Supplemental Biologics License Application (sBLA) seeks second indi­ca­tion for dara­tu­mu­mab in combi­na­tion with standard of care regi­mens for patients with multiple myeloma who have received at least one prior ther­apy

Raritan, NJ (Press Release) – Janssen Biotech, Inc. announced today a supple­mental Biologics License Application (sBLA) for dara­tu­mu­mab (DARZALEX®) has been submitted to the U.S. Food and Drug Admin­is­tra­tion (FDA). The appli­ca­tion seeks to expand the current indi­ca­tion, using dara­tu­mu­mab in com­bi­na­tion with lena­lido­mide (an immuno­modu­la­tory agent) and dexa­meth­a­sone, or bor­tez­o­mib (a pro­te­a­some inhibitor [PI]) and dexa­meth­a­sone, for the treat­ment of patients with multiple myeloma who have received at least one prior ther­apy. Dara­tu­mu­mab received Break­through Therapy Desig­na­tion from the FDA for this pending indi­ca­tion on July 25, 2016.

"Daratumumab has been shown to provide clin­i­cally meaningful benefit as a back­bone ther­apy in combi­na­tion with two of the most widely used treat­ment regi­mens for multiple myeloma," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development, LLC. "Today's sub­mission marks an im­por­tant step for­ward in realizing the full poten­tial of dara­tu­mu­mab earlier in the treat­ment path­way, and we look for­ward to work­ing with the FDA during its review of our appli­ca­tion."

Janssen has also submitted a request for Priority Review of this sBLA. The FDA will inform Janssen whether a Priority Review has been granted within the next 60 days. If the FDA grants Priority Review, the review should be com­pleted within six months from today.

The regu­la­tory sub­mission for dara­tu­mu­mab is sup­ported by data from two Phase 3 studies:

• The CASTOR (MMY3004) clinical study which showed daratumumab in combination with bortezomib 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 received at least one prior therapy (Hazard Ratio [HR]=0.39; 95 percent CI [0.28-0.53], p<0.0001). Overall, the safety of the daratumumab combination therapy was consistent with the known safety profile of daratumumab monotherapy and bortezomib plus dexamethasone, respectively.
  • These results were presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in June 2016.
• The POLLUX (MMY3003) clin­i­cal study which showed dara­tu­mu­mab in com­bi­na­tion with lena­lido­mide 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 at least one prior ther­apy (HR=0.37; 95 per­cent CI [0.27-0.52], p<0.0001). Overall, the safety of the dara­tu­mu­mab com­bi­na­tion ther­apy was con­sis­tent with the known safety profile of dara­tu­mu­mab mono­therapy and lena­lido­mide plus dexa­meth­a­sone, re­spec­tive­ly.
  • These results were presented at the 21st Annual Congress of the European Hematology Association (EHA) in June 2016.

The sub­mission also in­cluded data from the Phase 1 study of dara­tu­mu­mab in com­bi­na­tion with poma­lido­mide and dexa­meth­a­sone in patients who received at least two prior lines of ther­apy.

These data will be used as the basis for a poten­tial regu­la­tory sub­mission to the European Medicines Agency (EMA). More in­­for­ma­tion about these studies can be found at www.ClinicalTrials.gov (NCT02076009; NCT02136134; NCT01998971).

In November 2015, DARZALEX® was approved as a mono­therapy by the FDA for the treat­ment of 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 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 a con­firmatory trial.1 DARZALEX received Break­through Therapy Desig­na­tion from the FDA for this indi­ca­tion in May 2013.

In May 2016, the European Com­mis­sion (EC) granted con­di­tional approval to DARZALEX mono­therapy for the treat­ment of adult patients with re­lapsed and refractory multiple myeloma, whose prior ther­apy in­cluded a PI and an immu­no­modu­latory agent and who have dem­onstrated disease pro­gres­sion on the last ther­apy.

About DARZALEX® (dara­tu­mu­mab)

DARZALEX® (dara­tu­mu­mab) injection for in­tra­venous use is the first CD38-directed mono­clonal anti­body (mAb) approved any­where in the world.¹ CD38 is a surface protein that is highly ex­pressed across multiple myeloma cells, re­gard­less of disease stage.² 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.¹ Dara­tu­mu­mab also dem­onstrates other effects on the immune sys­tem, in­­clud­ing lysis of immuno­sup­pres­sive CD38+ regu­la­tory T cells (Tregs) and myeloid derived sup­pressor cells (MDSCs).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. 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. DARZALEX was the first mAb 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. 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.^3,4 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.^5,6 Relapsed cancer means the disease has returned after a period of initial partial or com­plete remission.^7,11 Globally, it is esti­mated that 124,225 people were diag­nosed, and 87,084 died from the disease in 2015.^7,8 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.⁹ Patients who relapse after treat­ment with standard ther­a­pies (including PIs or immuno­modu­la­tory agents) typically have poor prognoses and few remaining options.⁵

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: 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 - No drug inter­action studies have been per­formed

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 prod­uct devel­op­ment and the poten­tial benefits 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. 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; com­pe­ti­tion, in­­clud­ing technological ad­vances, new prod­ucts and patents attained by com­pet­i­tors; chal­lenges to patents; manu­fac­tur­ing dif­fi­culties and delays; changes in behavior and spending patterns or financial distress 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 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 2015.
2. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121:482–488. doi: 10.1309/74R4TB90BUWH27JX.
3. American Cancer Society. "Multiple Myeloma Overview." Available at: http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-what-is-multiple-myeloma. Accessed August 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 August 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. 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.
8. 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 August 2016.
9. American Cancer Society. "How is Multiple Myeloma Diagnosed?" Available at: http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiple-myeloma-diagnosis. Accessed August 2016.

Source: Janssen.