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Daratumumab (DARZALEX®) Combination Therapy Showed Consistent Clinical Benefit for Previously-Treated Patients with Multiple Myeloma

Post-hoc analyses of the Phase 3 POLLUX and CASTOR studies to be presented at the 58th American Society of Hematology (ASH) Annual Meeting

This release corresponds to abstracts #246, #489, #1150 and #1151

SAN DIEGO, CA and RARITAN, NJ, December 5, 2016 – Janssen Research & Development, LLC today announced new data from two post-hoc analyses of the pivotal Phase 3 POLLUX and CASTOR clinical studies, demonstrating that daratumumab (DARZALEX®) in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, significantly improved progression-free survival (PFS) and overall response rates (ORRs) for previously-treated patients with multiple myeloma, regardless of prior treatment exposure or cytogenetic risk. Data from the CASTOR study will be featured in an oral presentation at the 58th American Society of Hematology (ASH) Annual Meeting on Monday, December 5 at 5:15 p.m. PT (Abstract #1150). Data from the POLLUX study will be presented on Monday, December 5 at 5:30 p.m. PT (Abstract #1151).

According to a post-hoc analysis of the POLLUX study, daratumumab in combination with lenalidomide (an immunomodulatory agent) and dexamethasone reduced the risk of disease progression or death by 64 percent, compared to lenalidomide and dexamethasone alone, in patients with multiple myeloma who had received one to three prior lines of therapy (Hazard Ratio [HR]=0.36; 95 percent CI [0.26-0.49], p<0.0001). Among patients with one to three prior lines of therapy with high-risk cytogenetic status, the addition of daratumumab improved PFS by 56 percent, compared to lenalidomide and dexamethasone alone (HR=0.44; 95 percent CI [0.19-1.03], p=0.0475). Additionally, the clinical benefit of daratumumab combination therapy was maintained among patients who stopped their previous treatment more than 12 months prior to study entry (HR=0.37; 95 percent CI [0.23-0.61], p<0.0001) and those who were refractory to their last line of therapy (HR=0.47; 95 percent CI [0.29-0.76], p=0.0015).

According to a post-hoc analysis of the CASTOR study, daratumumab in combination with bortezomib (a proteasome inhibitor [PI]) and dexamethasone reduced the risk of disease progression or death by 61 percent, compared to bortezomib and dexamethasone alone, in patients with multiple myeloma who had received one to three prior lines of therapy (HR=0.39; 95 percent CI [0.28-0.53], p<0.0001). Among patients with one prior line of therapy, the addition of daratumumab reduced the risk of disease progression or death by 78 percent, compared to bortezomib and dexamethasone alone (HR=0.22; 95 percent CI [0.14-0.34], p<0.0001). Additionally, the clinical benefit of daratumumab combination therapy was maintained among patients with standard risk cytogenetic status (HR=0.29; 95 percent CI [0.20-0.43], p<0.0001) and those with high-risk cytogenetic status (HR=0.49; 95 percent CI [0.27-0.89], p=0.0167).

“In combination with standard of care regimens, daratumumab enabled deep and durable responses that were maintained across previously-treated patients included in this post-hoc analysis,” said Saad Z. Usmani, M.D., FACP, primary author of the POLLUX study and Director of Clinical Research (Hematologic Malignancies), Director of Plasma Cell Disorders at Levine Cancer Institute, Carolinas HealthCare System. “These data help underscore the potential of daratumumab in this patient population, regardless of prior treatment exposure or cytogenetic risk.”

In the POLLUX study, in addition to improving PFS in patients with one to three prior lines of therapy, daratumumab in combination with lenalidomide and dexamethasone significantly increased ORRs compared to lenalidomide and dexamethasone alone (94 percent vs. 78 percent), doubled rates of complete response (CR) or better (47 percent vs. 20 percent, p<0.0001) and significantly increased rates of very good partial response (VGPR) or better (78 percent vs. 46 percent, p<0.0001). The median PFS in the daratumumab arm has not been reached, compared with a median PFS of 18.4 months for patients who received lenalidomide and dexamethasone alone.

In the CASTOR study, in addition to significantly lengthening PFS in patients with one to three prior lines of therapy, daratumumab in combination with bortezomib and dexamethasone significantly increased ORRs compared to bortezomib and dexamethasone alone (85 percent vs. 67 percent, p<0.0001) and attained higher rates of VGPR or better (64 percent vs. 32 percent, p<0.0001). The median PFS in the daratumumab arm has not been reached, compared with a median PFS of 7.2 months for patients who received bortezomib and dexamethasone alone.

“These results, along with other data at the meeting, show the versatility of daratumumab, which now has approvals in the relapsed or refractory setting as both a monotherapy and in combination with two standard of care regimens, lenalidomide and dexamethasone, or bortezomib and dexamethasone,” said Peter F. Lebowitz, M.D., Ph.D., Oncology Therapeutic Area Head, Janssen Research & Development. “We look forward to continued study of this compound to better understand its utility in various combinations and for patients across the treatment continuum.”

In November 2016, DARZALEX earned its second approval from the U.S. Food and Drug Administration (FDA) for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, in patients with multiple myeloma who have received at least one prior therapy, based on data from the CASTOR and POLLUX studies. It was first approved by the FDA in November 2015 as a monotherapy 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.[i]

Additional daratumumab data at ASH
Additional daratumumab data at the meeting include:

  • Data from the first and most comprehensive prospective assessment of minimal residual disease (MRD) – a measure of cancer cells that remain after treatment – from Phase 3 trials in the relapsed/refractory setting for multiple myeloma. These data from the CASTOR and POLLUX studies showed daratumumab demonstrated a three-fold increase in MRD negative rates in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone. These data were presented orally at 5:15 p.m. PT on Saturday, December 3 (Abstract #246).
  • According to a post-hoc analysis of the POLLUX study, daratumumab combination therapy significantly reduced the risk of disease progression or death, compared to lenalidomide and dexamethasone alone, among patients who were lenalidomide-naïve (HR=0.37; 95 percent CI [0.26-0.51], p<0.0001), patients who were bortezomib-naïve (HR=0.33; 95 percent CI [0.15-0.74], p=0.0048) and those who were refractory to bortezomib (HR=0.51; 95 percent CI [0.28-0.91], p=0.021). These data, showing the consistent benefit of this daratumumab combination therapy regardless of prior treatment exposure, were presented orally at 5:00 p.m. PT on Sunday, December 4 (Abstract #489).

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.[ii] Daratumumab 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.[iii] A subset of myeloid derived suppressor cells (MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by daratumumab.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 the frontline and relapsed settings.[iv],[v],[vi],[vii],[viii] 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.[ix],[x],[xi] 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.[xii] 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.[xiii],[xiv] 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.[xv],[xvi] Relapsed cancer means the disease has returned after a period of initial partial or complete remission.[xvii] Globally, it is estimated that 124,225 people were diagnosed and 87,084 died from the disease in 2015.[xviii],[xix] 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.[xx]


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 the promise of daratumumab and expectations for its further development. 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; 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.


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[i] 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.
[ii] 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
[iii] DARZALEX Prescribing Information, November 2016.
[iv] Janssen Research & Development, LLC. A Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Nov 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT02076009?term=mmy3003&rank=1 NLM Identifier: NCT02136134.
[v] Janssen Research & Development, LLC. Addition of Daratumumab to Combination of Bortezomib and Dexamethasone in Participants With Relapsed or Refractory Multiple Myeloma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Nov 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT02136134?term=mmy3004&rank=1 NLM Identifier: NCT02076009.
[vi] Janssen Research & Development, LLC. A Study to Evaluate Daratumumab in Transplant Eligible Participants With Previously Untreated Multiple Myeloma (Cassiopeia). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Nov 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT02541383?term=mmy3006&rank=2 NLM Identifier: NCT02541383.
[vii] Janssen Research & Development, LLC. A Study of Combination of Daratumumab and Velcade (Bortezomib) Melphalan-Prednisone (DVMP) Compared to Velcade Melphalan-Prednisone (VMP) in Participants With Previously Untreated Multiple Myeloma In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Nov 11]. https://clinicaltrials.gov/ct2/show/NCT02195479?term=mmy3007&rank=1 Identifier: NCT02195479.
[viii] Janssen Research & Development, LLC. Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Participants With Previously Untreated Multiple MyelomaIn: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Nov 11]. https://clinicaltrials.gov/ct2/show/NCT02252172?term=mmy3008&rank=1Identifier: NCT02252172.
[ix] Janssen Research & Development, LLC. “Janssen Announces the Initiation of Two Studies Evaluating Daratumumab (DARZALEX®) and Atezolizumab in Multiple Myeloma and Solid Tumor.” Issued March 21, 2016
[x] Janssen Research & Development, LLC. A Study to Evaluate 3 Dose Schedules of Daratumumab in Participants With Smoldering Multiple Myeloma In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2016 Nov 11]. https://clinicaltrials.gov/ct2/show/NCT02316106?term=smm2001&rank=1 Identifier: NCT02316106.
[xi] 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.
[xii] Janssen Biotech, Inc. “Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab” Issued August 30, 2012.
[xiii] Kumar, SK et al. Leukemia. 2012 Jan; 26(1):149-57.
[xiv] American Cancer Society. "Multiple Myeloma Overview." http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-what-is-multiple-myeloma. Accessed November 2015.
[xv] National Cancer Institute. “NCI Dictionary of Cancer Terms: Refractory.” Available at http://www.cancer.gov/publications/dictionaries/cancer-terms?expand=R. Accessed November 2015.
[xvi] Richardson, et al. “The Treatment of Relapsed and Refractory Multiple Myeloma.” ASH Education Book January 1, 2007 vol. 2007 no. 1 317-323.
[xvii] National Cancer Institute. “NCI Dictionary of Cancer Terms: Relapsed.” Available at http://www.cancer.gov/publications/dictionaries/cancer-terms?expand=R. Accessed November 2015.
[xviii] GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide: Number of New Cancers in 2015. Available at: http://globocan.iarc.fr/old/burden.asp?selection_pop=224900&Text-p=World&selection_cancer=17270&Text-c=Multiple+myeloma&pYear=3&type=0&window=1&submit=%C2%A0Execute. Accessed August 2016.
[xix] GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide: Number of Cancer Deaths in 2015. Available at http://globocan.iarc.fr/old/burden.asp?selection_pop=224900&Text-p=World&selection_cancer=17270&Text-c=Multiple+myeloma&pYear=3&type=1&window=1&submit=%C2%A0Execute. Accessed November 2015.
[xx] American Cancer Society. "How is Multiple Myeloma Diagnosed?" http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-diagnosis. Accessed November 2015.