Janssen-Cilag Announces Submission of Type 2 Variation App for DARZALEX in Europe (JNJ)

August 23, 2016 7:57 AM EDT

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Janssen-Cilag International NV today announced the submission of a Type II variation application to the European Medicines Agency (EMA), seeking to broaden the existing marketing authorisation for the immunotherapy DARZALEX (daratumumab) to include treatment of adult patients with relapsed multiple myeloma who have received at least one prior therapy. The expanded indication is based on daratumumab in combination with lenalidomide (an immmunomodulatory agent) and dexamethasone, or bortezomib (a PI) and dexamethasone.

Daratumumab is currently approved by the European Commission (EC) for monotherapy of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent, and who have demonstrated disease progression on the last therapy.1

“Despite remarkable advances over recent years, multiple myeloma remains an incurable illness. We are therefore excited to take an important step forward in further realising the potential of daratumumab, and its possible benefit as a backbone therapy in multiple myeloma treatment,” said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa. “We look forward to working closely with the EMA throughout the review process and remain committed to exploring the full clinical benefit of this compound for patients who are awaiting new options.”

The regulatory submission is now pending validation by the EMA and is primarily supported by data from two Phase 3 studies, in patients with multiple myeloma who have received one or more prior lines of therapy, showing combination of daratumumab with a PI or immunomodulatory agent resulted in a >60% reduction in the risk of disease progression or death.2,3

  • The MMY3004 (CASTOR) clinical trial evaluated daratumumab in combination with bortezomib and dexamethasone, compared to bortezomib and dexamethasone alone. Study results were previously presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) and at the 21st Annual Congress of the European Hematology Association (EHA) in June 2016.2
  • The MMY3003 (POLLUX) clinical trial evaluated daratumumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone. Findings were presented at EHA in June 2016.3

The submission also included data from the Phase 1 study of daratumumab in combination with pomalidomide and dexamethasone in patients who received at least two prior lines of therapy. More information on these trials can be found at www.clinicaltrials.gov (NCT02076009, NCT02136134 and NCT01998971).

The Type II variation application follows the recent submission to the U.S. Food and Drug Administration (FDA) of a supplemental Biologics License Application for daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone for treatment of patients with multiple myeloma who have received at least one prior therapy. In addition, on 25 July, 2016 Janssen announced that the FDA granted a Breakthrough Therapy Designation for daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. This marks the second Breakthrough Therapy Designation for daratumumab in the U.S., which is intended to expedite the development and review timelines of potential new medicines to treat serious or life-threatening diseases, where preliminary clinical evidence shows that the medicine may provide substantial improvement over existing therapies.4


1. European Medicines Agency. DARZALEX summary of product characteristics, May 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004077/WC500207296.pdf Last accessed August 2016.

2. Palumbo A, Chanan-Khan AA, Weisel K, et al. Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study. J Clin Oncol. 2016;34(Suppl.)(abstract LBA4).

3. Dimopoulos M, Oriol A, Nahi H, et al. An open-label, randomised phase 3 study of daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): Pollux. Haematologica. 2016;101(Suppl.1):342 (abstract LB2238).

4. Janssen Research & Development, LLC. Daratumumab (DARZALEX®) Granted Breakthrough Therapy Designation by U.S. Food and Drug Administration (FDA) for Use in Combination with Standard of Care Regimens for Patients with Multiple Myeloma. Available at: http://www.jnj.com/news/all/Daratumumab-DARZALEX-Granted-Breakthrough-Therapy-Designation-by-US-Food-and-Drug-Administration-for-Use-in-Combination-with-Standard-of-Care-Regimens-for-Patients-with-Multiple-Myeloma Last accessed August 2016.

5. American Society of Clinical Oncology. Multiple myeloma: overview. Available at: http://www.cancer.net/cancer-types/multiple-myeloma/overview Last accessed August 2016.

6. GLOBOCAN 2012. Multiple myeloma. Available at: http://globocan.iarc.fr/old/burden.asp?selection_pop=62968&Textp=Europe&selection_cancer=17270&Text-c=Multiple+myeloma&pYear=13&type=0&window=1&submit=%C2%A0Execute Last accessed August 2016.

7. American Cancer Society. Multiple myeloma: detailed guide. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf. Last accessed August 2016.

8. De Angelis R, Minicozzi P, Sant M, et al. Survival variations by country and age for lymphoid and myeloid malignancies in Europe 2000-2007: results of EUROCARE-5 population-based study. Eur J Cancer. 2015;51:2254-68.

9. Costa LJ, Gonsalves WI, Kumar SK. Early mortality in multiple myeloma. Leukemia. 2015;29:1616-8.

10. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26:149-57.

11. Fedele G, di Girolamo M, Recine U, et al. CD38 ligation in peripheral blood mononuclear cells of myeloma patients induces release of protumorigenic IL-6 and impaired secretion of IFNgamma cytokines and proliferation. Mediat Inflamm. 2013;2013:564687.

12. Lin P, Owens R, Tricot G, et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121:482-8.

13. Santoconito AM, Consoli U, Bagnato S et al. Flow cytometric detection of aneuploid CD38++ plasmacells and CD19+ B-lymphocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma patients. Leuk Res. 2004;28:469-77.

14. Overdijk MB, Jansen JH, Nederend M, et al. The Therapeutic CD38 Monoclonal Antibody Daratumumab Induces Programmed Cell Death via Fcy Receptor-Mediated Cross-Linking. J Immunol. 2016;197(3):807-13.

15. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186:1840-8.

16. Overdijk MB, Verploegen S, Bögels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7:311-21.

17. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384-94.

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KATOMKI H on 2016-08-30 05:18:17
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YUMIKA T on 2016-08-30 05:08:24
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GREG N Guyen on 2016-08-30 05:04:29
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Sandy Cartman on 2016-08-30 04:57:16
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