TOPICS

Pipeline Perspectives and Therapy Updates: Dual Inhibition of IL-17 Cytokines and Expanding the Therapeutic Reach of Dupilumab

J Clin Aesthet Dermatol. 2020;13(11):32–34

by James Q. Del Rosso, DO, FAAD, FAOCD

Dr. Del Rosso is Research Director at JDR Dermatology Research in Las Vegas, Nevada, is with Thomas Dermatology in Las Vegas, Nevada, and is an adjunct clinical professor of dermatology at Touro University Nevada in Henderson, Nevada.

FUNDING: No funding was provided for this publication.

DISCLOSURES: Dr. Del Rosso is a researcher, consultant, and/or speaker for Almirall, Amgen, Anaptys Bio, Arcutis, Bausch Health, Biorasi, Cara Therapeutics, Encore, Galderma, Incyte, Leo Pharma, LaRoche Posay, Lilly, MC2 Therapeutics, Pfizer, Ralexar, Regeneron, Sanofi-Genzyme, Sonoma, Sun Pharma.


In Pipeline Perspectives & Therapy Updates, my goal is to provide a “quick read” review of new information on therapies in dermatology along with selected important updates on currently available agents. This can serve as a starting point for the reader who can then look further into additional references for more in-depth information and data. This format also includes what I believe to be the clinical relevance of the information that is presented, with each “therapeutorial” usually covering two specific subject areas. This article will cover the concept of dual inhibition of IL-17 cytokines for psoriasis and a discussion of additional uses for dupilumab in disease states other than classic cases of atopic dermatitis. I hope you find this helpful.

Dual Inhibition of IL-17 Cytokines: Is It Clinically Significant?

Background. The interleukin (IL)-17 family of cytokines includes six members (IL-17A through IL-17F). Among them, IL-17A, IL-17-C, and IL-17F have been associated with the pathogenesis of psoriasis and psoriatic arthritis, with marked expression in psoriatic lesions.1–4 Although IL-17C and IL-17F are present in higher quantities, IL-17A is more biologically active, up to 30-fold greater biological activity than IL-17F reported.1,2 Also, IL-17A inhibition alone normalizes many more genes than does inhibition of TNF-alpha.1,2 Nevertheless, there is evidence that antagonism of IL-17F independently reduces inflammation associated with psoriasis, and that dual inhibition of both IL-17A and IL-17F may further augment suppression of inflammation over that which is achieved with IL-17A inhibition alone.1–6 Secukinumab and ixekizumab are monoclonal antibody antagonists of IL-17A, are approved by the United States (US) Food and Drug Administration (FDA) and widely used in the marketplace, with well-established efficacy and overall safety for treatment of chronic plaque psoriasis (PsO) and psoriatic arthritis (PsA).1–3 Bimekizumab is an investigational humanized monoclonal IgG1 antibody that inhibits both IL-17A and IL-17F.1,7,8 Results of Phase III studies were presented at the 2020 American Academy of Dermatology Virtual Experience Meeting; efficacy outcomes are discussed below.7,8 Overall, safety was favorable in the Phase III trials with no new safety signals observed related to compounds that inhibit IL-17 activity.

Study outcomes. In an active comparator randomized controlled trial (RCT) of adults with moderate-to-severe PsO, bimekizumab demonstrated markedly superior efficacy to both ustekinumab or placebo over 16 weeks, based on assessments of PASI90 outcomes and Investigator Global Assessments (IGA) endpoint success ratings of 0 (clear) or 1 (almost clear).7 Approximately 40 percent of actively treated subjects had previously received biologic therapy, including anti-TNF, anti-IL-17, and/or anti-IL-23 agents. At Week 16, subjects treated with bimekizumab 320mg every four weeks achieved PASI90 in 85.0 percent and IGA success in 84.1 percent, compared to 49.7 percent and 53.4 percent treated with ustekinumab, and 4.8 percent and 4.8 percent treated with placebo, respectively (p<0.001, all comparisons).7 Interestingly, 76.9 percent of subjects who received one dose of bimekizumab reached PASI75 by Week 4, which was markedly higher than with ustekinumab or placebo. By Week 16, 58.6 percent of bimekizumab-treated subjects achieved PASI100, versus 20.9 percent in ustekinumab-treated subjects. At Week 52, bimekizumab demonstrated markedly superior skin clearance as compared to ustekinumab, based on evaluations of PASI90, PASI100, and IGA success ratings.7 For example, PASI100 was noted in 64.2 percent of subjects treated with bimekizumab and in 38 percent of those treated with ustekinumab. In a separate 56-week RCT, after achievement of PASI 90 at Week 16, subjects were re-randomized to receive either continuous bimekizumab or be withdrawn from active therapy (treated with placebo) and followed through Week 56.8 Those subjects who were maintained on a dosing regimen with either bimekizumab 320mg every four weeks or every eight weeks after Week 16 maintained a PASI90 response in 86.8 percent and 91 percent through Week 56, respectively, compared to 16.2 percent in those who did not receive continuous bimekizumab therapy after Week 16 (re-randomized to placebo arm).8

Clinical relevance. With regard to efficacy, these data with bimekizumab suggest simplified dosing without the need for an extended “up front” loading schedule requiring frequent injections, show a quick onset of clinical response with very high skin clearance rates, and demonstrate sustained suppression of psoriasis with continued use, likely with less frequent administration in many patients (fewer injections). In a nutshell, 9 out of 10 patients achieved PASI90 and almost 6 out of 10 patients were completely clear of PsO (PASI100) after four months of therapy with bimekizumab given every four weeks. After one year, almost two-thirds of patients who received continuous bimekizumab therapy achieved complete clearance of PsO (PASI100). In the re-randomization study, 9 out of 10 subjects who reached PASI 90 at Week 16, maintained this improvement level through Week 56 with dosing either every four weeks or every eight weeks. The outcomes of these Phase III studies do suggest that dual inhibition of both IL-17A and IL-17F contributes to clinical efficacy of IL-17 inhibition. Bimekizumab is also under study for PsA and hidradenitis suppurativa. If bimekizumab eventually achieves FDA approval for PsO and other dermatologic indications, which I expect will occur, the data supports that it will be a highly effective addition to our treatment armamentarium.  

Expanding the Therapeutic Reach of Dupilumab: Important Considerations for the Clinician

Background. Dupilumab is an injectable human IgG4 monoclonal antibody that antagonizes IL-4 receptor-alpha which results in inhibition of Th2-induced inflammation via blockade of both IL-4 and IL-13.9 High efficacy and overall favorable safety have been shown in patients with atopic dermatitis with FDA approval in those affected by moderate-to-severe disease that are older than six years of age and not adequately controlled by conventional topical therapies. Other FDA-approved indications include add-on/maintenance treatment of patients older than 12 years of age with moderate-to-severe asthma that is oral corticosteroid-dependent or of eosinophilic phenotype, and in adults with inadequately controlled chronic rhinosinusitis and nasal polyposis.9 Collectively, these indications tell us that Th2 inflammation is a major component of the pathophysiology of atopic diseases affecting not only “external skin” and ocular mucosa, but also the “internal skin”, the latter comprised of epithelium lining the nasopharyneal, respiratory, and gastrointestinal tracts.10 Over time, with continued experience using dupilumab, both clinicians and researchers continue to encounter potential off-label disease states where dupilumab has been shown to be effective, and in some cases, supported by potential modes of action related to the drug.11 The list of potential off-label uses of dupilumab continues to grow, which is the subject of this review. Clinicians are seeing more and more cases of challenging pruritic and sometimes eczematous disease states that only loosely fall under the umbrella diagnosis of atopic dermatitis and are sometimes recalcitrant to conventional therapies. These patients need our help, and dupilumab demonstrates efficacy in many of these cases. So where does that leave us? Steps to identify the underlying pathophysiologic connections between these variant presentations of both atopic disease and non-atopic disease, and why certain mode(s) of action prove to be effective in specific disease states are needed in order to strongly support the use of dupilumab when called upon to treat an off-label indication.

Literature review outcomes. The starting point is to identify which skin disease states dupilumab has been used for, outside of the “garden variety” cases of atopic dermatitis, and determine whether it has been effective and safe. A literature search including the ClinicalTrials.gov database was completed to find uses of dupilumab beyond atopic dermatitis in dermatology, including ongoing studies on new uses for dupilumab. Off-label reports identified uses of dupilumab for a variety of dermatologic conditions, presenting in some cases with eczematous dermatitis as a common denominator, including allergic contact dermatitis, hand dermatitis, dyshidrotic eczema, chronic spontaneous urticaria, prurigo nodularis, alopecia areata, and bullous pemphigoid.11–16 In some cases, these “distinct dermatologic diagnoses” were occurring in patients who are atopic based on family and/or personal history, including hand dermatitis and prurigo nodularis. One published review identified several cases, including allergic contact dermatitis (n=4), atopic hand eczema (n=1), dyshidrotic eczema (n=2), alopecia areata/totalis/universalis (n=3), prurigo nodularis (N=2), chronic spontaneous urticaria and atopic dermatitis (n=1), and bullous pemphigoid (n=1).12 Another report identified effective dupilumab use in non-atopic disease states (N=33) including chronic pruritus, prurigo nodularis, eczematous eruption of aging, allergic contact dermatitis, chronic hand eczema, alopecia areata, urticaria, eosinophilic annular erythema, bullous pemphigoid, and papuloerythroderma of Ofuji.11 A case report series of non-atopic adults with dyshidrotic eczema (N=15) that failed topical corticosteroid therapy, with many cases also refractory to oral immunosuppressive treatments or phototherapy, showed that dupilumab therapy provided partial clearance in 100 percent and complete clearance in 40 percent of patients (average treatment duration 12.5 months).17 Another report on six non-atopic adults with nummular dermatitis that failed standard therapy showed that dupilumab treatment induced a durable response over two years in five of the patients.18 Multiple reports have demonstrated marked improvement of prurigo nodularis with significant reduction in pruritus with dupilumab therapy, with atopy present in many of these patients.13–15 Additionally, dupilumab therapy has shown to be effective in several cases of bullous pemphigoid in elderly adult patients, including some who were not good candidates for systemic immunosuppressive agents or systemic corticosteroids due to risk factors. In one case series of adults with bullous pemphigoid (N=13), 92.3 percent responded satisfactorily and desired to remain on therapy, with 53.8 percent achieving complete clearance.19

Pipeline Perspectives and Therapy UpdatesClinical relevance. Based on data available to date, overlap in immune signaling pathways between atopic dermatitis and other skin disorders support the use of dupilumab therapy for the refractory conditions discussed above when standard treatments have been ineffective or are contraindicated. With additional case reports and hopefully RCTs in some of these disorders, dosing regimens will be fine-tuned if necessary and more detailed efficacy and safety data will be collected. Thus far, dupilumab therapy appears to be helpful in many of the patients described in the reports. With increased awareness of adults with atopic dermatitis noted in several publications, and as a common clinical diagnosis in real world practice, it is important for clinicians to recognize that the diagnosis and management of adult-onset atopic dermatitis is often challenging. In fact, it can be very difficult to clearly define these patients as exhibiting atopic skin disease as this is a clinical diagnosis with no definitive diagnostic laboratory test. As cutaneous T-cell lymphoma (CTCL) can simulate atopic dermatitis in adult patients in both clinical appearance and symptomatology (pruritus), it is important that clinicians maintain a high index of suspicion and perform a thorough history and physical examination and appropriate diagnostic testing (ie skin biopsies) in selected cases based on the suspicion of possible CTCL.21 It is easy to diagnose atopic dermatitis as a knee-jerk reflex as it is seen very commonly, however, some cases, especially adult-onset atopic disease, warrant a closer look.

References

  1. Blauvelt A, Chiricozzi A. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clin Rev Allergy Immunol. 2018;55:3709-390.
  2. Prinz I, Sandrock I, Mrowietz U. Interleukin-17 cytokines: effects and targets in psoriasis – a breakthrough in understanding and treatment. J Exper Med. 2019:1-9.
  3. Brembilla NC, Senra L, Boehncke WH. The IL-17 family of cytokines in psoriasis: IL-17A and beyond. Front Immunol. 2018;9:1-13 (Article 1682).
  4. Hawkes JE, Yan BY, Chan TC, Krueger JG. Discovery of the IL-23/IL-17 Signaling pathway and the treatment of psoriasis. J Immunol. 2018;201(6):1605-1613.
  5. Glatt S, Baeten D, Baker T, et al. Dual IL-17A and IL-17F neutralization by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomized placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation. Ann Rheum Dis. 2018;77(4):523-532.
  6. Maroof A, Okoye R, Smallie T, et al. Bimekizumab dual inflammation of IL-17A and IL-17F provides evidence of IL-17F contribution to chronic inflammation in disease-relevant cells. Ann Rheum Dis. 2017;76(2):213.
  7. Reich K, Papp KA, Blauvelt A, et al. Efficacy and safety of bimekizumab in patients with moderate-to-severe plaque psoriasis: results from BE VIVID, a 52-week phase 3, randomized, double-blinded, ustekinumab- and placebo-controlled study. Presented at American Academy of Dermatology Virtual Meeting Experience 2020; June 12-14, 2020.
  8. Gordon K, Foley P, Krueger J, et al. Efficacy and safety of bimekizumab in patients with moderate-to-severe plaque psoriasis: results from BE READY, a 56-week phase 3, randomized, double-blinded, placebo-controlled study with randomized withdrawal. Presented at American Academy of Dermatology Virtual Meeting Experience 2020; June 12-14, 2020.
  9. Dupilumab injection (Dupixent) for subcutaneous use. Package insert. Regeneron, Tarrytown, NY, Sanofi-Genzyme, Bridgewater, NJ, Approval 2017, Revised June 2020.
  10. Silverberg JI, Kantor R. The role of interleukins 4 and/or 13 in the pathophysiology and treatment of atopic dermatitis. Dermatol Clin. 2017;35:327-334.
  11. Hendricks AJ, Yosipovitch G, Shi VY. Dupilumab use in dermatologic conditions beyond atopic dermatitis – a systematic review. J Dermatol Treat. 2019;12;1-10.
  12. Maloney NJ, et al. Dupilumab in Dermatology: Potential for Uses Beyond Atopic Dermatitis. J Drugs Dermatol. 2019;18(10):1053-1055.
  13. Chiricozzi A, Maurelli M, Gori N, et al. Dupilumab improves clinical manifestations, symptoms, and quality of life in adult patients with chronic nodular prurigo. J Am Acad Dermatol. 2020;83:39-45.
  14. Napolitano M, Fabbrocini G, Scalvenzi M, et al. Effectiveness of dupilumab for the treatment of generalized prurigo nodularis clinical phenotype of adult atopic dermatitis. Dermatitis. 2019; Sep 11. doi: 10.1097DER. [Epub ahead of print].
  15. Calugareanu A, Jachiet M, Tauber M, et al. Effectiveness and safety of dupilumab for the treatment of prurigo nodularis in a French multicenter adult cohort of 16 patients. J Eur Acad Dermatol Venereol. 2019; Sep 17. [Epub ahead of print].
  16. Kaye A, Gordon SC, Deverapalli SC. Dupilumab for treatment of recalcitrant bullous pemphigoid. JAMA Dermatol. August 22, 2018, doi: 10.1001/jamadermatol.2018.2526 (published on line).
  17. Waldman RA, DeWane ME, Sloan B, et al. Dupilumab for the treatment of dyshidrotic eczema in 15 consecutive patients. J Am Acad Dermatol. 2020;82(5):1251-1252.
  18. Choi S, Gefei Z, Lewis M, et al. Dupiliumab treatment of nummular dermatitis: a retrospective cohort study. J Am Acad Dermatol. 2020;82(5):1252-1254.
  19. Abdat R, Waldman RA, de Bedout V, et al. Dupilumab as a novel therapy for bullous pemphigoid: a multicenter case series. J Am Acad Dermatol. 2020;83(1):46-52.
  20. Hanifin JM. Adult-onset atopic dermatitis: fact or fancy? Dermatol Clin. 2017;35:299-302.
  21. Espinosa M, Nguyen MT, Aguirre AS, et al. Progression of cutaneous T-cell lymphoma after dupilumab: case review of 7 patients. J Am Acad Dermatol. 2020;83(1):197-198.
Share on facebook
Facebook
Share on twitter
Twitter
Share on linkedin
LinkedIn