An orally active LSD1 inhibitor showing promising results in Phase 2 clinical trials for patients with limited treatment options.
For patients living with advanced myelofibrosis, a rare and chronic bone marrow cancer, the treatment journey is often fraught with challenges. This serious condition disrupts the body's normal production of blood cells, leading to debilitating symptoms such as severe fatigue, night sweats, bone pain, and enlarged spleen (splenomegaly). For many, the available therapies eventually lose their effectiveness, leaving them with dwindling options. However, a new class of drug is generating significant excitement in the medical community. Bomedemstat (IMG-7289), an orally active LSD1 inhibitor, has emerged as a promising candidate in late-stage clinical trials, offering new hope where it is needed most 1 7 .
This article delves into the groundbreaking science behind bomedemstat and explores the compelling clinical evidence that suggests it could become a vital tool in managing advanced myelofibrosis.
To understand the innovation behind bomedemstat, we must first look at its target: Lysine-specific demethylase 1 (LSD1).
LSD1 is an enzyme that plays a critical role in regulating how our genes are read and expressed, a process known as epigenetic control.
In healthy cells, LSD1 helps maintain the delicate balance of blood stem cell self-renewal and their maturation into various blood components.
Think of it as a master switch inside bone marrow cells. In healthy cells, LSD1 helps maintain the delicate balance of blood stem cell self-renewal and their maturation into various blood components, such as platelets and granulocytes 1 7 .
In myelofibrosis and other myeloproliferative neoplasms, this process goes awry. LSD1 becomes overexpressed, effectively keeping malignant cells in a state of perpetual growth and preventing them from maturing properly. This leads to the hallmark symptoms of the disease: overproduction of abnormal cells, bone marrow scarring (fibrosis), and rampant inflammation 7 .
Bomedemstat is designed as an irreversible inhibitor of LSD1, binding to the enzyme and blocking its activity 3 6 .
This action increases methylation of histones, altering gene expression patterns in malignant cells.
The drug restrains cancer cell proliferation and prompts apoptosis (programmed cell death) in malignant cells.
By targeting this fundamental epigenetic mechanism, bomedemstat attacks the root cause of myelofibrosis rather than just managing its symptoms.
The promise of bomedemstat is being rigorously tested in an ongoing global, open-label Phase 2 clinical trial known as IMG-7289-CTP-102 (NCT03136185). This study is specifically designed for patients with advanced primary or secondary myelofibrosis who are no longer responding to, or cannot tolerate, existing approved therapies like ruxolitinib 1 4 .
Measured by MRI/CT scans to assess reduction in spleen size
Patient-reported questionnaire covering key MF symptoms
Close monitoring of all adverse events and side effects
The results, presented at major congresses like the European Hematology Association (EHA) Congress, have been consistently encouraging 1 7 .
| Endpoint | Patient Group | Result |
|---|---|---|
| Spleen Volume Reduction (SVR) | All evaluable patients | 64% experienced any SVR; 28% achieved ≥20% SVR 1 |
| Total Symptom Score (TSS) | All evaluable patients | 55% experienced a decrease in TSS; 22% achieved ≥50% reduction 1 |
| TSS (High Burden, TSS>20) | Patients with high symptom burden | 94% recorded a reduction in TSS; 31% had a decrease of ≥50% 7 |
| Anemia Impact | Transfusion-independent patients at baseline | 90% had stable or improved hemoglobin levels 1 |
| Bone Marrow Fibrosis | Patients with post-baseline biopsy | 85% had improved or stable fibrosis scoring 1 |
| Adverse Event | Frequency | Severity |
|---|---|---|
| Thrombocytopenia (low platelets) | 48% |
|
| Dysgeusia (taste distortion) | 36% |
|
| Anemia | 34% |
|
| Diarrhea | 33% |
|
| Nausea | 30% |
|
| Fatigue | 26% |
|
Tracking the mutant allele frequency (VAF) revealed that 44% of evaluable patients experienced a reduction in their mutational burden, with clones harboring high-risk mutations like ASXL1 showing particular sensitivity 7 .
The safety profile has been deemed manageable. While thrombocytopenia and taste disturbances were common, most side effects were low-grade. Importantly, no treatment-related deaths have been reported, and the drug was generally well-tolerated by a patient population with limited treatment options 1 7 .
Bringing a new drug from concept to clinic requires a sophisticated array of tools and reagents. The following table outlines some of the essential components used in the development and evaluation of bomedemstat.
| Tool/Reagent | Function in Research |
|---|---|
| Bomedemstat (IMG-7289) | The investigational compound itself; an irreversible, oral LSD1 inhibitor used for in vitro (cells) and in vivo (animal) studies 3 6 . |
| MV-4-11 & SET-2 Cell Lines | Human leukemia (MV-4-11) and myelofibrosis (SET-2) cell lines used in laboratory dishes to study the drug's anti-proliferative and pro-apoptotic effects 1 5 8 . |
| Mx-Jak2V617F Mouse Model | A genetically engineered mouse model that replicates key features of human MPNs, used to test bomedemstat's efficacy in a living organism before human trials 6 . |
| MPN-SAF TSS (Questionnaire) | The Myeloproliferative Neoplasm Symptom Assessment Form. A patient-reported tool critical for quantifying improvements in quality of life and symptom burden during clinical trials 4 . |
| PCR/DNA Sequencing | Techniques like Polymerase Chain Reaction and next-generation sequencing used to track changes in mutant allele frequencies (VAF) in patient blood samples, measuring the drug's effect on the malignant clone 1 7 . |
"The development of bomedemstat represents a convergence of epigenetic research and clinical oncology, showcasing how fundamental biological insights can translate into meaningful therapeutic advances for patients with limited options."
The journey of bomedemstat represents a significant stride forward in the treatment of advanced myelofibrosis. By precision-targeting the epigenetic regulator LSD1, it offers a distinct mechanism of action for patients who have exhausted other therapies. The phase 2 trial data paints a picture of a drug that can meaningfully improve patients' lives by reducing spleen size, alleviating debilitating symptoms, stabilizing blood counts, and potentially altering the disease's genetic foundation.
Targets LSD1, an epigenetic regulator, offering a new approach to treatment
Demonstrated efficacy in reducing spleen volume and symptom burden
Potential to alter the genetic foundation of myelofibrosis
While further research and longer-term follow-up are needed, bomedemstat has firmly established itself as a beacon of hope. It stands as a powerful example of how unraveling the basic science of cancer biology can lead to innovative therapies that truly make a difference for patients facing complex diseases.