Inclusion Criteria:

• Male or female subjects, ≥18 years old.
• Subjects diagnosed with high-risk ET (either older than 60 years and JAK2V617-positive at screening, or having disease-related thrombosis or hemorrhage in the past), diagnosed according to the World Health Organization (WHO) 2016 criteria.
• Subjects have received prior HU for ET, while the washout between the last dose of HU and the screening visit should not be shorter than 14 days.
• Interferon treatment-naïve.
• Documented resistance/intolerance to prior HU for ET, as defined by ELN criteria (Barosi, et al, 2007), whereby at least one of the following criteria is met:
  • Platelet count > 600 x 10^9 /L at ≥ 2 g/day (or ≥ 2.5 g/day if subject body weight > 80 kg); or maximally tolerated dose if < 2 g/day after at least 3 months of HU; or
  • Platelet count >400 x 109 /L and WBC count <2.5 x 109 /L at any dose and any duration of HU; or
  • Platelet count > 400 x 10^9 /L and WBC count 400 x 10^9 /L and hemoglobin (HGB) 450 x 10^9 /L at screening; or
  • Presence of HU-related toxicities at any dose and any duration of therapy (e.g., leg ulcers, mucocutaneous manifestations, pneumonitis, or HU-related fever).
• Platelets > 450 x 10^9 /L at screening.
• WBC >10 x 10^9 /L at screening.
• HGB ≥11 g/dL at screening for males and 10 g/dL at screening for females.
• Neutrophil count ≥1.0 x 10^9 /L at screening.
• Adequate hepatic function defined as bilirubin ≤ 1.5 x upper limit normal (ULN), international normalized ratio ≤ 1.5 x ULN, albumin > 3.5 g/dL, alanine aminotransferase ≤ 2.0 x ULN, aspartate aminotransferase ≤ 2.0 x ULN at screening.
• Creatinine clearance ≥ 40 mL/min (by Cockcroft-Gault equation).
• Males and females of childbearing potential, as well as all women < 2 years after the onset of menopause, must agree to use an acceptable form of birth control until 28 days following the last dose of the study drug, and females must agree to not breastfeed during the study.
• Written informed consent obtained from the subjectand ability for the subject to comply with the requirements of the study

Exclusion Criteria:

• Any subject requiring a legally authorized representative.
• Any contraindications or hypersensitivity to IFN-α or ANA and their excipients.
• Known risk factors for QT-prolongation (e.g., congenital long QT, known history of acquired QT-prolongations).
• Co-morbidity with severe or serious condition that, in the Investigator’s opinion, would jeopardize the safety of the subject or their compliance with the protocol, including significant cardiac disease (including New York Heart Association Class III-IV congestive heart failure and clinically significant arrhythmias) and pulmonary hypertension.
• History of major organ transplantation.
• Pregnant or lactating females.
• Subjects with any other significant medical conditions that, in the opinion of the Investigator, would compromise the results of the study or may impair compliance with the requirements of the protocol, including but not limited to:
  • Documented autoimmune disease at screening or in the history (e.g., thyroid dysfunction, hepatitis, idiopathic thrombocytopenic purpura, scleroderma, psoriasis, or any arthritis of autoimmune origin);
  • Clinically relevant pulmonary infiltrates, pneumonia, and pneumonitis at screening that, in the Investigator’s opinion, would jeopardize the safety of the subject or their compliance with the protocol;
  • Infections with systemic manifestations (e.g., bacterial, fungal, or human immunodeficiency virus [HIV], except hepatitis B [HBV] and/or hepatitis C [HCV], at screening);
  • Evidence of severe retinopathy (e.g., cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension);
  • History or presence of clinically relevant depression;
  • Previous suicide attempts or at any risk of suicide at screening, in the judgement of the Investigator;
  • History or presence of clinically significant neurologic diseases;
  • History of any malignancy within 5 years (except Stage 0 chronic lymphocytic leukemia, basal cell, squamous cell, and superficial melanoma);
  • History of alcohol or drug abuse within the last year;
  • History or evidence of any other (than ET) MPN.
• Use of any investigational drug < 4 weeks prior to the first dose of study drug or not recovered from effects of prior administration of any investigational agent.
• Subjects with documented ANA resistance or intolerance.
• At screening, in-depth medical history data will be collected, including thrombosis/ hemorrhage history, JAK-2, CALR, and MPL mutation status, acquired von Willebrand disease in the past, presence of progressive/symptomatic splenomegaly, symptomatic thrombocytosis, progressive leukocytosis, progressive disease-related symptoms, and vasomotor/microvascular disturbances not responsive to aspirin (acetylsalicylic acid). Regarding aspirin, the following contraindications are known for low-dose aspirin: active peptic ulceration or history of peptic ulceration, hemophilia, hypersensitivity to aspirin or any other nonsteroidal anti-inflammatory drugs (NSAIDs), including those in whom attacks of asthma, angioedema, urticaria, and rhinitis have been precipitated by aspirin or any other NSAID, and hypersensitivity to any of the other constituents. If any of the contraindications are observed, the subject may still participate in the study without being administered aspirin. Medications that can prolong QTc and induce hypokalemia will not be allowed in the study.