STL Volume 27 Number 2 – Skin Therapy Letter https://www.skintherapyletter.com Written by Dermatologists for Dermatologists Thu, 14 Apr 2022 19:54:37 +0000 en-US hourly 1 https://wordpress.org/?v=6.8.1 Plerixafor on a WHIM – Promise or Fantasy of a New CXCR4 Inhibitor for This Rare, but Important Syndrome? https://www.skintherapyletter.com/warts/whim-syndrome-new-plerixafor-cxcr4/ Fri, 01 Apr 2022 21:44:14 +0000 https://www.skintherapyletter.com/?p=13286 Nickoo Merati, MSc1; Sriraam Sivachandran1; Abdulhadi Jfri, MD1; Moshe Ben-Shoshan, MD2; Donald C. Vinh, MD, FRCPC2,3; Gizelle Popradi, MD, FRCPC4; Ivan V. Litvinov, MD, PhD, FRCPC1

1Division of Dermatology, McGill University Health Centre, Montréal, QC, Canada
2Division of Allergy and Immunology, McGill University Health Centre, Montréal, QC, Canada
3Division of Infectious Diseases, McGill University Health Centre, Montréal, QC, Canada
4Division of Hematology, McGill University Health Centre, Montréal, QC, Canada

Authorship statement:
N. Merati: reviewed literature, prepared the manuscript;
S. Sivachandran: addressed reviewer comments, reviewed literature and co-wrote the paper;
A. Jfri: contributed to the review of literature and preparation of the manuscript;
M. Ben-Shoshan: contributed to the review of literature and preparation of the manuscript;
D. C. Vinh: contributed to the review of literature and preparation of the manuscript;
G. Popradi: contributed to the review of literature and preparation of the manuscript;
I. V. Litvinov: supervised the study, reviewed literature and co-wrote the paper.

Conflict of interest:
The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: None.

Abstract:
Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) is a primary immunodeficiency syndrome. Patients with WHIM syndrome are more susceptible to human papillomavirus (HPV) infections and commonly present to a dermatologist with recalcitrant to treatment warts. Other cardinal features of WHIM syndrome include recurrent sinopulmonary bacterial infections, neutropenia/lymphopenia, low levels of immunoglobulins (IgG, IgA, IgM) and myelokathexis. Research demonstrated that truncating gain-of-function mutations of the C-X-C chemokine receptor type 4 gene (CXCR4) are responsible for this disease. Plerixafor, a specific small molecule antagonist of CXCR4, is currently used for peripheral blood hematopoietic stem cell (HSC) mobilization in stem cell transplant recipients. It has recently shown promise for the treatment of WHIM syndrome in phase I/II clinical trials. In this paper we review the emerging patient clinical data for this medication and highlight the role of CXCR4 in other important skin diseases including keratinocyte carcinomas, psoriasis and cutaneous T-cell lymphoma.

Key Words:
plerixafor, warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome, C-X-C chemokine receptor type 4 (CXCR4), stromal cell-derived factor-1 (SDF-1), CXCL12, recalcitrant warts

Introduction

Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) is a primary immunodeficiency syndrome. As the name suggests, patients with WHIM syndrome are more susceptible to human papillomavirus (HPV),1 which can cause warts and potentially lead to squamous cell carcinomas; hypogammaglobulinemia; recurrent bacterial infections, such as otitis media, cellulitis, pneumonia and sinusitis; and bone marrow myelokathexis, characterized by a retention and apoptosis of mature neutrophils resulting neutropenia. The laboratory manifestations include severe neutropenia, significant lymphopenia, leukopenia, and monocytopenia.

WHIM syndrome is a rare disease with ~70 cases reported in the medical literature to date.2,3 In 2003, the cause of WHIM syndrome was traced to a heterozygous, truncating gain-of-function mutations of the C-X-C chemokine receptor type 4 gene (CXCR4) on chromosome 2 (2q22.1), resulting in a hyperactive signalling of this G-protein coupled receptor. While not yet fully deciphered, it is postulated that increased CXCR4 receptor activity upon binding of its cognate stromal cell-derived factor-1 (SDF-1; also known as CXCL12) ligand, prevents the release of mature neutrophils and promotes their apoptosis in the marrow (Figure 1A-B). This cellular mechanism drives myelokathexis that is observed clinically in affected patients. The CXCR4 mutations are inherited in autosomal dominant manner. Some patients with WHIM syndrome, however, do not have a detectable CXCR4 gene mutation, suggesting that mutations in other genes may be involved.

Plerixafor on a WHIM – Promise or Fantasy of a New CXCR4 Inhibitor for This Rare, but Important Syndrome? - image
Figure 1A. The chemokine stromal cell-derived factor-1 (SDF-1) binds to the transmembrane CXCR4 receptor (a G protein-coupled transmembrane protein) in the bone marrow. CXCR4 regulates the mobilization of neutrophils and lymphocytes from bone marrow by first blocking their release; as the neutrophils mature, SDF-1-CXCR4 is internalized and hence turned off, allowing for the release of neutrophils and lymphocytes and effective mobilization into the blood stream.
Plerixafor on a WHIM – Promise or Fantasy of a New CXCR4 Inhibitor for This Rare, but Important Syndrome? - image
Figure 1B. A gain-of-function mutation in patients with the WHIM syndrome leads to inappropriate hyperactivity of the CXCR4 receptor and failed internalization, leading to a prolonged retention of neutrophils and lymphocytes in the bone marrow leading to myelokathexis and immunodeficiency.

 

The diagnosis of WHIM syndrome relies on identifying the clinical features, a detailed patient medical history, family history, and genetic testing. In particular, patients with recalcitrant HPV warts and recurrent sinopulmonary bacterial infections should be further evaluated with a complete blood count and differential (to detect neutropenia and lymphopenia), and immunoglobulins (IgG, IgA, IgM) to detect hypogammaglobulinemia. Family history may reveal vertical transmission in autosomal dominant fashion, if more than one generation is affected. A bone marrow biopsy may be performed to detect myelokathexis.

While potential molecular mechanisms have been elucidated, the effectiveness of standard WHIM syndrome therapies is variable and more targeted therapies are urgently needed. Until recently most patients were managed using a combination of granulocyte colony stimulating factor (G-CSF), skin-directed treatments of warts, prophylactic antibiotics, and intravenous gamma globulin (IVIG) therapy.

In 2009, a group of researchers sought to therapeutically target the CXCR4 receptor. Plerixafor, a specific small molecule antagonist of CXCR4 (Figure 1C), was originally licensed by the United States Food and Drug Administration for peripheral blood hematopoietic stem cell (HSC) mobilization in stem cell transplant recipients. Plerixafor (Mozobil®) has been used in Canada and in the United States since 2012.4 Notably, a novel application for this medication has been defined, where McDermott and colleagues conducted a phase I clinical trial (NCT00967785) using plerixafor as a treatment for 20 patients with WHIM syndrome.3,5-7 They found that 9 patients who received low-dose plerixafor safely mobilized neutrophils and had an improvement in all other leukocyte subsets.3,5-7 A follow-up study in 3 of the participants demonstrated sustained responses for at least 6 months using a dosage of 0.02-0.04 mg/kg/day subcutaneously with no new warts developing and regression of old warts. In 2014, these promising results led the investigators to conduct a phase III randomized, double-blinded, crossover trial (NCT02231879) to establish safety and efficacy of plerixafor compared to standard G-CSF treatment in patients aged 10-75 years with WHIM syndrome. Nineteen patients were randomized to 1 year of G-CSF and 1 year of plerixafor using a crossover design, allowing direct comparison of infection severity during treatment with both agents. Doses were personalized to each patient’s neutrophil response. Study participants had a clinical diagnosis of WHIM syndrome and were proven to have a heterozygous mutation in the CXRC4 gene.8 While the trial is currently ongoing, some early data is beginning to emerge from this group.

Plerixafor on a WHIM – Promise or Fantasy of a New CXCR4 Inhibitor for This Rare, but Important Syndrome? - image
Figure 1C. Plerixafor binds to CXCR4 receptor in the bone marrow and blocks the SDF-1-CXCR4 interaction, allowing for normal mobilization of neutrophils and lymphocytes into the blood stream.

During recruitment, McDermott and colleagues identified 3 patients who were ineligible to participate in the larger study as they could not receive G-CSF. The researchers began a concomitant study with these patients, treating them with plerixafor (according to their phase 1 protocol) for 20-50 months. These findings have been published in the New England Journal of Medicine. McDermott et al. reported improvement in all 3 patients’ white cells counts, platelet counts and hemoglobin levels.9 In 2 out of 3 patients these results were observed after discontinuing G-CSF, which was deemed ineffective. Bone marrow biopsies revealed marked amelioration of severe pre-treatment myelofibrosis and myelokathexis in 2 of the patients after using plerixafor for 24 and 52 months.9 With the adjunct use of imiquimod in 2 of the patients and double HPV vaccination in 1 of the patients, HPV-associated wart burden improved noticeably on the hands, feet and genitals. Mixed results though were obtained with HPV-associated tumors, which were managed with debulking and surgery. Susceptibility to infections and inflammation also differed amongst the patients; however, 1 patient was noted to have a marked reduction in infection frequency compared to his pre-treatment baseline, and a significantly higher quality of life, where he was able to exercise, enjoy the outdoors and work without being fearful of recurrent infections and hospitalizations.

The results of these case studies are exciting and suggest that clinicians and patients with WHIM syndrome might expect favorable clinical outcomes with plerixafor. However, as with any new therapeutic indication, we must await the efficacy and safety results of the phase III trial, especially considering that chronic leukocyte mobilization from bone marrow with plerixafor could result in as of yet undescribed cumulative toxicities.10,11 It will also be crucial to determine the effect of plerixafor on immune cell function including mitogen induced T-cell proliferation and T-cell dependent humoral immunity.

Also, another phase II/III clinical trial (NCT03005327) is being conducted by researchers in Florida, investigating the use of mavorixafor (X4P-001), a different small molecule targeting hyperactive CXCR4 receptor.12 Funded by X4 Pharmaceuticals, researchers have demonstrated positive preliminary clinical findings using mavorixafor in a group of 6 WHIM patients, showing increased white cell counts and improved clinical outcomes. Unlike plerixafor, mavorixafor is administered orally.13 Additional phase II results published on 8 patients in Blood demonstrated that this medication was well tolerated by patients (with no treatment-related serious adverse events) using a dose of 400 mg daily and led to neutrophil mobilization, reduced infection rates and reduction in the number of warts.14

Conclusion

Emerging molecular experimental and clinical data suggests that CXCR4 may play an important role in other skin and systemic diseases including mycosis fungoides/Sézary syndrome, neurofibromatosis type 1 tumors, allergic reactions, Waldenström macroglobulinemia, melanoma, non-melanoma skin cancers and other solid tumors (Table 1). Hence, ability to target the CXCR4 may improve our abilities to treat a number of these diseases in the not-too-distant future. In fact, a number of trials using mavorixafor are underway evaluating efficacy in the treatment of Waldenström macroglobulinemia, renal cell carcinoma and other cancers, where CXCR4 inhibitors are actively being evaluated as cancer immunotherapy treatments.15,16

Disease Proposed Involvement of CXCR4 References
1. Sézary syndrome/cutaneous T-cell lymphoma Lymphocyte skin homing may involve CXCR4 signaling. The CXCR4 chemokine receptor may play a role in homing of malignant T lymphocytes in mycosis fungoides and Sézary syndrome. CD26 (a dipeptidylpeptidase) cleaves and inactivates SDF-1 (a CXCR4 ligand) produced by stromal cells and fibroblasts in the dermis. The loss of CD26 on Sézary cells may increase their ability to migrate to and/or survive in the skin. 17, 18
2. Skin warts and human papillomavirus (HPV)-related disease Observed in 61% of long-term WHIM syndrome patients with CXCR4 mutations. Expression of CXCR41013 (a WHIM-associated CXCR4 gain of function mutation) promotes stabilization of HPV oncoproteins. Thus, hyperactive CXCR4 could be an important facilitator in HPV-driven carcinogenesis. 19, 20
3. Squamous cell carcinoma (SCC) Drugs that inhibit SDF-1 induced endocytosis of CXCR4 can suppresses cutaneous SCC cell migration. The SDF-1/CXCR4 signaling may also be involved in the establishment of lymph node metastasis in oral SCC, via activation of both ERK1/2 and Akt/PKB induced by Src family kinases. Analysis of chemokine receptor expression showed upregulation of CXCR4 in potentially metastatic non‐melanoma skin cancers and invasive oral SCCs. 21-23
4. Basal cell carcinoma (BCC) CXCR4 expression may play a critical role in tumor progression and angiogenesis of certain subtypes of BCC with more aggressive phenotype. Functional blockade of CXCR4 signaling could be a potential therapeutic strategy for these tumors. 24
5. Neurofibromatosis type 1 (NF1) CXCR4 gene expression increased 3- to 120-fold and SDF-1 gene expression increased 33- to 512-fold in NF1 tumors. 25
6. Melanoma Melanoma cells use CXCR4 and CCR10 to enhance cell survival in the face of immune-mediated attack. 26
7. Waldenstrom macroglobulinemia (WM) Whole genome sequencing in WM patients found that 27% had WHIM syndrome-like mutations in the CXCR4 gene. 27
8. Allergic and eosinophil-related responses Glucocorticoids were found to significantly upregulate CXCR4 expression in eosinophils. It was suggested that upregulation of CXCR4 may mediate the antiallergic properties of the glucocorticoid therapy by sequestering eosinophils from the circulation to non-inflamed extravascular tissues. 28
9. Rheumatoid arthritis The SDF-1/CXCR4 ligand-receptor signaling is likely playing an important functional role in T-cell accumulation and positioning within the diseased synovium in rheumatoid arthritis patients. 29
10. Psoriasis Elevated mRNA levels of both SDF-1 and CXCR4 have been found in lesional psoriatic skin. 30
11. Breast, kidney and other solid tumors By quantitative RT-PCR, immunohistochemistry, and flow cytometric analysis CXCR4 was found to be highly expressed in primary and metastatic human breast cancer cells, but not in normal mammary tissues. RT-PCR detected peak expression levels of SDF-1 in lymph nodes, lung, liver, and bone marrow.31 This chemokine, as well as lung and liver extracts, induce directional migration of breast cancer cells in vitro, which can be blocked by specific CXCR4 antibodies. Histologic and RT-PCR analyses demonstrated that metastasis of breast cancer cells grown in mice could be significantly decreased by treatment with anti-CXCR4 antibodies.31 In kidney, von Hippel-Lindau tumor suppressor protein (VHL) decreases CXCR4 expression (by targeting hypoxia-inducible factor [HIF1-α] for degradation, a known transcriptional transactivator of CXCR4).32 Mutations in the VHL gene in clear cell carcinomas correlated with strong expression of CXCR4 and poor cancer-specific survival.32 Hence, high CXCR4 expression may promote cancer cell tendency to metastasize to specific organs. 31, 32
12. Response to West Nile virus (WNV) infection In mouse models of WNV encephalitis the downregulation of the beta isoform of SDF-1 (CXCL12) and a corresponding decrease in perivascular T cells and an increase in parenchymal T cells was observed. Treatment with a continuously administered CXCR4 antagonist increased the survival of WNV-infected mice and produced a reduction in WNV burden in the brain. CXCR4 antagonism enhanced T-cell penetration into the brain after WNV encephalitis, increased virus-specific CD8+ T-cell interaction with infected cells and decreased glial cell activation. 33
Table 1: Summary of studies documenting the importance of CXCR4 signaling in a number of important skin diseases and other
medical conditions.

References



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  2. Immune Deficiency Foundation (IDF). WHIM syndrome. Available from: https://primaryimmune.org/disease/whim-syndrome. Accessed February 6, 2022

  3. Dotta L, Tassone L, Badolato R. Clinical and genetic features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome. Curr Mol Med. 2011 Jun;11(4):317-25.

  4. Mozobil® (plerixafor) injection
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  6. Dale DC, Bolyard AA, Kelley ML, et al. The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome. Blood. 2011 Nov 3;118(18):4963-6.

  7. McDermott DH, Liu Q, Ulrick J, et al. The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome. Blood. 2011 Nov 3;118(18):4957-62.

  8. Ghazawi FM, Netchiporouk E, Rahme E, et al. Comprehensive analysis of cutaneous T-cell lymphoma (CTCL) incidence and mortality in Canada reveals changing trends and geographic clustering for this malignancy. Cancer. 2017 Sep 15;123(18):3550-67.

  9. McDermott DH, Pastrana DV, Calvo KR, et al. Plerixafor for the treatment of WHIM syndrome. N Engl J Med. 2019 Jan 10;380(2):163-70.

  10. Sanofi-aventis. Mozobil® (plerixafor) injection. Benefits and risks of Mozobil. Available from: https://www.mozobil.com/why-mozobil. Accessed February 6, 2022.

  11. Lexicomp® (Internet database). Plerixafor. Wolters Kluwer N.V. Available at: http://online.lexi.com. Accessed February 6, 2022.

  12. Hall S, Schulze K, Groome P, et al. Using cancer registry data for survival studies: the example of the Ontario Cancer Registry. J Clin Epidemiol. 2006 Jan;59(1):67-76.

  13. Dale DC, Firkin FC, Bolyard AA, et al. Determination of phase 3 dose for X4P-001 in patients with WHIM syndrome. Blood. 2018 Nov;132(Suppl 1):1102.

  14. Dale DC, Firkin F, Bolyard AA, et al. Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome. Blood. 2020 Dec 24;136(26):2994-3003.

  15. Castillo JJ, Treon SP. Management of Waldenstrom macroglobulinemia in 2020. Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):372-9.

  16. Choueiri TK, Atkins MB, Rose TL, et al. A phase 1b trial of the CXCR4 inhibitor mavorixafor and nivolumab in advanced renal cell carcinoma patients with no prior response to nivolumab monotherapy. Invest New Drugs. 2021 Aug;39(4):1019-27.

  17. Narducci MG, Scala E, Bresin A, et al. Skin homing of Sezary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV. Blood. 2006 Feb 1;107(3):1108-15.

  18. Wu XS, Lonsdorf AS, Hwang ST. Cutaneous T-cell lymphoma: roles for chemokines and chemokine receptors. J Invest Dermatol. 2009 May;129(5):1115-9.

  19. Dotta L, Notarangelo LD, Moratto D, et al. Long-term outcome of WHIM syndrome in 18 patients: high risk of lung disease and HPV-related malignancies. J Allergy Clin Immunol Pract. 2019 May-Jun;7(5):1568-77.

  20. Meuris F, Carthagena L, Jaracz-Ros A, et al. The CXCL12/CXCR4 signaling pathway: a new susceptibility factor in human papillomavirus pathogenesis. PLoS Pathog. 2016 Dec;12(12):e1006039.

  21. Gong T, Yu Y, Yang B, et al. Celecoxib suppresses cutaneous squamous-cell carcinoma cell migration via inhibition of SDF1-induced endocytosis of CXCR4. Onco Targets Ther. 2018 Nov 12;11:8063-71.

  22. Uchida D, Begum NM, Almofti A, et al. Possible role of stromal-cell-derived factor-1/CXCR4 signaling on lymph node metastasis of oral squamous cell carcinoma. Exp Cell Res. 2003 Nov 1;290(2):289-302.

  23. Basile J, Thiers B, Maize J, Sr., et al. Chemokine receptor expression in non-melanoma skin cancer. J Cutan Pathol. 2008 Jul;35(7):623-9.

  24. Chen GS, Yu HS, Lan CC, et al. CXC chemokine receptor CXCR4 expression enhances tumorigenesis and angiogenesis of basal cell carcinoma. Br J Dermatol. 2006 May;154(5):910-8.

  25. Karaosmanoglu B, Kocaefe CY, Soylemezoglu F, et al. Heightened CXCR4 and CXCL12 expression in NF1-associated neurofibromas. Childs Nerv Syst. 2018 May;34(5):877-82.

  26. Kakinuma T, Hwang ST. Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol. 2006 Apr;79(4):639-51.

  27. Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIMlike CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014 Mar 13;123(11):1637-46.

  28. Nagase H, Miyamasu M, Yamaguchi M, et al. Glucocorticoids preferentially upregulate functional CXCR4 expression in eosinophils. J Allergy Clin Immunol. 2000 Dec;106(6):1132-9.

  29. Bradfield PF, Amft N, Vernon-Wilson E, et al. Rheumatoid fibroblastlike synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis Rheum. 2003 Sep;48(9):2472-82.

  30. Suarez-Farinas M, Fuentes-Duculan J, Lowes MA, et al. Resolved psoriasis lesions retain expression of a subset of disease-related genes. J Invest Dermatol. 2011 Feb;131(2):391-400.

  31. Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001 Mar 1;410(6824):50-6.

  32. Staller P, Sulitkova J, Lisztwan J, et al. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature. 2003 Sep 18;425(6955):307-11.

  33. McCandless EE, Zhang B, Diamond MS, et al. CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis. Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11270-5.


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]]> Transition of Topical Therapy Formulation in Psoriasis: Insights from a Canadian Practice Reflective https://www.skintherapyletter.com/psoriasis/transition-topical-therapy/ Fri, 01 Apr 2022 20:00:38 +0000 https://www.skintherapyletter.com/?p=13288 David N. Adam, MD, FRCPC1-3; Sonya J. Abdulla, MD, FRCPC4; Patrick Fleming, MD, FRCPC1; Melinda J. Gooderham, MD, FRCPC5; John Ashkenas, PhD6; Clinton B. McCracken, PhD7

1Division of Dermatology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
2Baywood Dermatology and CCA Medical Research, Ajax, ON, Canada
3Probity Medical Research, Waterloo, ON, Canada
4Dermatology on Bloor, Toronto ON, Canada
5Skin Centre for Dermatology, Peterborough, ON, Canada
6imc North America, Toronto, ON, Canada
7LEO Pharma Inc. Canada, Thornhill, ON, Canada

Conflict of interest:
D. Adam has been an investigator, speaker, or advisory board member for LEO Pharma, AbbVie, Amgen, Arcutis, Bausch Health, Boehringer Ingelheim, BMS, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, Incyte, Janssen, Merck, Novatrtis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB. S. Abdulla has been a speaker or advisory board member for LEO Pharma, AbbVie, Celgene, Eli Lilly, Galderma, Janssen, Novartis, Pfizer, Sanofi Genzyme, UCB, and Bausch/Valeant. P. Fleming has received honorarium and/or consulting and/or advisory boards and/or speaking fees for AbbVie, Altius, Aralez, Bausch Health, Cipher, Galderma, Eli Lilly, UCB, Janssen, Novartis, Pfizer, and Sanofi-Genzyme. M. Gooderham has been an investigator, speaker, or advisory board member for LEO Pharma, AbbVie, Amgen, Akros, Arcutis, Boehringer Ingelheim, BMS, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Janssen, Kyowa Kirin, Medimmune, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, UCB, and Bausch/Valeant. J. Ashkenas received support via imc North America (Toronto, ON) from LEO Pharma Inc. Canada for participating in the development of the practice reflective and for analyzing the findings. He has no other financial interest to declare. C. McCracken is employed by LEO Pharma Inc. Canada.

Abstract:
Patient preferences for psoriasis treatment may affect treatment adherence and disease control; changing topical formulation may improve adherence and patient acceptance of treatment. This study explored dermatologists’ reasons for transitioning psoriasis patients from an ointment or gel (Dovobet®) formulation to an aerosol foam (Enstilar®) formulation of calcipotriol and betamethasone dipropionate (Cal/BD), and to assess the success of this transition. Medical records of 81 Canadian patients from 9 dermatologists were retrospectively reviewed for symptoms affecting quality of life, reasons for transitioning treatment, and whether transition was successful. Reasons for transition included efficacy, quality of life, and patient adherence. At follow-up, median psoriasis severity and body surface area affected had decreased from baseline, and patients experienced improved quality of life. Itch and itch-related sleep loss, which were identified as burdensome in 63% of patients at baseline, had resolved in 33% and improved in 54% of patients at follow-up. Dermatologists deemed the transition successful in 85% of patients, with the most common reasons being patient-reported success, clearance of signs/symptoms, and continued prescription refills. Transition from Cal/BD ointment or gel to aerosol foam was generally deemed successful by patients and dermatologists, and was associated with improved quality of life and improved itch control.

Key Words:
psoriasis; topical treatment; foam; formulation; fixed combination

Introduction

Psoriasis is a chronic condition that commonly requires topical treatment, either as monotherapy or in combination with phototherapy or systemic treatment. Given the challenge of consistent long-term adherence to treatment for psoriasis,1-3 patient acceptance of topical treatment is an important consideration.4,5 Formulations with more appealing cosmetic features could affect patient acceptance, and therefore adherence and ultimately disease control.6-9

Calcipotriol and betamethasone dipropionate (Cal/BD) are the active ingredients in Dovobet® ointment or gel (Cal/BD ointment or gel) and Enstilar® aerosol foam (Cal/BD foam). Cal/BD aerosol foam has improved skin penetration and is reported to be better accepted by patients, relative to Cal/BD ointment or gel.10 Switching to Cal/BD foam can improve disease control. Significantly more patients using Cal/BD foam achieved a 2-grade improvement according to the physician’s global assessment of disease severity, with their psoriasis being clear or almost clear, by week 4 compared with patients using Cal/BD gel by week 8 (38.3% vs. 22.5%, respectively; P < 0.001).11,12 Given that the active ingredients are the same, comparisons between the products relate purely to formulation.

In this study, medical records of Canadian psoriasis patients who transitioned from Cal/BD ointment or gel to Cal/BD foam were examined retrospectively. The objective was to explore Canadian dermatologists’ reasons for changing topical treatment formulation in these patients and to assess reasons the transition was judged successful or unsuccessful. As patients on topical monotherapy may have different motivations for and success with treatment transition, compared with those receiving concomitant topical and non-topical therapies (i.e., systemic treatment or phototherapy), the study included patients from both populations.

Patients and Methods

In this retrospective chart review, 9 Canadian dermatologists reviewed the medical records of their patients with plaque psoriasis who were previously treated with Cal/BD ointment or gel and were switched to treatment with Cal/BD foam. The study protocol was approved by RRB (Research Review Board Inc., Waterloo, ON, Canada; approval # 2019.538). The need for informed consent was waived due to the retrospective design of the study.

The dermatologists reviewed the medical records from their 10 most recent patients meeting all inclusion criteria: ≥18 years of age, with active psoriasis, and transitioned from Cal/BD ointment or gel to Cal/BD foam at the baseline visit (defined as the visit where the change in treatment occurred). Patients could not have made any change in prescribed systemic treatment or phototherapy from 3 months before to 1 month after the switch to Cal/BD foam. Baseline findings were from the visit during which the dermatologist first prescribed Cal/BD aerosol foam. Follow-up data were from the first subsequent visit, no less than 4 weeks and no more than 32 weeks after the baseline visit.

Using the data collected from the medical records, the dermatologists completed an online questionnaire developed from a pilot study carried out by 3 authors of the current study. The pilot study sought to identify classes of data that could be reliably found in medical records for psoriasis patients seen in normal Canadian dermatology practice. Pilot study data were not included in the current report.

Demographic and clinical characteristics extracted from the baseline visit records included age, gender, symptoms affecting quality of life, the dermatologist’s reasons for transitioning the patient to Cal/BD foam, the number of clinic visits in the 12 months prior to baseline, and history of psoriasis therapies in the 24 months prior to baseline. Patients were considered to be on topical monotherapy if they were using Cal/BD ointment or gel with or without other prescription or non-prescription topical agents, but without systemic treatment or phototherapy. Conversely, patients were considered as on combination therapy if they were using Cal/BD ointment or gel concomitant with phototherapy or systemic therapy. Physicians submitted their findings for each patient electronically until they had completed 10 reports. After the seventh report of patients in one class of treatment (topical monotherapy or combination therapy), the physician received an automatic reminder that both classes should be represented among their 10 reports.

The dermatologist’s assessments of psoriasis severity, as noted in the medical records, for the patient’s lifetime worst severity, severity at baseline, and severity at follow-up, were reported in the questionnaire using a 5-point scale (0 = absent; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe). Estimated percent body surface area (BSA) affected by psoriasis was extracted from the baseline and follow-up visits. The dermatologist’s assessments of improvement in quality of life, the impact of Cal/BD foam on overall psoriasis disease and itch or itch-related sleep loss, and whether the transition to Cal/BD was successful, were extracted from the records of the follow-up visit. Improvement in quality of life was rated on a 4-point scale (0 = no improvement; 4 = significant improvement). The level of impact on overall psoriasis disease and itch or itch-related sleep loss was rated as ‘Worsened’, ‘Same’, ‘Improved’, or ‘Resolved’. Dermatologists were asked to identify one or more specific signs or symptoms with the greatest impact on quality of life. If the patient’s record did not include the relevant information, dermatologists indicated ‘Unknown/Not documented’.

Descriptive statistics were analyzed using Microsoft® Excel for Mac version 16.40 and reported as mean ± standard deviation (SD), median (range), and proportions. Missing data were not imputed, and the results for each variable were reported based on the number of patients for whom data were available.

Results

Nine dermatologists completed questionnaires for 10 patients each. Of those 90 questionnaires, 9 were excluded, leaving 81 patient records for analysis. Reasons for exclusion were that insufficient data were included (n = 1), Cal/BD foam was not used between baseline and follow-up (n = 4), and the follow-up visit was not within the 4 to 32-week timeframe (n = 4).

Baseline demographic and clinical characteristics are shown in Table 1. More patients were on monotherapy than on combination therapy. Psoriasis at lifetime worst was less severe in patients on topical monotherapy vs. combination therapy. The most commonly affected body areas were the legs, arms, trunk, and scalp.

Baseline characteristic All patients
(N = 81)		 Patients on monotherapy
(n = 48)		 Patients on combination therapy
(n = 33)
Na

 Mean ± SD or n (%)

 Na

 Mean ± SD or n (%)

 Na

 Mean ± SD or n (%)
Male 45 (55.6) 26 (54.2) 19 (57.6)
Age, years 51.2 ± 17.5 51.8 ± 17.7 50.5 ± 17.6
Duration of psoriasis, years 46 11.1 ± 8.6 25 11.2 ± 9.1 21 11.0 ± 8.1
Psoriasis severity at worst 75 2.5 ± 0.9 44 2.3 ± 0.9 31 2.9 ± 0.8
Affected body areas 73 41 32
Scalp 31 (42.5) 14 (34.2) 17 (53.1)
Face 12 (16.4) 7 (17.1) 5 (15.6)
Body 65 (89.0) 34 (82.9) 31 (96.9)
Arms 65 (89.0) 34 (82.9) 31 (96.9)
Trunk 39 (53.4) 14 (34.2) 25 (78.1)
Legs 50 (68.5) 25 (61.0) 25 (78.1)
Hands 13 (17.8) 5 (12.2) 8 (25.0)
Skin folds 1 (1.4) 0 (0.0) 1 (3.1)
Other 9 (12.3) 4 (9.8) 5 (15.6)
Table 1: Patient demographics and baseline characteristics
aNumber of patient records from which the relevant data were available if less than the total.

 

Complete data for psoriasis severity (at worst, at baseline, and at follow-up) were available for 72 patients (Figure 1); with the remainder missing data from at least one of those time points. In those patients with complete data, severity at worst was mild or moderate in 36 (50%) patients. At baseline and at follow-up, 53 (74%) patients and 62 (86%) patients, respectively, experienced mild or moderate disease.

Bar chart of number of patients per category of psoriasis severity for psoriasis at its worst, at baseline, and at follow-up in patients for whom psoriasis severity was reported all timepoints (n = 72).
Figure 1. Number of patients per category of psoriasis severity for psoriasis at its worst, at baseline, and at follow-up in patients for whom psoriasis severity was reported all timepoints (n = 72).
Severity score: 0 = absent; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe.

Patients who had experienced severe, or very severe psoriasis at its worst, were more likely to be on combination therapy and had greater baseline psoriasis severity and BSA affected, relative to those with mild or moderate psoriasis at worst (Table 2). For patients with severe or very severe disease, scaling, itch or itch-related sleep loss, and redness were identified as the signs and symptoms with the greatest impact on the quality of life. Among patients with mild or moderate psoriasis at worst, itch or itch-related sleep loss had the greatest impact on the quality of life. Similarly, redness had the greatest impact on quality of life for 8 of 14 (57%) patients on combination therapy but 3 of 14 (21%) patients on monotherapy, whereas itch or itch-related sleep loss had the greatest impact in 10 of 14 (71%) patients on monotherapy but 7 of 14 (50%) patients on combination therapy.

Baseline characteristic Severity score for psoriasis at worst Patients on monotherapy Patients on combination therapy
1 or 2
(N = 37)

 3 or 4
(N = 38)

 (N = 48)

 (N = 33)
Na mean ± SD or n (%) Na mean ± SD or n (%) Na mean ± SD or n (%) Na mean ± SD or n (%)
Psoriasis severity at baseline 1.9 ± 0.7 37 2.3 ± 0.9 45 2.1 ± 0.8 32 2.1 ± 0.8
BSA at baseline 27 4.9 ± 5.5 29 10.9 ± 11.9 36 8.0 ± 9.9 23 7.5 ± 9.2
Symptoms with greatest impact on QoL 11 16 14 14
Itch/itch-related sleep loss 8 (72.7) 9 (56.3) 10 (71.4) 7 (50.0)
Scaling 5 (45.5) 10 (62.5) 8 (57.1) 7 (50.0)
Redness 3 (27.3) 8 (50.0) 3 (21.4) 8 (57.1)
Stigma 4 (36.4) 5 (31.3) 6 (42.9) 4 (28.6)
Dryness 3 (27.3) 5 (31.3) 3 (21.4) 5 (35.7)
Poor sleep 0 (0.0) 1 (6.3) 0 (0.0) 1 (7.1)
Other 1 (9.1) 2 (12.5) 0 (0.0) 3 (21.4)
Type of therapy
Monotherapy 27 (73.0) 17 (44.7) – –
Combination therapy 10 (27.0) 21 (55.3) – –
Table 2: Correlates of psoriasis severity at its worst
aNumber of patient records from which the relevant data were available if less than the total. QoL, quality of life.

 

The most common reasons cited for transitioning to Cal/BD foam were to improve clinical efficacy (74/81; 91%), quality of life (49/81; 61%), and treatment adherence (41/81; 51%). These reasons were ranked similarly for patients on monotherapy and on combination therapy (data not shown).

In patients for whom data were available at both baseline and follow-up, median psoriasis severity score (range) was 2.0 (1.0-4.0) at baseline and 1.0 (0.0-4.0) at follow-up. Median BSA was 4.0 (1.0-45.0) at baseline and 1.5 (0.0-25.0) at follow-up. The median and overall ranges for psoriasis severity and BSA were similar for patients on mono- and combination therapy. These findings were comparable across all 9 dermatologists’ patient sets.

At follow-up, quality of life as assessed by the investigator had improved for 79% and worsened for 4% of the 80 patients for whom quality of life data were reported (Figure 2A). Improvement was also experienced by 5/10 (50%) patients for whom stigma was reported as having a major impact on quality of life. Itch or itch-related sleep loss resolved in 33% and improved in 54% of patients overall (Figure 2B). Of note, very similar improvements were observed for both quality of life and itch/itch-related sleep loss measures in subsets of patients who cited those specific respective factors as the reason for seeking to transition. Overall, disease resolved in 16%, improved in 66%, and stayed the same in 15% but worsened in 3% of patients (n = 79) at the follow-up visit.

Transition of Topical Therapy Formulation in Psoriasis: Insights from a Canadian Practice Reflective - image
Figure 2. The proportion of patients for whom (A) quality of life and (B) itch or itch-related sleep loss worsened, stayed the same, improved, or resolved after transitioning from a Cal/BD ointment or gel to a Cal/BD foam. Cal/BD, calcipotriol and betamethasone dipropionate.

In each category of psoriasis severity at baseline, at least half of patients experienced improved quality of life, improved or resolved overall disease, and improved or resolved itch or itch-related sleep loss (Table 3). When grouped by baseline severity, the proportions of patients showing improved quality of life (mild: 15/17, 88%; moderate: 33/40, 83%; severe/very severe: 12/20, 60%) and improved itch or itch-related sleep loss (mild: 11/17, 65%; moderate: 20/40, 50%; severe: 11/20, 60%) were highest for the mild severity patients but roughly similar across groups; the study was not powered to draw any conclusions with respect to improvement according to baseline severity.

Outcome Psoriasis severity at baseline
Mild
n (%)		 Moderate
n (%)		 Severe/Very severe
n (%)
Number of patients 17 40 20
QoL improved 15 (88.2) 33 (82.5) 12 (60.0)
Overall disease improved or resolved 14 (82.4) 65 (87.5) 13 (65.0)
Itch or itch-related sleep loss improved or resolved 11 (64.7) 20 (50.0) 11 (55.0)
Table 3: Outcomes correlated with baseline psoriasis severity
Reported for the 77 patients for whom the baseline severity data were available. QoL, quality of life.

 

Transition was considered successful in 69 of 81 (85%) patients. Of the 12 patients for whom transition was deemed unsuccessful, 7 needed systemic treatment, including biologics (3 and 4 patients on monotherapy and combination therapy, respectively), and no improvement was seen in 2 (1 on monotherapy; 1 on combination therapy). In addition, 1 patient disliked the cosmetic features of the aerosol foam; for 2 patients, no reason was cited. The most common reasons cited for considering transition successful were that the patient reported success (40/69; 58%), signs and symptoms of psoriasis had cleared at follow-up (32/69; 46%), and the patient continued to fill prescriptions (22/69; 32%).

Discussion

In this retrospective chart review, the transition from a Cal/ BD ointment or gel formulation (Dovobet®) to a Cal/BD foam formulation (Enstilar®) was rated successful in most cases. The most common reason cited was patient-reported success, and most patients experienced improvement in the specific measure (e.g., itch or itch-related sleep loss) cited as a reason for wanting to transition. These findings are supported by results of a previous survey in which Canadian respondents generally rated Cal/BD foam as more pleasant cosmetically, relative to previously used topical products,8,9 consistent with other data that foam products are well accepted relative to other formulations.6

Transition success in the current study did not appear related to whether the patient was on mono- vs. combination therapy, as similar benefits were found in both groups. These benefits included improvements in overall disease, quality of life, and itch and itch-related sleep loss.

Itch is a pervasive challenge for psoriasis management, and itch severity is broadly associated with clinical severity.13 In this population, itch or itch-related sleep loss was reported in all severity groups. Following transition to Cal/BD foam, most patients with mild disease at baseline, as well as approximately half of others, experienced improvement or resolution of itch or itch-related sleep loss. Resolution was reported at a similar rate in the overall population and in patients for whom itch control was identified as a reason for treatment change. Given the clear disease burden associated with itch, dermatologists should ask their patients about their experience of itch and itch-related sleep loss, regardless of overall disease severity, and they should consider a change of topical treatment regimen in those who are dissatisfied with their current level of itch control.

Strengths and Limitations

This was a retrospective chart review of individuals transitioning between topical formulations, namely Cal/BD ointment or gel, to Cal/BD foam. The population may not be fully representative of Canadian psoriasis patients under a dermatologist’s care, since it would be expected to disproportionately include patients who are unsatisfied with Cal/BD gel or ointment. Due to the absence of a control group, no firm conclusions can be drawn regarding changes in symptoms of psoriasis related to the use of Cal/BD foam. For similar reasons, the findings here may not be generalized to other topical formulation transitions, including other transitions to foam formulations.

Conversely, strengths of this study include the real-world setting of treatment and the fact that the questionnaire used was developed through a pilot study that helped ensure that sufficient data could be captured for most variables of interest. It is also reassuring to note that the 9 physicians reported similar levels of treatment success among their individual patient sets, suggesting that the questionnaire was reliable and transparent to the respondents.

Conclusion

The benefits of transitioning from Cal/BD ointment or gel to aerosol foam formulation in this Canadian patient population were similar to those reported in clinical studies and were seen consistently among patients with a range of treatment priorities and with differing history of psoriasis severity and treatment history. Changing the topical treatment formulation, even without a change in active ingredients, should be considered for patients who are dissatisfied with their current topical treatment, independent of their psoriasis severity.

Acknowledgements

The authors thank the dermatologists who participated in the survey, Alice Kowalczyk, PharmD (LEO Pharma Inc. Canada) and Kristel Bermejo, PhD (imc North America, integrated medhealth communication) for contributing to the study design, and Celeste Lavallee, MSc (imc North America, integrated medhealth communication) for contributing to the data analysis and writing the article.

References



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  9. Vender R, Gooderham MJ, Guenther LC, et al. Psoriasis patients’ preference for an aerosol foam topical formulation. J Eur Acad Dermatol Venereol. 2018 Nov;32(11):e400-e1.

  10. Lind M, Nielsen KT, Schefe LH, et al. Supersaturation of calcipotriene and betamethasone dipropionate in a novel aerosol foam formulation for topical treatment of psoriasis provides enhanced bioavailability of the active ingredients. Dermatol Ther (Heidelb). 2016 Sep;6(3):413-25.

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]]> Update on Drugs & Devices: March-April 2022 https://www.skintherapyletter.com/drug-updates/march-april-2022/ Fri, 01 Apr 2022 13:25:34 +0000 https://www.skintherapyletter.com/?p=13282 Adalimumab biosimilar

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Approval Dates/Comments: In December 2021, Health Canada approved this fully human anti-tumor necrosis factor-alpha monoclonal antibody. Yuflyma™ is a high-concentration (100 mg/mL), low-volume, citrate-free, and latex-free biosimilar to Humira® (adalimumab). It is approved across all 10 intended indications for treating multiple chronic inflammatory diseases, including plaque psoriasis, psoriatic arthritis, and hidradenitis suppurativa.

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Company: Alvotech/JAMP Pharma

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Trade Name: Cibinqo®
Company: Pfizer

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Company: AbbVie

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Approval Dates/Comments: The FDA granted a new indication for this hyaluronic acid (HA)-based injectable dermal filler in February 2022 for improvement of infraorbital hollows in adults aged >21 years. This approval carries the requirement that Allergan Aesthetics must provide a product training program for all potential providers, which includes facial anatomy and considerations for safe injection in this area, as well as identification and management of complications.

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