Evaluation of Bomedemstat Versus Best Available Therapy in Essential Thrombocythemia Patients with Hydroxyurea Intolerance or Inadequate Response

The primary objective of this clinical study is to compare **bomedemstat** to the best available therapy in terms of durable DCHR (Durable Clinico-Hematologic Response) in participants with Essential Thrombocythemia who have an inadequate response to or are intolerant of hydroxyurea. This objective is clinically relevant as it aims to establish the efficacy of bomedemstat in achieving sustained hematologic response, which is crucial for managing symptoms and reducing the risk of complications in these patients.

Secondary objectives include:

• Comparing bomedemstat to the best available therapy with respect to changes in fatigue score based on MFSAF v4.0 and PROMIS Fatigue SF-7a.
• Assessing changes in total symptom score based on MFSAF v4.0.
• Evaluating DOCHR (Duration of Clinico-Hematologic Response) and DOHR (Duration of Hematologic Remission) for both treatment arms.
• Evaluating the incidence of thrombotic and major hemorrhagic events, as well as disease progression for both treatment arms.
• Assessing EFS (Event-Free Survival) and the safety and tolerability of bomedemstat.

The clinical trial involves a total of **229 participants** diagnosed with **Essential Thrombocythemia** who have shown an inadequate response to or intolerance of hydroxyurea. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a diagnosis of essential thrombocythemia per the World Health Organization 2016 diagnostic criteria for myeloproliferative neoplasms, and a bone marrow fibrosis score of Grade 0 or Grade 1. The trial also considers individuals with a history of inadequate response to or intolerance of hydroxyurea, as well as those requiring a change in cytoreductive therapy due to inadequate or loss of response to their most recent prior ET therapy. Participants may have received up to three prior lines of therapy, including hydroxyurea. The trial population includes individuals with a platelet count greater than 450 × 10^9/L and an absolute neutrophil count of at least 0.75 × 10^9/L, assessed up to 72 hours before the first dose of the study intervention. The study does not exclude vulnerable populations, indicating a comprehensive approach to understanding the effects of the intervention across a diverse group of individuals.

The clinical trial is designed as a **randomized**, open-label, active-comparator-controlled study to evaluate the safety and efficacy of **bomedemstat** (MK-3543) compared to the best available therapy (BAT) in participants with **essential thrombocythemia** who have an inadequate response to or are intolerant of hydroxyurea. The trial aims to assess the durable clinicohematologic response (DCHR) rate as the primary endpoint, with secondary endpoints including changes in fatigue scores, duration of response, and the incidence of thrombotic and hemorrhagic events. The study is expected to commence recruitment on February 1, 2024, and conclude by October 13, 2028, with a maximum treatment period of 36 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of essential thrombocythemia per WHO 2016 criteria, a bone marrow fibrosis score of Grade 0 or 1, and a history of inadequate response to hydroxyurea. Following the screening, participants will be randomized to receive either bomedemstat or BAT, with the treatment administered orally or via subcutaneous injection, depending on the assigned therapy. Regular follow-up visits will be scheduled to monitor safety, efficacy, and any adverse events, with assessments including blood counts and symptom evaluations. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participant involvement is anticipated to last up to 36 months, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results, contributing valuable data to the understanding and management of essential thrombocythemia in patients with limited treatment options.

The clinical trial involves the evaluation of **bomedemstat** (MK-3543), an experimental medication, which is administered in the form of a hard capsule. The active substance, bomedemstat, is of chemical origin and is provided by Merck & Co. Inc. The maximum daily dose is 175 mg, with a total maximum dose of 191,625 mg over a treatment period of 36 months. The route of administration is oral, and participant compliance is monitored throughout the study.

**Peginterferon alfa-2a** is used as a comparator treatment in the study. It is a biological product administered as a solution for subcutaneous injection. The maximum daily dose is 6.43 µg, with a total maximum dose of 7,020 µg over the same treatment period of 36 months. This treatment is not a pediatric formulation and is used to compare the efficacy and safety against the experimental medication.

Another comparator in the study is **anagrelide hydrochloride monohydrate**, which is administered orally in capsule form. The chemical origin of the active substance allows for a maximum daily dose of 10 mg and a total maximum dose of 3,650 mg over 36 months. This treatment is also monitored for compliance and efficacy in comparison to bomedemstat.

**Ruxolitinib** is included as a comparator treatment, provided in tablet form for oral administration. The chemical substance allows for a maximum daily dose of 20 mg and a total maximum dose of 21,900 mg over the 36-month period. This treatment is evaluated alongside other comparators to assess its effectiveness against the experimental drug.

**Busulfan** is another comparator treatment, administered orally in tablet form. The chemical nature of the active substance permits a maximum daily dose of 4 mg and a total maximum dose of 2,016 mg over the course of the study. This treatment is part of the best available therapy (BAT) group used for comparison with bomedemstat.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the Durable Clinicohematologic Response (DCHR) Rate. Secondary endpoints include changes from baseline in the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 Individual Fatigue Symptom Item Score, changes in the Patient-reported Outcomes Measurement Information System (PROMIS) Fatigue SF-7a Total Fatigue Score, and changes in the Total Symptom Score as measured on the MFSAF v4.0. Additional secondary endpoints are the Duration of Clinicohematologic Response (DOCHR), Duration of Hematologic Remission (DOHR), percentage of participants with thrombotic events, percentage of participants with major hemorrhagic events, disease progression rate, Event Free Survival (EFS), number of participants with an adverse event (AE), and number of participants discontinuing from study therapy due to an AE.

The trial will compare **bomedemstat** to the best available therapy in participants with Essential Thrombocythemia who have an inadequate response to or are intolerant of hydroxyurea. Efficacy parameters will be collected and analyzed at various timepoints throughout the study, with specific tools and instruments such as the MFSAF v4.0 and PROMIS Fatigue SF-7a being utilized to measure symptom changes. The trial is designed to ensure a comprehensive evaluation of the therapeutic effects of bomedemstat in the target population.