KYOWA-KIRIN-INTERNATIONA

Kyowa Kirin International PLC (Kyowa Kirin), a wholly owned subsidiary of Kyowa Kirin Co., Ltd., today announced data from a post hoc analysis of the MAVORIC trial. The analysis compared the efficacy and safety of POTELIGEO^® ▼ (mogamulizumab) with vorinostat by patient blood classification in adult patients with mycosis fungoides (MF) and Sézary syndrome (SS), two types of CTCL.¹ The data showed that higher levels of blood tumour involvement were associated with better patient outcomes in patients treated with mogamulizumab, compared to vorinostat.¹

MF and SS are subtypes of CTCL, a rare type of non-Hodgkin's lymphoma that can affect the skin, blood, lymph nodes and internal organs.² In MAVORIC, overall investigator-assessed progression-free survival (PFS) was significantly greater for patients treated with mogamulizumab compared to vorinostat, at 7.7 months and 3.1 months, respectively (P <0.0001).^{1 When data were stratified by blood classification, PFS was found to be significantly greater for mogamulizumab compared to vorinostat in patients with higher levels of blood involvement, known as B1 and B2 blood classifications.1}

Professor Julia Scarisbrick, Consultant Dermatologist, lead author of this analysis from the study said: “In MF and SS, assessing the stage of the disease is key to prognosis, appropriate treatment and patient outcome. Assessment of blood involvement is part of this staging process. The data highlights that mogamulizumab is more effective in MF and SS patients who have blood involvement as part of their disease. Blood involvement is relatively common in the more advanced stages of CTCL and may be present in as many as 20% of less advanced cases.³ This new information could help improve the clinical management of MF and SS patients and highlights the need for blood monitoring.”

Overall response rate (ORR) was also significantly greater for mogamulizumab than vorinostat in the MAVORIC trial at 28% and 5% respectively (P<0.0001).^{1 In this analysis, ORR was also found to be significantly greater for mogamulizumab than vorinostat in patients with B2 blood classification.1 Difference in ORR for patients with B1 blood classification was not significant between the two treatment groups.1 Difference in time-to-next-treatment (TTNT) was not significant for patients without blood involvement (B0 classification), but was significantly greater for mogamulizumab in patients with B1 or B2 blood involvement, 13.70 vs 3.30 months for mogamulizumab and vorinostat, respectively (P <0.0001).1 Drug-related treatment-emergent adverse events (TEAEs) were similar in patients regardless of blood involvement and were lower for mogamulizumab than vorinostat at each blood classification level.1}

Danie du Plessis, Executive Vice President, Medical Affairs (EMEA) at Kyowa Kirin, commented: “We welcome the results of this analysis in furthering our understanding of the role of mogamulizumab in treating MF and SS patients. Research suggests that patients with B1 and B2 blood classifications may have reductions in median survival and an increased risk of disease progression, compared to those classified as B0.⁴ Through our work with this therapy, we are aiming to address the unmet needs in these patient populations and are dedicated to improving outcomes for people with MF and SS.”

The data will be presented today in a poster session at the 16^th European Association of Dermato Oncology (EADO) Congress.¹

About Mycosis Fungoides (MF) and Sézary syndrome (SS)
MF and SS are subtypes of cutaneous T-cell lymphoma (CTCL), a rare type of non-Hodgkin's lymphoma that can affect the skin, blood, lymph nodes and internal organs.² CTCL is rare. For every 100,000 people in Europe, there are approximately 24 cases of CTCL.⁵ Together they represent approximately 65% of all cases of CTCL.² Individuals with this disease often suffer from disfiguring, itchy, painful and unpredictable skin symptoms, which can lead to further complications that can impact their life expectancy.^6,7

MF and SS are characterised by localisation of cancerous white blood cells called T lymphocytes (T cells), to the skin.^8,9 These cancerous T cells consistently express a protein called CC-chemokine receptor 4 (CCR4), which enables them to move from the blood to the skin.^10,11,12 When these cancerous T cells move to the skin, they can create a localised inflammatory immune skin response, commonly resulting in visible skin symptoms of red patches or plaques, ^{10,13,14,15,16} which can resemble psoriasis or eczema.⁸

MF and SS can affect the skin, blood, lymph nodes (part of the body’s immune system which is spread throughout the body) and internal organs.² All four areas of the body are used to assess disease stage^17,18 and clinically significant involvement of the blood, particularly in more advanced disease, is linked with increased morbidity and an overall reduction in patient survival.^17,19,20

Due to its likeness to more common skin conditions such as eczema and psoriasis,⁸ CTCL can take, on average, between 2 and 7 years for individuals to receive a confirmed diagnosis.²¹ It is critical for doctors to diagnose CTCL as early as possible as the patient’s prognosis can be affected if the disease progresses to later stages.⁴ Whilst most individuals that present with early stage do not progress to a more advanced stage,²² patients with advanced disease have significantly poorer outcomes with only around half of patients (52%) surviving for just 5 years.¹⁷

About POTELIGEO ^® (mogamulizumab)
POTELIGEO is a first-in-class humanised monoclonal antibody (mAb), designed to bind to CC chemokine receptor 4 (CCR4).⁷ After POTELIGEO binds to CCR4, it increases affinity of immune cells from the immune system to target the cancerous cells.²³ POTELIGEO uses Kyowa Kirin’s proprietary POTELLIGENT^® technology.²³

Following a positive opinion from Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), the European Commission (EC) granted marketing authorisation for POTELIGEO in November 2018 for the treatment of adult patients with MF or SS who have received at least one prior systemic therapy.²⁴ The CHMP’s opinion was based on results of the MAVORIC trial, the largest randomised study of systemic therapy in MF and SS,⁷ and the first trial to compare systemic therapies using progression-free survival as a primary endpoint.⁷

About the MAVORIC Trial

• The MAVORIC trial is the largest randomised study of systemic therapy conducted in MF and SS,⁷ and the first trial to compare systemic therapies using ‘progression-free survival’ (PFS) as a primary endpoint, which incorporates looking at disease progression in four different compartments of the body (skin, blood, lymph nodes and internal organs).⁷
• Secondary endpoints were overall response rate; duration of response (time from first achievement of an overall response to progression or death); the proportion of patients with an overall response in the crossover portion of the trial; assessment of quality of life; immunogenicity (immune response) and safety.⁷
• Results showed that:
  • In patients taking POTELIGEO disease was controlled for more than twice as long as in those taking the comparator treatment, vorinostat^* (PFS of 7.7 mths vs 3.1 mths) (HR=0.53, 95% CI: 0.41–0.69; p<0.0001).⁷
  • Overall significantly more patients responded to POTELIGEO than vorinostat^* (Overall Response Rate [ORR] 28% versus 5%; Risk Ratio [RR]: 23.1; 95% CI 12.8–33.1, P<0.0001).⁷
  • Response to treatment lasted 43% longer in people taking POTELIGEO versus those taking vorinostat^* (14.1 months versus 9.1 months).⁷
  • More patients responded to POTELIGEO, across all studied MF/SS disease stages than with vorinostat.^{* 7}
  • POTELIGEO has overall good tolerability with a manageable safety profile.^7,25
  • The most common adverse reactions with POTELIGEO are constipation, diarrhoea, nausea, stomatitis, fatigue, oedema (peripheral), pyrexia, infections, infusion related reactions, headache and drug eruption (including skin rash).²⁴

^{-------------------------------------------------------------------------------------------
*} Vorinostat is a USA FDA-licensed existing treatment for MF and SS and is currently unlicensed in the EU

Important Safety Information
Refer to the full Summary of Product Characteristics (SmPC) for full safety information: https://www.ema.europa.eu/en/medicines/human/EPAR/poteligeo#product-information-section

About Kyowa Kirin
Kyowa Kirin commits to innovative drug discovery driven by state-of-the-art technologies. The company focuses on creating new values in the four therapeutic areas: nephrology, oncology, immunology/allergy and neurology. Under the Kyowa Kirin brand, the employees from 40 group companies across North America, EMEA, and Asia/Oceania unite to champion the interests of patients and their caregivers in discovering solutions wherever there are unmet medical needs.

You can learn more about Kyowa Kirin at: https://www.kyowakirin.com/

Kyowa Kirin International
http://www.international.kyowa-kirin.com / www.kyowakirin.com
Galabank Business Park
Galashiels, TD1 1QH
United Kingdom

References

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¹ Scarisbrick J, et al. Efficacy and Safety of Mogamulizumab by Patient Blood Classification. Abstract from 16 European Association of Dermato Oncology Congress. 2020;1-4.

² Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110(6):1713-22.

³ Scarisbrick JJ, Quaglino P, Prince HM, et al. The PROCLIPI international registry of early-stage mycosis fungoides identifies substantial diagnostic delay in most patients. Br J Dermatol. 2019;181:350–357.

⁴ Agar N, et al. Survival Outcomes and Prognostic Factors in Mycosis Fungoides/Sezary Syndrome: Validation of the Revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer Staging Proposal. J Clin Ocol. 2010;28(31):4730-4739.

⁵ Orphanet: Prevalence and incidence of rare diseases: Bibliographic data. Available from: https://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_decreasing_prevalence_or_cases.pdf . Last accessed: September 2020.

⁶ Haun P, et al. Fast Facts: Diagnosing Cutaneous T-Cell Lymphoma. Karger Publishing. 2016.

⁷ Kim YH, Bagot M, Pinter-Brown L, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(9):1192-1204.

⁸ Cutaneous Lymphoma Foundation, Lymphoma Action and Lymphoma Coalition Europe. Cutaneous lymphoma – a patient’s guide. 2019. Available from: https://lymphoma-action.org.uk/sites/default/files/media/documents/2019-06/Cutaneous%20lymphoma%20-%20patient%26%23039%3Bs%20guide%20-%20English%20language%20source%20document%20-%20final%20version%20for%20publication%20-%20April%202019.pdf . Last accessed: September 2020.

⁹ Mariani M, Lang R, Binda E, et al. Dominance of CCL22 over CCL17 in induction of chemokine receptor CCR4 desensitization and internalization on human Th2 cells. Eur J Immunol. 2004;34(1):231-240.

¹⁰ Ferenczi K, Fuhlbrigge RC, Pinkus J, et al. Increased CCR4 expression in cutaneous T cell lymphoma. J Invest Dermatol. 2002;119:1405-10.

¹¹ Yoshie O, et al. Frequent Expression of CCR4 in Adult T-Cell Leukemia and Human T-cell Leukemia Virus Type 1-transformed T cells. Blood. 2002;99(5):1505-11.

¹² Ishida T, et al. Clinical Significance of CCR4 Expression in Adult T-cell Leukemia/Lymphoma: Its Close Association With Skin Involvement and Unfavorable Outcome. Clin Cancer Res. 2003;9:3625-34.

¹³ Wilcox RA. Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(1):151-65.

¹⁴ Ni X, Jorgensen JL, Goswami M, et al. Reduction of regulatory T cells by Mogamulizumab, a defucosylated anti-CC chemokine receptor 4 antibody, in patients with aggressive/refractory mycosis fungoides and Sézary syndrome. Clin Cancer Res. 2014;21(2):274-85.

¹⁵ Kakinuma T, Sugaya M, Nakamura K, et al. Hymus and activation-regulated chemokine (TARC/CCL17) in mycosis fungoides: serum TARC levels reflect the disease activity of mycosis fungoides. J Am Acad Dermatol. 2003;48(1):23-30.

¹⁶ Girardi M, Heald PW, Wilson LD. The Pathogenesis of Mycosis Fungoides. NEJM. 2004;350(19):1978-88.

¹⁷ Scarisbrick JJ, Prince M, Vermeer MH, et al. Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model. J Clin Oncol. 2015;33(32):3766-3773.

¹⁸ Willemze R, Hodak E, Zinzani PL et al. Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(4):1-29.

¹⁹ Kim EJ, Hess S, Richardson SK, et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest. 2005;115(4):798-812.

²⁰ Scarisbrick JJ, Whittaker, S, Evans, AV, et al. Prognostic significance of tumor burden in the blood of patients with erythrodermic primary cutaneous T-cell lymphoma. Blood. 2001;97(3):624-30.

²¹ CL Foundation: A Patient’s Guide. Available from: https://www.clfoundation.org/sites/default/files/2018-04/a_patients_guide.pdf . Last Accessed: September 2020

²² Krejsgaard T, Lindahl LM, Mongan NP, et al. Malignant inflammation in cutaneous T-cell lymphoma—a hostile takeover. Semin Immunopathol. 2017;39(3):269–282.

²³ Duvic M, et al. Mogamulizumab for the treatment of cutaneous T-cell lymphoma: recent advances and clinical potential. Ther Adv Hematol. 2016;7(3):171-174.

²⁴ POTELIGEO SMPC. Available from: https://www.ema.europa.eu/en/documents/product-information/poteligeo-epar-product-information_en.pdf Last accessed: September 2020.

²⁵ Kim YH, Bagot M, Zinzani PL et al. Safety of Mogamulizumab in Mycosis Fungoides and Sézary Syndrome: Final Results from the Phase 3 Mavoric Study. Blood. 2019;134 (1):5300.

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