Momelotinib - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

Momelotinib is an exciting option for myelofibrosis patients with anemia due to its distinctive inhibitory effect on the BMP6 (bone morphogenic protein 6), ACVR1 (activin A receptor type 1), and SMAD (suppressor of mothers against decapentaplegic), and IL-6 (Interleukin-6), JAK (Janus kinase), and STAT3 (Signal transducer and activator of transcription 3) pathways. This reduces hepcidin expression, increases serum iron and hemoglobin levels, and restores erythropoiesis (red blood cell production process).

On September 15, 2023, the United States Food and Drug Administration (US FDA) authorized Momelotinib to treat individuals with intermediate - or high-risk myelofibrosis who have anemia. The MOMENTUM trial found that patients with symptomatic and anemic myelofibrosis treated with Momelotinib had better symptoms, spleen size, and anemia (low red blood cells) than those treated with Danazol. The MOMENTUM study results are keenly expected because they may lead to Momelotinib's regulatory approval.

Drug Group

Momelotinib is a competitive inhibitor of Janus kinase 1 (JAK1) and 2 (JAK2), classified as Janus Kinase inhibitors. This class of medications inhibits the faulty protein that causes cancer cells to proliferate, slowing or stopping their spread. Momelotinib is prescribed to manage intermediate or high-risk myelofibrosis (extensive bone marrow scarring leading to severe anemia).

Indications

Momelotinib is a kinase inhibitor used to treat intermediate or high-risk myelofibrosis (MF), comprising primary and secondary MF (post-polycythemia vera (a blood cancer that results from excessive red blood cell production in the bone marrow) and post-essential thrombocythemia (a rare genetic disorder that affects platelets, the blood cells responsible for controlling bleeding)), in individuals with anemia.

Dosage Forms and Available Strengths

Momelotinib tablets come in three dosages: 100 mg (milligrams), 150 mg, and 200 mg.

Warnings and Precautions

• Risk of Infections: To reduce infection risk, avoid starting Momelotinib for individuals with active infections. Observe for signs and symptoms of infection, including reactivation of hepatitis B (serious liver infection due to hepatitis B virus), and seek immediate treatment.

• Thrombocytopenia and Neutropenia: Manage thrombocytopenia (low platelet count) and neutropenia (low neutrophil count) with dose reduction or stoppage.

• Hepatotoxicity: To avoid hepatotoxicity (drug-induced liver injury), get liver testing before starting Momelotinib and frequently during treatment.

• Major Adverse Cardiovascular Events (MACE): Monitor for Major Adverse Cardiovascular Events (MACE) symptoms and treat them promptly.

• Thrombosis: Thrombosis (blood clot formation within the blood vessels) symptoms should be evaluated and treated promptly.

• Malignancies: Monitor for secondary cancers, especially in smokers (current or previous).

For Patients

What Is Myelofibrosis With Anemia?

Myelofibrosis is a rare bone marrow malignancy that inhibits blood cell synthesis, resulting in significant scarring and severe anemia. This illness can induce weakness and fatigue, commonly leading to an enlarged spleen. Anemia, low red blood cells or hemoglobin (Hb), is a significant prognostic factor in myelofibrosis. Symptoms are fatigue, weakness, and shortness of breath. Myelofibrosis can occur by itself or as a result of another bone marrow condition. Some individuals may not require immediate therapy, whereas more serious conditions may necessitate vigorous treatment.

How Does Momelotinib Work?

Momelotinib suppresses the JAK-STAT (Janus kinase - signal transducers and activators of transcription) signaling system, frequently disrupted in myelofibrosis. This JAK-STAT signaling pathway blockage slows the progression of cancer cells. Despite its effects on cancer cells, Momelotinib has a distinctive mechanism of action that aids in anemia treatment in myelofibrosis patients. It suppresses the BMP6, ACVR1, and SMAD and IL-6, JAK, and STAT3 pathways, resulting in decreased hepcidin expression, increased serum iron and hemoglobin levels, and restored erythropoiesis, which improves anemic symptoms, a typical consequence of myelofibrosis.

What Are the Clinical Uses of Momelotinib?

Momelotinib treats myelofibrosis, a bone marrow malignancy that affects normal blood cell production. It is intended for moderate or high-risk myelofibrosis in adults with anemia.

Myelofibrosis can be defined as primary myelofibrosis (PMF), post-polycythemia vera (PV) myelofibrosis, and post-essential thrombocythemia (ET) myelofibrosis. Myelofibrosis can cause anemia and thrombocytosis.

Momelotinib inhibits the JAK-STAT signaling system, which is frequently disrupted in myelofibrosis. It also improves anemia, a frequent consequence of myelofibrosis. This JAK-STAT signaling pathway blockage limits the spread of cancer cells.

Momelotinib, a cancer cell-killing medicine, also helps to treat anemia in myelofibrosis patients by blocking the BMP6, ACVR1, and SMAD and IL-6, JAK, and STAT3 pathways, which reduce hepcidin expression, boost iron and hemoglobin levels, and restore erythropoiesis.

How Is Momelotinib Administered?

• Momelotinib is available in the form of an orally administered tablet. Momelotinib is usually taken once per day, with or without food. Take Momelotinib at roughly the same time every day. Follow the instructions on the prescription label carefully and ask the pharmacist or physician to explain the sections that are not understood. Take Momelotinib precisely as prescribed. Avoid taking more or less of it or more frequently than the physician recommends.

• Swallow the tablets without splitting, chewing, or crushing them.

• The physician will perform blood tests before and during therapy to determine how this medicine affects people. The physician may reduce the dose of Momelotinib during therapy or tell people to stop taking Momelotinib temporarily or permanently.

• The effectiveness of the medication determines this, as the results of the lab tests and whether there are any side effects. Inform the physician on how one feels during treatment.

• Ask the doctor or pharmacist for a duplicate of the manufacturer's information for the treated individual.

What Are the Side Effects of Momelotinib?

Momelotinib may produce adverse effects. Inform the physician if any of the following symptoms are severe or do not resolve:

• Diarrhea (loose and watery stools).

• Headache.

• Numbness and tingling in the extremities.

• Fatigue.

• Dizziness.

• Back, arm, or leg ache.

• Swelling of the body parts.

• Redness.

• Itching.

• Blurred vision.

Certain adverse effects of Momelotinib can be severe. If people suffer any of the following symptoms, call the physician right away or seek emergency medical attention:

• Excessive bleeding or bruises.

• Black or tarry feces.

• Yellowing of the skin or eyes.

• Loss of appetite.

• Pain in the upper right side of the stomach.

• Dark (tea-colored) urine.

• Excessive fatigue.

• Crushing chest ache or chest heaviness.

• Swelling, discomfort, tenderness, heat, or redness in one or both legs.

• Shortness of breath (dyspnea).

• Breathing problems.

• Chest, arms, back, neck, jaw, or stomach aches.

• Nausea or vomiting.

• Lightheadedness.

• Sluggish or difficult speech.

• Weakness or numbness in the face, arm, or leg on a specific body side.

Momelotinib may raise the possibility of developing other cancers, such as lymphoma (a malignancy that starts in the cells that fight infection).

Consult the physician about the risks of taking Momelotinib. Momelotinib may produce additional adverse effects. If people experience any unexpected symptoms while taking Momelotinib, contact the physician.

What Are the Things to Inform the Doctor Before Taking Momelotinib?

1. Before using Momelotinib, inform the physician and pharmacist if patients are allergic to Momelotinib, other drugs, or any of the substances in the Momelotinib tablets.

2. Inform the pharmacist and physician about any other prescription or nonprescription drugs, vitamins, nutritional supplements, or herbal products that patients are taking or intend to use. The healthcare provider may need to modify the doses of drugs or closely monitor for side effects.

3. Tell the physician whether patients smoke or have previously smoked. Also, inform the physician if patients are currently or previously experiencing low levels of white blood cells or platelets; bleeding difficulties; cancer; blood clots, particularly a pulmonary embolism (a clot of blood within the lung); a stroke; a heart attack or other cardiac problems; or liver illness.

4. Inform the physician if patients are pregnant or intend to get pregnant. People should not fall pregnant while using Momelotinib or one week after the last dosage. Consult the physician about birth control options that patients can use during their therapy. If patients do become pregnant while on Momelotinib, call the physician right away. Momelotinib could harm the fetus.

5. Inform the physician if patients are breastfeeding or want to breastfeed. One should not breastfeed while using Momelotinib or for one week following the last dose.

6. If the patient is scheduled for surgery, including dental surgery, inform the dentist or physician that the patient is taking Momelotinib.

7. Patients should be aware that Momelotinib may reduce their capacity to fight infections caused by bacteria, viruses, and fungi, increasing their chance of developing a serious infection. Tell the physician if patients frequently have infections or if patients have or suspect that they have an infection right now. Tell the physician if patients are currently or previously suffering from hepatitis B virus infection (HBV; a chronic liver infection). If patients suffer from any of the following symptoms during or shortly after Momelotinib treatment, contact the physician immediately:

• Fever, sweats, or chills.

• Sore throat.

• Cough.

• Warm, red, or painful skin or sores on the body.

• Frequent, urgent, or painful urination.

• Other symptoms of infection.

Dietary Considerations: Maintain the same diet unless otherwise directed by the physician.

Missed Dose: Avoid consuming a double dose to make up for a missed dose of Momelotinib and stick to the usual dosing plan.

Overdose: There is no known antidote for Momelotinib overdose; if it is suspected, patients should be watched for adverse reactions and treated immediately. Further care is required, and hemodialysis (a medical procedure involving a dialysis machine and an artificial kidney or dialyzer to purify blood) will unlikely improve Momelotinib elimination.

Storage and Handling

• Keep Momelotinib tablets in their original container, properly closed, and out of children's reach. Keep Momelotinib tablets at room temperature, away from heat and moisture, and not in the bathroom.

• Dispose of unused Momelotinib tablets in designated containers to keep pets, children, and others from consuming them.

• Dispose of Momelotinib drugs using a medicine take-back program, which can be found by speaking to the pharmacist or calling the city's garbage or recycling department.

For Doctors

Pharmacodynamics: Momelotinib blocks Janus Kinase 1 and 2 (JAK1/2) with IC50 (half-maximal inhibitory concentration) values of 11 and 18 nM (nanometers), respectively. It also suppresses JAK3 (IC50 = 155 nM) and TYK2 (IC50 = 17 nM) with lower selectivity. Momelotinib reduced STAT3 phosphorylation in the whole blood of patients with myelofibrosis (MF). The maximum suppression of STAT3 phosphorylation happened two hours after Momelotinib administration and continued for at least six hours. Iron availability and erythropoiesis were measured using circulating hepcidin concentrations; an immediate and sustained drop in circulating hepcidin was seen after the 24-week treatment of Momelotinib in MF patients.

Chemical Taxonomy: Momelotinib is a small molecule with an average weight of 414.469 g/mol, and its IUPAC name is N-(Cyanomethyl)-4-{2-[4-(morpholin-4-yl)anilino]pyrimidin-4-yl}benzamide.

Mechanism of Action: Momelotinib is an adenosine triphosphate-competitive inhibitor of wild-type and mutant JAK1 and JAK2, which participate in the signaling of cytokines and growth factors required for hematopoiesis and immunity. Momelotinib and its main human circulating metabolite, M21, show greater inhibitory activity for JAK2 than other members of the JAK family. Momelotinib and M21 also block activin A receptor type 1 (ACVR1), which is also referred to as activin receptor-like kinase 2 (ALK2), which reduces liver hepcidin expression and increases iron availability, resulting in more red blood cell synthesis. Dysregulated JAK signaling may potentially lead to inflammation and ACVR1 hyperactivation. Momelotinib suppresses hepcidin, increasing circulating iron and hemoglobin and stimulating erythropoiesis in the bone marrow.

Pharmacokinetics

• Absorption: Momelotinib is a medicine that absorbs quickly after oral administration and has a 97 percent bioavailability. The steady-state Cmax (maximum drug concentration) is 479 ng/mL (nanograms per milliliter) (61 percent), and the area under the curve (AUC) is 3,288 ng x h/mL (nanograms x hours per milliliter) (60 percent) at the maximum recommended dosage. Momelotinib exposure increases the dose proportionately from 100 mg to 300 mg but decreases it from 400 mg to 800 mg. There is no clinically significant accumulation, and the Tmax (time to achieve Cmax) at a steady state occurs two hours after the dose. No significant variations in Momelotinib pharmacokinetics were detected following high-fat or low-fat diets.

• Distribution: The mean apparent volume of distribution at steady-state is 984 L (liters) (118 percent), with 91 percent of Momelotinib bound to plasma proteins in healthy participants.

• Metabolism: Momelotinib is metabolized by various cytochrome P450 enzymes, with the M21 metabolite produced through morpholine ring oxidation and then processed by aldehyde oxidase. M21 preserves 40 percent of Momelotinib's pharmacological action, with an average AUC ratio of 1.4 to 2.1. Momelotinib can undergo amide hydrolysis, N-dealkylation, nitrile hydrolysis, nitrile oxidation, and glucuronidation.

• Excretion: Momelotinib is predominantly removed through feces and, to a lesser extent, urine. After a single oral dose of radiolabeled Momelotinib in healthy participants, roughly 69 percent of the entire radioactive dose was recovered in feces, with M14 metabolite accounting for 21.4 percent, Momelotinib and M21 metabolite each accounting for 13 percent, and the remaining 22 percent accounted for the other 12 metabolites. M21 was the most common species collected in urine, accounting for around 28 percent of the radioactivity. Momelotinib and its metabolite, M21, have an elimination half-life of four to eight hours.

Drug Interactions

• Organic Anion Transporting Polypeptide (OATP) 1B1/B3 Inhibitors: Momelotinib, an OATP1B1/B3 substrate, may raise its maximum concentrations (Cmax) and AUC when combined with an OATP1B1/B3 inhibitor, thus increasing the risk of adverse events and necessitating dose modifications.

• Substrates for Breast Cancer Resistance Protein (BCRP): Momelotinib, a BCRP inhibitor, might raise exposure to BCRP substrates, increasing the possibility of adverse effects. When used with Momelotinib, start Rosuvastatin at 5 mg daily and no more than 10 mg. Other BCRP substrates may require dose adjustments, and product information recommendations should be followed.

Clinical Studies

The MOMENTUM and SIMPLIFY-1 trials demonstrated the efficacy of Momelotinib in treating individuals with intermediate, intermediate 2, or high-risk MF, including primary MF, post-PV MF, or post-ET MF, with a starting dose of 200 mg once a day. Eligible patients exhibited a baseline platelet count of 25 × 109/L or 50 × 109/L.

• MOMENTUM: The MOMENTUM trial randomly assigned 195 individuals with myelofibrosis (MF) to either Momelotinib or Danazol for 24 weeks. The patients were primarily white, with a median age of 71. The study discovered that Momelotinib was more successful than Danazol in treating primary or secondary MF and anemia, with a 50 percent decrease in the myelofibrosis symptom assessment form (MFSAF v4.0) Total symptom score at week 24. Other outcomes were transfusion independence, spleen volume response, and the percentage of patients who had no transfusions.

• SIMPLIFY-1: The SIMPLIFY-1 trial compared Momelotinib 200 mg once daily to Ruxolitinib adjusted dosage twice daily for 24 weeks in 432 individuals with MF. The efficacy of Momelotinib was determined by spleen volume response, with 25 percent of patients observing a 50 percent or greater reduction in Total Symptom Score compared to 36 percent with Ruxolitinib.

Specific Considerations

• Pregnancy: Animal studies have found signs of embryofetal toxicity in medication, with reactions occurring at dosages more than three times the recommended human dose. In pregnant rats, embryofetal toxicity occurred at the same level as maternal toxicity, whereas skeletal alterations occurred in the absence of maternal toxicity. No developmental harm was seen at a dose corresponding to the recommended dose. The US FDA has changed the pregnancy labeling requirement for prescription medicine products to require a summary of risks, discussion of supporting facts, and relevant information to assist healthcare providers in prescribing decisions and support women about drug use during pregnancy.

• Breastfeeding: Breastfeeding is not recommended during or after the last dose of Momelotinib, as it is excreted in human and animal milk. It reduced the newborn survival rate in nursing rats.

• Pediatric Use: The safety and efficacy of Momelotinib in pediatric patients have not been proven.

• Geriatric Use: The clinical trials for MF included 275 patients aged 65 and older, with 75 percent of Momelotinib-treated patients aged 65 and older and 25 percent aged 75 and older. There were no significant variations in safety or efficacy between older and younger adult patients.

• Hepatic Impairment: Momelotinib's recommended starting dose is 150 mg orally once daily in patients with severe hepatic impairment (Child-Pugh C), with no dose change for mild or moderate impairment (Child-Pugh A or B). Momelotinib exposure rises with severe hepatic impairment, but no significant differences were found in mild or moderate impairment.