PF-04965842

PF 04965842, Abrocitinib

UNII: 73SM5SF3OR

CAS Number 1622902-68-4, Empirical Formula  C₁₄H₂₁N₅O₂S, Molecular Weight 323.41

N-[cis-3-(Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]-1-propanesulfonamide,

N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide

1-Propanesulfonamide, N-(cis-3-(methyl-7H-pyrrolo(2,3-d)pyrimidin-4-ylamino)cyclobutyl)-

N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide

PHASE 3, for the potential oral treatment of moderate-to-severe atopic dermatitis (AD)

Jak1 tyrosine kinase inhibitor

UPDATE…… JAPAN APPROVED, 2021, 2021/9/27, CIBINQO

ALSO

fda 2022, APPROVALS 2022, 1/14/2022

THE US

In February 2018, the FDA granted Breakthrough Therapy designation for the treatment of patients with moderate-to-severe AD

PHASEIII

In December 2017, a randomized, double-blind, placebo-controlled, parallel-group, phase III trial (NCT03349060; JADE Mono-1; JADE; B7451012; 2017-003651-29) of PF-04965842 began in patients aged 12 years and older (expected n = 375) with moderate-to-severe AD

PRODUCT PATENT

EXPIRY  Roughly 2034

Biochem/physiol Actions

• PF-04965842 is a Janus Kinase (JAK) inhibitor selective for JAK1 with an IC50value of 29 nM for JAK1 compared to 803 nM for JAK2, >10000 nM for JAK3 and 1250 nM for Tyk2. JAKs mediate cytokine signaling, and are involved in cell proliferation and differentiation. PF-04965842 has been investigated as a possible treatment for psoriasis.

• Originator Pfizer
• Class Skin disorder therapies; Small molecules
• Mechanism of Action Janus kinase 1 inhibitors

Highest Development Phases

• Phase IIIAtopic dermatitis
• DiscontinuedLupus vulgaris; Plaque psoriasis

Most Recent Events

• 08 Mar 2018Phase-III clinical trials in Atopic dermatitis (In children, In adults, In adolescents) in USA (PO) (NCT03422822)
• 14 Feb 2018PF 4965842 receives Breakthrough Therapy status for Atopic dermatitis in USA
• 06 Feb 2018Pfizer plans the phase III JADE EXTEND trial for Atopic Dermatitis (In children, In adults, In adolescents) in March 2018 (PO) (NCT03422822)

This compound was developed by Pfizer for Kinase Phosphatase Biology research. To learn more about Sigma′s partnership with Pfizer and view other authentic, high-quality Pfizer compounds,

PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for treatment of plaque psoriasis.

Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been i mplicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune d iseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer’s disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation , survival, apoptosis, mitogenesis, cell cycle control, and cel l mobility implicated in the aforementioned and related diseases.

Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play a central role in cytoki ne signaling (Kisseleva et al., Gene, 2002, 285 , 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include, the IFN family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL- 10, IL- 19, IL-20, IL-22), the gp 130 family (IL-6, IL- 11, OSM, LIF, CNTF, NNT- 1//SF-3, G-CSF, CT- 1, Leptin, IL- 12 , I L-23), gamma C family (IL-2 , I L-7, TSLP, IL-9, IL- 15 , IL-21, IL-4, I L- 13), IL-3 family (IL-3 , IL-5 , GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF- 1, HGF), and G-protein coupled receptors (ATI).

Abrocitinib, sold under the brand name Cibinqo, is a Janus kinase inhibitor medication used for the treatment of atopic dermatitis (eczema).^[2] It was developed by Pfizer.^[2]

Medical uses

Abrocitinib is indicated for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy.^[2]

Side effects

The most common adverse effects in studies were upper respiratory tract infection, headache, nausea, and diarrhea.^[3]

Pharmacology

Mechanism of action

It is a selective inhibitor of the enzyme janus kinase 1 (JAK1).^[3]

Pharmacokinetics

Abrocitinib is quickly absorbed from the gut and generally reaches highest blood plasma concentrations within one hour. Only 1.0 to 4.4% of the dose are found unmetabolized in the urine.^[4]

History

• April 2016: initiation of Phase 2b trial
• December 2017: initiation of JADE Mono-1 Phase 3 trial^[5]
• May 2018: Results of Phase 2b trial posted
• October 2019: Results of Phase 3 trial presented^[6]
• June 2020: Results of second Phase 3 trial published^[7]

Society and culture

Legal status

In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Cibinqo, intended for the treatment of atopic dermatitis.^[8] The applicant for this medicinal product is Pfizer Europe MA EEIG.^[8] In December 2021, the European Commission approved abrocitinib for the treatment of atopic dermatitis.^[2][9]

In January 2022, the United States Food and Drug Administration (FDA) approved abrocitinib for adults with moderate-to-severe atopic dermatitis.^[10]

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EU

Click to access cibinqo-epar-public-assessment-report_en.pdf

Introduction
The finished product is presented as immediate release film-coated tablets containing 50 mg, 100 mg
or 200 mg of abrocitinib as active substance.
Other ingredients are:
Tablet core: microcrystalline cellulose (E460i), anhydrous dibasic calcium phosphate (E341ii), sodium
starch glycolate and magnesium stearate (E470b).
Film-coat: hypromellose (E464), titanium dioxide (E171), lactose monohydrate, macrogol (E1521),
triacetin (E1518) and red iron oxide (E172).
The product is available in high-density polyethylene (HDPE) bottles with polypropylene closure or
polyvinylidene chloride (PVDC) blisters with aluminium foil lidding film, as described in section 6.5 of
the SmPC.

The chemical name of abrocitinib is N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclobutyl)propane-1-sulfonamide corresponding to the molecular formula C14H21N5O2S. It
has a relative molecular mass of 323.42 Daltons and the following structure depicted in Figure 1:

The chemical structure of abrocitinib was elucidated by a combination of UV/VIS and IR spectroscopy,
mass spectrometry, NMR spectroscopy and X-ray diffraction.
The active substance is a white to pale-purple or pale pink crystalline powder. It is non-hygroscopic
and its solubility is pH dependent. Abrocitinib is classified as BCS Class II. The impact of particle size
on finished product uniformity of dosage units and dissolution has been studied (see finished product
section). Based on the abrocitinib finished product biopharmaceutics performance, stability, and
manufacturing experience, the active substance particle size specification was established.
Abrocitinib is an achiral molecule, but with 2 stereocentres.
Only one crystalline anhydrous form (Form 1) of abrocitinib has been identified. This form has been the
only form used in all toxicology and clinical studies. Extensive polymorph and hydrate screening have
been conducted to investigate if additional solid forms of abrocitinib could be discovered. Abrocitinib,
Form 1 was the only anhydrous crystalline form identified from these studies. No new anhydrous
polymorphs, hydrates or amorphous solids of abrocitinib were isolated from these screens.
Experiments with 1,4 dioxane and dimethyl sulfoxide yielded solvated forms of abrocitinib. When these
solvated structures were subjected to high temperature, these materials desolvated and converted to
Form 1, free base anhydrous form of abrocitinib. However, these are not relevant since the commercial
crystallisation step does not utilise either of these solvent systems.
It has been confirmed that the manufacturing process consistently yields polymorphic form I. This form
is physically and chemically stable under normal manufacturing and storage conditions as well as
under accelerated conditions. Hence the absence of control of form I is justified.

FDA

U.S. FDA Approves Pfizer’s CIBINQO® (abrocitinib) for Adults with Moderate-to-Severe Atopic Dermatitis

https://www.pfizer.com/news/press-release/press-release-detail/us-fda-approves-pfizers-cibinqor-abrocitinib-adults

NEW YORK–(BUSINESS WIRE)– Pfizer Inc. (NYSE: PFE) announced today that the United States (U.S.) Food and Drug Administration (FDA) approved CIBINQO^® (abrocitinib), an oral, once-daily, Janus kinase 1 (JAK1) inhibitor, for the treatment of adults living with refractory, moderate-to-severe atopic dermatitis (AD) whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.

CIBINQO is approved at the recommended doses of 100 mg and 200 mg, with the 200 mg dose being recommended for patients who are not responding to the 100 mg dose. Additionally, a 50 mg dose was approved to treat moderate-to-severe AD specifically in patients with moderate renal impairment (kidney failure), certain patients receiving treatment with inhibitors of cytochrome P450 (CYP) 2C19, or patients who are known or suspected to be poor metabolizers of CYP2C19. For patients with moderate renal impairment who are not responding to 50 mg once daily, 100 mg once daily may also be prescribed.

“The reality for patients living with chronic inflammatory skin disease such as moderate-to-severe atopic dermatitis is that many experience debilitating symptoms that are not managed by current treatment options. Today’s approval of CIBINQO will provide an important new oral option that could help those who have yet to find relief,” said Jonathan Silverberg, MD, PhD, MPH, Department of Dermatology, The George Washington University School of Medicine and Health Sciences. “In multiple large-scale clinical trials, CIBINQO demonstrated strong efficacy at clearing skin, improving itch, and managing the extent and severity of eczema, offering a benefit-risk profile that supports the use of this treatment in the FDA-approved patient population.”

The FDA approval was based on results of five clinical trials from a large-scale clinical trial program of more than 1,600 patients. The safety and efficacy of CIBINQO was evaluated in three randomized, placebo-controlled, Phase 3 trials. Additionally, safety was evaluated through a randomized, placebo-controlled, dose-ranging trial and an ongoing long-term open-label extension trial. Across the trials, CIBINQO demonstrated a consistent safety profile and profound improvements in skin clearance, extent of disease, and severity, as well as rapid improvement in itch after two weeks, for some people living with AD versus placebo. In addition, a higher proportion of subjects treated with CIBINQO in two monotherapy trials achieved improvement in itching at week 12 compared to placebo.

“The FDA’s approval offers hope to the millions of patients across the U.S. who are suffering daily with an immuno-inflammatory condition that can cause intense and persistent itching, pain, discomfort, and distress if left uncontrolled,” said Mike Gladstone, Global President of Pfizer Inflammation & Immunology. “CIBINQO, an efficacious once-daily pill, is a medical breakthrough made possible by Pfizer researchers and the people living with moderate-to-severe atopic dermatitis who participated in our clinical trials.”

“Atopic dermatitis is so much more than just a rash, and it goes beyond the surface of the skin. It’s a chronic condition that can both significantly disrupt patients’ daily lives and negatively impact their emotional well-being,” said Julie Block, President and CEO, National Eczema Association. “We appreciate Pfizer’s commitment to this resilient patient community and eagerly await the positive impact CIBINQO could have on the treatment landscape for moderate-to-severe atopic dermatitis.”

The most common adverse events reported in ≥5% of patients with CIBINQO included nasopharyngitis (12.4% with CIBINQO 100 mg, 8.7% with CIBINQO 200 mg, and 7.9%, with placebo), nausea (6%, 14.5%, and 2.1%, respectively), and headache (6%, 7.8%, and 3.5%, respectively).

The full prescribing information for CIBINQO can be found here. CIBINQO will be made available in the coming weeks.

Additional Details on the CIBINQO Clinical Trial Program

Five clinical trials in the CIBINQO JAK1 Atopic Dermatitis Efficacy and Safety (JADE) global development program were included in the New Drug Application (NDA) to support the FDA approval.

The safety and efficacy of CIBINQO was evaluated in three Phase 3, randomized, placebo-controlled clinical trials. The trials evaluated measures of improvements in skin clearance, itch, disease extent, and severity, including the Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), and Peak Pruritus Numerical Ratings Scale (PP-NRS). In each of the trials, over 40% of patients had prior exposure to a systemic therapy:

• JADE MONO-1 and JADE MONO-2: A pair of randomized, double-blind, placebo-controlled trials designed to evaluate the efficacy and safety of two doses (100 mg and 200 mg once daily) of CIBINQO monotherapy in 778 patients 12 years of age and older with moderate-to-severe AD. The trials assessed the co-primary endpoints of IGA and EASI-75 responses at Week 12.
• JADE COMPARE: A randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of two doses (100 mg and 200 mg once daily) of CIBINQO in 837 adult patients with moderate-to-severe AD on background topical medicated therapy. The trial also included an active control arm with dupilumab, a biologic treatment administered by subcutaneous injection, compared with placebo. The trial assessed the co-primary endpoints of IGA and EASI-75 responses at Week 12.

Select findings for CIBINQO 100 mg, 200 mg, and placebo follow (*p<0.01 or **p<0.001):

• JADE MONO-1:
  • IGA Response Rate (Week 12): 24%*, 44%**, and 8%, respectively
  • EASI-75 Response Rate (Week 12): 40%**, 62%**, and 12%, respectively
• JADE MONO-2
  • IGA Response Rate (Week 12): 28%**, 38%**, and 9%, respectively
  • EASI-75 Response Rate (Week 12): 44%**, 61%**, and 10%, respectively
• JADE COMPARE
  • IGA Response Rate (Week 12): 36%**, 47%**, and 14%, respectively
  • EASI-75 Response Rate (Week 12): 58%**, 68%**, and 27%, respectively

Safety was additionally evaluated through a randomized dose-ranging trial and a long-term, open-label, extension trial (JADE EXTEND).

U.S. IMPORTANT SAFETY INFORMATION

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS

Serious Infections

Patients treated with CIBINQO may be at increased risk for developing serious infections that may lead to hospitalization or death. The most frequent serious infections reported with CIBINQO were herpes simplex, herpes zoster, and pneumonia.

If a serious or opportunistic infection develops, discontinue CIBINQO and control the infection.

Reported infections from Janus kinase (JAK) inhibitors used to treat inflammatory conditions:

• Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative, latent TB test.
• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
• Bacterial, viral (including herpes zoster), and other infections due to opportunistic pathogens.

Avoid use of CIBINQO in patients with an active, serious infection, including localized infections. The risks and benefits of treatment with CIBINQO should be carefully considered prior to initiating therapy in patients with chronic or recurrent infections or those who have resided or traveled in areas of endemic tuberculosis or endemic mycoses.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIBINQO, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Consider yearly screening for patients in highly endemic areas for TB. CIBINQO is not recommended for use in patients with active TB. For patients with a new diagnosis of latent TB or prior untreated latent TB, or for patients with a negative test for latent TB but who are at high risk for TB infection, start preventive therapy for latent TB prior to initiation of CIBINQO.

Viral reactivation, including herpes virus reactivation (eg, herpes zoster, herpes simplex), was reported in clinical studies with CIBINQO. If a patient develops herpes zoster, consider interrupting CIBINQO until the episode resolves. Hepatitis B virus reactivation has been reported in patients receiving JAK inhibitors. Perform viral hepatitis screening and monitoring for reactivation in accordance with clinical guidelines before starting therapy and during therapy with CIBINQO. CIBINQO is not recommended for use in patients with active hepatitis B or hepatitis C.

Mortality

In a large, randomized postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blocker treatment, a higher rate of all-cause mortality (including sudden cardiovascular death) was observed with the JAK inhibitor. CIBINQO is not approved for use in RA patients.

Malignancies

Malignancies, including non-melanoma skin cancer (NMSC), were reported in patients treated with CIBINQO. Lymphoma and other malignancies have been observed in patients receiving JAK inhibitors used to treat inflammatory conditions. Perform periodic skin examination for patients who are at increased risk for skin cancer. Exposure to sunlight and UV light should be limited by wearing protective clothing and using broad-spectrum sunscreen.

In a large, randomized postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. CIBINQO is not approved for use in RA patients. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers.

Major Adverse Cardiovascular Events

Major adverse cardiovascular events were reported in patients treated with CIBINQO. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), was observed when compared with TNF blockers. CIBINQO is not approved for use in RA patients. Patients who are current or past smokers are at additional increased risk. Discontinue CIBINQO in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.

Thrombosis

Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients treated with CIBINQO. Thrombosis, including PE, DVT, and arterial thrombosis have been reported in patients receiving JAK inhibitors used to treat inflammatory conditions. Many of these adverse reactions were serious and some resulted in death. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of overall thrombosis, DVT, and PE were observed when compared with TNF blockers. CIBINQO is not approved for use in RA patients.

Avoid CIBINQO in patients that may be at increased risk of thrombosis. If symptoms of thrombosis occur, discontinue CIBINQO and treat patients appropriately.

Contraindication

CIBINQO is contraindicated in patients taking antiplatelet therapies, except for low-dose aspirin (≤81 mg daily), during the first 3 months of treatment.

Laboratory Abnormalities

Hematologic Abnormalities: Treatment with CIBINQO was associated with an increased incidence of thrombocytopenia and lymphopenia. Prior to CIBINQO initiation, perform a complete blood count (CBC). CBC evaluations are recommended at 4 weeks after initiation and 4 weeks after dose increase of CIBINQO. Discontinuation of CIBINQO therapy is required for certain laboratory abnormalities.

Lipid Elevations: Dose-dependent increase in blood lipid parameters were reported in patients treated with CIBINQO. Lipid parameters should be assessed approximately 4 weeks following initiation of CIBINQO therapy, and thereafter patients should be managed according to clinical guidelines for hyperlipidemia. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Immunizations

Prior to initiating CIBINQO, complete all age-appropriate vaccinations as recommended by current immunization guidelines, including prophylactic herpes zoster vaccinations. Avoid vaccination with live vaccines immediately prior to, during, and immediately after CIBINQO therapy.

Renal Impairment

Avoid use in patients with severe renal impairment or end stage renal disease, including those on renal replacement therapy.

Hepatic Impairment

Avoid use in patients with severe hepatic impairment.

Adverse Reactions

Most common adverse reactions (≥1%) in subjects receiving 100 mg and 200 mg include: nasopharyngitis, nausea, headache, herpes simplex, increased blood creatinine phosphokinase, dizziness, urinary tract infection, fatigue, acne, vomiting, oropharyngeal pain, influenza, gastroenteritis.

Most common adverse reactions (≥1%) in subjects receiving either 100 mg or 200 mg also include: impetigo, hypertension, contact dermatitis, upper abdominal pain, abdominal discomfort, herpes zoster, and thrombocytopenia.

Use in Pregnancy

Available data from pregnancies reported in clinical trials with CIBINQO are not sufficient to establish a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise females of reproductive potential that CIBINQO may impair fertility.

There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIBINQO during pregnancy. Pregnant women exposed to CIBINQO and health care providers are encouraged to call 1-877-311-3770.

Lactation

Advise women not to breastfeed during treatment with CIBINQO and for one day after the last dose.

Indication

CIBINQO is indicated for the treatment of adults with refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.

Limitations of Use: CIBINQO is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants.

About CIBINQO^® (abrocitinib)

CIBINQO is an oral small molecule that selectively inhibits Janus kinase (JAK) 1. Inhibition of JAK1 is thought to modulate multiple cytokines involved in pathophysiology of AD, including interleukin IL-4, IL-13, IL-31, IL-22, and thymic stromal lymphopoietin (TSLP).

In addition to receiving regulatory approval in the U.S., CIBINQO has received marketing authorization in the European Union, Great Britain, Japan, Korea, the United Arab Emirates, Norway, Iceland, and Singapore.

About Atopic Dermatitis

AD is a chronic skin disease characterized by inflammation of the skin and skin barrier defects.^i,ii Most people know AD is a skin condition. But many don’t realize it can be caused in part by an abnormal immune response beneath the skin. This dysregulated immune response is thought to contribute to inflammation within the skin and the signs of AD on the surface. Lesions of AD are characterized by erythema (red/pink or discolored skin patches, depending on normal skin color), itching, lichenification (thick/leathery skin), induration (hardening)/papulation (formulation of papules), and oozing/crusting.^i,ii

AD is one of the most common inflammatory skin diseases, affecting approximately 5-10% of adults in the U.S.^iii,iv Approximately 1 in 3 adults with AD have moderate-to-severe disease.^v,vi

About Pfizer Inflammation & Immunology

At Pfizer Inflammation & Immunology, we strive to deliver breakthroughs that enable freedom from day-to-day suffering for people living with autoimmune and chronic inflammatory diseases, which can be debilitating, disfiguring and distressing, dramatically affecting what they can do. With a focus on immuno-inflammatory conditions in Rheumatology, Gastroenterology and Medical Dermatology, our current portfolio of approved medicines and investigational molecules spans multiple action and delivery mechanisms, from topicals to small molecules, biologics and biosimilars. The root cause of many immunological diseases is immuno-inflammation, which requires specifically designed agents. Our differentiated R&D approach resulted in one of the broadest pipelines in the industry, where we purposefully match molecules to diseases where we believe they can make the biggest difference. Building on our decades-long commitment and pioneering science, we continue to advance the standard of care for patients living with immuno-inflammatory diseases and are working hand-in-hand with patients, caregivers and the broader healthcare community on healthcare solutions for the many challenges of managing chronic inflammatory diseases, allowing patients to live their best lives.

Pfizer Inc.: Breakthroughs that Change Patients’ Lives

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety, and value in the discovery, development, and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments, and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments, and local communities to support and expand access to reliable, affordable health care around the world. For more than 170 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.

There remains a need for new compounds that effectively and selectively inhibit specific JAK enzymes, and JAK1 in particular, vs. JAK2. JAK1 is a member of the Janus family of protein kinases composed of JAK1, JAK2, JAK3 and TYK2. JAK1 is expressed to various levels in all tissues. Many cytokine receptors signal through pairs of JAK kinases in the following combinations: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2 , JAK2/TYK2 or JAK2/JAK2. JAK1 is the most broadly

paired JAK kinase in this context and is required for signaling by γ-common (IL-2Rγ) cytokine receptors, IL—6 receptor family, Type I, II and III receptor families and IL- 10 receptor family. Animal studies have shown that JAK1 is required for the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK1 kinase activity can prove useful in the treatment of various immune disorders (Murray, P.J.

J. Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285 , 1-24 (2002); O’Shea, J . J., et al., Ceil , 109, (suppl .) S121-S131 (2002)) while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer H., et al., Cell, 93(3), 397-409 (1998);

Parganas E., et al., Cell, 93(3), 385-95 (1998)).

Tofacitinib (1), baricitinib (2), and ruxolitinib (3)

SYNTHESIS 5+1 =6 steps

Main synthesis

Journal of Medicinal Chemistry, 61(3), 1130-1152; 2018

INTERMEDIATE

CN 105732637

ONE STEP

CAS 479633-63-1,  7H-Pyrrolo[2,3-d]pyrimidine, 4-chloro-7-[(4- methylphenyl)sulfonyl]-

• Originator Pfizer
• Class Anti-inflammatories; Antipsoriatics; Pyrimidines; Pyrroles; Skin disorder therapies; Small molecules; Sulfonamides
• Mechanism of Action Janus kinase 1 inhibitors

• Phase III Atopic dermatitis
• Discontinued Lupus vulgaris; Plaque psoriasis

• 21 May 2019Pfizer initiates enrolment in a phase I trial in Healthy volunteers in USA (PO) (NCT03937258)
• 09 May 2019 Pfizer plans a phase I pharmacokinetic and drug-drug interaction trial in healthy volunteers in May 2019 (NCT03937258)
• 30 Apr 2019 Pfizer completes a phase I trial (In volunteers) in USA (PO) (NCT03626415)

References[

External links

• “Abrocitinib”. Drug Information Portal. U.S. National Library of Medicine.
• Clinical trial number NCT03349060 for “Study to Evaluate Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-1)” at ClinicalTrials.gov
• Clinical trial number NCT03575871 for “Study Evaluating Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-2)” at ClinicalTrials.gov
• {{ClinicalTrialsGov|NCT03720470|Study Evaluating Efficacy and Safety of PF-04965842 and Dupilumab in Adult Subjects With Moderate to Severe Atopic Dermatitis on Background Topical Therapy (JADE Compare)}

Abrocitinib

Clinical data
Trade names	Cibinqo
Other names	PF-04965842
License data	EU EMA: by INN US DailyMed: Abrocitinib
Routes of administration	By mouth
ATC code	D11AH08 (WHO)
Legal status
Legal status	US: ℞-only [1] EU: Rx-only [2]
Pharmacokinetic data
Elimination half-life	2.8–5.2 h
Excretion	1.0–4.4% unchanged in urine
Identifiers
CAS Number	1622902-68-4
PubChem CID	78323835
DrugBank	DB14973
ChemSpider	68006894
UNII	73SM5SF3OR
KEGG	D11400
ChEMBL	ChEMBL3655081
ECHA InfoCard	100.251.498
Chemical and physical data
Formula	C14H21N5O2S
Molar mass	323.42 g·mol−1
3D model (JSmol)	Interactive image
show SMILES

/////////PF 04965842, Abrocitinib, Phase III,  Atopic dermatitis, pfizer, fda 2022, APPROVALS 2022

CCCS(=O)(N[C@H]1C[C@@H](N(C)C2=C3C(NC=C3)=NC=N2)C1)=O

CCCS(=O)(=O)N[C@@H]1C[C@@H](C1)N(C)c2ncnc3[nH]ccc23

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