What is Ruxolitinib? Its Good and Bad Health Impacts

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What is Ruxolitinib? Its Good and Bad Health Impacts

Ruxolitinib, also known by the brand names Jakafi and Jakavi, is a drug used to treat intermediate and high-risk myelofibrosis, a type of myeloproliferative disorder that affects the bone marrow; polycythemia vera (PCV).

It occurs when hydroxyurea treatment is ineffective or is intolerable. It is also used to treat steroid-refractory acute graft-versus-host disease. Ruxolitinib is a kinase inhibitor that inhibits Janus kinase.

Incyte Corp developed and sold it in the United States under the brand name Jakafi, and Novartis developed and marketed it in the rest of the world under the brand name Jakavi.

Ruxolitinib cream (marketed as Opzelura) was approved for medical use in the United States in September 2021 to treat mild to moderate atopic dermatitis (AD). It’s the first topical Janus kinase inhibitor to get FDA approval in the US.

What Is Ruxolitinib and its Structure?

what is ruxolitinib

Ruxolitinib is a derivative1 of the 7H-pyrrolo[2,3-d]pyrimidine molecule. It is a pyrazole with a pyrrolo[2,3-d]pyrimidin-4-yl group at position 1 and a 2-cyano-1-cyclopentylethyl group at position 3.

Its IUPAC name can be written as (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile.

This substance is a colorless oil.2 Soluble in aqueous buffers with a pH range of 1 to 8. At 25 °C, it has a solubility in water is 100.8 mg/L.

 It solidifies at room temperature and comes in various colors, from white to off-white to light pink powder.

Synthesis Of Ruxolitinib

synthesis of ruxolitinib
patents.google.com

To synthesize3 ruxolitinib, a compound of formula II is combined with a compound of formula IV or salt to form a compound of formula III.

It is then subjected to an acyl halogenation reaction, an amidation reaction, and a reaction dehydrating an amide to form a cyano group or removing the protecting group.

The approach features short stages, strong stereoselectivity, a high atom utilization ratio, mild reaction conditions, and easy post-treatment.

The approach is appropriate for industrial manufacturing and avoids expensive asymmetric reaction catalysts.Patent.google.com

What Is Link Between Jakafi And Ruxolitinib?

Jakafi4 is a Ruxolitinib medication, a costly drug that targets proteins in cells and inhibits their growth. It’s used to treat polycythemia vera(PV) and myelofibrosis.

 It has a little higher popularity than similar medications. Jakafi does not have a generic equivalent at this time.

Jakafi isn’t the same as chemotherapy. It’s a targeted treatment that helps to keep blood cell production under control.5

Is Jakafi Useful In The Treatment Of Polycythemia Vera (PV)?

PV is a form of myeloproliferative neoplasm (MPN) in which the body generates more red blood cells than necessary.

PV patients are more likely to develop blood clots and cardiovascular events, as well as an enlarged spleen.

They also develop weariness, itching, night sweats, bone pain, fever, and weight loss. PV affects around 100,000 people in the United States today.

PV can be treated with phlebotomy (blood removal from the body) and aspirin (to reduce the risk of blood clots). Patients can undergo hydroxyurea or interferon treatment if phlebotomy treatment fails.

Researchers recently released results from the RESPONSE-2 study, a phase 3 trial aimed at determining the efficacy of Jakafi in the treatment of PV.

The studies6 comprised 149 individuals with PV who had failed to respond to hydroxyurea or were intolerant.

Patients needed phlebotomy to keep their hematocrit levels in check, but they didn’t have an enlarged spleen.

Patients were given Jakafi or the best available therapy (BAT) and were compared side by side. The data presented at the 2016 EHA meeting was based on 28 weeks of patient follow-up.

Hematocrit levels were maintained in 62.2 percent of Jakafi-treated individuals, compared to only 18.7% of BAT-treated patients.

Complete recovery was attained in 23 percent of Jakafi-treated patients versus 5.3 percent of BAT-treated individuals.

Compared to 7.7% of individuals treated with BAT, 50% of patients treated with Jakafi experienced an improvement in PV symptoms. Jakafi was generally well tolerated by patients.

Why Is Jakafi Superior To Use Than Hydroxyurea?

Jakafi is a drug that blocks the JAK1/JAK2 pathway linked to the advancement of PV7. It is the first-in-class JAK1/JAK2 pathway inhibitor.

It has been licensed by the US Food and Drug Administration (FDA) to treat PV, which does not respond to hydroxyurea, or for patients who cannot take hydroxyurea.

The researchers found that Jakafi outperforms BAT in individuals with PV who have stopped responding to hydroxyurea or are intolerant to it.

These findings are encouraging because they suggest a therapy option for patients with uncontrolled PV that is both efficacious and well-tolerated.

Is Ruxolitinib Useful in The Treatment of Myelofibrosis?

Myelofibrosis (MF)8 is a chronic and progressive blood cancer characterized as a myeloproliferative neoplasm. It is characterized by defective development and the function of bone marrow cells that make blood cells.

It results in the production of scar tissue in the marrow. When the bone marrow becomes damaged, it loses its ability to create enough blood cells.

Anemia, spleen and liver enlargement, impaired renal function, tiredness, and other complications can result from myelofibrosis.

Acute myeloid leukemia, an aggressive kind of leukemia, develops in certain patients with MF.

Ruxolitinib was tested and authorized by the FDA9 in less than six years after the Jakafi mutation JAK2V617F was originally discovered.

Jakafi was the first myelofibrosis medication to get FDA approval. It is given orally and inhibits two enzymes that contribute to myelofibrosis: JAK1 and JAK2.

The current study included 309 patients from 89 different medical sites across the United States.

Patients with intermediate-2 or high-risk myelofibrosis were included in the study. Jakafi was given to half of the participants, while the other half received a placebo.

According to the research10 presented, this medicine significantly impacts splenomegaly, proliferative blood counts, and constitutional symptoms.

Forty-two percent of Jakafi patients had a significant reduction in spleen size (a 35 percent or greater drop in volume), compared to less than 1% of placebo patients.

46% of patients in the Jakafi group and 5% of patients in the placebo group saw a 50% or higher reduction in overall symptom score.

After a year, 8% of Jakafi patients and 16% of placebo patients died.

Anemia and low platelet counts were more common in the Jakafi group than in the placebo group, but they were manageable in most cases.

Myelofibrosis had damaged the bone marrow, and Jakafi did not restore the damage.

Patients treated with ruxolitinib live longer, even if they do not become cured. As a result, ruxolitinib represents a significant therapeutic development that can potentially treat a large number of people with MF.

Is Ruxolitinib Useful In Acute Graft-Versus-Host Disease?

According to findings from a large clinical trial, patients with blood cancers who develop graft-versus-host disease (GVHD) within the first few months after receiving a stem cell transplant and do not respond to steroids are more likely to respond to the drug ruxolitinib (Jakafi) than to other treatments.

The findings come from the first successful clinical trial11 of therapy for GVHD. The study’s findings back up those of a smaller trial that led to the FDA’s approval of ruxolitinib for some patients with GVHD in 2019.

Both trials looked at the medicine in patients with steroid-refractory acute GVHD, a disease.

GVHD occurs in these individuals within weeks or months of receiving a stem cell transplant from a healthy donor, commonly known as an allogeneic stem cell transplant. The condition is resistant to steroids12.

During a transplant, the patient’s cells that have been destroyed by radiation therapy or chemotherapy are replaced with healthy stem cells from the donor.

However, in certain transplant recipients, the given cells assault the recipient’s cells, causing damage to the recipient’s tissues and organs, resulting in GVHD. A widespread rash, diarrhea, and liver damage are all symptoms of the disease.

Patients in the new REACH2 trial13 were given ruxolitinib or one of nine other regularly used therapies for steroid-refractory acute GVHD (control group).

Compared to the patients in the control group, more patients receiving ruxolitinib exhibited a full or partial response after 28 days of treatment (62 percent versus 39 percent ).

This disparity in response rates continued after 56 days of treatment, and the two groups’ side effects were similar.

Does Ruxolitinib Have Any Effect On Vitiligo?

Vitiligo is a chronic autoimmune illness14 that causes depigmentation of the skin and a lower quality of life.

There is no FDA-approved treatment for vitiligo repigmentation, and current off-label treatments are ineffective, highlighting the need for more therapeutic choices.

In a clinical trial, the therapeutic potential of ruxolitinib cream in vitiligo patients was searched and reported efficacy and safety data after 52 weeks of double-blind treatment.

Ruxolitinib (Opzelura; Incyte) cream, a topical Janise Kinase (JAK) inhibitor, has been approved by the European Medicines Agency (EMA)15 for the treatment of non-segmental vitiligo with facial involvement in patients aged 12 years and older.

More than 600 patients with vitiligo aged 12 and older participated in the clinical study16 program, which assessed the safety and efficacy of ruxolitinib cream.

The trials found that after 24 weeks of treatment with ruxolitinib cream, patients with vitiligo had significant improvements in facial and total body repigmentation.

According to the statement, patients using ruxolitinib cream had no clinically significant application site responses in the studies, and the overall safety profile was comparable with previous study findings.

Up to 52 weeks of treatment with ruxolitinib cream resulted in significant repigmentation of vitiligo lesions, and they tolerated all doses.

These findings17 imply that ruxolitinib cream could be a viable therapeutic option for vitiligo patients.

Is Ruxolitinib Having Any Impact on Hair Growth In Alopecia?

There are presently no universally effective or authorized therapies for alopecia areata (AA) by the US Food and Drug Administration.

Alopecia areata18 is a common dermatologic ailment that primarily affects preadolescent and adolescent children and significantly impacts their quality of life.

Recent research19 into the pathophysiology of alopecia areata has indicated that interferon-γ and interleukin 15 have a role in the disease’s progression.

 Many studies have shown a 50 percent or higher improvement in the Severity of Alopecia Tool score in one- to two-thirds of individuals treated with the JAKIs tofacitinib and ruxolitinib.

Although reactions in adults and adolescents have been studied, few research20 have looked at the effects of oral JAKI (tofacitinib) in preadolescents.

Oral ruxolitinib has been demonstrated to be effective in treating widespread AA. Ruxolitinib cream could help to prevent systemic side effects.

More than 600 patients with vitiligo aged 12 and older participated in the clinical study programme21, which assessed the safety and efficacy of ruxolitinib cream.

The trials found that after 24 weeks of treatment with ruxolitinib cream, patients with vitiligo had significant improvements in facial and total body repigmentation.

 Patients who used ruxolitinib cream had no clinically significant application site responses in the studies, and the overall safety profile was comparable with earlier research.

Adverse Impacts and Precautions to Handle the Adverse Effects of Ruxolitinib

A drug may have some undesired side effects in addition to its intended effects. Although not all of these side effects are likely to occur, medical treatment is necessary.

Your doctor must monitor your progress at frequent intervals to ensure that this treatment works appropriately. In the investigation of bad impacts, blood tests will be required. Consult your doctor if your problem does not improve after six months or worsens.

This medication reduces the quantity of certain blood cell22 types in your body. You may bleed or become infected due to this (e.g., herpes, tuberculosis, hepatitis B, progressive multifocal leukoencephalopathy, fungal infection).

While using this medication, stay away from being unwell or having infections.

Avoid hard sports and other circumstances where you can get bruised, cut, or hurt. Gently brush and floss your teeth. Exercise caution when utilizing sharp devices, such as razors and fingernail clippers.

This medication may increase your risk of developing progressive multifocal leukoencephalopathy, a dangerous brain infection.

Suppose you have weakness on one side of your body. In that case, loss of coordination, clumsiness, memory issues, trouble thinking clearly, or a loss of interest in activities, see your doctor straight once.

If you experience painful blisters on the trunk of your body, see your doctor right soon. These could be herpes zoster symptoms (shingles).

Someone must not stop using this medicine without first consulting their doctor. You may need to reduce your dose before totally discontinuing it gradually.

This may help prevent your illness from worsening and lessen the risk of withdrawal symptoms such a fever, chest tightness, difficulty breathing, lightheadedness, dizziness, or fainting.

This medication may increase your cancer risk (e.g., lymphoma, non-melanoma skin cancer). If you experience black, tarry stools, a general feeling of illness, swollen glands, weight loss, yellow skin and eyes, a prolonged non-healing sore, a reddish patch, or irritated skin, call your doctor immediately away.

This medication may increase your chances of developing significant heart or blood vessel problems, such as a heart attack or stroke.

If you have anxiety, chest pain, cough, dizziness, lightheadedness, or fainting, fast heartbeat, pain, redness, or swelling in the arm or leg, pains in the chest, groin, or legs, especially calves of the legs, severe headaches, or sudden dizziness, lightheadedness, or fainting, see your doctor right away.

While taking ruxolitinib, do not get any vaccinations or immunizations without consulting your doctor.

Before beginning this treatment, tell your doctor if you are pregnant or think you might be. C-category pregnancy (use in pregnancy only when benefit to the mother outweighs the risk to the fetus).

Both men and women should use the following opportunities: While taking ruxolitinib, do not conceive or become pregnant.

During treatment, barrier contraception like condoms is advised. Consult your doctor about when you might be able to get pregnant or have a child after treatment. While using this drug, you should not breastfeed.

The Bottom Line

Ruxolitinib, in the name of Jakafi, has proved an effective medicine. It has proved to be an important drug in various blood cancer disorders, alopecia, vitiligo, and acute graft versus host disease, along with significant results.

Anyhow, along with its significant role, it has shown a lot of adverse effects along with. It is important to consult your doctor properly before using this medicine.   

Ruxolitinib is available as a tablet that is swallowed. It’s commonly taken twice a day, with or without food. Every day, take ruxolitinib at the same time.

Follow the directions that are mentioned on your prescription label carefully, and if there is anything you don’t understand, ask your doctor or pharmacist to explain it to you.

Ruxolitinib should be taken exactly as prescribed. Please do not take more or less of it or take it more frequently than your doctor has suggested.

Ruxolitinib is a drug with much more potential, and further trials and investigations are needed to know its effectiveness.

References

1-Fleischmann, R. (2017). Small molecule immunosuppressants in inflammatory disease. In Comprehensive Medicinal Chemistry III (pp. 420–438). Elsevier.

2-PubChem. (n.d.). Ruxolitinib. Nih.Gov. Retrieved December 28, 2021.

3- Synthesis process of ruxolitinib (Patent No. 2017114461:A1). In World Patent (2017114461:A1),(2017).

4-(N.d.). Goodrx.Com. Retrieved December 28, 2021.

5-Jakafi® (ruxolitinib) Prescription Medicine. (n.d.). Jakafi.Com. Retrieved December 28, 2021,

6-Jakafi superior to standard treatment in polycythemia vera. (2016, June 21). Hematology-Oncology Associates of Fredericksburg.

7-Jakafi superior to standard treatment in polycythemia vera. (2016, June 21). Hematology-Oncology Associates of Fredericksburg

8-CancerConnect. (2019, December 7). Long-term survival in myelofibrosis improved with early use of Jakafi®. CancerConnect.

9-Keohane, C., & Harrison, C. (2012). Ruxolitinib for myelofibrosis. Clinical Investigation, 2(10), 1023–1031. https://doi.org/10.4155/cli.12.94

10-(N.d.-b). Cancerconnect.Com. Retrieved December 28, 2021.

11-NCI Dictionary of Cancer Terms. (2011, February 2). National Cancer Institute.

12-Blood-forming stem cell transplants. (2005, September 9). National Cancer Institute.

13-Zeiser, R., von Bubnoff, N., Butler, J., Mohty, M., Niederwieser, D., Or, R., Szer, J., Wagner,

E. M., Zuckerman, T., Mahuzier, B., Xu, J., Wilke, C., Gandhi, K. K., Socié, G., & REACH2 Trial Group. (2020). Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. The New England Journal of Medicine, 382(19), 1800–1810.

14-Rosmarin, D., Pandya, A. G., Lebwohl, M., Grimes, P., Hamzavi, I., Gottlieb, A. B., Butler, K., Kuo, F., Sun, K., Ji, T., Howell, M. D., & Harris, J. E. (2020). Ruxolitinib cream for the treatment of vitiligo: a randomized, controlled, phase 2 trial. Lancet, 396(10244), 110–120.

15-Incyte announces the validation of the European Marketing Authorization Application for ruxolitinib cream in vitiligo. (n.d.). Incyte.Com. Retrieved December 28, 2021, from

16-Linda Stocum, A. E. (2021, November 5). Ruxolitinib receives MMA validation from EMA for vitiligo. Dermatology Times.

17-Rosmarin, D., Pandya, A. G., Lebwohl, M., Grimes, P., Hamzavi, I., Gottlieb, A. B., Butler, K., Kuo, F., Sun, K., Ji, T., Howell, M. D., & Harris, J. E. (2020). Ruxolitinib cream for the treatment of vitiligo: a randomized, controlled, phase 2 trial. Lancet, 396(10244), 110–120.

18-Peterson, D. M., & Vesely, M. D. (2020). Successful treatment of alopecia totalis with ruxolitinib in a preadolescent patient. JAAD Case Reports, 6(4), 257–259.

19-Peterson, D. M., & Vesely, M. D. (2020). Successful treatment of alopecia totalis with ruxolitinib in a preadolescent patient. JAAD Case Reports, 6(4), 257–259.

20-Peterson, D. M., & Vesely, M. D. (2020). Successful treatment of alopecia totalis with ruxolitinib in a preadolescent patient. JAAD Case Reports, 6(4), 257–259.

21-Linda Stocum, A. E. (2021, November 5). Ruxolitinib receives MMA validation from EMA for vitiligo. Dermatology Times.

22-Ruxolitinib (oral route). (n.d.). Mayoclinic.Org. Retrieved December 28, 2021.

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