Raritan, NJ and Beerse, Belgium (Press Release) – The Janssen Pharma­ceu­tical Com­panies of Johnson & Johnson announced today the sub­mission of a supple­mental Biologics License Application (sBLA) to the U.S. Food and Drug Admin­istra­tion (FDA) and a Type II Variation to the European Medicines Agency (EMA) seeking approval of a split dosing regi­men for DARZALEX^® (dara­tu­mu­mab). The appli­ca­tions seek to update the Prescribing Information and Summary of Product Characteristics to provide health care professionals with the option to split the first in­fusion of DARZALEX^® over two consecutive days. The sub­missions are sup­ported by data from the Phase 1b MMY1001 clin­i­cal trial, which dem­onstrated DARZALEX^® phar­ma­co­ki­netics (PK) con­cen­tra­tions were com­parable re­gard­less of whether the first dose was admin­istered as a split in­fusion or single first in­fusion in patients with multiple myeloma.¹ The safety profile of DARZALEX^® was com­parable when admin­istered initially as a split or single dose.¹

"We are committed to exploring options that may im­prove the admin­istra­tion profile of DARZALEX^® and the over­all treat­ment ex­peri­ence for patients and physicians," said Craig Tendler, MD, Vice Pres­i­dent, Clinical Development and Global Medical Affairs, Janssen Research & Development, LLC. "We look for­ward to reviewing the data in sup­port of these appli­ca­tions with regulators and hope to make a DARZALEX^® split-dose option avail­able to patients and health care professionals to provide addi­tional flexibility in admin­istra­tion of the initial in­fusion."

The regu­la­tory sub­mission is based on data from the global, multi-arm Phase 1b MMY1001 study in multiple myeloma, which eval­u­ated DARZALEX^® in com­bi­na­tion with various treat­ment regi­mens.¹ Splitting the first dose of DARZALEX^® effectively reduced the duration of the first in­fusion and resulted in a similar rate and pattern of in­fusion reac­tions.¹ Data from MMY1001 dem­onstrated that DARZALEX^® con­cen­tra­tions were com­parable after admin­istra­tion of the first 16 mg/kg dose re­gard­less of whether it was admin­istered as a split in­fusion or single first in­fusion in all approved indi­ca­tions.¹ No new safety events were observed with split dosing.¹

In the U.S., DARZALEX^® first received FDA approval in November 2015 as a mono­therapy for patients with multiple myeloma who have received at least three prior lines of ther­apy, in­­clud­ing a pro­te­a­some inhibitor (PI) and an immuno­modu­la­tory agent, or who are double refractory to a PI and an immuno­modu­la­tory agent.² DARZALEX^® received addi­tional approvals in November 2016 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.³ In June 2017, DARZALEX^® received approval in com­bi­na­tion with poma­lido­mide and dexa­meth­a­sone for the treat­ment of patients with multiple myeloma who have received at least two prior ther­a­pies, in­­clud­ing lena­lido­mide and a PI.⁴ Most recently, in May 2018, DARZALEX^® received approval in com­bi­na­tion with bor­tez­o­mib, mel­phalan and pred­ni­sone for the treat­ment of patients with newly diag­nosed multiple myeloma who are in­eli­gible for au­tol­o­gous stem cell trans­plant (ASCT), making it the first mono­clonal anti­body approved for newly diag­nosed patients with this disease.⁵

In the European Union (EU), DARZALEX^® first received European Com­mis­sion approval in May 2016 as a mono­therapy for the treat­ment 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.⁶ DARZALEX^® received an addi­tional approval in April 2017 for use in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone, or bor­tez­o­mib and dexa­meth­a­sone, for the treat­ment of adult patients with multiple myeloma who have received at least one prior ther­apy.⁶ Finally, in July 2018, DARZALEX^® received a pos­i­tive opinion from the Committee for Medicinal Products for Human Use (CHMP) rec­om­mending broadening the existing mar­ket­ing authori­za­tion for use in com­bi­na­tion with bor­tez­o­mib, mel­phalan and pred­ni­sone for the treat­ment of adult patients with newly diag­nosed multiple myeloma who are in­eli­gible for au­tol­o­gous stem cell trans­plant (ASCT).

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered into a global license and devel­op­ment agree­ment, which granted Janssen an exclusive license to develop, manu­fac­ture and com­mer­cial­ize DARZALEX^®.⁷ For the full U.S. Prescribing Information, please visit www.DARZALEX.com. For the full EU Summary of Product Characteristics, please click here.

About DARZALEX^® (dara­tu­mu­mab) Injection, for Intravenous Infusion

DARZALEX^® (dara­tu­mu­mab) injection for in­tra­venous use is the first CD38-directed anti­body approved any­where in the world.⁵ CD38 is a surface protein that is highly ex­pressed across multiple myeloma cells, re­gard­less of disease stage.⁸ DARZALEX^® is believed to induce tumor cell death through multiple immune-mediated mech­a­nisms of action, in­­clud­ing complement-dependent cyto­tox­icity (CDC), anti­body-dependent cell-mediated cyto­tox­icity (ADCC) and anti­body-dependent cellular phago­cytosis (ADCP), as well as through apop­tosis, in which a series of molecular steps in a cell lead to its death.⁵ Subsets of myeloid derived sup­pressor cells (MDSCs), CD38+ regu­la­tory T cells (Tregs) and CD38+ B cells (Bregs) were de­creased by DARZALEX^®.⁵ DARZALEX^® is being eval­u­ated in a com­pre­hen­sive clin­i­cal devel­op­ment pro­gram across a range of treat­ment settings in multiple myeloma, such as in frontline and re­lapsed settings.^{9,10,11,12,13,14,15,16} Additional studies are ongoing or planned to assess its poten­tial in other malignant and pre-malignant hema­to­logic diseases in which CD38 is ex­pressed, such as smol­der­ing myeloma, as well as in solid tumors.^17,18,19 DARZALEX^® is the first and only CD38-directed anti­body to receive regu­la­tory approval to treat multiple myeloma.⁵

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow un­con­trol­lably in the bone marrow.^20,21 Refractory cancer occurs when a patient's disease is resistant to treat­ment or in the case of multiple myeloma, patients progress within 60 days of their last ther­apy.^22,23 Relapsed cancer means the disease has returned after a period of initial, partial or com­plete remission.²⁴ In 2018, it is esti­mated that 30,700 people will be diag­nosed, and 12,770 will die from the disease in the United States.²⁵ Additionally, there were 40,570 new cases of multiple myeloma in Europe in 2015.26 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.²⁷ While some patients with multiple myeloma have no symp­toms at all, most patients are diag­nosed due to symp­toms, which can in­clude bone fracture or pain, low red blood counts, fatigue, cal­cium elevation, kidney problems or in­fec­tions.²⁸

IMPORTANT SAFETY INFORMATION⁵

CONTRAINDICATIONS

DARZALEX^® is con­tra­in­di­cated in patients with a history of severe hypersensitivity (eg, anaphylactic reac­tions) to dara­tu­mu­mab or any of the components of the for­mu­la­tion.

WARNINGS AND PRECAUTIONS

Infusion Reactions – DARZALEX^® can cause severe and/or serious in­fusion reac­tions, in­­clud­ing anaphylactic reac­tions. In clin­i­cal trials, approx­i­mately half of all patients ex­peri­enced an in­fusion reac­tion. Most in­fusion reac­tions occurred during the first in­fusion and were grade 1-2. Infusion reac­tions can also occur with sub­se­quent in­fusions. Nearly all reac­tions occurred during in­fusion or within 4 hours of com­plet­ing an in­fusion. Prior to the in­tro­duc­tion of post-infusion medication in clin­i­cal trials, in­fusion reac­tions occurred up to 48 hours after in­fusion. Severe reac­tions have occurred, in­­clud­ing bron­cho­spasm, hypoxia, dyspnea, hyper­tension, laryngeal edema and pul­mo­nary edema. Signs and symp­toms may in­clude res­pira­tory symp­toms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting and nausea. Less common symp­toms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypo­­tension.

Pre-medicate patients with antihistamines, anti­pyretics, and corticosteroids. Frequently monitor patients during the entire in­fusion. Interrupt in­fusion for reac­tions of any severity and institute medical man­agement as needed. Permanently dis­con­tinue ther­apy if an anaphylactic reac­tion or life-threatening (Grade 4) reac­tion occurs and institute appro­pri­ate emergency care. For patients with Grade 1, 2, or 3 reac­tions, reduce the in­fusion rate when re-starting the in­fusion.

To reduce the risk of delayed in­fusion reac­tions, admin­ister oral corticosteroids to all patients fol­low­ing DARZALEX^® in­fusions. Patients with a history of chronic obstructive pul­mo­nary disease may require addi­tional post-infusion medications to man­age res­pira­tory com­pli­ca­tions. Consider pre­scrib­ing short- and long-acting bron­cho­di­lators and inhaled corticosteroids for patients with chronic obstructive pul­mo­nary disease.

Interference with Serological Testing – Dara­tu­mu­mab binds to CD38 on red blood cells (RBCs) and results in a pos­i­tive Indirect Antiglobulin Test (Indirect Coombs test). Dara­tu­mu­mab-mediated pos­i­tive indirect antiglobulin test may persist for up to 6 months after the last dara­tu­mu­mab in­fusion. Dara­tu­mu­mab bound to RBCs masks detection of anti­bodies to minor an­ti­gens in the patient's serum. The deter­mi­na­tion of a patient's ABO and Rh blood type are not impacted. Notify blood transfusion centers of this inter­fer­ence with serological testing and inform blood banks that a patient has received DARZALEX^®. Type and screen patients prior to starting DARZALEX^®.

Neutropenia – DARZALEX^® may in­­crease neu­tro­penia induced by back­ground ther­apy. Monitor com­plete blood cell counts periodically during treat­ment according to manu­­fac­­turer's pre­scrib­ing in­­for­ma­tion for back­ground ther­a­pies. Monitor patients with neu­tro­penia for signs of in­fec­tion. DARZALEX^® dose delay may be required to allow re­cov­ery of neu­tro­phils. No dose reduction of DARZALEX^® is rec­om­mended. Consider sup­port­ive care with growth factors.

Thrombocytopenia – DARZALEX^® may in­­crease thrombo­cytopenia induced by back­ground ther­apy. Monitor com­plete blood cell counts periodically during treat­ment according to manu­­fac­­turer's pre­scrib­ing in­­for­ma­tion for back­ground ther­a­pies. DARZALEX^® dose delay may be required to allow re­cov­ery of platelets. No dose reduction of DARZALEX^® is rec­om­mended. Consider sup­port­ive care with transfusions.

Interference with Determination of Complete Response – Dara­tu­mu­mab is a human IgG kappa mono­clonal anti­body that can be detected on both the serum protein electrophoresis (SPE) and immuno­fix­a­tion (IFE) assays used for the clin­i­cal monitoring of endogenous M-protein. This inter­fer­ence can impact the deter­mi­na­tion of com­plete response and of disease pro­gres­sion in some patients with IgG kappa myeloma protein.

Adverse Reactions – The most frequently reported adverse reac­tions (incidence ≥20%) in clin­i­cal trials were: in­fusion reac­tions, neu­tro­penia, thrombo­cytopenia, fatigue, nausea, diarrhea, con­sti­pa­tion, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizzi­ness, insomnia, cough, dyspnea, periph­eral edema, periph­eral sensory neu­rop­athy and upper res­pira­tory tract in­fec­tion.

In patients who received DARZALEX^® in com­bi­na­tion with bor­tez­o­mib, mel­phalan, and pred­ni­sone (DVMP), the most frequently reported adverse reac­tions (incidence ≥20%) were: upper res­pira­tory tract in­fec­tion (48%), in­fusion reac­tions (28%), and periph­eral edema (21%). Serious adverse reac­tions (≥2% com­pared to the VMP arm) were pneu­monia (11%), upper res­pira­tory tract in­fec­tion (5%), and pul­mo­nary edema (2%). Treatment-emergent Grade 3-4 hematology laboratory ab­nor­mal­i­ties ≥20% were lymphopenia (58%), neu­tro­penia (44%), and thrombo­cytopenia (38%).

In patients who received DARZALEX^® in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone, the most frequently reported adverse reac­tions (incidence ≥20%) were: upper res­pira­tory tract in­fec­tion (65%), in­fusion reac­tions (48%), diarrhea (43%), fatigue (35%), cough (30%), muscle spasms (26%), nausea (24%), dyspnea (21%) and pyrexia (20%). The over­all in­ci­dence of serious adverse reac­tions was 49%. Serious adverse reac­tions (≥2% com­pared to Rd) were pneu­monia (12%), upper res­pira­tory tract in­fec­tion (7%), influenza (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory ab­nor­mal­i­ties ≥20% were neu­tro­penia (53%) and lymphopenia (52%).

In patients who received DARZALEX^® in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone, the most frequently reported adverse reac­tions (incidence ≥20%) were: periph­eral sensory neu­rop­athy (47%), in­fusion reac­tions (45%), upper res­pira­tory tract in­fec­tion (44%), diarrhea (32%), cough (27%), periph­eral edema (22%), and dyspnea (21%). The over­all in­ci­dence of serious adverse reac­tions was 42%. Serious adverse reac­tions (≥2% com­pared to Vd) were upper res­pira­tory tract in­fec­tion (5%), diarrhea (2%) and atrial fibrillation (2%). Treatment-emergent Grade 3-4 hematology laboratory ab­nor­mal­i­ties ≥20% were lymphopenia (48%) and thrombo­cytopenia (47%).

In patients who received DARZALEX^® in com­bi­na­tion with poma­lido­mide and dexa­meth­a­sone, the most frequent adverse reac­tions (>20%) were fatigue (50%), in­fusion reac­tions (50%), upper res­pira­tory tract in­fec­tion (50%), cough (43%), diarrhea (38%), con­sti­pa­tion (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizzi­ness (21%), and vomiting (21%). The over­all in­ci­dence of serious adverse reac­tions was 49%. Serious adverse reac­tions reported in ≥5% patients in­cluded pneu­monia (7%). Treatment-emergent hematology Grade 3-4 laboratory ab­nor­mal­i­ties ≥20% were anemia (30%), neu­tro­penia (82%), and lymphopenia (71%).

In patients who received DARZALEX^® as mono­therapy, the most frequently reported adverse reac­tions (incidence ≥20%) were: in­fusion reac­tions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper res­pira­tory tract in­fec­tion (20%). The over­all in­ci­dence of serious adverse reac­tions was 33%. The most frequent serious adverse reac­tions were pneu­monia (6%), general physical health deterioration (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory ab­nor­mal­i­ties ≥20% were lymphopenia (40%) and neu­tro­penia (20%).

DRUG INTERACTIONS

Effect of Other Drugs on Dara­tu­mu­mab: The coadministration of lena­lido­mide, poma­lido­mide or bor­tez­o­mib with DARZALEX^® did not affect the phar­ma­co­ki­netics of dara­tu­mu­mab.

Effect of Dara­tu­mu­mab on Other Drugs: The coadministration of DARZALEX^® with bor­tez­o­mib or poma­lido­mide did not affect the phar­ma­co­ki­netics of bor­tez­o­mib or poma­lido­mide.

About the Janssen Pharma­ceu­tical Com­panies of Johnson & Johnson

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

This press release con­tains "forward-looking state­ments" as defined in the Private Se­cu­ri­ties Lit­i­ga­tion Reform Act of 1995 re­gard­ing the benefits of DARZALEX^® (dara­tu­mu­mab) for the treat­ment of patients with multiple myeloma. 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 Research & Development, LLC, Janssen Biotech, Inc., Janssen-Cilag Inter­na­tional NV and 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 research and 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 behavior and spending patterns 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 descriptions 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 31, 2017, in­­clud­ing in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in the com­pany's sub­se­quent Quarterly Reports on Form 10-Q and other 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. Neither the Janssen Pharma­ceu­tical Com­panies of Johnson & Johnson nor Johnson & Johnson under­takes to update any for­ward-looking state­ment as a result of new in­­for­ma­tion or future events or devel­op­ments.

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Source: Janssen.