Simultaneous applications submitted to FDA and EMA for siltuximab for the treatment of MCD, a rare blood disorder

Janssen Research & Development, LLC (“Janssen”) announced the simultaneous submissions of a Biologic License Application (BLA) to the United States Food and Drug Administration (U.S. FDA) and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for siltuximab for the treatment of patients with multicentric Castleman disease (MCD) who are HIV-negative and human herpes virus-8 (HHV-8)-negative.

MCD is a rare disorder in which lymphocytes, a certain type of white blood cells, are over-produced and lead to enlargement of lymph nodes.[1,2] This can cause a variety of symptoms and weaken the immune system, making it hard to fight infection. Infections in people with MCD can be very serious and may even be fatal.[3] Currently, there are no approved treatments in the U.S. or European Union (EU) for this rare blood disorder.

“We’re proud of our work on siltuximab. As a rare disease with a small patient population, MCD is an area of significant unmet need,” said Peter F. Lebowitz, M.D., Ph.D., global oncology therapeutic area head, Janssen. “Siltuximab works by targeting interleukin-6 which appears to be the critical driver of this disease. By focusing on core biologic mechanisms, we now have the potential of helping patients with a condition that is challenging to treat.”

Siltuximab has been granted orphan drug status in MCD in the U.S. and EU. The siltuximab regulatory submissions include data from a randomized, multi-national, double-blind, placebo-controlled study (MCD2001) and data from two non-randomized supportive studies. The MCD2001 study assessed the efficacy and safety of siltuximab plus best supportive care (BSC) compared with placebo plus BSC in patients with MCD.[4] In the study, 79 patients were randomly assigned in a 2:1 ratio to one of the two treatment groups, with 53 receiving siltuximab and BSC, and 26 receiving placebo and BSC.[5] Results of the primary study analysis have been submitted for presentation at a medical meeting later this year.

About Multicentric Castleman Disease

Unlike “unicentric” Castleman disease, which is localized and affects only a single area or group of lymph nodes,[6] patients with MCD have more than one group of lymph nodes in different anatomical areas that are affected.[3] Unicentric disease can be treated by surgically removing the diseased lymph node,[7] while multicentric disease is usually much more difficult to treat.[8] Currently, the focus of care is to reduce lymph node masses[9], [10] and to attempt to put the disease in remission through a combination of treatments, including corticosteroids, chemotherapy and immunotherapy. While such treatments may initially help, the disease often returns.[8]

MCD can also affect lymphoid tissue of internal organs, causing the liver, spleen, or other organs to enlarge.[11] Some symptoms can be life threatening.[9,10] The most common symptoms include fever, weakness, fatigue, night sweats, weight loss, loss of appetite, nausea, vomiting and nerve damage that leads to numbness and weakness.[3] Infections, renal failure, and malignancies including malignant lymphoma and Kaposi’s sarcoma are common causes of death in patients with MCD.[9,10] Castleman disease is formally diagnosed through a biopsy.[11] The number of people diagnosed with Castleman disease is unknown, but the disease is known to be rare.[12]

About Siltuximab

Siltuximab is an investigational, anti Interleukin-6 (IL-6) chimeric monoclonal antibody that targets and binds to human IL-6. IL-6 is a multifunctional cytokine produced by various cells such as T cells, B cells, monocytes, fibroblasts and endothelial cells.[6] Dysregulated, or imbalanced, overproduction of IL-6 from activated B cells in affected lymph nodes has been implicated in the pathogenesis of MCD.[6] Information about ongoing studies with siltuximab can be found on clinicaltrials.gov.

References:

1. American Cancer Society. What is Castleman disease? Available from: http://www.cancer.org/cancer/castlemandisease/detailedguide/castleman-disease-what-is-castleman-disease. Accessed August 2013
2. Memorial Sloan Kettering Cancer Center. Uncommon Lymphoproliferative Disorders. Available from: http://www.mskcc.org/cancer-care/adult/rare-hematologic-disorders/uncommon-lymphoproliferative-disorders. Accessed August 2013.
3. National Center for Advancing Translational Sciences. Multicentric Castleman’s Disease. Available from: http://rarediseases.info.nih.gov/gard/9644/idiopathic-multicentric-castlemans-disease/resources/1 Accessed August 2013.
4. A Study to Evaluate the Efficacy and Safety of CNTO328 Plus Best Supportive Care in Multicentric Castleman’s Disease: Available from: http://clinicaltrials.gov/ct2/show/NCT01024036?term=MCD2001&rank=1.Accessed August 2013
5. Internal data on file
6. El-Osta HE, Kurzrock R. Castleman’s disease: from basic mechanisms to molecular therapeutics. Oncologist. 2011;16(4):497-511.
7. American Cancer Society. Treatment of localized (unicentric) Castleman disease. Available from: http://www.cancer.org/cancer/castlemandisease/detailedguide/castleman-disease-treating-treating-localized. Accessed August 2013
8. American Cancer Society. Treatment of multicentric Castleman disease. Available from: http://www.cancer.org/cancer/castlemandisease/detailedguide/castleman-disease-treating-treating-multicentric. Accessed August 2013
9. Peterson, B. Seminars in Oncology. Multicentric Castleman’s disease. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8296200 Accessed August 2013
10. Greiner, T. Hematology Am Soc Hematol Educ Program. Atypical Lymphoproliferative Diseases. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11701539 Accessed August 2013
11. American Cancer Society. How is Castleman disease diagnosed? Available from: http://www.cancer.org/cancer/castlemandisease/detailedguide/castleman-disease-diagnosis Accessed August 2013
12. American Cancer Society.What are the key statistics about Castleman disease? Available from: http://www.cancer.org/cancer/castlemandisease/detailedguide/castleman-disease-key-statistics . Accessed August 2013