"Merck has announced it will acquire biopharma Imago BioSciences, Inc for around $1.35 billion in total equity value, to facilitate development of Imago’s lead candidate bomedemstat (IMG-7289)"
I'm one of the 73 bomedemstat guinea pigs and so far so good. My dose has shifted over the course of the study due to unrelated health issues which caused blood loss, anemia. But at the moment I'm "in the zone" for my platelet count and side effects are acceptable.
I’ve read that the inhibition of LSD1 from Bomedemstat is irreversible. I know inhibition is the aim, but terminology like ‘irreversible’ makes me nervous.
I've not heard about that before. Good point and a reason to check. I found there are both irrev and reversible LSD1 inhibs. This report suggests a reversible one could be better:
"Although a wide range of irreversible inhibitors of LSD1 have been reported (such as Bomed) ... this work represents one of the first reported examples of a reversible small molecule inhibitor of LSD1 ... and could provide a platform for the development of more potent reversible inhibitors"
Implication is reversible is preferable and is a future goal. But it's not yet available. My take is irrev is not toxic but reversible should work better. But I can't find actual details of the implications beyond the obvious wording difference.
I saw this article in the Wall Street journal. Encouraging. I see irreversible above, but not sure what to make of it. What is the implication? Can you get off of the drug at some point and maintain effect?
In spite of a good search effort, I can't find a lay person's explanation of the difference beyond the obvious name implication. But there is a consistent pattern that reversible is the focus of current research, providing more potent action. This is anti intuitive since irreversible would seem more potent. But it's beyond my grasp for now.
I do expect there is work ongoing to get a reversible MPN LSD1 agent that should work better than Bomed, where Bomed is a 1st gen drug like Rux is. But could be not.
I can't say that I can explain the difference in this specific case, but there may be a parallel case that might be analogous.
In the case of anti-platelet activity, aspirin irreversibly disables any and all platelets that are formed while it is present in the blood/serum- that means its effects last approx. 14-21 days until a new population of platelets has replaced those.
Most, if not all of the other medications termed NSAIDs [non-steroidal anti-inflammatory drugs] exhibit reversible anti-platelet activity, meaning that they inhibit platelets from being active in clotting while the drug is present in the bloodstream, but as soon as it has been cleared from the blood, the platelets resume their ability to clot.
FYI, I just looked and Plavix [clopidogrel] is also an irreversible platelet inhibitor.
In reviewing available information about your main topic here, the drug Bomedemstat, I was somewhat dismayed to see that they included some misinformation on their official website [I boldfaced the specific statement I think is misinformation]:
"Polycythemia Vera (PV)
LSD1 inhibition modulates the proliferation of malignant blood cells and therefore represents a viable therapeutic approach to treating PV, an MPN characterized by the excessive production of red blood cells. While there are some available treatments for PV, namely phlebotomy for low-risk patients and hydroxyurea or ruxolitinib for high-risk patients, there are no disease-modifying therapies for the disease. Bomedemstat represents a novel therapeutic option for this patient population. An ongoing investigator-sponsored trial is evaluating bomedemstat in PV patients who have failed at least one standard therapy. For more information about our investigator-sponsored trial investigating bomedemstat for PV visit clinicaltrials.gov."
I don't like that they are essentially ignoring the evidence for IFN's.
Otherwise, I'm always looking for the next new thing, just in case my trial of IFN fails, or the S-E become intolerable [although I haven't ecperienced any as of yet].
As I understand your info, it concerns the life of the cells being acted upon.
-Irrev permanently modifies the cells, and its effect goes away when the modified cells die.
-Reversible has its effect on living cells, and goes away as the drug dissipates even if the cells persist.
Assuming that, both are "reversible" if the target cells eventually die.
Next hypothetical question then is whether persistence is relevant to LSD1, does LSD1 have a set life? Or is there a relevant precursor? Assuming LSD1 is not permanent ie it gets renewed, then an irreversible agent (Bom) gets can be reversed or neutralized when the target cells die and therapy stops.
Yes, that's the general idea, although in the case of platelets, they are not actually living cells as we typically understand them, they are biologically active fragments of a precursor cell called megakaryocytes.
"Megakaryocytes are hematopoietic cells, which are responsible for the production of blood platelets. The traditional view of megakaryopoiesis describes the cellular journey from hematopoietic stem cells, through a hierarchical series of progenitor cells, ultimately to a mature megakaryocyte."
from: New Insights Into the Differentiation of Megakaryocytes From Hematopoietic Progenitors
As regards LSD1, I tried to see if I could find any reference to LSD1's longevity and/or regeneration, but I wasn't able to find much information that was relevant or even really understandable, except that inhibiting it seems to be helpful in a lot of different disease states, both cancer-related and not [e.g., autism].
"LSD1 (Lysine-Specific Demethylase; also known as KDM1A) is a critical regulator of cell-fate determination. It is required for embryonic development in mice and controls stem cell identity as well as differentiation pathways of diverse cell types (Foster et al., 2010; Hino et al., 2016; Whyte et al., 2012)"
vs
"PLETHORA (PLT) transcription factor gradients are unique in their ability to guide the progression of cell differentiation at different positions in the growing Arabidopsis thaliana root, which contrasts with well-described transcription factor gradients in animals specifying distinct cell fates within an essentially static context. To understand the output of the PLT gradient, we studied the gene set transcriptionally controlled by PLTs. Our work reveals how the PLT gradient can regulate cell state by region-specific induction of cell proliferation genes and repression of differentiation. Moreover, PLT targets include major patterning genes and auto-regulatory feedback components, enforcing their role as master regulators of organ development."
I thought that knowing more about what LSD1 [aka KDM1A] is and does might help us understand the reversible vs irreversible quandary.
The wiki page for KDM1A, found by searching for LSD1, states:
Clinical significance
[A statement about its activity in embryonic/fetal development starts the entry] then...
KDM1A is also thought to play a role in cancer, as poorer outcomes can be correlated with higher expression of this gene.[18][19] Therefore, the inhibition of KDM1A may be a possible treatment for cancer.[20][21][22][23] KDM1A tends to be overexpressed in the tumor cells of certain cancers such as bladder, lung, and colorectal cancers. The specificity of KDM1A overexpression in these cancers creates the potential for targeted molecular therapy treatments, through the use of KDM1A-specific siRNAs.[24]"
...and now apparently through chemical inhibitor[s].
"An Enzyme Inhibitor, Bomedemstat, for the Treatment of Essential Thrombocythemia or Polycythemia Vera That Has Failed at Least One Standard Therapy
This phase II trial studies the side effects and how well bomedemstat works in treating patients with essential thrombocythemia or polycythemia vera that has not responded adequately to standard therapies. Bomedemstat, is a new oral (taken by mouth) medication that works by turning off the activity of an enzyme called LSD1 (lysine specific demethylase 1) which is present at low levels in cells of all people. High levels of LSD1 inside the abnormal stem cells of essential thrombocythemia or polycythemia vera patients are believed to block the cells from becoming mature cells that function normally; instead, the abnormal cells continue to be made. This, in turn, lowers the abnormal red cell and platelet counts seen in patients with essential thrombocythemia or polycythemia vera."
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