New Data for DARZALEX® (daratumumab) Presented at ASH 2017 Showed Feasibility of Subcutaneous Use and Promise of DARZALEX as a Treatment for Smoldering Multiple Myeloma

ATLANTA and RARITAN, N.J., Dec. 11, 2017 /PRNewswire/ -- Janssen Research & Development, LLC today announced new data from the Phase 1b PAVO clinical study, which demonstrated that the subcutaneous delivery of DARZALEX^® (daratumumab) had a manageable safety profile and a 12 percent rate of infusion reactions (IRs) in patients with relapsed or refractory multiple myeloma.¹ These data were featured as an oral presentation today at the 59^th American Society of Hematology (ASH) Annual Meeting in Atlanta (Abstract #838). DARZALEX is currently approved for intravenous (IV) administration, and results from the PAVO trial serve as the basis for an actively enrolling Phase 3 study comparing subcutaneous administration of DARZALEX over 3-5 minutes with the approved IV administration in relapsed or refractory multiple myeloma patients.¹

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Additionally, results from the Phase 2 CENTAURUS clinical study showed DARZALEX monotherapy had a manageable safety profile in patients with intermediate or high-risk smoldering multiple myeloma, with the most common treatment-emergent adverse events (TEAEs) being fatigue, cough, upper respiratory tract infection, insomnia and headache.² These data were featured as an oral presentation at ASH on December 10 (Abstract #510).² Smoldering multiple myeloma is an asymptomatic precursor stage to multiple myeloma during which early intervention to delay the progression to active disease may potentially benefit patients.² These results serve as the basis for an actively enrolling Phase 3 study for DARZALEX vs. observation in smoldering multiple myeloma. 

Key Findings from PAVO Study
Updated data from Part 2 of the open-label, multicenter, dose-finding Phase 1b PAVO (MMY1004) study showed initial safety and efficacy of DARZALEX co-formulated with recombinant human hyaluronidase enzyme (rHuPH20) delivered by manual subcutaneous injection (DARZALEX-SC).¹ According to findings, IRs were reported in 12 percent of patients receiving DARZALEX-SC 1800 mg, with no Grade 4 IRs reported.¹ Subcutaneous administration was well-tolerated in the DARZALEX-SC 1800 mg cohort, with 20 percent of patients experiencing reversible and short-lasting erythema at the injection site.¹

In the DARZALEX-SC 1800 mg cohort, drug-related TEAEs occurred in 48 percent of patients; the most common TEAEs included lymphopenia, thrombocytopenia, insomnia and pyrexia.¹ Data for this new investigational delivery method demonstrated that subcutaneous administration of DARZALEX and rHuPH20 was well-tolerated, with rates of IRs lower than those observed with IV administration of DARZALEX.¹ Additionally, an overall response rate (ORR) of 44 percent was observed in the DARZALEX-SC 1800 mg cohort, with a median follow-up of 4.6 months.¹

"Results from the PAVO study show that subcutaneous delivery of DARZALEX offered consistent efficacy with shorter infusion times and lower risk of infusion reactions, which may benefit patients, physicians and healthcare systems alike," said Mark Wildgust, Ph.D., Vice President, Global Medical Affairs, Oncology, Janssen Research & Development. "These compelling findings support the continued study of alternative dosing for DARZALEX, with a Phase 3 study already underway."

Key Findings from CENTAURUS Study
Preliminary data presented from the randomized, open-label, Phase 2 CENTAURUS (SMM2001) study evaluated three dosing schedules for DARZALEX monotherapy in patients with intermediate or high-risk smoldering multiple myeloma.² A total of 123 patients were randomized to one of three treatment arms receiving DARZALEX 16 mg/kg intravenously in eight-week cycles: 1.) a long-intense dosing schedule (LONG) in which DARZALEX was administered weekly in Cycle 1, every other week in Cycle 2-3, every four weeks in Cycle 4-7 and every eight weeks up to Cycle 20; 2.) an intermediate dosing schedule (INT), in which DARZALEX was given weekly in Cycle 1, and every eight weeks up to Cycle 20 and; 3.) a short intense dosing schedule (SHORT), in which DARZALEX was given weekly for one cycle.²

Study findings indicated that DARZALEX was well-tolerated, with a safety profile comparable to DARZALEX in the relapsed or refractory multiple myeloma setting.² Hematologic TEAEs occurred in less than 10 percent of patients across all arms. Rates of Grade 3/4 infection were less than or equal to 5 percent in all arms.² Any-grade IRs occurred in 56 percent, 42 percent and 55 percent of patients in the LONG, INT and SHORT dosing cohorts, respectively.² At the time of clinical cut-off, one death due to disease progression in the SHORT dosing cohort was confirmed.² With a median follow-up of 15.8 months (range: 0.0-23.9), the ORR was numerically higher in the LONG arm than in INT or SHORT arms (56 percent, 54 percent and 38 percent, respectively).² The estimated 12-month progression-free survival (PFS) rates were 95 percent, 88 percent and 81 percent in the LONG, INT and SHORT arms, respectively.²

"These findings demonstrate that prolonged DARZALEX dosing in smoldering myeloma produced a significant response in just over half of patients treated," said Craig C. Hofmeister, M.D., Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio. "Treating patients in this precursor stage is an important step to intercepting the disease before patients' bones begin to fracture, they become anemic or develop kidney failure."

Approved and Investigational Uses for DARZALEX
DARZALEX was first approved by the U.S. Food and Drug Administration (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 proteasome inhibitor (PI) and an immunomodulatory agent, or who are double refractory to a PI and immunomodulatory agent.³ It received additional approvals in November 2016 by the FDA in combination with lenalidomide (an immunomodulatory agent) and dexamethasone, or bortezomib (a PI) and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.⁴  DARZALEX was most recently approved by the FDA in June 2017 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.⁵

On November 21, 2017, Janssen submitted a supplemental Biologics License Application (sBLA) to the FDA for DARZALEX in combination with bortezomib, melphalan and prednisone for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation. Janssen requested Priority Review of this sBLA, which would shorten FDA review to six months, compared to ten months for Standard Review. If approved, this would be the fifth indication for DARZALEX in the U.S. and its first in the frontline setting. On November 21, 2017, Janssen also submitted an application for this indication to the European Medicines Agency (EMA).  

About DARZALEX^® (daratumumab) Injection, for Intravenous Infusion
DARZALEX^® (daratumumab) injection for intravenous use is the first CD38-directed antibody approved anywhere in the world.⁶ CD38 is a surface protein that is highly expressed across multiple myeloma cells.⁷  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.⁶ A subset of myeloid derived suppressor cells (MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by DARZALEX.³ DARZALEX is being evaluated in a comprehensive clinical development program across a range of treatment settings in multiple myeloma, such as in the frontline and relapsed settings.^8,9,10,11,12 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.^13,14,15 DARZALEX was the first antibody to receive regulatory approval to treat relapsed or refractory multiple myeloma.⁴

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.¹⁶ DARZALEX is commercialized in the U.S. by Janssen Biotech, Inc.¹⁶ 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.^17,18 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 It is estimated that 30,280 people will be diagnosed and 12,590 will die from the disease in the United States in 2017.²² 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.²³

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%).

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

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 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 implications of data from two clinical studies evaluating DARZALEX^® (daratumumab), including feasibility of alternative dosing approaches and the potential of DARZALEX as a treatment for smoldering 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. 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 for new products and indications; 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 January 1, 2017, including under "Item 1A. Risk Factors," its most recently filed Quarterly Report on Form 10-Q, including under the caption "Cautionary Note Regarding Forward-Looking Statements," 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. Neither the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

¹ Chari A et al. Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (RRMM): PAVO, an Open-label, Multicenter, Dose Escalation Phase 1b Study. 2017 American Society of Hematology Annual Meeting. December 2017.
² Hofmeister C et al. Daratumumab monotherapy for patients with intermediate or high-risk smoldering multiple myeloma (SMM): CENTAURUS, a randomized, open-label, multicenter phase 2 study. 2017 American Society of Hematology Annual Meeting. December 2017.
³ 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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⁶ DARZALEX Prescribing Information, June 2017.
⁷ 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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⁹ 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 at: https://clinicaltrials.gov/ct2/show/NCT02136134?term=mmy3004&rank=1 NLM Identifier: NCT02076009.
¹⁰ 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 at: https://clinicaltrials.gov/ct2/show/NCT02541383?term=mmy3006&rank=2 NLM Identifier: NCT02541383.
¹¹ 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]. Available at: https://clinicaltrials.gov/ct2/show/NCT02195479?term=mmy3007&rank=1 Identifier: NCT02195479.
¹² 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]. Available at: https://clinicaltrials.gov/ct2/show/NCT02252172?term=mmy3008&rank=1Identifier: NCT02252172.
¹³ 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.
¹⁴ 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]. Available at: https://clinicaltrials.gov/ct2/show/NCT02316106?term=smm2001&rank=1 Identifier: NCT02316106.
¹⁵ 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]. Available at: https://clinicaltrials.gov/ct2/show/NCT02413489?term=lym2001&rank=1 Identifier: NCT02413489.
¹⁶ Janssen Biotech, Inc. "Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab" Issued August 30, 2012.
¹⁷ Kumar, SK et al. Leukemia. 2012 Jan; 26(1):149-57.
¹⁸American Cancer Society. "Multiple Myeloma Overview." Available at: http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-what-is-multiple-myeloma. Accessed December 2017.
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²⁰ Richardson, et al. "The Treatment of Relapsed and Refractory Multiple Myeloma." ASH Education Book January 1, 2007 vol. 2007 no. 1 317-323.
²¹ National Cancer Institute. "NCI Dictionary of Cancer Terms: Relapsed." Available at: http://www.cancer.gov/publications/dictionaries/cancer-terms?expand=R. Accessed December 2017.
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²³ American Cancer Society. "How is Multiple Myeloma Diagnosed?" Available at: http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-diagnosis. Accessed December 2017.

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