Independent Data Monitoring Committee rec­om­mends Phase 3 trial be stopped early based on pos­i­tive results of planned interim analysis

Raritan, NJ (Press Release) – Janssen Research & Development, LLC announced today pos­i­tive results of a pre-planned interim analysis of the Phase 3 MMY3004 (CASTOR) trial eval­u­ating the efficacy and safety of dara­tu­mu­mab, a CD38-directed mono­clonal anti­body (mAb), in com­bi­na­tion with bor­tez­o­mib and dexa­metha­sone, com­pared to bor­tez­o­mib and dexa­metha­sone alone, in patients with re­lapsed or refractory multiple myeloma. The interim analysis, conducted by an Independent Data Monitoring Committee (IDMC), found that the dara­tu­mu­mab com­bi­na­tion treat­ment regi­men im­proved pro­gres­sion-free survival (PFS) com­pared with bor­tez­o­mib and dexa­metha­sone alone, achieving the pri­mary study end­point (p < 0.0001). Based on the recom­men­da­tion of the IDMC, the study will be stopped early. Study patients originally assigned to the standard treat­ment group (bor­tez­o­mib plus dexa­meth­a­sone) will be offered the option of receiving dara­tu­mu­mab fol­low­ing con­firmed disease pro­gres­sion. All patients con­tinue to be followed for long-term safety and over­all survival.

"These results suggest dara­tu­mu­mab could poten­tially be used in com­bi­na­tion with standard ther­apy in patients with re­lapsed or refractory multiple myeloma," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development. "We are especially proud that Janssen was involved in the devel­op­ment of two of the med­i­cines in this trial, dara­tu­mu­mab and bor­tez­o­mib." Janssen licensed dara­tumu­mab from Genmab A/S and is responsible for devel­op­ment and mar­ket­ing. Janssen co-developed bor­tezo­mib with Takeda Pharma­ceu­tical Company Limited through its wholly owned sub­sid­i­ary Millennium Pharma­ceuticals Inc. and com­mer­cial­izes the treat­ment outside of the U.S.

MMY3004 is a Phase 3, multinational, open-label, ran­domized, multi­center, active-controlled study in approx­i­mately 490 patients with re­lapsed or refractory multiple myeloma. Patients were ran­domized to receive either dara­tu­mu­mab com­bined with sub­cu­tane­ous bor­tez­o­mib (a pro­te­a­some inhibitor) and dexa­metha­sone (a corticosteroid), or bor­tez­o­mib and dexa­metha­sone alone. Participants were treated until disease pro­gres­sion, unacceptable toxicity, or if they had other reasons to dis­con­tinue the study. The pri­mary end­point of the study is PFS.¹

These results are planned to be submitted for presentation at an upcoming medical congress, as well as for publication in a peer-reviewed journal. A full study report is being prepared for sub­mission and will be shared with health author­i­ties. Janssen will ini­ti­ate discussions about the poten­tial for a regu­la­tory sub­mission for this indi­ca­tion. For addi­tional study in­­for­ma­tion, visit ClinicalTrials.gov.

In November 2015, dara­tu­mu­mab (DARZALEX®) was approved by the U.S. Food and Drug Admin­istra­tion for the treat­ment of 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. This indi­ca­tion is approved under accelerated approval based on re­sponse rate. Continued approval for this indi­ca­tion may be contingent upon veri­fi­ca­tion and description of clin­i­cal benefit in con­firmatory trials.²

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow un­con­trol­lably in the bone marrow.^3,4 Refractory cancer occurs when a patient's disease is resistant to treat­ment or in the case of multiple myeloma, the disease progresses within 60 days of their last ther­apy.^5,6 Relapsed cancer means the disease has returned after a period of initial, partial or com­plete remission.⁵ Accounting for ap­prox­i­mately one per­cent of all cancers and 15 per­cent to 20 per­cent of haematologic malig­nan­cies world­wide, multiple myeloma is designated as an orphan disease in both the U.S. and Europe.⁷ Globally, it is esti­mated that 124,225 people were diag­nosed, and 87,084 died from the disease in 2015.^8,9 While some patients with multiple myeloma have no symp­toms at all, most patients are diag­nosed due to symp­toms which can in­clude bone problems, low blood counts, cal­cium elevation, kidney problems or in­fec­tions.¹⁰ Patients who relapse after treat­ment with standard ther­a­pies (including PIs or immuno­modu­la­tory agents) typically have poor prognoses and few remaining options.⁴

About DARZALEX® (dara­tu­mu­mab)

DARZALEX® (dara­tu­mu­mab) injection for in­tra­venous use is the first CD38-directed mono­clonal anti­body (mAb) approved any­where in the world.2 CD38 is a surface protein that is highly ex­pressed across multiple myeloma cells, re­gard­less of disease stage.¹¹ Dara­tu­mu­mab is believed to induce tumor cell death through apop­tosis, in which a series of molecular steps in a cell lead to its death^2,12 as well as immuno­modu­la­tory effects and multiple immune-mediated mech­a­nisms of action, in­­clud­ing complement-dependent cyto­tox­icity (CDC), anti­body-dependent cellular cyto­tox­icity (ADCC) and anti­body-dependent cellular phago­cytosis (ADCP).^2,13,14 Five Phase 3 clin­i­cal studies with dara­tu­mu­mab in re­lapsed and frontline settings are cur­rently ongoing. Additional studies are ongoing or planned to assess its poten­tial in other malignant and pre-malignant diseases on which CD38 is ex­pressed, such as smol­der­ing myeloma and non-Hodgkin's lym­phoma. DARZALEX is the first mAb to receive regu­la­tory approval to treat re­lapsed or refractory multiple myeloma.²

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. DARZALEX is com­mer­cial­ized in the U.S. by Janssen Biotech, Inc.¹⁵

DARZALEX® (dara­tu­mu­mab) Important Safety Information – Professional

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, and hyper­tension. Signs and symp­toms may in­clude res­pira­tory symp­toms, such as cough, wheezing, larynx and throat tightness and irritation, laryngeal edema, pul­mo­nary edema, nasal congestion, and allergic rhinitis. Less common symp­toms were hypo­­tension, headache, rash, urticaria, pruritus, nausea, vomiting, and chills.

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 the first and second day after all in­fusions. Patients with a history of obstructive pul­mo­nary disorders may require addi­tional post-infusion medications to man­age res­pira­tory com­pli­ca­tions. Consider pre­scrib­ing short- and long-acting bron­cho­di­lators and inhaled corticosteroids for patients with obstructive pul­mo­nary disorders.

Interference with Serological Testing - Dara­tu­mu­mab binds to CD38 on red blood cells (RBCs) and results in a pos­i­tive Indirect Antiglobulin Test (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.

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%) were: fatigue, nausea, back pain, pyrexia, cough, and upper res­pira­tory tract in­fec­tion.

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 - No drug inter­action studies have been per­formed.

About Janssen Research & Development, LLC

At Janssen, we are dedicated to addressing and solving some of the most im­por­tant unmet medical needs of our time in on­col­ogy, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop inno­va­tive prod­ucts, services and health­care solu­tions to help people through­out the world. Janssen Research & Development, LLC; and Janssen Biotech, Inc. are part of the Janssen Pharma­ceu­tical Com­panies of Johnson & Johnson. Please visit www.janssen.com for more in­­for­ma­tion.

Janssen in Oncology

Our goal is to fundamentally alter the way cancer is under­stood, diag­nosed and man­aged, reinforcing our commitment to the patients who in­spire us. In looking to find inno­va­tive ways to address the cancer chal­lenge, our pri­mary efforts focus on several treat­ment and prevention solu­tions. These in­clude a focus on hema­to­logic malig­nan­cies, prostate cancer and lung cancer; cancer interception with the goal of devel­op­ing prod­ucts that interrupt the carcinogenic process; bio­­markers that may help guide targeted, individualized use of our ther­a­pies; as well as safe and effective identi­fi­ca­tion and treat­ment of early changes in the tumor microenvironment. Please visit http://www.janssen.com for more in­­for­ma­tion.

Cautions Concerning Forward-Looking Statements

This press release con­tains "forward-looking state­ments" as defined in the Private Se­cu­ri­ties Lit­i­ga­tion Reform Act of 1995 re­gard­ing a clin­i­cal trial col­lab­o­ra­tion and prod­uct 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 Research & Development, LLC and/or Johnson & Johnson. Risks and un­cer­tain­ties in­clude, but are not limited to: chal­lenges and un­cer­tain­ties in­her­ent in new prod­uct devel­op­ment, in­­clud­ing the uncertainty of clin­i­cal success and of obtaining regu­la­tory approvals; 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. ClinicalTrials.gov. Addition of Daratumumab to Combination of Bortezomib and Dexamethasone in Participants With Relapsed or Refractory Multiple Myeloma. Available at https://clinicaltrials.gov/ct2/show/NCT02136134. Accessed March 2016.
2. DARZALEX Prescribing Information, November 2015. Available at https://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-information.pdf. Accessed March 2016.
3. American Cancer Society. "Multiple Myeloma Overview." http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-what-is-multiple-myeloma. Accessed March 2016.
4. Kumar, SK et al. Leukemia. 2012 Jan; 26(1):149-57.
5. National Cancer Institute. "NCI Dictionary of Cancer Terms: Refractory." Available at http://www.cancer.gov/publications/dictionaries/cancer-terms?expand=R. Accessed March 2016.
6. Richardson, et al. "The Treatment of Relapsed and Refractory Multiple Myeloma." ASH Education Book January 1, 2007 vol. 2007 no. 1 317-323.
7. Becker N. Epidemiology of multiple myeloma. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer. 2011;183:25-35.
8. 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 March 2016.
9. 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 March 2016.
10. American Cancer Society. "How is Multiple Myeloma Diagnosed?" http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-diagnosis. Accessed March 2016.
11. 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.
12. Jansen, JH et al. Blood. 2012; 120.2974.
13. de Weers, M et al. Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors. The Journal of Immunology. February 1, 2011. Vol. 186, No. 3 1840-1848.
14. Overdijk, M et al. Phagocytosis Is A Mechanism of Action for Daratumumab. Available at https://ash.confex.com/ash/2012/webprogram/Paper51257.html. Accessed March 2016.
15. Janssen Biotech, Inc. "Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab." Issued August 30, 2012.

Source: Janssen.