Phase 3 data sup­porting sub­mission suggests poten­tial clin­i­cal benefit of dara­tu­mu­mab as a back­bone ther­apy in com­bi­na­tion with either a pro­te­a­some inhibitor (PI) or an immuno­modu­la­tory agent for re­lapsed multiple myeloma patients

Beerse, Belgium (Press Release) – 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 immuno­modu­la­tory 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

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is char­ac­ter­ised by an excessive proliferation of plasma cells.⁵ MM is the second most common form of blood cancer, with around 39,000 new cases world­wide in 2012.⁶ MM most commonly affects people over the age of 65 and is more common in men than in women.⁷ The most recent five-year survival data for 2000-2007 show that across Europe, up to half of newly diag­nosed patients do not reach five-year survival.⁸ Almost 29% of patients with MM will die within one year of diag­nosis.⁹ Although treat­ment may result in remission, unfortunately, patients will most likely relapse as there is cur­rently no cure. While some patients with MM have no symp­toms at all, most patients are diag­nosed due to symp­toms that can in­clude bone problems, low blood counts, cal­cium elevation, kidney problems or in­fec­tions.⁷ Patients who relapse after treat­ment with standard ther­a­pies, in­­clud­ing PIs and immuno­modu­la­tory agents, have poor prognoses and few treat­ment options avail­able.¹⁰

About Dara­tu­mu­mab

Daratumumab is a first-in-class biologic targeting CD38, a surface protein that is highly ex­pressed across multiple myeloma cells, re­gard­less of disease stage.^11-13 Dara­tu­mu­mab induces rapid tumour cell death through apop­tosis (programmed cell death)^1,14 and multiple immune-mediated mech­a­nisms of action, in­­clud­ing complement-dependent cyto­tox­icity (CDC), anti­body-dependent cellular cyto­tox­icity (ADCC) and anti­body-dependent cellular phago­cytosis (ADCP).^1,15,16 Dara­tu­mu­mab has also dem­onstrated immuno­modu­la­tory effects that con­trib­ute to tumour cell death via a de­crease in immune sup­pres­sive cells in­­clud­ing T-regs, B-regs and myeloid-derived sup­pressor cells.^1,17 Dara­tu­mu­mab is being eval­u­ated in a com­pre­hen­sive clin­i­cal devel­op­ment pro­gramme that in­cludes five Phase 3 studies across a range of treat­ment settings in multiple myeloma. Additional studies are ongoing or planned to assess its poten­tial in other malignant and pre-malignant diseases in which CD38 is ex­pressed. For more in­­for­ma­tion, please see www.clinicaltrials.gov.

The most frequently reported adverse reac­tions are in­fusion-related reac­tions (IRRs) (48%). Other frequently reported adverse reac­tions (≥ 20%) were fatigue (39%), pyrexia (21%), cough (21%), nausea (27%), back pain (23%), upper res­pira­tory tract in­fec­tion (20%), anaemia (27%), neu­tro­penia (22%) and thrombo­cytopenia (20%).¹ For further in­­for­ma­tion, please see www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004077/WC500207296.pdf.

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a world­wide agree­ment, which granted Janssen an exclusive license to develop, manu­fac­ture and commercialise dara­tu­mu­mab.

About the Janssen Pharma­ceu­tical Com­panies

At the Janssen Pharma­ceu­tical Com­panies of Johnson & Johnson, we are work­ing to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease in­spires us. We bring together the best minds and pursue the most promising science. We are Janssen. We col­lab­o­rate with the world for the health of everyone in it. Learn more at www.janssen.com/emea. Follow us at www.twitter.com/janssenEMEA.

Cautions Concerning Forward-Looking Statements

This press release con­tains "forward-looking state­ments" as defined in the Private Se­cu­ri­ties Lit­i­ga­tion Reform Act of 1995 re­gard­ing the poten­tial benefits of, and expanded indi­ca­tion for, DARZALEX® (dara­tu­mu­mab). The reader is cautioned not to rely on these for­ward-looking state­ments. These state­ments are based on current ex­pec­ta­tions of future events. If under­lying assump­tions prove inaccurate or known or unknown risks or un­cer­tain­ties ma­teri­alise, actual results could vary ma­teri­ally from the ex­pec­ta­tions and projections of Janssen-Cilag Inter­na­tional NV, any of the other Janssen Pharma­ceu­tical Com­panies and/or Johnson & Johnson. Risks and un­cer­tain­ties in­clude, but are not limited to: the un­cer­tain­ties in­her­ent in prod­uct devel­op­ment, in­­clud­ing the uncertainty of clin­i­cal success and of obtaining regu­la­tory approvals; uncertainty of commercial success; manu­fac­tur­ing dif­fi­culties and delays; com­pe­ti­tion, in­­clud­ing technological ad­vances, new prod­ucts and patents attained by com­pet­i­tors; chal­lenges to patents; prod­uct efficacy or safety con­cerns resulting in prod­uct recalls or regu­la­tory action; changes in behaviour and spending patterns or financial distress of purchasers of health care prod­ucts and services; changes to appli­­cable laws and reg­u­la­tions, in­­clud­ing global health care reforms; and trends to­ward health care cost con­tainment. A further list and description of these risks, un­cer­tain­ties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 3, 2016, in­­clud­ing in Exhibit 99 thereto, and the com­pany's sub­se­quent filings with the Se­cu­ri­ties and Exchange Com­mis­sion. Copies of these filings are avail­able online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharma­ceu­tical Com­panies or Johnson & Johnson under­takes to update any for­ward-looking state­ment as a result of new in­­for­ma­tion or future events or devel­op­ments.

References

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.

Source: Janssen.