On August 8, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) and a Type II Variation to the European Medicines Agency (EMA) seeking approval of a split dosing regimen for DARZALEX (daratumumab) (Press release, Johnson & Johnson, AUG 8, 2018, View Source [SID1234528659]). The applications seek to update the Prescribing Information and Summary of Product Characteristics to provide health care professionals with the option to split the first infusion of DARZALEX over two consecutive days. The submissions are supported by data from the Phase 1b MMY1001 clinical trial, which demonstrated DARZALEX pharmacokinetics (PK) concentrations were comparable regardless of whether the first dose was administered as a split infusion or single first infusion in patients with multiple myeloma.
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1 The safety profile of DARZALEX was comparable when administered initially as a split or single dose.1
"We are committed to exploring options that may improve the administration profile of DARZALEX and the overall
treatment experience for patients and physicians," said Craig Tendler, MD, Vice President, Clinical Development
and Global Medical Affairs, Janssen Research & Development, LLC. "We look forward to reviewing the data in
support of these applications with regulators and hope to make a DARZALEX split-dose option available to
patients and health care professionals to provide additional flexibility in administration of the initial infusion."
The regulatory submission is based on data from the global, multi-arm Phase 1b MMY1001 study in multiple
myeloma, which evaluated DARZALEX in combination with various treatment regimens.
1 Splitting the first dose of
DARZALEX effectively reduced the duration of the first infusion and resulted in a similar rate and pattern of
infusion reactions.
1 Data from MMY1001 demonstrated that DARZALEX concentrations were comparable after
administration of the first 16 mg/kg dose regardless of whether it was administered as a split infusion or single first
infusion in all approved indications.
1 No new safety events were observed with split dosing.
1
In the U.S., DARZALEX first received FDA approval in November 2015 as a monotherapy 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 an immunomodulatory agent.2 DARZALEX
received additional approvals in November 2016 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.3
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.4 Most recently, 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 autologous stem cell transplant (ASCT), making it the first monoclonal antibody approved for
newly diagnosed patients with this disease.5
In the European Union (EU), DARZALEX first received European Commission approval in May 2016 as a
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.
6 DARZALEX received an additional approval in April 2017 for use in combination with lenalidomide and
dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who
have received at least one prior therapy.
6 Finally, in July 2018, DARZALEX received a positive opinion from the
Committee for Medicinal Products for Human Use (CHMP) recommending broadening the existing marketing
authorization for use in combination with bortezomib, melphalan and prednisone for the treatment of adult patients
with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT).
In August 2012, Janssen Biotech, Inc. and Genmab A/S entered into a global license and development agreement,
which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX.
7 For the full
U.S. Prescribing Information, please visit www.DARZALEX.com. For the full EU Summary of Product
Characteristics, please click here.
About DARZALEX (daratumumab) Injection, for Intravenous Infusion
DARZALEX (daratumumab) injection for intravenous use is the first CD38-directed antibody approved anywhere
in the world.5 CD38 is a surface protein that is highly expressed across multiple myeloma cells, regardless of
3
disease stage.8 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.5 Subsets of myeloid derived suppressor cells (MDSCs),
CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by DARZALEX.
5 DARZALEX is
being evaluated in a comprehensive clinical development program across a range of treatment settings in multiple
myeloma, such as in frontline and relapsed settings.
9,10,11,12,13,14,15,16 Additional studies are ongoing or planned to
assess its potential in other malignant and pre-malignant hematologic diseases in which CD38 is expressed, such
as smoldering myeloma, as well as in solid tumors.
17,18,19 DARZALEX is the first and only CD38-directed antibody
to receive regulatory approval to treat multiple myeloma.5
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the
bone marrow.20,21 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.22,23 Relapsed cancer means the disease
has returned after a period of initial, partial or complete remission.24
In 2018, it is estimated that 30,700 people will
be diagnosed, and 12,770 will die from the disease in the United States.25 Additionally, there were 40,570 new
cases of multiple myeloma in Europe in 2015.26 The most recent five-year survival data for 2000-2007 show that
across Europe, up to half of newly diagnosed patients do not reach five-year survival.27 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.28
IMPORTANT SAFETY INFORMATION5
CONTRAINDICATIONS
DARZALEX is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to
daratumumab or any of the components of the formulation.
WARNINGS AND PRECAUTIONS
Infusion Reactions – DARZALEX can cause severe and/or serious infusion reactions, including
anaphylactic reactions. In clinical trials, approximately half of all patients experienced an infusion reaction.
Most infusion reactions occurred during the first infusion and were grade 1-2. 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
4
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 if an anaphylactic reaction or life-threatening (Grade 4) reaction
occurs and institute appropriate emergency care. 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
5
myeloma protein.
Adverse Reactions – The most frequently reported adverse reactions (incidence ≥20%) in clinical trials were:
infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle
spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral
sensory neuropathy and upper respiratory tract infection.
In patients who received DARZALEX in combination with bortezomib, melphalan, and prednisone (DVMP), the
most frequently reported adverse reactions (incidence ≥20%) were: upper respiratory tract infection (48%), infusion
reactions (28%), and peripheral edema (21%). Serious adverse reactions (≥2% compared to the VMP arm) were
pneumonia (11%), upper respiratory tract infection (5%), and pulmonary edema (2%). Treatment-emergent Grade
3-4 hematology laboratory abnormalities ≥20% were lymphopenia (58%), neutropenia (44%), and
thrombocytopenia (38%).
In patients who received DARZALEX in combination with lenalidomide and dexamethasone, the most
frequently reported adverse reactions (incidence ≥20%) were: 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 (≥2% compared to Rd) were pneumonia (12%), upper respiratory tract infection (7%), influenza
(3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were
neutropenia (53%) and lymphopenia (52%).
In patients who received DARZALEX in combination with bortezomib and dexamethasone, the most
frequently reported adverse reactions (incidence ≥20%) were: 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 (≥2% compared to Vd) were upper respiratory tract infection (5%), diarrhea (2%) and atrial fibrillation
(2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities ≥20% were lymphopenia (48%)
and thrombocytopenia (47%).
In patients who received DARZALEX in combination with pomalidomide and dexamethasone, the most
frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection
(50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%),
back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The
overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients
included pneumonia (7%). Treatment-emergent hematology Grade 3-4 laboratory abnormalities ≥20% were
anemia (30%), neutropenia (82%), and lymphopenia (71%).
6
In patients who received DARZALEX as monotherapy, 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%). The overall incidence of serious adverse
reactions was 33%. The most frequent serious adverse reactions were pneumonia (6%), general physical
health deterioration (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory
abnormalities ≥20% were lymphopenia (40%) and neutropenia (20%).
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 or
pomalidomide did not affect the pharmacokinetics of bortezomib or pomalidomide.