First-in-class CD38-directed active immuno­therapy provides new treat­ment option for MM patients who have exhausted other approved treat­ment options

Beerse, Belgium (Press Release) – Janssen-Cilag Inter­na­tional NV (“Janssen”) today announced that the European Com­mis­sion (EC) has granted con­di­tional approval to DARZALEX® (dara­tu­mu­mab) for mono­therapy of adult patients with re­lapsed and refractory multiple myeloma (MM), whose prior ther­apy in­cluded a pro­te­a­some inhibitor (PI) and an immuno­modu­la­tory agent and who have dem­onstrated disease pro­gres­sion on the last ther­apy. Dara­tu­mu­mab was approved under an accelerated assess­ment, a process reserved for medicinal prod­ucts ex­pec­ted to be of major public health interest, particularly from the point of view of thera­peutic inno­va­tion.¹

Daratumumab is the first CD38-directed mono­clonal anti­body (mAb) approved in Europe. It works by binding to CD38, a signalling molecule highly ex­pressed on the surface of multiple myeloma cells re­gard­less of stage of disease.^2-4 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 mech­a­nisms of action and through immuno­modu­la­tory effects, in addi­tion to direct tumour cell death via apop­tosis (programmed cell death).^5-9

“Despite recent ad­vances, multiple myeloma remains a complex, incurable disease, with relapse being in­ev­i­table in almost all patients. With each relapse, the disease typically be­comes more aggressive and more chal­leng­ing to treat,” said Pro­fessor Jesús San Miguel, Director of Clinical & Translational Medicine, Universidad de Navarra, Spain. “Daratumumab has shown promising efficacy results and a man­ageable safety profile as a single agent for heavily pre-treated and refractory myeloma patients. Overall survival im­proved sig­nif­i­cantly in these patients, whose prognosis is typically very poor, and who there­fore have the greatest need for new treat­ments.”

The approval of dara­tu­mu­mab was based on data from the Phase 2 MMY2002 (SIRIUS) study, published in The Lancet; the Phase 1/2 GEN501 study, published in The New England Journal of Medicine;^10,11 and data from three addi­tional sup­port­ive studies. Findings from a com­bined efficacy analysis of the GEN501 and MMY2002 (SIRIUS) trials dem­onstrated that after a mean follow-up of 14.8 months, the esti­mated median OS for single-agent dara­tu­mu­mab (16 mg/kg) in these heavily pre-treated patients was 20 months (95 per­cent CI, 15-not estimable). The over­all response rate (ORR) for the com­bined analysis was 31 per­cent, and 83 per­cent of patients achieved stable disease or better.¹² Dara­tu­mu­mab dem­onstrated a tolerable and clin­i­cally man­ageable safety profile as a mono­therapy in heavily pre-treated patients. ^10,11 The most common adverse events (AEs) in the Phase 2 MMY2002 (SIRIUS) trial, which occurred in more than 20 per­cent of patients, were fatigue, anaemia, nausea, thrombo­cyto­penia, back pain, neutro­penia and cough.10 The most common adverse events (AEs) in the Phase 1/2 GEN501 trial were fatigue, allergic rhinitis, and pyrexia (fever).¹¹

“Today’s de­ci­sion on dara­tu­mu­mab is fantastic news for patients as it will help to address a major area of unmet need in people with re­lapsed or refractory myeloma,” said Sarper Diler, MD, PhD, Pres­i­dent of Myeloma Patients Europe. “However, there is still a lot of work to be done to ensure that dara­tu­mu­mab is avail­able for patients in health sys­tems across Europe.”

“The approval of dara­tu­mu­mab within an accelerated timeframe is a result of work­ing with patient-focused urgency, delivering against unmet needs with transformational science and through strong col­lab­o­rations,” said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa. “We are delighted that dara­tu­mu­mab has been approved in Europe and will con­tinue to study its poten­tial across the treat­ment con­tin­uum in multiple myeloma and other tumour types.”

The mar­ket­ing authori­sa­tion approval follows a pos­i­tive opinion from the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued on 01 April 2016.¹³ This approval allows for the mar­ket­ing of dara­tu­mu­mab in all 28 member states and the three European Economic Area countries of the European Union.

Janssen has exclusive world­wide rights to the devel­op­ment, manu­fac­tur­ing and commercialisation of dara­tumumab. Janssen licensed dara­tu­mu­mab from Genmab A/S in August 2012.

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.¹⁴ MM is the second most common form of blood cancer, with around 39,000 new cases world­wide in 2012.¹⁵ MM most commonly affects people over the age of 65 and is more common in men than in women.¹⁶ 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.¹⁷ Almost 29 per­cent of patients with MM will die within one year of diag­nosis.¹⁸ 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.¹⁴ Patients who relapse after treat­ment with stan­dard ther­a­pies, in­­clud­ing PIs and immuno­modu­la­tory agents, have poor prognoses and few treat­ment options avail­able.¹⁹

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.^2-4 Dara­tu­mu­mab induces rapid tumour cell death through apop­tosis (programmed cell death)6,7 and multiple immune-mediated mech­a­nisms of action, in­clud­ing complement-dependent cyto­tox­icity (CDC), anti­body-dependent cellular cyto­tox­icity (ADCC) and anti­body-dependent cellular phago­cytosis (ADCP).^5,6,8 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.⁹ 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 on which CD38 is ex­pressed. For more in­­for­ma­tion, please see www.clinicaltrials.gov.

About MMY2002 (SIRIUS) and GEN501

These studies in­cluded heavily pre-treated patients with re­lapsed and refractory multiple myeloma who had exhausted other approved treat­ment options and whose disease was progressive at enrolment. Safety data from the MMY2002 (SIRIUS) and GEN501 trials suggested that dara­tu­mu­mab (16 mg/kg) has a tolerable and clin­i­cally man­ageable safety profile as a mono­therapy.10,11

The most common adverse events (AEs) in the Phase 2 MMY2002 (SIRIUS) trial, which occurred in more than 20 per­cent of patients, were fatigue (40 per­cent), anaemia (33 per­cent), nausea (29 per­cent), thrombo­cyto­penia (25 per­cent), back pain (22 per­cent), neu­tro­penia (23 per­cent) and cough (21 per­cent).¹⁰ The most common adverse events (AEs) in part 2 of the Phase 1/2 GEN501 trial were fatigue, allergic rhinitis, and pyrexia (fever).¹¹ The most frequent haematologic 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.¹¹

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. Follow us at www.twitter.com/janssenEMEA.

Janssen 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 antic­i­pated benefits and poten­tial of a newly approved prod­uct. 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 Janssen-Cilag Inter­na­tional NV and/or Johnson & Johnson. Risks and un­cer­tain­ties in­clude, but are not limited to: the un­cer­tain­ties in­her­ent in research and devel­op­ment, in­­clud­ing further in­ves­ti­ga­tion of the clin­i­cal benefits of the prod­uct; 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 behavior 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 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. Johnson & Johnson. Janssen’s daratumumab accepted for accelerated CHMP assessment for treatment of European patients with heavily pre-treated multiple myeloma. Available at: http://www.jnj.com/news/all/Janssens-daratumumab-accepted-for-accelerated-CHMP-assessment-for-treatment-of-European-patients-with-heavily-pre-treated-multiple-myeloma. Last accessed May 2016.
2. 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.
3. 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.
4. 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.
5. 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.
6. DARZALEX® Prescribing Information November 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/761036Orig1s000lbledt.pdf. Last accessed May 2016.
7. Jansen JH, Bross P, Overdijk MB, et al. Daratumumab, a human CD38 antibody induces apoptosis of myeloma tumor cells via Fc receptor-mediated crosslinking. Blood. 2012;120(21):abstract 2974.
8. 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(2):311-21.
9. Krejcik J, Casneuf T, Nijhof I, et al. Immunomodulatory effects and adaptive immune response to daratumumab in multiple myeloma. Blood 2015:126(23):abstract 3037.
10. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387:1551-60.
11. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207-19.
12. Usmani S, Ahmadi T, Ng Y, et al. Analyses of real world data on overall survival in multiple myeloma patients with at least 3 prior lines of therapy including a PI and an IMiD, or double refractory to a PI and an IMiD. Blood. 2015:126(23):abstract 4498.
13. European Medicines Agency. Committee for Medicinal Products for Human Use: Summary of opinion. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004077/WC500203957.pdf. Last accessed May 2016.
14. American Society of Clinical Oncology. Multiple myeloma: overview. Available at: http://www.cancer.net/cancer-types/multiple-myeloma/overview. Last accessed May 2016.
15. 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 2016.
16. American Cancer Society. Multiple myeloma: detailed guide. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf. Last accessed May 2016.
17. 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.
18. Costa LJ, Gonsalves WI, Kumar SK. Early mortality in multiple myeloma. Leukemia. 2015;29:1616-8.
19. 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.

Source: Janssen.