HORSHAM, Pa., May 1, 2020 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson announced today the U.S. Food and Drug Administration (FDA) approved Darzalex Faspro (daratumumab and hyaluronidase-fihj), a new subcutaneous formulation of daratumumab. Darzalex Faspro™ is approved in four regimens across five indications in multiple myeloma patients, including newly diagnosed, transplant-ineligible patients as well as relapsed or refractory patients. As a fixed-dose formulation, Darzalex Faspro™ can be administered over approximately three to five minutes, significantly less time than Darzalex®, which is given intravenously over hours. In the Phase 3 COLUMBA study supporting the approval, Darzalex Faspro™ demonstrated a consistent overall response rate (ORR) and pharmacokinetics and a similar safety profile compared with intravenous Darzalex® in patients with relapsed or refractory multiple myeloma. In addition, there was a nearly two-thirds reduction in systemic administration-related reactions (ARRs) for Darzalex Faspro™ compared to intravenous Darzalex® (13 percent vs. 34 percent, respectively).

"This approval exemplifies Janssen's mission and commitment to bringing together passion, science and ingenuity to advance novel solutions for patients," said Mathai Mammen, M.D., Ph.D., Global Head, Janssen Research & Development, LLC. "We are excited about the potential of this meaningful innovation in transforming the treatment experience for patients with multiple myeloma where Darzalex Faspro can be administered in approximately three to five minutes, significantly less time than intravenous Darzalex, which is given over hours. Based on its favorable profile, we are accelerating the development of Darzalex Faspro and evaluating its potential in multiple ongoing studies."

The approval is based on data from the Phase 3 COLUMBA (MMY3012) and Phase 2 PLEIADES (MMY2040) studies.1,2 In the COLUMBA study, the ORR was non-inferior for patients taking Darzalex Faspro™ as monotherapy compared to those taking intravenous Darzalex® as monotherapy (41 percent vs. 37 percent, respectively). In addition, there were fewer systemic ARRs with Darzalex Faspro™ versus intravenous Darzalex® (13 percent vs. 34 percent, respectively). In a pooled safety population of 490 patients who received Darzalex Faspro™ as monotherapy or in combination, the ARR rate wFas 11 percent. The safety profiles of intravenous Darzalex® and Darzalex Faspro™ were otherwise similar.1 Additionally, in the Phase 2 PLEIADES study evaluating the efficacy and safety of Darzalex Faspro™ in combination therapies, objective responses were demonstrated in combination with bortezomib, melphalan and prednisone (D-VMP) in newly diagnosed transplant ineligible patients. In addition, objective responses were demonstrated in combination with lenalidomide and dexamethasone (D-Rd) in relapsed or refractory patients who received one prior line of therapy.2

"The Multiple Myeloma Research Foundation shares a common goal with Janssen in advancing treatments for multiple myeloma and addressing the unmet needs of this patient community," said Paul Giusti, President and CEO of the Multiple Myeloma Research Foundation (MMRF). "The approval of Darzalex Faspro marks an important milestone which will help make a positive difference in the lives of patients who depend on this effective therapy."

"Since the approval of daratumumab, a robust body of evidence has established its use as a treatment for multiple myeloma in both the frontline and relapsed and refractory settings," said Saad Z. Usmani, M.D., Division Chief of Plasma Cell Disorders, Levine Cancer Institute. "With Darzalex Faspro there may be fewer administration-related reactions compared to intravenous Darzalex, providing an additional treatment option that may help patients, oncologists and nursing staff."

Darzalex Faspro™ is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20) [Halozyme's ENHANZE® drug delivery technology]. Darzalex Faspro™ will be available to patients and physicians as soon as the week of May 11, 2020. The intravenous Darzalex® formulation will also remain available as an option for patients and their physicians.

Darzalex Faspro™ is approved in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant, in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy, in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy, as monotherapy, in patients 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.

The U.S. FDA approval of Darzalex Faspro™ marks the first approval for this innovative subcutaneous formulation globally, and Janssen continues to work with health authorities around the world in an effort to bring this new treatment option to patients living with multiple myeloma.

Access to Darzalex Faspro™ (daratumumab and hyaluronidase-fihj)
Janssen offers comprehensive access and support information, resources and services to assist U.S. patients in gaining access to Darzalex Faspro™ through the Janssen CarePath Program. Through the program, eligible commercial patients pay no more than $5 per injection, regardless of individual income level. Information on the enrollment process is available online at www.CarePathSavingsProgram.com/Darzalex.

For more information, healthcare providers or patients can contact: 1-844-55DARZA (1-844-553-2792). Information will also be available at www.Darzalex.com. Dedicated case coordinators are available to work with both healthcare providers and patients.

About the COLUMBA Study 1
The randomized, open-label, multicenter Phase 3 COLUMBA study (MMY3012) included 522 patients (median age of 67 years) with multiple myeloma who had received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease was refractory to both a PI and an IMiD. In the arm that received Darzalex Faspro™ (n=263), patients received a fixed dose of Darzalex Faspro™ 1,800 milligrams (mg), co-formulated with recombinant human hyaluronidase PH20 (rHuPH20) 2,000 Units per milliliter (U/mL), subcutaneously weekly for Cycles 1 – 2, every two weeks for Cycles 3 – 6 and every four weeks for Cycle 7 and thereafter. In the intravenous Darzalex® arm (n=259), patients received Darzalex® for intravenous infusion 16 milligrams per kilogram (mg/kg) weekly for Cycles 1 – 2, every two weeks for Cycles 3 – 6 and every four weeks for Cycle 7 and thereafter. Each cycle was 28 days. In the arm that received Darzalex Faspro™, it was given in a fixed volume of 15 mL over three to five minutes; the median injection time was five minutes. In the arm that received the intravenous administration, the median durations of the first, second and subsequent intravenous Darzalex® infusions were 7.0, 4.3 and 3.4 hours, respectively. Patients in both arms continued treatment until disease progression or unacceptable toxicity.

About the PLEIADES Study 2
The non-randomized, open-label, parallel assignment Phase 2 PLEIADES study (MMY2040) included more than 240 adults with multiple myeloma, including 67 patients with newly diagnosed multiple myeloma who were treated with 1,800 mg of Darzalex Faspro™ in combination with bortezomib, melphalan, and prednisone (D-VMP) and 65 patients with relapsed or refractory disease who were treated with 1,800 mg of Darzalex Faspro™ plus lenalidomide and dexamethasone (D-Rd). The primary endpoint for the D-VMP and D-Rd cohorts was overall response rate.

About Darzalex® and Darzalex Faspro™

Janssen is committed to exploring the potential of Darzalex® (daratumumab) for patients with multiple myeloma across the spectrum of the disease. Darzalex® has been approved in seven indications, three of which are in the frontline setting, including newly diagnosed patients who are transplant eligible and ineligible.

Darzalex® has become a backbone therapy in the treatment of multiple myeloma, having been used in the treatment of more than 58,000 patients in the U.S. alone since its U.S. FDA approval in 2015. Darzalex® is the first CD38-directed antibody approved globally to treat multiple myeloma and in 2020, Darzalex Faspro™ (daratumumab and hyaluronidase human-fihj) follows as the only subcutaneous CD38-directed antibody approved to treat patients with multiple myeloma.2

CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.4 Darzalex® binds to CD38 and inhibits tumor cell growth causing myeloma cell death.5 Darzalex® may also have an effect on normal cells.3 Data across seven Phase 3 clinical trials, in both the frontline and relapsed settings, have shown that Darzalex®-based regimens resulted in significant improvement in progression-free survival and/or overall survival. 4,5,6,7,8,9,10,11 Additional studies are underway to assess the efficacy and safety of Darzalex Faspro™ in the treatment of other malignant and pre-malignant hematologic diseases in which CD38 is expressed, including smoldering myeloma and in amyloidosis.12,13

Key Darzalex® Milestones:

• In August 2012, Janssen entered into an exclusive global license and development agreement with Genmab A/S to develop, manufacture, and commercialize Darzalex®.14
• In November 2015 Darzalex® received initial U.S. FDA approval as a monotherapy 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.15
• In November 2016 Darzalex® received an additional approval in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.16
• In June 2017, Darzalex® received approval 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.17 
• In May 2018, Darzalex® received approval in combination with bortezomib, melphalan, and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT, making it the first monoclonal antibody approved for newly diagnosed patients with this disease.18
• In June 2019, Darzalex® received approval in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are transplant ineligible.19
• In September 2019, Darzalex® received approval in combination with bortezomib, thalidomide, and dexamethasone for the treatment of newly diagnosed patients who are eligible for autologous stem cell transplant.20
• In April 2020, Darzalex Faspro™, a subcutaneous formulation of Darzalex®, received approval for the treatment of certain patients with newly diagnosed or relapsed/refractory multiple myeloma, including in combination with bortezomib, melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant, in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy, in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy, as monotherapy, in patients 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.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.21,22 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow. In 2020, it is estimated that 32,270 people will be diagnosed and 12,830 will die from the disease in the U.S.24 While some patients with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.23 

Darzalex Faspro™ Important Safety Information

CONTRAINDICATIONS
Darzalex Faspro™ is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Hypersensitivity And Other Administration Reactions

Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with Darzalex Faspro™.

Systemic Reactions

In a pooled safety population of 490 patients who received Darzalex Faspro™ as monotherapy or in combination, 11% of patients experienced a systemic administration-related reaction (Grade 2: 3.9%, Grade 3: 1.4%). Systemic administration-related reactions occurred in 10% of patients with the first injection, 0.2% with the second injection, and cumulatively 0.8% with subsequent injections. The median time to onset was 3.7 hours (range: 9 minutes to 3.5 days). Of the 84 systemic administration-related reactions that occurred in 52 patients, 73 (87%) occurred on the day of Darzalex Faspro™ administration. Delayed systemic administration-related reactions have occurred in less than 1% of the patients.

Severe reactions included hypoxia, dyspnea, hypertension and tachycardia. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritis, chills, vomiting, nausea, and hypotension.

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue Darzalex Faspro™. Consider administering corticosteroids and other medications after the administration of Darzalex Faspro™ depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.

Local Reactions

In this pooled safety population, injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 0.6%. The most frequent (>1%) injection-site reaction was injection site erythema. These local reactions occurred a median of 7 minutes (range: 0 minutes to 4.7 days) after starting administration of Darzalex Faspro™. Monitor for local reactions and consider symptomatic management.

Neutropenia

Daratumumab 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. Consider withholding Darzalex Faspro™ until recovery of neutrophils. In lower body weight patients receiving Darzalex Faspro™, higher rates of Grade 3-4 neutropenia were observed.

Thrombocytopenia

Daratumumab may increase thrombocytopenia induced by background therapy.  Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Consider withholding Darzalex Faspro™ until recovery of platelets.

Embryo-Fetal Toxicity

Based on the mechanism of action, Darzalex Faspro™ can cause fetal harm when administered to a pregnant woman. Darzalex Faspro™ may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with Darzalex Faspro™ and for 3 months after the last dose.

The combination of Darzalex Faspro™ with lenalidomide is contraindicated in pregnant women, because lenalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide prescribing information on use during pregnancy.

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 administration. 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 Faspro™. Type and screen patients prior to starting Darzalex Faspro™.

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 Darzalex Faspro™ -treated patients with IgG kappa myeloma protein.

Adverse Reactions

The most common adverse reaction (≥20%) with Darzalex Faspro™ monotherapy is: upper respiratory tracts infection.

The most common adverse reactions (≥20%) with D-VMP are upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain. The most common adverse reactions (≥20%) with D-Rd are fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia and dyspnea.

The most common hematology laboratory abnormalities (≥40%) with Darzalex Faspro™ are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.

Please see full Prescribing Information at www.Darzalex.com.