ≥2 g/dL within the 2 weeks prior to screening, unless evaluated and a bleeding source has been excluded or treated and clinically stabilized. * Red blood cell transfusion within the 2 weeks prior to screening, unless hemoglobin is clinically stable after correction and there is no evidence of ongoing bleeding (A patient is considered as clinically stabilized if there is no clinically overt bleeding for ≥7 days and no planned urgent endoscopic/urologic intervention for bleeding during the immediate treatment initiation period. A hemoglobin stability is defined as no further decrease \>1 g/dL over ≥72 hours \[without additional transfusion\] with the patient being clinically stable). 7. Hepatic disease with coagulopathy, including but not limited to: * Ascites, cirrhosis, encephalopathy, or jaundice * Hypoalbuminemia \<3.5 g/dL * Total bilirubin \>1.5 × ULN * Transaminases \>2 × the ULN * Biochemical evidence of biliary obstruction 8. Cancer types not eligible as the sole diagnosis: * Basal cell or squamous cell carcinoma of the skin only * Acute leukemia * Myeloproliferative neoplasm