Phase 3 Randomized Study of Bomedemstat vs. Hydroxycarbamide in Cytoreductive Therapy-Naïve Essential Thrombocythemia Patients

The primary objective of this clinical study is to compare **bomedemstat** to **hydroxyurea** with respect to DCHR (Disease Control Hematologic Response) in participants with **essential thrombocythemia** who are naive to cytoreductive therapy. This comparison is clinically relevant as it aims to evaluate the efficacy of bomedemstat, a novel therapeutic agent, against the established treatment, hydroxyurea, in managing this hematologic disorder.

Secondary objectives include:

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

These secondary objectives are crucial for understanding the broader impact of bomedemstat on patient quality of life, safety profile, and overall disease management compared to hydroxyurea.

The clinical trial involves a total of **243 participants** diagnosed with **Essential thrombocythemia**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific inclusion criteria, such as a diagnosis of Essential Thrombocythemia according to the World Health Organization Criteria for myeloproliferative neoplasms, and an indication for cytoreductive therapy. The trial does not include a vulnerable population. Participants are required to have a bone marrow fibrosis score of Grade 0 or Grade 1 and must not have received prior cytoreductive treatment for their condition. Additionally, individuals with controlled HIV on antiretroviral therapy, those with Hepatitis B who have undetectable viral loads after antiviral therapy, and those with a history of Hepatitis C with undetectable viral loads are eligible. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, active-comparator-controlled study to evaluate the efficacy and safety of **bomedemstat** (MK-3543) versus **hydroxycarbamide** in participants with **essential thrombocythemia**. The trial aims to compare the two treatments with respect to the Durable Clinicohematologic Response (DCHR) rate. The study is expected to last until May 14, 2029, with recruitment starting on October 7, 2024. Participants will be involved in the study for a maximum treatment period of 36 months.

The trial will include several study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as a diagnosis of essential thrombocythemia and no prior cytoreductive treatment. Participants will then be randomized to receive either bomedemstat or hydroxycarbamide, with follow-up visits scheduled to monitor treatment efficacy and safety. These visits will include assessments of clinicohematologic response, symptom scores, and adverse events. The end-of-study visit will conclude the participant's involvement, with final evaluations of treatment outcomes.

Participants may be terminated early from the study if they experience significant adverse events, disease progression, or if they choose to withdraw consent. The primary endpoint of the study is the DCHR rate, while secondary endpoints include changes in symptom scores, duration of response, and the incidence of thrombotic and hemorrhagic events. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **Bomedemstat**, also known by its sponsor product code MK-3543. Bomedemstat is provided in the form of a hard capsule and is administered orally. The maximum daily dose is 175 mg, with a total maximum dose of 191,625 mg over a treatment period of up to 36 weeks. The active substance, Bomedemstat, is a chemical compound with the EU substance number SUB194612. The compound is manufactured by Merck & Co. Inc. and is also known by the chemical name N-[(2S)-5-{[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl]-4-(1H-1,2,3-triazol-1-yl)benzamide. Participant compliance with the dosing schedule is monitored throughout the trial.

The trial also includes a **placebo** for Bomedemstat, which serves as a control to evaluate the efficacy of the experimental treatment. The placebo is designed to mimic the appearance and administration route of the Bomedemstat capsules but does not contain the active substance. The placebo is administered orally, following the same dosing schedule as the active treatment.

Additionally, the trial involves the use of **Hydroxycarbamide**, also known as Hydroxyurea, as an active comparator. Hydroxycarbamide is administered orally, and the pharmaceutical form is over-encapsulated to maintain blinding in the study. The maximum treatment period for Hydroxycarbamide is also 36 weeks. The active substance is a chemical compound with the EU substance number SUB08076MIG. The administration and dosing of Hydroxycarbamide are closely monitored to ensure participant compliance and to facilitate accurate 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**, which will be used to compare the efficacy of **bomedemstat** (MK-3543) versus **hydroxyurea** in participants with Essential Thrombocythemia. Secondary endpoints include changes from baseline in the Myelofibrosis Symptom Assessment Form version 4.0 (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 MFSAF v4.0 Total Symptom Score. Additional secondary endpoints are the Duration of Clinicohematologic Response (DOCHR), Duration of Hematologic Remission (DOHR), the number of participants experiencing thrombotic or major hemorrhagic events, disease progression rate, and the number of participants experiencing adverse events or discontinuing the study intervention due to an adverse event.

These efficacy parameters will be measured and collected at various timepoints throughout the trial, with specific methods and tools such as validated scales and patient-reported outcomes being employed. The trial is designed to ensure a comprehensive evaluation of the treatment's impact on the participants' condition, with data being analyzed to determine the comparative efficacy of the investigational product against the active comparator. The trial is scheduled to conclude by May 14, 2029, with recruitment starting on October 7, 2024.