• DARZALEX sig­nif­i­cantly im­proved pro­gres­sion-free survival (PFS) in com­bi­na­tion with two standard of care regi­mens versus standard of care regi­mens alone
• Approval based on two Phase 3 studies showing con­sis­tent and pronounced clin­i­cal benefit of DARZALEX in com­bi­na­tion with two of the most widely used treat­ment classes for multiple myeloma

Horsham, PA (Press Release) – Janssen Biotech, Inc. announced today the U.S. Food and Drug Admin­is­tra­tion (FDA) has approved DARZALEX® (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.¹ Clinical studies have shown that DARZALEX, in com­bi­na­tion with lena­lido­mide (an immuno­modu­la­tory agent) and dexa­meth­a­sone, reduced the risk of disease pro­gres­sion or death by 63 per­cent, com­pared to lena­lido­mide and dexa­meth­a­sone alone, in patients with multiple myeloma who received a median of one prior ther­apy (Hazard Ratio [HR]=0.37; 95 per­cent CI [0.27, 0.52], p<0.0001).¹ In com­bi­na­tion with bor­tez­o­mib (a pro­te­a­some inhibitor [PI]) and dexa­meth­a­sone, DARZALEX reduced the risk of disease pro­gres­sion or death by 61 per­cent, com­pared to bor­tez­o­mib and dexa­meth­a­sone alone, in patients with multiple myeloma who received a median of two prior lines of ther­apy (HR=0.39; 95 per­cent CI [0.28, 0.53], p<0.0001).¹ Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow un­con­trol­lably in the bone marrow.^2,3

The approval comes three months after a supple­mental Biologics License Application (sBLA) was submitted to the FDA in August 2016.⁴ DARZALEX received Break­through Therapy Desig­na­tion from the FDA for this indi­ca­tion in July 2016.⁵

“While tremendous progress in the treat­ment of multiple myeloma has been made in the past decade, patients and their physicians con­tinue to need new treat­ment options,” said Meletios A. Dimopoulos, M.D., Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece, a DARZALEX clin­i­cal trial investigator. “With DARZALEX, we have a poten­tial new back­bone ther­apy, which has shown pronounced efficacy as either a single agent or in com­bi­na­tion with standard of care regi­mens. The addi­tion of DARZALEX also sig­nif­i­cantly im­proved pro­gres­sion-free survival in com­bi­na­tion with two of the most widely used treat­ment classes, making it a versatile option for patients who have received at least one prior ther­apy.”

DARZALEX is the first CD38-directed cytolytic anti­body approved any­where in the world.⁶ It was first ap­proved by the FDA in November 2015 as a mono­therapy treat­ment for 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 immuno­modu­la­tory agent.¹

Today’s approval is sup­ported by data from two Phase 3 studies:

• According to results from the open-label POLLUX (MMY3003) clinical study, the median progression-free survival (PFS) in the DARZALEX arm has not been reached, compared with a median PFS of 18.4 months for patients who received lena­lido­mide and dexa­meth­a­sone alone, with a median follow-up of 13.5 months.¹ In addition to meeting the primary endpoint of improved PFS, DARZALEX significantly increased the overall response rate (ORR) [91 percent vs. 75 percent, p<0.0001], compared to lena­lido­mide and dexa­meth­a­sone alone, including doubling rates of complete response (CR) [25 percent vs. 12 percent, p<0.0001] and significantly increasing very good partial response (VGPR) [32 percent vs. 24 percent, p<0.0001].¹ These results were published in The New England Journal of Medicine, with an accompanying editorial, in October 2016.⁷
• According to results from the open-label CASTOR (MMY3004) clinical study, the median PFS in the DARZALEX arm has not been reached, compared with a median PFS of 7.2 months for patients who received bortezomib and dexa­meth­a­sone alone, with a median follow-up of 7.4 months.¹ In addition to meeting the primary endpoint of improved PFS, DARZALEX also significantly increased ORR [79 percent vs. 60 percent, p<0.0001], compared to bortezomib and dexa­meth­a­sone alone, including doubling rates of CR [14 percent vs. 7 percent, p<0.0001] and significantly increasing VGPR [38 percent vs. 19 percent, p<0.0001].¹ These results were published in The New England Journal of Medicine in August 2016.⁸

Updated results from these clin­i­cal studies will be presented as oral presentations at the 58th American Society of Hematology (ASH) Annual Meeting to be held in San Diego, CA from December 3-6, 2016 (Abstract #1150; Abstract #1151).

“The approval of dara­tu­mu­mab provides multiple myeloma patients with another versatile treat­ment option to help address their urgent medical needs,” said Paul Giusti, Pres­i­dent and Chief Executive Officer of the Multiple Myeloma Research Foundation (MMRF). “At the MMRF, we are excited by the groundbreaking work being done to bring effective, new treat­ments to patients.”

“We are proud of the rapid devel­op­ment and approval of DARZALEX for use earlier in the treat­ment path­way, but our work does not stop here,” said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development, LLC. “We are only starting to uncover the full poten­tial of this com­­pound, and we remain committed to the con­tinued study of dara­tu­mu­mab to more fully under­stand its utility for patients with multiple myeloma and other cancer types.”

Overall, the safety of the DARZALEX com­bi­na­tion ther­apy was con­sis­tent with the known safety profiles of DARZALEX mono­therapy (D) and lena­lido­mide plus dexa­meth­a­sone (Rd), re­spec­tive­ly. In data from the POLLUX trial, the most frequent (≥20 per­cent) adverse reac­tions (ARs) [DRd/Rd] were in­fusion reac­tions (48 per­cent/0 per­cent), diarrhea (43 per­cent/25 per­cent), nausea (24 per­cent/14 per­cent), fatigue (35 per­cent/28 per­cent), pyrexia (20 per­cent/11 per­cent), upper res­pira­tory tract in­fec­tion (65 per­cent/51 per­cent), muscle spasms (26 per­cent/19 per­cent), cough (30 per­cent/15 per­cent) and dyspnea (21 per­cent/12 per­cent).¹ The over­all in­ci­dence of serious ARs was 49 per­cent (DRd) com­pared with 42 per­cent (Rd).¹ Serious ARs (Grade 3/4) – which had at least a 2 per­cent greater in­ci­dence in the DRd arm com­pared to the Rd arm – were pneu­monia (12 per­cent/10 per­cent), upper res­pira­tory tract in­fec­tion (7 per­cent/4 per­cent), influenza (3 per­cent/1 per­cent) and pyrexia (3 per­cent/1 per­cent).¹ Seven per­cent/8 per­cent of patients dis­con­tinued ther­apy due to an AR.¹ The most common treat­ment-emergent hematology laboratory ab­nor­mal­i­ties [DRd/Rd] were lympho­penia (95 per­cent/87 per­cent), neu­tro­penia (92 per­cent/87 per­cent), throm­bo­cyto­penia (73 per­cent/67 per­cent) and anemia (52 per­cent/57 per­cent).¹ The most common Grade 3/4 treat­ment-emergent hematology laboratory ab­nor­mal­i­ties were neu­tro­penia (53 per­cent/40 per­cent), lymphopenia (52 per­cent/38 per­cent), throm­bo­cyto­penia (13 per­cent/15 per­cent) and anemia (13 per­cent/19 per­cent).¹

In data from the CASTOR study, the safety of the DARZALEX com­bi­na­tion ther­apy was con­sis­tent with the known safety profiles of DARZALEX mono­therapy (D) and bor­tez­o­mib plus dexa­meth­a­sone (Vd), re­spec­tively. The most frequent ARs [DVd/Vd] (>20 per­cent) were in­fusion reac­tions (45 per­cent/0 per­cent), diarrhea (32 per­cent/22 per­cent), periph­eral edema (22 per­cent/13 per­cent), upper res­pira­tory tract in­fec­tion (44 per­cent/30 per­cent), periph­eral sensory neu­rop­athy (47 per­cent/38 per­cent), cough (27 per­cent/14 per­cent) and dyspnea (21 per­cent/11 per­cent).¹ The over­all in­ci­dence of serious ARs was 42 per­cent (DVd) com­pared with 34 per­cent (Vd).¹ Serious ARs (Grade 3/4) – which had at least a 2 per­cent greater in­ci­dence in the DVd arm com­pared to the Vd arm – in­cluded upper res­pira­tory tract in­fec­tion (5 per­cent/2 per­cent), diarrhea (2 per­cent/0 per­cent) and atrial fibrillation (2 per­cent/0 per­cent).¹ Seven per­cent/9 per­cent of patients dis­con­tinued ther­apy due to an AR.¹ The most common treat­ment-emergent hematology laboratory ab­nor­mal­i­ties were throm­bo­cyto­penia (90 per­cent/85 per­cent), lympho­penia (89 per­cent/81 per­cent), neu­tro­penia (58 per­cent/40 per­cent) and anemia (48 per­cent/56 per­cent).¹ The most common Grade 3/4 treat­ment-emergent hematology laboratory ab­nor­mal­i­ties were lymphopenia (48 per­cent/27 per­cent), throm­bo­cytopenia (47 per­cent/35 per­cent), neutro­penia (15 per­cent/6 per­cent) and anemia (13 per­cent/14 per­cent).¹

The rec­om­mended dose of DARZALEX is 16 mg/kg body weight admin­istered as an in­tra­venous in­fusion.¹ The dosing schedule for DARZALEX in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone begins with weekly admin­istra­tion (weeks 1-8) and reduces in frequency over time to every two weeks (weeks 9-24) and ultimately every four weeks (week 25 onwards) until disease pro­gres­sion.¹ The dosing schedule for DARZALEX in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone begins with weekly admin­istra­tion (weeks 1-9) and reduces in frequency over time to every three weeks (weeks 10-24) and ultimately every four weeks (weeks 25 and onwards) until disease pro­gres­sion.¹

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a world­wide agree­ment, which granted Janssen an exclusive license to develop, manu­fac­ture and com­mer­cial­ize DARZALEX.⁹ DARZALEX is com­mer­cial­ized in the U.S. by Janssen Biotech, Inc. For the full Prescribing Information, please visit www.DARZALEX.com.⁹

About DARZALEX® (dara­tu­mu­mab) Injection, for Intravenous Infusion

DARZALEX® (dara­tu­mu­mab) injection for in­tra­venous use is the first CD38-directed cytolytic anti­body ap­proved any­where in the world.⁶ CD38 is a surface protein that is highly ex­pressed across multiple myeloma cells, re­gard­less of disease stage.¹⁰ 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.¹ A subset of myeloid derived sup­pressor cells (MDSCs), CD38+ regu­la­tory T cells (Tregs) and CD38+ B cells (Bregs) were de­creased by DARZALEX.¹ DARZALEX is being eval­u­ated in a com­pre­hen­sive clin­i­cal devel­op­ment pro­gram that in­cludes five Phase 3 studies across a range of treat­ment settings in multiple myeloma, such as in frontline and re­lapsed settings.^{11,12,13,14,15} Addi­tional studies are ongoing or planned to assess its poten­tial for a solid tumor indi­ca­tion and in other malignant and pre-malignant diseases in which CD38 is ex­pressed, such as smol­der­ing myeloma and non-Hodgkin's lym­phoma.^16,17,18 DARZALEX was the first cytolytic anti­body to receive regu­la­tory approval to treat re­lapsed or refractory multiple myeloma.⁶

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow un­con­trol­lably in the bone marrow.^2,3 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.^19,20 Relapsed cancer means the disease has returned after a period of initial partial or com­plete remission.²¹ Globally, it is esti­mated that 124,225 people were diag­nosed and 87,084 died from the disease in 2015.^22,23 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.²⁴

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS - None

WARNINGS AND PRECAUTIONS

Infusion Reactions – DARZALEX can cause severe in­fusion reac­tions. Approximately half of all patients ex­peri­enced a reac­tion, most during the first in­fusion. 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 for life-threatening (Grade 4) reac­tions. 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 – In patients who received Darzalex in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone, the most frequently reported adverse reac­tions (incidence ≥20%) were: neu­tro­penia (92%), throm­bo­cyto­penia (73%), 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 were pneu­monia (12%), upper res­pira­tory tract in­fec­tion (7%), influenza (3%) and pyrexia (3%).

In patients who received Darzalex in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone, the most frequently reported adverse reac­tions (incidence ≥20%) were: thrombo­cytopenia (90%), neu­tro­penia (58%), 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 were upper res­pira­tory tract in­fec­tion (5%), diarrhea (2%) and atrial fibrillation (2%).

In patients who received Darzalex as mono­therapy, the most frequently reported adverse reac­tions (in­ci­dence ≥20%) were: neu­tro­penia (60%), thrombo­cytopenia (48%), in­fusion reac­tions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper res­pira­tory tract in­fec­tion (20%). Serious adverse reac­tions were reported in 51 (33%) patients. The most frequent serious adverse reac­tions were pneu­monia (6%), general physical health deterioration (3%), and pyrexia (3%).

DRUG INTERACTIONS

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

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

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/JanssenUS and www.twitter.com/JanssenGlobal.

This press release con­tains "forward-looking state­ments" as defined in the Private Se­cu­ri­ties Lit­i­ga­tion Reform Act of 1995 re­gard­ing DARZALEX’s poten­tial and further devel­op­ment of 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 ma­teri­alize, actual results could vary ma­teri­ally from the ex­pec­ta­tions and projections of Janssen Biotech, Inc., Janssen Research & Development, LLC and/or Johnson & Johnson. Risks and un­cer­tain­ties in­clude, but are not limited to: chal­lenges in­her­ent in prod­uct research and devel­op­ment, in­­clud­ing the uncertainty of clin­i­cal success and obtaining regu­la­tory approvals; uncertainty of commercial success for new prod­ucts or new indi­ca­tions; manu­fac­tur­ing dif­fi­culties or delays; com­pe­ti­tion, in­­clud­ing technological ad­vances, new prod­ucts and patents attained by com­pet­i­tors; chal­lenges to patents; 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. DARZALEX Prescribing Information, November 2016.
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Source: Janssen Biotech Inc.