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Opzelura® (ruxolitinib) cream mechanism of action

Opzelura® is indicated for the treatment of non-segmental vitiligo with facial involvement in adults and adolescents from 12 years of age1

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Opzelura® is a Janus kinase (JAK) inhibitor1,2

Janus kinase (JAK) inhibitors are a class of targeted drugs that inhibit the activity of the JAK family of enzymes, interfering with the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signalling pathway. As the JAK-STAT pathway drives the pathogenesis of vitiligo, JAK inhibitors are an ideal therapeutic option for patients with non-segmental vitiligo.3

Opzelura® is the first and only approved topical JAK1/2 inhibitor for non-segmental vitiligo.1,2

Role of the JAK-STAT pathway

The JAK-STAT pathway facilitates signalling from the cell membrane to the nucleus, inducing the expression of a host of vital regulators in the inflammatory response.4

Over 50 cytokines and growth factors are recognised in the JAK-STAT signalling cascade, with JAK-STAT-mediated downstream events including immune cell development, inflammatory responses, haematopoiesis, tissue regeneration and a host of other physiological processes. Loss or mutant components of the pathway are related to many human diseases; namely malignancies and autoimmune diseases.4

The JAK-STAT pathway plays a critical role in immune regulation, mediating the effect of various cytokines on different immune cells. From fighting infection, maintaining immune tolerance and preventing cancer, the pathway has a host of different functions in the immune system.5

The JAK-STAT pathway and vitiligo

The pathogenesis of vitiligo can be summarised into three stages3,6–11

The pathogenesis of vitiligo can be summarised into three stages

THE JAK-STAT PATHWAY FUELS VITILIGO PROGRESSION AND PERSISTENCE3,6

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JAK-STAT pathway: progression and persistence of vitiligo further explained

The interferon-gamma (IFN-ɣ)-chemokine axis is central to the pathogenesis of vitiligo. IFN-ɣ is the key cytokine produced by CD8 + T cells. Being a type II interferon, IFN-ɣ activates the JAK/STAT1 pathway by binding to its cell-surface receptor (IFN-ɣR), specifically to interferon-gamma receptor 1 and 2 (IFNGR1/2).13 These subunits (IFNGR1/2) are associated with both JAK1 and JAK2 and the binding of these subunits leads to the phosphorylation of STAT1, which initiates gene transcription. 14

T cell chemokine receptor CXCR3 and its multiple ligands (CXCL9, CXCL10) are specifically upregulated in depigmented skin lesions.7,13 Moreover, CXCL10 recruits T cells within the skin through the CXCR3 receptor, prolonging and exacerbating the established vitiligo lesion.13

Opzelura® facilitates repigmentation in vitiligo1

As IFN-ɣ binds to JAK1/2-related receptors, the inhibition of JAK1/2 provides a potentially powerful therapeutic target for the treatment of vitiligo.13 The mechanism of action for Opzelura®, a selective JAK1 and JAK2 inhibitor, involves inhibiting IFN-ɣ-mediated JAK-STAT signalling.

With Opzelura®, a topical JAK inhibitor, quality repigmentation can be facilitated in three stages:7

Halt depigmentation icon
Halt depigmentation diagram
Induce repigmentation icon
Induce repigmentation diagram
Induce repigmentation icon
Prevent relapse diagram

Halting depigmentation

In the disease state, IFN-ɣ-mediated JAK-STAT signalling perpetuates an inflammatory cycle and a hostile immune microenvironment whereby CD8+ T cells target melanocytes for degradation.3 These melanocyte-destroying CD8+ T cells also release IFN-ɣ, activating the JAK-STAT pathway in keratinocytes.3 Subsequently, this leads to CXCL9 and CXCL10 production.7 Together these signals and chemokines attract autoreactive CD8+ T cells to the site, initiating further melanocyte destruction through a positive feedback loop.7

To halt depigmentation, Opzelura® inhibits IFN-ɣ-driven JAK-STAT signalling by selectively binding to ATP-binding pockets on JAK1 and JAK2 enzymes.16 Such binding to JAK1 and JAK2 is thought to result in fewer CD8+ T cell-destroying melanocytes, and thus a more stable environment to enable continuous melanocyte return.3,16

The TRuE-V1 and TRuE-V2 studies, which included patients aged 12 years of age or older with non-segmental vitiligo, showed favourable results for patients with depigmentation covering 10% or less of total body surface area (BSA). After 52 weeks, 1 in 2 patients (91/173) achieved a 75% improvement in facial repigmentation according to the Vitiligo Area Scoring Index (VASI).17

Inducing repigmentation

Melanocytes induce repigmentation by repopulating the lesion from the hair follicles and lesion borders over time.15 Repigmentation is an active process reversing the loss of epidermal melanocytes and usually develops in hair-bearing areas. The hair follicle is the main source of pigment cells and is considered an immunoprivileged zone not vulnerable to cytotoxic CD8+ T cell attack.15

With the ongoing use of Opzelura®, sustained JAK1 inhibition interrupts interleukin-15 (IL-15) signalling by binding JAK1. IL-15 is an important cytokine for memory CD8+ T cell function in various autoimmune diseases; inhibiting JAK reduces effector memory CD8+ T cell activity, allowing the return of melanocytes.6

Clinical trials have seen favourable repigmentation results: at Week 52 in the TRuE-V1 study, 1 in 3 patients (n=82) achieved 90% or greater facial repigmentation, with 15.3% showing a F-VASI90 response at Week 24 vs 2.2% with vehicle.17

Preventing relapse

Sustained use of Opzelura® and subsequent inhibition of JAK1 interrupts IL-15 signalling and reduces effector memory CD8+ T cell activity which is hypothesised to prevent relapse.6,12

Relapse is often observed during the first year after halting treatment due to the presence of resident memory CD8+ T cells (which can express CXCR3, IFN-ɣ and TNF-α), leading to the recruitment of CD8+ T cell, which continue destroying melanocytes.18

The TRuE-V1 and TRuE-V2 studies achieved the primary endpoint and showed a significant improvement in F-VASI75 at Week 24 with Opzelura® (66/221) vs vehicle cream (8/109) with further improvements with continued use (P<0.001). Long-term extension (LTE) data built on the previous studies and found that ≥75% facial repigmentation was achieved by ~1 in 2 patients (91/173) who used Opzelura® at Week 52 compared to baseline.17

Many patients that achieved a high level of facial repigmentation (≥F-VASI90) at Week 52 from the TRuE V1 and TRuE V2 studies maintained a durable response one year following the withdrawal of treatment.19,20

Opzelura® is contraindicated during pregnancy and breastfeeding.

Abbreviations

BSA, body-surface area; CD8+, cluster of differentiation 8 positive; CXCR3, chemokine receptor 3; CXCL9/10, C-X-C motif chemokine ligand 9/10; F-VASI, Facial Vitiligo Area Scoring Index; IFN-ɣ, interferon-gamma; IFN-ɣR, interferon-gamma receptor; IFNGR1/2, interferon-gamma receptor 1 and 2; IL-15, interleukin 15; JAK, Janus kinase; JAK-STAT, Janus kinase/signal transducer and activator of transcription; LTE, long-term extension; NK cell, natural killer cell; TNF-α, tumour necrosis factor-α; TRuE-V, topical ruxolitinib evaluation in vitiligo study; VASI, Vitiligo Area Scoring index.

References

  1. Opzelura® (ruxolitinib cream) Summary of Product Characteristics. Incyte Biosciences UK Ltd. November 2023.
  2. Hospital Pharmacy Europe. Ruxolitinib cream gains MHRA approval for non-segmental vitiligo. Available at: https://hospitalpharmacyeurope.com/clinical-zones/dermatology/ruxolitinib- cream-gains-mhra-approval-for-non-segmental-vitiligo/ (Accessed March 2024).
  3. Strassner JP, et al. Curr Opin Immunol. 2016;43:81–88.
  4. Hu X, et al. Signal Transduct Target Ther. 2021;6(1):402.
  5. Hu Q, et al. Front Bioeng Biotechnol. 2023;11:1110765.
  6. Chen X, et al. Free Radic Biol Med. 2019;139:80–91.
  7. Frisoli ML, et al. Annu Rev Immunol. 2020;38:621–648.
  8. Richmond JM, et al. Curr Opin Immunol. 2013;25(6):676–682.
  9. Howell MD, et al. Front Immunol. 2019;10:2342.
  10. Rashighi M, et al. Dermatol Clin. 2017;35(2): 257–265.
  11. Rosmarin D, et al. Lancet. 2020;396(10244):110–120.
  12. Nolz JC, et al. Mol Immunol. 2020;117:180-188.
  13. Qi F, et al. Front Immunol. 2021;12:790125.
  14. Platanias LC. Nat Rev Immunol. 2005;5(5):375–386.
  15. Birlea SA, et al. Dermatol Clin. 2017;35(2):205–218.
  16. Lin CM, et al. Mediterr J Rheumatol. 2020;31(Suppl 1):100–104.
  17. Rosmarin D, et al. N Engl J Med. 2022;387(16):1445–1455.
  18. Riding RL, et al. J Immunol. 2019;203(1):11–19.
  19. Harris JE, et al. Presented at American Academy of Dermatology 2023. Late-breaker presentation.
  20. Data featured as oral presentations in two late-breaking abstract sessions at the 2023 American Academy of Dermatology (AAD) Annual Meeting.

UNITED KINGDOM
Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to Incyte immediately by calling 03301003677 (Great Britain) 00-800-0002-7423 (United Kingdom (Northern Ireland)).

REPUBLIC OF IRELAND
Adverse events should be reported. Reporting forms and information can be found at: HPRA Pharmacovigilance website: www.hpra.ie Adverse events should also be reported to Incyte by calling 00-800-0002-7423.