Genmab, a biotechnology company headquartered in Copenhagen, Denmark, and its licence partner, Janssen Biotech, confirmed that, based on data from Phase III COLUMBA and Phase II PLEIADES studies, the companies submitted an application for the extention of the subcutaneous formulation of the marketing authorization for daratumumab (Darzalex®) to the European Medicines Agency.
Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. Daratumumab triggers a person’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death, via apoptosis (programmed cell death).
The drug is being developed by Janssen Biotech under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab.
In the application the companies seek approval for the use of the subcutaneous (SubQ) formulation of daratumumab in multiple myeloma indications where the intravenous formulation of daratumumab is currently approved.
In August 2012, Genmab granted Janssen an exclusive worldwide license to develop, manufacture and commercialize daratumumab.
“Janssen has now submitted applications for approval of the subcutaneous formulation of daratumumab in both the Food and Drug Administration in the United States and the European Medicines Agency and we are looking forward to the possibility of multiple myeloma patients in both regions having access to this more convenient formulation of daratumumab, which allows for both faster dosing and fewer infusion-related reactions according to recently presented data from the COLUMBA study,” noted Jan Van de Winkel, Ph.D., Chief Executive Officer of Genmab.
Ongoing clinical trials
A comprehensive clinical development program for daratumumab is ongoing, including multiple Phase III studies in smoldering, relapsed and refractory and frontline multiple myeloma settings. Additional studies are ongoing or planned to assess the potential of daratumumab in other malignant and pre-malignant diseases in which CD38 is expressed, such as amyloidosis, NKT-cell lymphoma and B-cell and T-cell ALL.
Daratumumab has received two Breakthrough Therapy Designations from the U.S. FDA for certain indications of multiple myeloma, including as a monotherapy for heavily pretreated multiple myeloma and in combination with certain other therapies for second-line treatment of multiple myeloma.
The submission of the marketing extension is based on data from two ongoing clinical trials: Columba and Pleiades.
The Phase III non-inferiority COLUMBA (MMY3012) study (NCT03277105) compares the subcutaneous formulation of daratumumab to the intravenous formulation in patients with relapsed or refractory multiple myeloma.
The Phase III trial is a randomized, open-label, parallel assignment study that includes 522 adults diagnosed with relapsed and refractory multiple myeloma.
Participating patients were randomized to receive either: SubQ daratumumab, as 1,800 mg daratumumab with rHuPH20 2000 U/mL once weekly in Cycle 1 and 2, every two weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study; or 16 mg/kg IV daratumumab once weekly in Cycle 1 and 2, every two weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study.
The co-primary endpoints of the study are overall response rate and Maximum trough concentration of daratumumab (Ctrough; defined as the serum pre-dose concentration of daratumumab on Cycle 3 Day 1).
The topline results from the COLUMBA data were announced in February 2019 and subsequently presented in oral sessions at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting and the 24th European Hematology Association (EHA) Annual Congress.
The preliminary non-public data from the Phase II PLEIADES (MMY2040) study (NCT03412565) evaluates daratumumab in combination with certain standard multiple myeloma regimens.
The Phase II trial is a non-randomized, open-label, parallel assignment study that includes 240 adults either newly diagnosed or with relapsed or refractory multiple myeloma. Patients with newly diagnosed multiple myeloma are being treated with 1,800 mg subcutaneous daratumumab in combination with either bortezomib, lenalidomide and dexamethasone (D-VRd) or bortezomib, melphalan and prednisone (D-VMP).
Patients with relapsed or refractory multiple myeloma are being treated with 1,800 mg subcutaneous daratumumab plus lenalidomide and dexamethasone (D-Rd). An additional cohort of patients with relapsed and refractory multiple myeloma treated with daratumumab plus carfilzomib and dexamethasone (D-Kd) was subsequently added to the study. The primary endpoint for the D-VMP, D-Kd and D-Rd cohorts is overall response rate. The primary endpoint for the D-VRd cohort is very good partial response or better rate.
- A Study of Subcutaneous Versus (vs.) Intravenous Administration of Daratumumab in Participants With Relapsed or Refractory Multiple Myeloma – NCT03277105
- A Study to Evaluate Subcutaneous Daratumumab in Combination With Standard Multiple Myeloma Treatment Regimens – NCT03412565
 DARZALEX Prescribing information, July 2019. Online. Last accessed July 18, 2019
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