First-in-class mono­clonal anti­body targeting CD38 for the treat­ment of multiple myeloma

Beerse, Belgium (Press Release) – Janssen-Cilag Inter­na­tional NV ("Janssen") announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a Positive Opinion rec­om­mending a con­di­tional mar­ket­ing authori­sa­tion for first-in-class CD38 immuno­therapy DARZALEX® (dara­tu­mu­mab) in the European Union. The rec­om­mended indi­ca­tion is 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.¹ This appli­ca­tion was reviewed under an accelerated assess­ment by the CHMP, a process reserved for medicinal prod­ucts ex­pec­ted to be of major public health interest, particularly from the point of view of thera­peutic inno­va­t.

MM is a blood cancer that occurs when malignant plasma cells grow un­con­trol­lably in the bone marrow.² In cases of refractory MM, the disease has progressed on or within 60 days of the last ther­apy.³ The prognosis for patients with re­lapsed and refractory MM remains poor. For patients with refractory MM, the median over­all survival (OS) ranges from nine months to only five months.⁴

The Opinion of the CHMP was based on a review of data from the Phase 2 MMY2002 (SIRIUS) study, pub­lished in The Lancet,⁵ the Phase 1/2 GEN501 study, pub­lished in The New England Journal of Medicine,⁶ and data from three addi­tional sup­port­ive studies. 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. 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.⁷

Daratumumab is the first CD38-directed mono­clonal anti­body (mAb) rec­om­mended for approval 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. 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).^8-11

“We are committed to delivering inno­va­tive new ther­a­pies to patients living with complex blood cancers, and have been work­ing closely with the CHMP on the sub­mission of dara­tu­mu­mab to ensure the assess­ment could be com­pleted under the accelerated timeline,” said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa. “We are delighted to receive this Positive Opinion, which brings us one step closer to making dara­tu­mu­mab avail­able to multiple myeloma patients in Europe.”

The CHMP's Positive Opinion will now be reviewed by the European Com­mis­sion, which has the authority to grant mar­ket­ing authori­sa­tion for med­i­cines in the European Economic Area. The European Com­mis­sion’s final de­ci­sion on dara­tu­mu­mab is antic­i­pated in the coming months.

This announcement follows dara­tu­mu­mab being granted its first regu­la­tory approval by the U.S. Food and Drug Admin­istra­tion (FDA) for the treat­ment of patients with multiple myeloma who have received at least three prior lines of ther­apy, in­­clud­ing a PI and an immuno­modu­la­tory agent, or who are double-refractory to a PI and an immuno­modu­la­tory agent, in November 2015 after a four month Priority Review by the FDA.⁹

Janssen has exclusive world­wide rights to the devel­op­ment, manu­fac­tur­ing and commercialisation of dara­tu­mu­mab for all poten­tial indi­ca­tions. 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.² MM is the second most common form of blood cancer, with around 39,000 new cases world­wide in 2012.¹² MM most commonly affects people over the age of 65 and is more common in men than in women.¹³ Across Europe, five-year survival rates are 23 per­cent to 47 per­cent of people diag­nosed.¹⁴ Almost 29 per­cent of patients with MM will die within one year of diag­nosis.¹⁵ 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.¹³ Patients who relapse after treat­ment with standard ther­a­pies, in­­clud­ing PIs and immuno­modu­latory agents, have poor prognoses and few treat­ment options avail­able.¹⁶

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.¹⁷ Dara­tu­mu­mab induces rapid tumour cell death through apop­tosis (programmed cell death)^9,10 and multiple immune-mediated mech­a­nisms of action, in­­clud­ing complement-dependent cyto­tox­icity (CDC), anti­body-dependent cellular cyto­tox­icity (ADCC) and anti­body-dependent cellular phago­cytosis (ADCP).^8,9,11 Dara­tu­mu­mab has also dem­onstrated immuno­modu­latory effects that con­trib­utes to tumour cell death via a de­crease in immune sup­pres­sive cells in­­clud­ing T-regs, B-regs and myeloid-derived sup­pressor cells.¹⁸ 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 favourable and clin­i­cally man­ageable safety profile as a mono­therapy.^5,6

In the MMY2002 (SIRIUS) trial, no patients dis­con­tinued treat­ment due to in­fusion-related reac­tions (IRRs) and only five patients (5 per­cent) dis­con­tinued treat­ment due to adverse events (AEs) (all grade), none of which were con­sidered drug-related.⁵ AEs, which occurred in less 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).⁵ Infusion-related reac­tions (IRR) were reported in 42 per­cent of patients and were predominantly grade 1 or 2 (5 per­cent grade 3; no grade 4 reported).⁵ These occurred mainly during the first in­fusion. The most common IRRs in­cluded nasal congestion (12 per­cent), throat irritation (7 per­cent), cough, dyspnoea, chills, and vomiting (6 per­cent each)⁵ – all of which were treated with standard of care and slower in­fusion rates.¹⁹

In the GEN501 trial, serious AEs occurred in 33 per­cent of patients in the cohort that received 16 mg/kg in part 2 of the study.6 Infusion-related reac­tions (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.⁶ The majority of IRRs occurred during the first in­fusion, with notably fewer during sub­se­quent in­fusions.6 No patient dis­con­tinued treat­ment due to an IRR. The most common AEs in either treat­ment group were fatigue, allergic rhinitis, and pyrexia (fever).⁶ 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.6 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.⁶

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 www.janssen.com/EMEA. Follow us on www.twitter.com/janssenEMEA for our latest news.

Cilag GmbH Inter­na­tional; Janssen Biotech, Inc.; and Janssen-Cilag Inter­na­tional NV are part of the Janssen Pharma­ceu­tical Com­panies of Johnson & Johnson.

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 prod­uct devel­op­ment, in­­clud­ing poten­tial regu­la­tory approval of a new 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, any of the other Janssen Pharma­ceu­tical Com­panies and/or Johnson & Johnson. Risks and un­cer­tain­ties in­clude, but are not limited to: chal­lenges and un­cer­tain­ties in­her­ent in prod­uct devel­op­ment, in­­clud­ing the uncertainty of clin­i­cal success and of obtaining regu­la­tory approvals; uncertainty of commercial success; com­pe­ti­tion, in­­clud­ing technological ad­vances, new prod­ucts and patents attained by com­pet­i­tors; chal­lenges to patents; manu­fac­tur­ing dif­fi­culties or delays; prod­uct efficacy or safety con­cerns resulting in prod­uct recalls or regu­la­tory action; 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

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Source: Janssen.