FDA, EU Approvals Sought for Split Dose Regimen of Daratumumab for Multiple Myeloma

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Submission of the ssBLA is based on data from the phase 1b MMY1001 study in multiple myeloma.
Submission of the ssBLA is based on data from the phase 1b MMY1001 study in multiple myeloma.

The Janssen Pharmaceutical Companies of Johnson & Johnson is seeking US Food and Drug Administration (FDA) approval for a split dosing regimen for daratumumab (Darzalex). Approval would give clinicians the option to split administration of the first infusion of daratumumab over 2 consecutive days, according to a news release from Janssen.1

Submission of the supplemental biologics license application (sBLA) is based on data from the phase 1b MMY1001 study in multiple myeloma (ClinicalTrials.gov Identifier: NCT01998971). A type II variation was also submitted to the European Medicines Agency (EMA) seeking approval for the split dosing regimen.

Daratumumab is an antibody that targets CD38, a surface protein highly expressed across multiple myeloma cells at all stages of the disease, and induces tumor cell death through multiple immune-mediated mechanisms of action. 

Recommended dose is 16 mg/kg actual body weight administered as an IV infusion weekly for weeks 1 to 8, every 2 weeks (monotherapy or with lenalidomide and dexamethasone) or every 3 weeks (with bortezomib and dexamethasone) for weeks 9 to 24, and every 4 weeks from week 25 until disease progression. Of note, daratumumab can cause severe infusion reactions. Dosing is immediately interrupted for infusion reactions of any grade/severity, which are experienced by approximately half of all patients and most often during the first infusion.2

In the phase 1b MMY1001, splitting the first dose reduced the duration of the first infusion, with a similar rate and pattern of infusion reactions. Pharmacokinetics concentrations after administration of the first dose were comparable between the single and split doses. Safety profile also was comparable, with no new safety events observed with split dosing.

In the United States, Daratumumab was first approved as a monotherapy treatment of multiple myeloma in patients who have received at least 3 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. 

Additional FDA approvals include treatment of multiple myeloma in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone in patients who have received at least 1 prior therapy; or in patients who have received at least 2 prior therapies, including lenalidomide and a PI; or in patients with newly diagnosed disease who are ineligible for autologous stem cell transplant (ASCT).

In the European Union, daratumumab has been granted approvals similar to US indications for previously treated multiple myeloma, and the Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion regarding expanding its use in combination with bortezomib, melphalan, and prednisone for newly diagnosed multiple myeloma in adult patients who are ineligible for ASCT.

Janssen reports that daratumumab is being evaluated across a range of treatment settings in multiple myeloma. Plus additional studies to assess its potential in other malignant and premalignant hematologic diseases in which CD38 is expressed are ongoing or planned. 

References 

1. Janssen submits U.S. & EU regulatory applications seeking approval of Darzalex (daratumumab) split dosing regimen [news release]. Raritan, NJ, and Beerse, Belgium: Janseen Pharmaceutical Companies of Johnson & Johnson; August 8, 2018. https://www.prnewswire.com/news-releases/janssen-submits-us--eu-regulatory-applications-seeking-approval-of-darzalex-daratumumab-split-dosing-regimen-300693635.html?tc=eml_cleartime. Accessed August 13, 2018.

2. Darzalex [package insert]. Horsham, PA: Janssen Biotech Inc; 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761036s004lbl.pdf. Accessed August 13, 2018.

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