Vortosiran for VTE Prevention

Venous thromboembolism, encompassing DVT and PE, is a common condition with a durable risk of recurrence after completion of initial therapy with systemic anticoagulation. In a systematic review and meta-analysis of patients with a first unprovoked VTE who completed at least 3 months of anticoagulant therapy and then discontinued treatment, the cumulative incidence of recurrent VTE was approximately 10% in the first year, 25% at 5 years, and 36% at 10 years, with recurrent events carrying measurable case fatality (Khan et al, 2019). Decisions about extended therapy are frequently individualized because continued anticoagulation reduces VTE recurrence but also exposes patients to ongoing bleeding risk, treatment burden, and complexity of care.

Venous thromboembolism, including in patients with cancer and chemotherapy, remains a major cause of morbidity and mortality. Despite effective anticoagulants, long-term management is constrained by clinically meaningful bleeding risk, drug-drug interactions with anticoagulation therapy, and the need for continuous dosing and adherence. Furthermore, many patients discontinue therapy when they perceive recurrence risk to be moderate or when bleeding risk, treatment burden, or patient preference argues against indefinite anticoagulation. These combined factors constitute an unmet need for a convenient strategy that can reduce recurrent VTE risk with a lower risk of bleeding.

Vortosiran is a subcutaneously administered siRNA designed to selectively inhibit hepatic synthesis of FXI, resulting in robust and durable suppression of FXI activity. FXI inhibition is novel and innovative anti-thrombotic strategy inhibiting blood clot formation by the intrinsic pathway without interfering with hemostatic control through the extrinsic and commen clotting pathways. Thereby reducing blood clot formation and VTE without increasing the risk of bleeding compared to current available anti-coagulant treatments.

This Phase II trial is designed to establish dose-related FXI suppression, characterize safety with repeated dosing, and generate an initial signal on clinical outcomes in two VTE prevention settings.

This multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase II trial will be conducted in two cohorts. Cohort A and Cohort B are independently enrolled and randomized. Participants are randomized (2:2:1) to low-dose vortosiran, high-dose vortosiran, or matched placebo, with dosing on Day X and Day Y and follow-up through Week 56. This trial aims to evaluate vortosiran in two complementary populations where FXI suppression could provide clinically relevant benefit and where the risk-benefit of conventional anticoagulation is often challenging.

* Cohort A (post-VTE, with participants judged to be at equipoise for extended therapy): Participants have completed 3 to 12 months of standard anticoagulation for symptomatic proximal DVT and/or PE as originally prescribed, and have had no recurrence during that initial treatment period. The cohort is restricted to patients for whom discontinuation of anticoagulation is consistent with local standard of care and where there is true equipoise about extended therapy vs only follow-up and observation.
* Cohort B (active cancer; high VTE risk): Ambulatory patients initiating a new course of systemic chemotherapy and with intermediate to high VTE risk (Khorana score ≥2), but no history of prior VTE.

• Vortosiran (Drug): Vortosiran, active drug.
• Placebo (Drug): Placebo that is identical in appearance of active IMP.

Primary outcomes

• Primary objective [At Week 8]: To evaluate the effect of two dose levels of vortosiran on coagulation Factor XI (FXI) activity.
• Primary endpoint [Baseline to Week 8.]: Percentage change from baseline in FXI activity, compared with placebo.

Secondary outcomes

• Secondary objective [Up to week 56]: To evaluate the safety of vortosiran at two dose levels.
• Secondary objective [0 [pre-dose] to 24 hours after dosing.]: To assess the plasma exposure of vortosiran after dosing
• Secondary objective [At week 16]: To evaluate the effect of 2 dose levels of vortosiran on FXI antigen concentration.
• Secondary Objective [At week 16]: To evaluate the effect of 2 dose levels of vortosiran on specific blood coagulation test aPTT.
• Secondary objective [At week 16]: To evaluate the effect of 2 doses of vortosiran on specific blood clotting test PT-INR.

Sex: All, ages: 18 Years to any

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

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• Anders Gabrielsen, MD, PhD, Study director, Ribocure Pharmaceuticals