Beerse, Belgium (Press Release) – Janssen-Cilag Inter­na­tional NV announced today it has submitted a new Marketing Authorisation Application to the European Medicines Agency (EMA) for dara­tu­mu­mab, an in­ves­ti­ga­tional, human anti-CD38 mono­clonal anti­body, for the treat­ment of patients with re­lapsed and refractory multiple myeloma.

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is char­ac­ter­ised by excess growth and survival of malignant plasma cells.^[1] Patients who are refractory to both pro­te­a­some inhibitors (PIs) or immuno­modu­la­tory agents (IMiDs) have a poor prognosis, with an esti­mated median over­all survival of nine months.^[2]

Daratumumab works by binding to CD38, a signalling molecule found on the surface of multiple myeloma cells.^{[3],[4],[5],[6]} In doing so, dara­tu­mu­mab triggers the patient's own immune sys­tem to attack the cancer cells, resulting in rapid tumour cell death through multiple immune-mediated and other mech­a­nisms of action.^[7]

The regu­la­tory sub­mission for dara­tu­mu­mab is now pending val­i­da­tion by the EMA and is based on data from the Phase 2 MMY2002 (SIRIUS) mono­therapy study, which was presented at the 51^st Annual Meeting of the American Society of Clinical Oncology (ASCO),^[8] data from the Phase 1/2 GEN501 mono­therapy study, which was recently published in The New England Journal of Medicine,^[9] and data from three sup­port­ive studies.

For MMY2002, the pri­mary efficacy end­point was over­all response rate (ORR). Ninety-five per­cent of patients in the study were double refractory to a PI and IMiD. Patients received three or more lines of prior ther­apy (median of five), in­­clud­ing a PI and an IMiD. Dara­tu­mu­mab achieved an ORR of 29 per­cent in the group of patients who received 16 mg/kg (n=106) as a single-agent ther­apy, with a well tolerated safety profile.^[8]

The ORR out­comes of MMY2002 are similar to the ORR data in the Phase 1/2 GEN501 study, in which safety was the pri­mary end­point. Patients enrolled in GEN501 received two or more lines of prior ther­apy (median four), in­­clud­ing a PI and an IMiD, and 64 per­cent were refractory to both PIs and IMiDs. In this study, dara­tu­mu­mab dem­onstrated a tolerable safety profile and achieved an ORR of 36 per­cent (11 partial responses, two very good partial responses and two com­plete responses) in the group of patients who received 16 mg/kg, with responses im­prov­ing over time. Median pro­gres­sion-free survival was 5.6 months (95% CI: 4.2, 8.1) and 65 per­cent (95% CI: 28, 68) of responders remained in remission at 12 months. The OS rate at 12 months was 77 per­cent (95% CI: 58, 88).^[9]

"For more than a decade Janssen has focused on addressing unmet needs in multiple myeloma which, despite im­por­tant ad­vances, still remains an incurable cancer," said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa. "Through our con­tinued commitment to research into new ther­a­pies and inno­va­tive mech­a­nisms, we are en­cour­aged to see the depth of thera­peutic response with dara­tu­mu­mab. This is particularly promising for re­lapsed and refractory patients who have a poor prognosis and may already have exhausted all existing treat­ment options. We look for­ward to work­ing with the EMA to make dara­tu­mu­mab avail­able for people with multiple myeloma."

In July 2013 dara­tu­mu­mab was granted Orphan Drug Status by the EMA for the treat­ment of plasma cell myeloma.^[10] Further­more, this new EMA sub­mission follows the acceptance for Priority Review of the Biologics License Application for dara­tu­mu­mab with the U.S. FDA on September 4, 2015.

In August 2012, Janssen Biotech, Inc. and Genmab entered an agree­ment which granted Janssen an exclusive world­wide license to develop, manu­fac­ture, and commercialise dara­tu­mu­mab. Janssen is cur­rently the sponsor of all but one study globally.

About MMY2002 Study

MMY2002 enrolled a pop­u­la­tion of patients with heavily pre-treated (three or more lines of prior ther­apy; median of five, in­­clud­ing a PI and an IMiD) or double refractory multiple myeloma who had exhausted effective treat­ments. In patients who received 16 mg/kg (n=106) as a single-agent ther­apy with a tolerable safety profile, stringent com­plete responses (sCR) were achieved in three patients, very good partial responses in 10 patients, and 18 partial responses (PR) were reported. No patients dis­con­tinued treat­ment due to in­fusion-related reac­tions (IRRs) and 4.7 per­cent of patients dis­con­tinued treat­ment due to adverse events (AEs), none of which were con­sidered drug-related.^[8]

About GEN501 Study

Safety was the pri­mary end­point in the GEN501 study, which enrolled a pop­u­la­tion of patients with heavily pre-treated (two or more lines of prior ther­apy; median of four, in­­clud­ing a PI and an IMiD) or double refractory multiple myeloma who have exhausted effective treat­ments. In the 16 mg/kg cohort, serious AEs occurred in 33 per­cent of patients. IRRs occurred in 71 per­cent of patients in the 8 mg/kg and 16 mg/kg cohorts, and all were Grades 1 and 2, with the occurrence of one patient with Grade 3 reac­tions. The majority of IRRs occurred during the first in­fusion, with notably fewer during sub­se­quent in­fusions. No patient dis­con­tinued treat­ment due to an IRR. The most common AEs in either treat­ment group were fatigue, allergic rhinitis, and pyrexia (fever). The most frequent hema­to­logic AE was neu­tro­penia (abnormally low levels of neu­tro­phils, a type of white blood cell), which occurred in 12 per­cent of patients (n=5) in the 16 mg/kg cohort. Grade 3 or 4 AEs were reported in 26 per­cent of patients in the 16 mg/kg cohort, with pneu­monia (n=5) and thrombo­cytopenia (abnormally low levels of platelets in the blood; n=4) as the most common in both the 8 mg/kg and 16 mg/kg cohorts.^[9]

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.^[1] MM is the second most common form of blood cancer, with around 39,000 new cases in Europe in 2012.^[11] MM most commonly affects people over the age of 65 and is more common in men than in women.^[12] Across Europe, five-year survival rates are 23 per­cent to 47 per­cent of people diag­nosed.^[13] Almost 29 per­cent of patients with MM will die within one year of diag­nosis.^[14] 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 which can in­clude bone problems, low blood counts, cal­cium elevation, kidney problems or in­fec­tions.^[12] Patients who relapse after treat­ment with standard ther­a­pies, in­­clud­ing PIs and IMiDs have poor prognoses and few treat­ment options avail­able.^[2]

About Dara­tu­mu­mab

Daratumumab is an inves­ti­ga­tional human mono­clonal anti­body that binds with high affinity to the CD38 molecule, which is found on the surface of multiple myeloma cells. It is believed to induce rapid tumour cell death through multiple immune-mediated mech­a­nisms, in­­clud­ing complement-dependent cyto­tox­icity, anti­body-dependent cellular phagocytosic and anti­body-dependent cellular cyto­tox­icity, as well as via induction of apop­tosis.^[7] Five Phase 3 clin­i­cal studies with dara­tu­mu­mab in re­lapsed and frontline settings are cur­rently ongoing. Additional studies are ongoing or planned to assess its poten­tial in other malignant and pre-malignant diseases in which CD38 is ex­pressed, such as smoul­der­ing myeloma and non-Hodgkin lym­phoma.

About Janssen

The Janssen Pharma­ceu­tical Com­panies of Johnson & Johnson are dedicated to addressing and solving the most im­por­tant unmet medical needs of our time, in­­clud­ing on­col­ogy (e.g. multiple myeloma and prostate cancer), immunology (e.g. psoriasis), neuroscience (e.g. schizophrenia, dementia and pain), infectious disease (e.g. HIV/AIDS, hepatitis C and tuberculosis), and cardiovascular and metabolic diseases (e.g. diabetes). Driven by our commitment to patients, we develop sustainable, integrated health­care solu­tions by work­ing side-by-side with health­care stakeholders, based on part­ner­ships of trust and transparency. More in­­for­ma­tion can be found on http://www.janssen-emea.com. Follow us on http://www.twitter.com/janssenEMEA for our latest news.

Janssen Pharma­ceu­tical NV, Janssen Research & Development, LLC, Janssen Biotech, Inc., and Janssen-Cilag Inter­na­tional NV are part of the Janssen Pharma­ceu­tical Com­panies of Johnson & Johnson.

Janssen in Oncology

In on­col­ogy, our goal is to fundamentally alter the way cancer is under­stood, diag­nosed and man­aged, reinforcing our commitment to the patients who in­spire us. In looking to find inno­va­tive ways to address the cancer chal­lenge, our pri­mary efforts focus on several treat­ment and prevention solu­tions. These in­clude a focus on haematologic malig­nan­cies, prostate cancer and lung cancer; cancer interception with the goal of devel­op­ing prod­ucts that interrupt the carcinogenic process; bio­­markers that may help guide targeted, individualised use of our ther­a­pies; as well as safe and effective identi­fi­ca­tion and treat­ment of early changes in the tumour microenvironment.

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 approval of a new indi­ca­tion. 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 ma­teri­alize, actual results could vary ma­teri­ally from the ex­pec­ta­tions and projections of any of the Janssen Pharma­ceu­tical Com­panies and/or Johnson & Johnson. Risks and un­cer­tain­ties in­clude, but are not limited to: chal­lenges and un­cer­tain­ties in­her­ent in new prod­uct devel­op­ment, in­­clud­ing uncertainty of clin­i­cal success and obtaining regu­la­tory approvals; uncertainty of commercial success; 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; manu­fac­tur­ing dif­fi­culties and delays; 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 December 28, 2014, 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 http://www.sec.gov, http://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. American Society of Clinical Oncology. Multiple myeloma: overview. Available at: http://www.cancer.net/cancer-types/multiple-myeloma/overview. Last accessed 18 May 2015.
2. 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(1):149-57.
3. Danylesko I, Beider K, Shimoni A, Nagler A. Monoclonal antibody-based immunotherapy for multiple myeloma. Immunotherapy. 2012;4:919-38.
4. Ocio EM, Richardson PG, Rajkumar SV, et al. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG). Leukemia. 2014;28:525-542.
5. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121:482-8.
6. 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.
7. 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.
8. Lonial S, Weiss BM, Usmani SZ, et al. Phase 2 Study of daratumumab Monotherapy in Patients with ≥3 Lines of Prior Therapy or Double Refractory Multiple Myeloma (MM). J Clin Oncol. 2015;33(Suppl.):abstract LBA 8512.
9. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015;Aug:1-13.
10. European Medicines Agency. Public Summary of Orphan Drug Designations - EU/3/13/1153. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2013/08/human_orphan_001232.jsp&mid=WC0b01ac058001d12b Last accessed 12 May 2015.
11. 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 May 13, 2014.
12. American Cancer Society. Multiple myeloma: detailed guide. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf Last accessed 18 May 2015.
13. Cancer Research UK. Myeloma Survival Statistics. Available at: http://www.cancerresearchuk.org/cancer-info/cancerstats/types/myeloma/survival/multiple-myeloma-survival-statistics Last accessed 18 May 2015.
14. Costa LJ, Gonsalves WI, Kumar SK. Early mortality in multiple myeloma. Leukemia. 2015;29:1616-8.

Source: Janssen-Cilag Inter­na­tional NV.