Evaluation of Ropeginterferon Alfa-2b Efficacy and Safety in Essential Thrombocythaemia Patients Intolerant, Refractory, or Ineligible for Cytoreductive Treatments

The primary objective of this Phase III multicenter study is to estimate the **disease response rates** of ropeginterferon alfa-2b in patients with **Essential Thrombocythaemia** who are intolerant, refractory, or not eligible for other cytoreductive treatments. This is clinically relevant as it aims to provide an alternative therapeutic option for patients who have limited treatment choices, potentially improving disease management and patient outcomes.

Secondary objectives include:

• Further assessment of the efficacy of ropeginterferon alfa-2b in terms of disease response, symptom improvement, vascular events, disease progression, and quality of life.
• Evaluation of the efficacy of ropeginterferon alfa-2b in terms of disease modification, defined by a sustained decline in mutant allele burden of driver mutations such as CALR, MPL, or mutant JAK-2.
• Assessment of the safety and tolerability of ropeginterferon alfa-2b in the study population.

The clinical trial involves participants diagnosed with **Essential Thrombocythaemia** who are intolerant, refractory, or ineligible for other cytoreductive treatments. The study population includes both male and female subjects aged 18 years and older. Participants are required to have adequate hepatic function and a Hospital Anxiety and Depression Scale (HADS) score of 0-7 on both subscales, although those with a score of 8-10 may be eligible following a psychiatric assessment. The trial population was selected based on specific inclusion criteria, including the need for cytoreductive treatment and prior intolerance or resistance to treatments such as hydroxyurea, anagrelide, busulfan, or pipobroman. The sponsor has not provided information regarding the total number of participants. The study also considers lifestyle factors, such as the ability to comply with study requirements and the absence of significant psychiatric symptoms that could interfere with treatment. Participants must be interferon treatment-naïve and have completed a washout period if they received prior cytoreductive treatment. The trial includes a vulnerable population, as indicated by the selection criteria.

The clinical trial is a Phase III, single-arm, multicenter study designed to evaluate the efficacy and safety of **ropeginterferon alfa-2b** in patients with **essential thrombocythaemia** who are intolerant, refractory, or not eligible for other cytoreductive treatments. The trial is expected to run until December 28, 2027, with recruitment starting on October 30, 2023. The study involves the administration of **Besremi** in two formulations: 250 micrograms/0.5 mL and 500 micrograms/0.5 mL solution for injection in pre-filled pens, administered subcutaneously. The maximum treatment period is 36 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment history. The primary endpoint is the rate of disease response at month 12, assessed according to modified European Leukemia Net (ELN) criteria. Secondary endpoints include response assessments at months 9, 18, 24, 30, and 36, as well as evaluations of symptomatic improvement and changes in inflammation markers. Follow-up visits will occur at regular intervals to monitor treatment response and safety, with the end-of-study visit marking the conclusion of the participant's involvement.

Participants are expected to be involved in the study for the full duration of the treatment period unless conditions arise that necessitate early termination. Such conditions may include significant adverse events, withdrawal of consent, or non-compliance with study protocols. The trial aims to provide comprehensive data on the long-term efficacy and safety of **ropeginterferon alfa-2b** in this patient population, contributing valuable insights into its potential as a treatment option for **essential thrombocythaemia**.

The clinical trial involves the administration of **ropeginterferon alfa-2b**, an experimental medication, in two different formulations. The first formulation is marketed as Besremi 250 micrograms/0.5 mL solution for injection in a pre-filled pen. This pharmaceutical form is a solution for injection, specifically designed for subcutaneous administration. The maximum daily dose for this formulation is 500 micrograms, with a total maximum dose of 32,500 micrograms over a treatment period of up to 36 months. The medication is repackaged and relabelled for clinical trial use in a different indication, ensuring compliance with trial-specific requirements.

The second formulation of the experimental medication is Besremi 500 micrograms/0.5 mL solution for injection in a pre-filled pen. Similar to the first formulation, it is a solution for injection intended for subcutaneous administration. The maximum daily dose remains at 500 micrograms, with a total maximum dose of 32,500 micrograms over a maximum treatment period of 36 months. This formulation is also repackaged and relabelled for the clinical trial to address a different indication. Both formulations are produced by AOP Orphan Pharmaceuticals GmbH and are classified under the ATC code L03AB15.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is designed to evaluate the efficacy and safety of ropeginterferon alfa-2b in patients with essential thrombocythaemia who are intolerant, refractory, or not eligible for other cytoreductive treatments. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the treatment's impact on disease response rates as defined by the European Leukemia Net criteria.

The efficacy of **ropeginterferon alfa-2b** in patients with essential thrombocythaemia will be assessed using several parameters. The primary endpoint is the rate of disease response at month 12, evaluated according to modified European Leukemia Net (ELN) criteria. This includes durable peripheral blood count remission, absence of haemorrhagic or thrombotic events, absence or non-progression in disease-related signs, and durable large symptoms improvement or maintenance of non-progression based on the MPN-SAF TSS.

Secondary endpoints include response rates at months 9, 18, 24, 30, and 36, as well as longitudinal changes in ELN response rates over 12 months. Additional measures include time to first response, duration of first response, duration of first durable response, time to first peripheral blood count remission response, and duration of first durable peripheral blood count remission response. The occurrence of thromboembolic and bleeding events, disease progression, and symptomatic improvement will also be assessed. Symptomatic improvement will be evaluated using the EQ-5D-5L questionnaire and the 10-item MPN-SAF TSS. Changes in inflammation markers and CALR, MPL, or JAK2 allelic burden over time will be monitored.