Phase 1b/Phase 2 studies planned in multiple myeloma and solid tumors

Horsham, PA (Press Release) – Janssen Biotech, Inc. today announced that the com­pany has entered a clin­i­cal trial col­lab­o­ration with Bristol-Myers Squibb Company (BMS) to eval­u­ate the com­bi­na­tion of the first CD38-directed cytolytic anti­body dara­tu­mu­mab (DARZALEX®) and checkpoint inhibitor nivolumab (OPDIVO®) in Phase 1b /Phase 2 clin­i­cal studies in multiple myeloma and several solid tumor types. Nivolumab is devel­oped and com­mer­cial­ized by BMS. Janssen licensed dara­tu­mu­mab from Genmab A/S and is responsible for all global devel­op­ment, mar­ket­ing and manu­fac­tur­ing.

The multiple myeloma study will eval­u­ate the safety and tolerability of dara­tu­mu­mab in com­bi­na­tion with nivolumab with or without poma­lido­mide and dexa­metha­sone in re­lapsed/refractory multiple myeloma. The solid tumor studies will eval­u­ate the safety, tolerability and clin­i­cal benefit of dara­tu­mu­mab com­bined with nivolumab in patients with ad­vanced or metastatic tumors, in­­clud­ing non-small cell lung, head and neck, pancreatic, colorectal and triple neg­a­tive breast cancers. Additional tumor types may also be eval­u­ated. Studies are ex­pec­ted to start this year.

"Immunotherapy has vastly changed the way cancer is treated. We are excited to study this novel com­bi­na­tion of two poten­tially synergistic immuno­therapies," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development, LLC. "This agree­ment allows us to extend our footprint in immuno-oncology and will be a sig­nif­i­cant addi­tion to the growing body of clin­i­cal data for dara­tu­mu­mab in com­bi­na­tion with other novel agents, in a variety of tumor types."

DARZALEX is the first CD38-directed cytolytic anti­body approved any­where in the world. It was first approved by the U.S. Food and Drug Admin­istra­tion (FDA) 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 immuno­modu­la­tory agent.¹ It is also approved in Europe, Canada and several other countries for a similar patient pop­u­la­tion.

DARZALEX was more recently approved by the FDA in November 2016 for use in com­bi­na­tion with lena­lido­mide (an immuno­modu­la­tory agent) and dexa­metha­sone, or bor­tez­o­mib (a PI) and dexa­metha­sone, in patients with multiple myeloma who have received at least one prior ther­apy.² DARZALEX received Break­through Therapy Desig­na­tion from the FDA for this indi­ca­tion in July 2016.³

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.¹ CD38 is a surface protein that is highly ex­pressed across multiple myeloma cells, re­gard­less of disease stage.⁴ dara­tu­mu­mab is believed to induce tumor cell death through multiple immune-mediated mech­a­nisms of action, in­­clud­ing complement-dependent cyto­tox­icity (CDC), anti­body-dependent cellular 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 A subset of myeloid derived sup­pressor cells (MDSCs), CD38+ regu­la­tory T cells (Tregs) and CD38+ B cells (Bregs) were de­creased by dara­tu­mu­mab.⁵ 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.^6,7,8,9,10 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.^11,12,13 DARZALEX was the first cytolytic anti­body to receive regu­la­tory approval to treat re­lapsed or refractory multiple myeloma.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.14 DARZALEX is com­mer­cial­ized in the U.S. by Janssen Biotech, Inc. For more in­­for­ma­tion, visit www.DARZALEX.com.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow un­con­trol­lably in the bone marrow.^15,16 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.^17,18 Relapsed cancer means the disease has returned after a period of initial partial or com­plete remission.¹⁹ Globally, it is esti­mated that 124,225 people were diag­nosed, and 87,084 died from the disease in 2015.^20,21 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.²² Patients who relapse after treat­ment with standard ther­a­pies (including PIs or immuno­modu­la­tory agents) typically have poor prognoses and few remaining options.¹⁶

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.

Cautions Concerning Forward-Looking Statements

This press release con­tains "forward-looking state­ments" as defined in the Private Se­cu­ri­ties Lit­i­ga­tion Reform Act of 1995 re­gard­ing planned clin­i­cal trials and ex­pec­ted expansion of clin­i­cal data on 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. 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; 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. Janssen Biotech, Inc. "DARZALEX® (daratumumab) Approved by U.S. FDA: First Human Anti-CD38 Monoclonal Antibody Available for the Treatment of Multiple Myeloma." Issued November 16, 2015.
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3. Janssen Research & Development, LLC. "Daratumumab (DARZALEX®) Granted Breakthrough Therapy Designation by U.S. Food and Drug Administration (FDA) for Use in Combination with Standard of Care Regimens for Patients with Multiple Myeloma." Issued July 25, 2016.
4. Fedele G et al. CD38 Ligation in Peripheral Blood Mononuclear Cells of Myeloma Patients Induces Release of Protumorigenic IL-6 and Impaired Secretion of IFNγ Cytokines and Proliferation. Mediators Inflamm. 2013;2013:564687.
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13. Janssen Research & Development, LLC. An Efficacy and Safety Proof of Concept Study of Daratumumab in Relapsed/Refractory Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Nov 11]. https://clinicaltrials.gov/ct2/show/NCT02413489?term=lym2001&rank=1 Identifier: NCT02413489.
14. Janssen Biotech, Inc. "Janssen Biotech Announces Global License and Development Agreement." Issued August 30, 2012
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Source: Janssen Biotech, Inc.