Arzerra®? (ofatumumab) receives conditional European marketing authorisation for refractory chronic lymphocytic leukaemia (CLL)

Novel small loop binding anti-CD20 antibody offers new option for refractory CLL patients who have limited remaining treatment options


GlaxoSmithKline (GSK) announced today that the European Medicines Agency (EMA) has granted a conditional marketing authorisation for Arzerra® (ofatumumab), for the treatment of chronic lymphocytic leukaemia (CLL) in patients who are refractory to fludarabine and alemtuzumab.1

Arzerra is a new monoclonal antibody that has a unique mode of action, which allows it to bind to the small loop of the CD20 molecule that is found on the surface of B-lymphocytes.2,3,4,5 This binding leads to the destruction of cancer cells by the body’s immune system.2,3,4,5

Nearly all patients with CLL ultimately relapse and it therefore remains an incurable disease.6,7 The overall aim is to reduce symptoms and delay disease progression.7 Patients with refractory CLL have limited therapeutic options and poor outcomes.8 The overall response rate (ORR) to existing salvage therapy for such patients is approximately 20%,8 and the prognosis for patients who are refractory to both fludarabine and alemtuzumab is very poor, with a median survival of 8 months.8 Such patients are also prone to infections due to disease and therapy-related immunosuppression.8

Professor of Haematology, Andrew Pettitt, from the Liverpool Cancer Research UK Centre commented, ‘Because CLL is a disease that keeps coming back each time it is treated, extending the life of patients with the disease means finding new treatments that can work when other treatments have failed. Ofatumumab does just that, and this is what makes the drug such an important development for patients with CLL.’

Arzerra data

Conditional marketing authorisation for Arzerra is based on the results from a clinical trial including 59 patients refractory to fludarabine and alemtuzumab therapy.1,9

A 58% overall response rate was observed in the study.1,9 Median progression free survival and overall survival were 5.7 and 13.7 months respectively.1,9 Complete resolution of lymphadenopathy (chronic abnormal enlargement of the lymph nodes) (nodes <1cm), splenomegaly (abnormal enlargement of the spleen), hepatomegaly (abnormal enlargement of the liver) and constitutional symptoms in patients were 16, 47, 50 and 48% respectively.1,9 Improvements in haemoglobin levels and platelet counts were also observed.9

Arzerra was shown to be generally well tolerated.9 The most common Arzerra-related grade III or IV adverse events were infections and neutropenia.9 Infusion site reactions are associated with the use of Arzerra, although these predominantly occur after the first infusion.1,9 Other very common side effects include lower respiratory tract infection, including pneumonia, upper respiratory tract infection, neutropenia and anaemia.1,9


About CLL

About 70-80% of all new cases of CLL are chance findings on a routine blood test, and between 40-60% of all patients are free of symptoms at the time of diagnosis.10

CLL is the most common leukaemia in the Western world, accounting for approximately 25% of all leukaemias.11

In the UK, approximately 2,750 new cases of CLL are diagnosed in each year11 and the disease was responsible for approximately 1,015 deaths in the UK in 2008.12


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Notes to editors:

About Arzerra: a novel human monoclonal antibody
Arzerra is a novel human monoclonal antibody with a unique mode of action.1 It targets unique parts of the CD20 molecule which is expressed on the surface of B-lymphocytes.2,3,4,5 The CD20 molecule is a key target in CLL therapy, because it is expressed in most B-cell malignancies.13 Once ofatumumab binds to the CD20 protein, it triggers the body’s immune system to destroy the cell.1,4,5

About the Arzerra licence
EMA has issued conditional marketing authorisation of Arzerra for infusion intended for the treatment of patients with CLL who are refractory to fludarabine and alemtuzumab.1 In addition, orphan drug designation was granted by the European Commission for Arzerra on 7 November 2008.14 A conditional marketing authorisation is granted to a medicinal product with a positive benefit/risk assessment that fulfils an unmet medical need when the benefit to public health of immediate availability outweighs the risk inherent in the fact that additional data are still required. A conditional marketing authorisation is renewable annually. As part of the conditions of the conditional marketing authorisation for Arzerra, GSK will be required to provide further data.

About GlaxoSmithKline in Oncology
GlaxoSmithKline Oncology is dedicated to producing innovations in cancer that will make profound differences in the lives of patients. Through GSK’s revolutionary ‘bench to bedside’ approach, we are transforming the way treatments are discovered and developed, resulting in one of the most robust pipelines in the oncology sector. Our worldwide research in oncology includes collaborations with more than 160 cancer centres. GSK is closing in on cancer from all sides with a new generation of patient-focused cancer treatments in prevention, supportive care, chemotherapy and targeted therapies.

About GlaxoSmithKline
GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information please visit www.gsk.com.


Enquiries:
UK Media enquiries: GSK: Philippa Mallaband 020 8990 2980
Packer Forbes 020 8772 1551



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Arzerra® is a registered trade mark of the GlaxoSmithKline group of companies in the US, Europe, Asia-Pacific, Japan and emerging countries.

References

1. Arzerra Summary of Product Characteristics

2. Polyak MJ, Deans JP. Alanine-170 and proline-172 are critical determinants for extracellular CD20 epitopes; heterogeneity in the fine specificity of CD20monoclonal antibodies is defined by additional requirements imposed by both amino acid sequence and quaternary structure. Blood 2002; 99: 3256-3262

3. Teeling JL, Mackus WJ, Wiegman LJ. et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 2006; 177: 362-71

4. Beum PV, Lindorfer MA, Beurskens F, Stukenberg PT, Lokhorst HM, Pawluczkowycz AW, et al. Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis. J Immunol 2008; 181: 822-832.

5. Pawluczkowycz AW, Beurskens FJ, Beum PV, Lindorfer MA, van deWinkel JG, Parren PW, et al. Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX. J Immunol 2009; 183: 749-758.

6. Dighiero G, Hamlin TJ. Chronic lymphocytic leukaemia. Lancet 2008; 371: 1017–1029

7. Shanafelt D, MD, Call T.G, MD. Current Approach to Diagnosis and Management of Chronic Lymphocytic Leukemia. Mayo Clin Proc. 2004;79:388-398

8. Tam CS, O'Brien S, Lerner S. et al. The natural history of fludarabine-refractory chronic lymphocytic leukaemia patients who fail alemtuzumab or have bulky lymphadenopathy. Leukemia and Lymphoma. 2007; 48(10): 1931-1939

9. Wierda W, Kipps T,Mayer J, Stilgenbauer S,Williams C, Hellmann A, et al. Ofatumumab as single agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. In press 2009.

10. Leukaemia Research Fund. Chronic Lymphocytic Leukaemia & CLL booklet. Available at http://www.lrf.org.uk/en/1/discllhome.html. Accessed February 2010

11. Kalil et al. Chronic Lymphocytic Leukaemia. The Oncologist. 1999;4:352-369

12. Office for National Statistics. Mortality statistics: Deaths registered in 2008. Available at http//www.statistics.gov.uk/downloads/theme_health/DR2008/DR_8.pdf. Accessed November 2009.

13. Cragg M S, Walshe CA, Ivanov AO. et al. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 2005; 8: 140-74

14. EMA Committee for Orphan Medicinal Products Public summary of positive opinion for orphan designation of ofatumumab for the treatment of chronic lymphocytic leukaemia. http://www.ema.europa.eu/pdfs/human/comp/opinion/48024408en.pdf. Accessed February 2010