Pharmacology assignment*

Name of the drug:

Momelotinib

General description:
A broad overview of Momelotinib is a highly selective and potent inhibitor
of kinase inhibitor and bone morphogenic protein receptor (BMPR) kinase
activin A receptor type 1 (ACVR1)/ALK2, which is involved in iron
metabolic pathways and regulates the expression of hepcidin.MMB, also
known as Ojjaara, is an anticancer medication used to treat myelofibrosis. It
is taken orally once daily and has FDA approval.

Description of the pharmacologic class:

Momelotinib is a benzamide that is produced by formally condensing the
primary amino group of aminoacetonitrile with the carboxy group of 4-{2-
[4-(morpholin-4-yl) anilino] pyrimidin-4-yl} benzoic acid. It is an ATP-
competitive inhibitor of JAK1/JAK2 with an IC50 of 11 nM and 18 nM, in
that order. used to treat myelofibrosis patients who are at intermediate or
high risk. It functions as an apoptosis inducer, antineoplastic, anti-anaemic,
and an inhibitor of EC 2.7.10.2 (non-specific protein tyrosine kinase). It is a
nitrile, an aminopyrimidine, a secondary amino compound, a tertiary amino
compound, a member of the benzamide family, and a member of the
morpholines.
Treatment trials for Polycythemia Vera, Primary Myelofibrosis, Post-
Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis
(PMF) have included the use of melotinib.
An oral bioavailable small-molecule inhibitor of Janus kinases 1 and 2
(JAK1/2) with possible anti-tumor effects is called melotinib. In JAK1/2-
expressing tumor cells, the JAK1/2 inhibitor CYT387 competes with
JAK1/2 for ATP binding, which may lead to the inhibition of JAK1/2
activation, the inhibition of the JAK-STAT signaling pathway, the induction
of apoptosis, and a decrease in tumor cell proliferation. In bcr-abl-negative
myeloproliferative disorders, JAK2 is the most frequently mutated gene. The
JAK2V617F gain-of-function mutation results in a valine-to-phenylalanine
modification at position 617. One important mediator of cytokine activity is
the JAK-STAT signaling pathway, which is frequently dysregulated in
different types of tumor cells.

An explanation of the action's mechanism:

It functions by specifically focusing on and blocking the JAK1 and JAK2
enzymes.
Overactive JAK1 and JAK2 enzymes are the result of a malfunction in the
signaling pathway that controls blood cell growth and development in
myelofibrosis. These enzymes act as messengers between cells, encouraging
aberrant erythropoiesis and the growth of fibrous tissue in the bone marrow.
Momelotinib disrupts this malfunctioning signaling pathway by blocking
JAK1 and JAK2. By lowering the synthesis of aberrant blood cells and
preventing the accumulation of fibrous tissue in the bone marrow, it aids in
the restoration of equilibrium.
Moreover, momelotinib's anti-inflammatory qualities have been noted. It
could control the release of some pro-inflammatory cytokines, which are
immune response-related chemicals. Momelotinib may help reduce
myelofibrosis symptoms by lowering the levels of these cytokines.
Momelotinib's exact mechanisms of action are still being investigated, and
more research is being done to clarify its interactions and possible
advantages in the management of myelofibrosis.

The adverse effects of the medication:

Side effect:
A medication may have some undesirable side effects in addition to its
intended ones. While not all these adverse effects are likely to happen, if
they do, they can require medical treatment.
If you have any of the following side effects, consult your doctor right away:
1)More prevalent
2)Tarry, black stools
3)bladder discomfort
4)gum bleeding
5)edema or bloating of the feet, hands, arms, or lower limbs.
6)blood found in the feces.
7)pee that is murky or bloody
8)hazy vision
9)stiffness or pain in the chest
10)bewilderment
11)spitting blood in the cough
12)hoarseness or coughing
13)diarrheal
14)Urinating that is tough, unpleasant, or scorching.
15)breathing or swallowing difficulties.
16)lightheadedness.
17)lightheadedness, faintness, or dizziness after abruptly standing up from a
seated or reclining position.
18)losing consciousness.
19)erratic, rapid, or slow heartbeat.
20)chills or a fever.
21)frequent need to go to the bathroom.
22)headache.
* Dizziness, diarrhea, nausea, vomiting, stomach pain, or tiredness may
occur. If any of these effects last or get worse, tell your doctor or pharmacist
promptly.

How this drug is different from the other drugs used for
similar indications:
Momelotinib has some unique characteristics that differentiate it from other
drugs used for similar indications, such as myelofibrosis:
1. Unique Inhibitory Activity: Momelotinib has a unique inhibitory activity
on the BMP6/ACVR1/SMAD and IL-6/JAK/STAT3 pathways, resulting in
decreased hepcidin (master iron regulator) expression, higher serum iron and
hemoglobin levels, and restored erythropoiesis.
2. Anemia Benefits: Clinical data from phase 2 and the two phase 3
SIMPLIFY trials consistently demonstrated high rates of sustained
transfusion-independence with momelotinib. In a recent phase 2 translational
study, 41% of the patients achieved transfusion independence for ≥12 weeks.
3. Comparison with Ruxolitinib: In the phase 3 trials SIMPLIFY-1 and
SIMPLIFY-2, 17% more JAK inhibitor-naïve patients and two-fold more
JAK inhibitor-treated patients achieved or maintained transfusion
independence with momelotinib versus ruxolitinib1. However, for total
symptom score (TSS) reduction, momelotinib was found to be inferior to
ruxolitinib.
4. Comparison with Danazol: In the MOMENTUM trial, patients with
symptomatic and anemic myelofibrosis who were treated with momelotinib
showed improved symptoms, spleen size, and anemia compared with
patients treated with danazol.
These unique characteristics make momelotinib a promising treatment
option for myelofibrosis patients with anemia.

References:
*https://go.drugbank.com/drugs/DB11763
* https://www.sciencedirect.com/topics/medicine-and-
dentistry/
* https://www.gsk.com/en-gb/media/press-releases/gsk-
regulatory-submission-for-momelotinib-for-the-treatment-of-
myelofibrosis-accepted-for-review-by-japanese-regulator/
* https://www.mayoclinic.org/drugs-supplements/momelotinib-
oral-route/side-effects/drg-20555953?p=1
*Momelotinib: an emerging treatment for myelofibrosis patients
with ...
*Momelotinib vs Ruxolitinib for Myelofibrosis: Phase 3 Trial
Yields ...
*FDA Approves Momelotinib for Myelofibrosis With Anemia
*Momelotinib ‘Stands On Its Own’ Compared With Other JAK ... -
CURE
*FDA Approves Momelotinib (Ojjaara) for Myelofibrosis Patients
With Anemia
* https://pubchem.ncbi.nlm.nih.gov/compound/Momelotinib