ropsacitinib (PF-06826647) / Pfizer, Priovant Therap - LARVOL DELTA

A systematic review of the efficacy of TYK2 inhibitors in patients with dermatological disease. (PubMed, Australas J Dermatol) - "Results indicate that Deucravacitinib is superior to placebo, Apremilast and Adalimumab in treating adult patients with moderate-to-severe plaque psoriasis and superior to placebo in the treatment of adults with systemic lupus erythematosus. Ropsacitinib demonstrated superiority over placebo in the management of plaque psoriasis. Brepocitinib and Ropsacitinib had more side effects than Deucravacitinib."

Journal • Review • Alopecia • Atopic Dermatitis • Dermatitis • Dermatology • Hidradenitis Suppurativa • Immunology • Inflammatory Arthritis • Lupus • Psoriasis • Systemic Lupus Erythematosus • TYK2

A Systematic Review of Pharmacological Interventions for Hidradenitis Suppurativa: A Focus on Clinical Response, Quality of Life, and Safety (ISPOR-EU 2024) - "Adalimumab, anakinra, apremilast, avacopan, bimekizumab, doxycycline, guselkumab, IFX-1, MABp1, PF-06650833, PF-06700841, PF-06826647, povorcitinib, risankizumab, RIST4721, secukinumab, upadacitinib all reported notable clinical benefits, with Hidradenitis Suppurativa Clinical Response (HiSCR) ranged from 10% (anakinra at week 24) to 88% (povorcitinib-90 mg at week 8)...In contrast, no SAEs were detected in spesolimab or anakinra, while bimekizumab had similar safety profiles to adalimumab. The results of this review demonstrate the possibility of highly personalized treatment approaches for HS management, including adalimumab and povorcitinib. The optimization of HS care requires further research on long-term outcomes."

Clinical • HEOR • Review • Dermatology • Hidradenitis Suppurativa • Immunology • Pain

Therapeutic Potential of Targeting the JAK/STAT Pathway in Psoriasis: Focus on TYK2 Inhibition. (PubMed, J Clin Med) - "New molecules are currently under investigation for the treatment of psoriasis, such as deucravacitinib, an oral selective inhibitor that binds to the regulatory domain of TYK2, brepocitinib (PF-06700841) and PF-06826647 that bind to the active site in the catalytic domain. Due to the selective TYK2 blockade allowing the inhibition of key cytokine-mediated signals, such as those induced by IL-12 and IL-23, anti-TYK2 agents appear to be very promising as the safety profile seems to be superior compared with pan-JAK inhibitors. The aim of our review is to thoroughly explore the rationale behind the usage of JAK inhibitors in PsO, their efficacy and safety profiles, with a special focus on oral TYK2 inhibitors, as well as to provide a forward-looking update on novel therapeutic strategies targeting the TYK2 pathway in psoriasis."

Journal • Review • Cardiovascular • Dermatology • Immunology • Infectious Disease • Oncology • Psoriasis • Venous Thromboembolism • IL12A • IL23A • TYK2

TYK2: an emerging therapeutic target in rheumatic disease. (PubMed, Nat Rev Rheumatol) - "Various inhibitors of TYK2 have now been studied in human disease, and one of these inhibitors, deucravacitinib, has now been approved for the treatment of psoriasis. Two other inhibitors of TYK2, brepocitinib and ropsacitinib, are also in earlier stages of clinical trials. Overall, TYK2 inhibitors hold promise for the treatment of a distinct spectrum of autoimmune diseases and could potentially have a safety profile that differs from other JAK inhibitors."

Journal • Review • Dermatology • Dermatomyositis • Immunology • Inflammatory Arthritis • Lupus • Myositis • Psoriasis • Psoriatic Arthritis • Rheumatology • Seronegative Spondyloarthropathies • Systemic Lupus Erythematosus • IL10 • IL12A • IL23A • JAK1 • JAK2 • JAK3 • TYK2

Brepocitinib, Zimlovisertib, and Ropsacitinib in Hidradenitis Suppurativa. (PubMed, NEJM Evid) - "At 16 weeks, only brepocitinib, a JAK1/TYK2 inhibitor, achieved a higher clinical response than placebo (52% vs. 33%). The other two agents were no better than placebo."

Journal • Dermatology • Hidradenitis Suppurativa • Immunology • JAK1 • TYK2

Oral small-molecule tyrosine kinase 2 and phosphodiesterase 4 inhibitors in plaque psoriasis: a network meta-analysis. (PubMed, Front Immunol) - "The study found that deucravacitinib at any dose (except for 3 mg QOD), ropsacitinib (200 and 400 mg QD), and apremilast (20 and 30 mg BID) had higher PASI and PGA response rates than placebo. More large-scale, long-term studies focusing on novel TYK2 inhibitors are needed. PROSPERO (ID: CRD42022384859), available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022384859, identifier CRD42022384859."

Clinical • Retrospective data • Review • Dermatology • Immunology • Psoriasis • TYK2

Development and Therapeutic Implications of Tyrosine Kinase 2 Inhibitors. (PubMed, J Med Chem) - "Substantial efforts have been made to develop selective TYK2 inhibitors: Deucravacitinib (BMS-986165) is a representative allosteric inhibitor that has been approved by the FDA, and ropsacitinib (PF-06826647) is an active site-directed inhibitor currently being evaluated in clinical trials. Herein, we outline the key roles of TYK2 in diseases, review the advances of selective TYK2 inhibitors, and finally discuss future perspectives and challenges in the development of TYK2 inhibitors."

Journal • Review • Immunology • TYK2

Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors. (PubMed, Dermatol Ther (Heidelb)) - "Two other tyrosine kinase 2 inhibitors in later stage clinical development, brepocitinib (PF-06700841) and ropsacitinib (PF-06826647), are orthosteric inhibitors that target the highly conserved catalytic domain. Two phase 3 psoriasis trials demonstrated deucravacitinib was efficacious and not associated with safety concerns characteristic of Janus kinase inhibitors, hence the new class designation (TYK2 inhibitor) by health authorities in the USA and Japan. Allosteric tyrosine kinase 2 inhibitors represent a promising new class of molecules for the treatment of psoriasis and psoriatic arthritis, and longer-term trials will establish their place in therapy."

Journal • Review • Dermatology • Immunology • Inflammatory Arthritis • Psoriasis • Psoriatic Arthritis • Pustular Psoriasis • Rheumatology • Seronegative Spondyloarthropathies • IL17A • TYK2

Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway. (PubMed, J Cutan Med Surg) - "Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors."

Journal • Dermatology • Immunology • Inflammation • Psoriasis • IL12A • IL17A • IL23A • JAK1 • TYK2

Tyrosine Kinase 2 and Janus Kinase‒Signal Transducer and Activator of Transcription Signaling and Inhibition in Plaque Psoriasis. (PubMed, J Am Acad Dermatol) - "Deucravacitinib, an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and PF-06826647, topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews JAK-STAT and TYK2 signaling, and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors."

Journal • Review • Dermatology • Gastrointestinal Disorder • Immunology • Inflammation • Psoriasis • IFNAR2 • JAK1 • TYK2

Efficacy and Safety of Oral Tyrosine Kinase 2 Inhibitor PF-06826647 in Managing Moderate to Severe Plaque Psoriasis (PracticeUpdate) - "In the quest to have a more perfect drug to treat our psoriasis patients, a new mechanism of action-the inhibition of the tyrosine kinase pathway-is being explored...Our patients will need to let us know how they feel about switching to an oral agent with comparable efficacy to some of our biologics, but one that requires daily administration and carries some possible side-effect risks. Psoriasis patients will at the very least appreciate the additional option."

Online posting

From Pfizer and Roivant was born Priovant Therapeutics, specialized in anti-inflammatory drugs [Google translation] (Daily Health Industry) - "Pfizer and Roivant Sciences formed Priovant Therapeutics, an anti-inflammatory drug development company. The new biotech will initially promote two Pfizer treatments for autoimmune diseases: big pharma USA will own 25% of Priovant. The first drug from Pfizer is brepocitinib...The second drug under the agreement, ropsacitinib, is an anti-inflammatory that targets the TYK2 protein."

M&A • Immunology • Inflammatory Bowel Disease

Real Promise for JAK-inhibitors That Target TYK2 (MedPageToday) - "Andrew Blauvelt, MD, MBA...Blauvelt recently discussed the review and its findings with the Reading Room. The exchange has been edited for length and clarity....Blauvelt: Deucravacitinib (an oral once-daily pill) is the TYK2 blocker that is farthest along in clinical development and will likely be approved by the FDA within the next year. More TYK2 blockers are in the pipeline, including topical TYK2."

Media quote

Oral tyrosine kinase 2 inhibitor PF-06826647 demonstrates efficacy and an acceptable safety profile in participants with moderate-to-severe plaque psoriasis in a phase 2b, randomized, double-blind, placebo-controlled study. (PubMed, J Am Acad Dermatol) - P2 | "PF-06826647 200 and 400 mg QD showed significant efficacy versus placebo at week 16 and was well tolerated over 40 weeks."

Clinical • Journal • P2b data • Dermatology • Immunology • Psoriasis • TYK2

A Study to Evaluate the Safety and Efficacy of PF-06650833, PF-06700841, and PF 06826647 in Adults With Hidradenitis Suppurativa (clinicaltrials.gov) - P2a | N=197 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed

Trial completion • Acne Vulgaris • Dermatology • Hidradenitis Suppurativa

[VIRTUAL] A Phase 2b, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of the oral TYK2 inhibitor PF-06826647 in participants with plaque psoriasis (EADV 2021) - No abstract available

Clinical • P2b data • Dermatology • Immunology • Psoriasis • TYK2

A Study to Evaluate the Safety and Efficacy of PF-06650833, PF-06700841, and PF 06826647 in Adults With Hidradenitis Suppurativa (clinicaltrials.gov) - P2a; N=192; Active, not recruiting; Sponsor: Pfizer; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Acne Vulgaris • Dermatology • Hidradenitis Suppurativa

Selective Tyrosine Kinase 2 Inhibition for Treatment of Inflammatory Bowel Disease: New Hope on the Rise. (PubMed, Inflamm Bowel Dis) - "Deucravacitinib, a novel, oral, selective TYK2 inhibitor, and brepocitinib and PF-06826647, TYK2 inhibitors that bind to the active site in the catalytic domain, are in development for IBD and other immune-mediated inflammatory diseases. Allosteric TYK2 inhibition is more selective than JAK1-3 inhibition and has the potential to limit toxicities typically associated with JAK1-3 inhibitors. Future studies will be important in establishing the role of selective, allosteric TYK2 inhibition in the management of IBD."

Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IFNAR2 • IL12A • JAK1 • TYK2

TYK 2 inhibitors for the treatment of dermatologic conditions: the evolution of JAK inhibitors. (PubMed, Int J Dermatol) - "Three key TYK2 inhibitors that have advanced furthest in clinical trials for treatment of dermatologic autoimmune conditions are deucravacitinib (BMS-986165), brepocitinib (PF-06700841), and PF-06826647. This review outlines the current understanding of the efficacy and safety of these three TYK2 inhibitors from completed phase I and II studies and summarizes studies currently in progress for dermatologic conditions."

Journal • Review • Dermatology • Immunology • JAK2 • JAK3 • TYK2

A Study To Asses Mass Balance And Absolute Bioavailability Of 14C PF-06826647 In Healthy Male Participants (clinicaltrials.gov) - P1; N=6; Completed; Sponsor: Pfizer; Recruiting ➔ Completed

Clinical • Trial completion

A Study To Asses Mass Balance And Absolute Bioavailability Of 14C PF-06826647 In Healthy Male Participants (clinicaltrials.gov) - P1; N=6; Recruiting; Sponsor: Pfizer; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

A Study To Evaluate The Safety And Efficacy Of PF-06826647 In Participants With Moderate To Severe Ulcerative Colitis (clinicaltrials.gov) - P2b; N=0; Withdrawn; Sponsor: Pfizer; N=202 ➔ 0; Recruiting ➔ Withdrawn

Clinical • Enrollment change • Trial withdrawal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

A Study to Evaluate Safety and Efficacy of PF-06826647 For Moderate To Severe Plaque Psoriasis (clinicaltrials.gov) - P2; N=179; Completed; Sponsor: Pfizer; Active, not recruiting ➔ Completed

Clinical • Trial completion • Dermatology • Immunology • Psoriasis

Safety and Pharmacokinetics of the Oral TYK2 Inhibitor PF-06826647: A Phase I, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study. (PubMed, Clin Transl Sci) - P1 | "PF-06826647 was rapidly absorbed with a median time to maximum plasma concentration of 2 hours in a fasted state, with modest accumulation (< 1.5-fold) after multiple dosing and low urinary recovery. PF-06826647 was well-tolerated, with an acceptable safety profile for doses up to 1,200 mg q.d. for 10 days, supporting further testing in patients."

Clinical • Journal • PK/PD data • TYK2

[VIRTUAL] A phase 1 study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of the oral TYK2 inhibitor PF-06826647 in participants with plaque psoriasis (EADV 2020) - No abstract available

Clinical • P1 data • PK/PD data • Dermatology • Immunology • Psoriasis • TYK2