Bomedemstat vs Hydroxyurea for Essential Thrombocythemia

Recruiting at 118 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme LLC

Disqualifiers: Gastrointestinal impairment, Malignancy, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

300 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the efficacy and safety of bomedemstat compared with hydroxyurea in cytoreductive therapy naïve essential thrombocythemia (ET) participants for whom cytoreductive therapy is indicated. Its primary objective is to compare bomedemstat to hydroxyurea with respect to durable clinicohematologic response (DCHR). The primary hypothesis is that bomedemstat is superior to hydroxyurea with respect to DCHR.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should not have received prior cytoreductive treatment for their condition.

What data supports the effectiveness of the drug Bomedemstat for treating essential thrombocythemia?

Bomedemstat is an LSD1 inhibitor, and similar drugs targeting LSD1 have shown promise in treating acute myeloid leukemia (AML) by inhibiting cancer cell growth and promoting cell differentiation. This suggests potential effectiveness in other blood-related conditions like essential thrombocythemia. ^{1 2 3 4 5}

Is hydroxyurea safe for treating essential thrombocythemia?

Hydroxyurea is generally well tolerated and has been used for a long time to treat essential thrombocythemia, but there is a concern about a potential risk of developing leukemia (a type of blood cancer) with its use. However, many studies suggest that it remains a preferred treatment option for this condition. ^{6 7 8 9 10}

How does the drug Bomedemstat differ from other treatments for essential thrombocythemia?

Bomedemstat is unique because it targets LSD1, an enzyme involved in cell cycle regulation and differentiation, which is not a common target in existing treatments for essential thrombocythemia. This mechanism is similar to its use in treating acute myeloid leukemia, where LSD1 inhibitors have shown promise. ^{1 2 11 12 13}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for individuals with Essential Thrombocythemia (ET) who need cytoreductive therapy but haven't had any such treatment before. Participants must meet specific criteria, including controlled HIV or hepatitis if present, and a low bone marrow fibrosis score.

Inclusion Criteria

I have been diagnosed with Essential Thrombocythemia and need treatment to reduce my blood cell count.

I have not had treatment to reduce my blood cell count.

My HIV is well controlled with medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either bomedemstat or hydroxyurea daily for up to 52 weeks, with dosage adjustments to safely inhibit thrombopoiesis and decrease platelet counts to the target range.

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of hematologic remission and adverse events.

4 weeks

Extended Treatment

Participants who complete the initial 52-week treatment phase are eligible to continue treatment in the extended treatment phase.

Treatment Details

Interventions

• Bomedemstat
• Hydroxyurea

Trial Overview The study compares the effectiveness and safety of bomedemstat to hydroxyurea in treating ET. Patients will be randomly assigned to receive either bomedemstat or hydroxyurea, aiming to see which one better achieves a durable clinicohematologic response.

Participant Groups

Group I: Bomedemstat Experimental Treatment 2 Interventions

Participants will receive active bomedemstat and hydroxyurea placebo daily for up to approximately 52 weeks. Dosage will be adjusted either up or down within specified time parameters for each participant to the dose that provides sufficient exposure to safely inhibit thrombopoiesis to decrease platelet counts to the target range. Participants who complete treatment at Week 52 will be eligible to continue treatment in the extended treatment phase. Unblinding will occur and placebo discontinued once all participants have completed at least 52 weeks of therapy or otherwise discontinued.

Group II: Hydroxyurea Active Control 2 Interventions

Participants will receive active hydroxyurea and bomedemstat placebo daily for up to 52 weeks. Dosage will be adjusted either up or down within specified time parameters for each participant to the dose that provides sufficient exposure to safely inhibit thrombopoiesis to decrease platelet counts to the target range. Participants who complete treatment at Week 52 will be eligible to continue treatment in the extended treatment phase. Unblinding will occur and placebo discontinued once all participants have completed at least 52 weeks of therapy or otherwise discontinued.

Who Is Running the Clinical Trial?

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

Histone lysine specific demethylase 1 (LSD1) is a promising therapeutic target for acute myeloid leukemia (AML) due to its role in promoting cancer cell proliferation and poor prognosis, with several LSD1 inhibitors currently in clinical trials.

Inhibitors like tranylcypromine (TCP), ORY-1001, GSK2879552, and IMG-7289 show potential for AML treatment, and combining these LSD1 inhibitors with other therapies may enhance their effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting LSD1 for acute myeloid leukemia (AML) treatment. Zhang, S., Liu, M., Yao, Y., et al.[2021]

Iadademstat, a selective LSD1 inhibitor, was found to be safe and well-tolerated in a phase I trial involving 27 patients with relapsed/refractory acute myeloid leukemia (R/R AML), with a recommended dose of 140 µg/m2/d established for further treatment.

The treatment showed promising signs of efficacy, including reductions in blood and bone marrow blast percentages and one complete remission, particularly in patients with MLL/KMT2A-rearranged AML, indicating its potential as a therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia. Salamero, O., Montesinos, P., Willekens, C., et al.[2021]

A new series of small molecule inhibitors targeting the histone demethylase LSD1 was developed, showing potent inhibition of its activity and effective performance in cell-based tests at low nanomolar concentrations.

The inhibitors were optimized to reduce potential side effects, such as hERG channel inhibition, and to enhance oral bioavailability, making them promising candidates for treating hematologic malignancies and certain solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure-based design and discovery of potent and selective lysine-specific demethylase 1 (LSD1) inhibitors. Nie, Z., Shi, L., Lai, C., et al.[2019]

The compound FY-21 is a potent and selective inhibitor of LSD1, with an IC50 value of 340 nM, showing promise as a cancer therapy.

In preclinical studies, FY-21 not only inhibited leukemia cell growth and promoted differentiation but also improved survival rates in leukemia mice, indicating its potential effectiveness in treating acute myeloid leukemia (AML).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of new tetrahydroisoquinolines as potent and selective LSD1 inhibitors for the treatment of MLL-rearranged leukemia. Yang, C., Fang, Y., Hu, Y., et al.[2023]

ORY-1001 is a highly potent and selective oral inhibitor of lysine-specific demethylase 1 (LSD1), showing promise in the treatment of acute myeloid leukemia (AML) based on both in vitro and in vivo studies.

The study includes correlative data from two AML patients treated with ORY-1001, suggesting potential clinical relevance and efficacy in real-world applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ORY-1001: Overcoming the Differentiation Block in AML. Bose, P., Konopleva, MY.[2018]

Hydroxyurea is an effective and well-tolerated treatment for high-risk essential thrombocythemia and polycythemia vera, proven to prevent thrombohemorrhagic complications in many studies.

Recent large studies have reassured clinicians about the safety of hydroxyurea, showing that the risk of progression to acute leukemia is relatively low, reinforcing its status as the preferred treatment for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydroxyurea: The drug of choice for polycythemia vera and essential thrombocythemia. Dingli, D., Tefferi, A.[2021]

Hydroxyurea was successfully used to treat secondary polycythemia in a 22-year-old man with cyanotic congenital heart disease, leading to significant clinical improvement and reduced need for phlebotomies over 8 months.

The treatment resulted in stable hematocrit levels below 60%, demonstrating hydroxyurea's potential as an effective alternative therapy for patients with secondary polycythemia when surgical options are not available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy against polycythemia due to a cyanotic congenital heart disease in adults. One case report]. Boussaada, R., Békir, S., Ben Romdhane, N., et al.[2013]

Hydroxyurea (HU) treatment effectively normalizes elevated blood cell counts in most patients with essential thrombocythemia, polycythemia vera, and primary myelofibrosis within weeks, as shown in a study of 27 patients.

Despite initial declines in the JAK2V617F allele burden and blood cell counts, HU does not lead to a sustained reduction in the JAK2V617F allele burden, which may contribute to the ongoing risk of thrombosis in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Data-driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Dam, MJB., Pedersen, RK., Knudsen, TA., et al.[2022]

In a study of 294 low-risk polycythemia vera patients, both hydroxyurea and pipobroman showed higher-than-expected hematologic toxicity, necessitating close monitoring and leading to treatment changes in 10% of cases.

Both drugs were found to have a leukemogenic potential with a 15% risk of developing leukemia by year 15, and hydroxyurea was associated with a significant risk of skin cancer, indicating that their long-term safety profiles are concerning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of polycythemia. II.--Comparison of hydroxyurea with pipobroman in 294 patients less than 65 years of age]. Najean, Y., Rain, JD., Lejeune, F., et al.[2013]

Asymptomatic thrombocytosis in young patients with myeloproliferative disorders (MPD) does not require treatment, but lowering platelet counts can reduce microvascular events in at-risk patients.

Hydroxyurea is the preferred treatment for thrombocytosis-related transient ischemic attacks, but it does not prevent venous thrombosis and has uncertain long-term safety; anagrelide is suggested as a first-line alternative due to its lower myelotoxicity, although its long-term safety is also under scrutiny.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anagrelide: 20 years later. Emadi, A., Spivak, JL.[2016]

The novel LSD1 antagonist SP2509 effectively inhibits the growth of acute myeloid leukemia (AML) cells by promoting differentiation and increasing apoptosis, particularly in cells with mutant NPM1, suggesting a targeted therapeutic approach.

Co-treatment with SP2509 and the pan-HDAC inhibitor panobinostat showed synergistic effects, significantly improving survival in mice with human AML without causing toxicity, indicating a promising combination therapy for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Fiskus, W., Sharma, S., Shah, B., et al.[2022]

The combination of the LSD1 inhibitor T-3775440 and the NEDD8-activating enzyme inhibitor pevonedistat showed synergistic effects in inhibiting the growth of acute myeloid leukemia (AML) cells, enhancing cell differentiation and increasing apoptosis.

In preclinical models, this combination treatment not only effectively reduced tumor growth but also led to tumor eradication or prolonged survival in mice, highlighting its potential as a promising therapeutic strategy for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic anti-AML effects of the LSD1 inhibitor T-3775440 and the NEDD8-activating enzyme inhibitor pevonedistat via transdifferentiation and DNA rereplication. Ishikawa, Y., Nakayama, K., Morimoto, M., et al.[2020]

Lysine-specific demethylase 1 (LSD1) is crucial for regulating cell differentiation and proliferation, and various inhibitors have been developed to target its activity in cancer treatment.

Among the LSD1 inhibitors studied, iadademstat (ORY-1001) was found to be the most potent, while many commonly used tool compounds showed low activity and selectivity, indicating that results from these compounds should be interpreted cautiously.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology. Sacilotto, N., Dessanti, P., Lufino, MMP., et al.[2022]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Targeting LSD1 for acute myeloid leukemia (AML) treatment. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Structure-based design and discovery of potent and selective lysine-specific demethylase 1 (LSD1) inhibitors. [2019]

4. France pubmed.ncbi.nlm.nih.gov

Discovery of new tetrahydroisoquinolines as potent and selective LSD1 inhibitors for the treatment of MLL-rearranged leukemia. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

ORY-1001: Overcoming the Differentiation Block in AML. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Hydroxyurea: The drug of choice for polycythemia vera and essential thrombocythemia. [2021]

7. Tunisia pubmed.ncbi.nlm.nih.gov

[Chemotherapy against polycythemia due to a cyanotic congenital heart disease in adults. One case report]. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Data-driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis. [2022]

9. France pubmed.ncbi.nlm.nih.gov

[Treatment of polycythemia. II.--Comparison of hydroxyurea with pipobroman in 294 patients less than 65 years of age]. [2013]

10. England pubmed.ncbi.nlm.nih.gov

Anagrelide: 20 years later. [2016]

11. England pubmed.ncbi.nlm.nih.gov

Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Synergistic anti-AML effects of the LSD1 inhibitor T-3775440 and the NEDD8-activating enzyme inhibitor pevonedistat via transdifferentiation and DNA rereplication. [2020]

13. United States pubmed.ncbi.nlm.nih.gov

Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology. [2022]