FDA Approval Sought for Subcutaneous Daratumumab Regimen for Light Chain Amyloidosis


A supplemental Biologics License Application has been submitted to the FDA seeking approval of a subcutaneous formulation of daratumumab with hyaluronidase-fihj as treatment of patients with light chain amyloidosis.

A supplemental Biologics License Application (sBLA) has been submitted to the FDA seeking approval of a subcutaneous formulation of daratumumab (Darzalex Faspro) with hyaluronidase-fihj as treatment of patients with light chain (AL) amyloidosis, Janssen Pharmaceutical Companies announced in a press release.1

Due to the rarity of AL amyloidosis as well as its potential to be fatal, approved therapies are needed, but currently none exist. The sBLA is supported by findings from the phase 3 ANDROMEDA clinical trial (NCT03201965), which was presented during the 25th European Hematology Association Annual Congress.

"We are excited about the potential of helping patients with AL amyloidosis who currently have no FDA-approved therapies for the treatment of their disease," said Craig Tendler, MD, vice president, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC, in a statement. "The results from the phase 3 ANDROMEDA study also provide preliminary evidence of DARZALEX FASPRO's potential to modify the organ damage that is a hallmark of this serious disease with high unmet needs and we look forward to collaborating with the agency in the review of the application."

The ANDROMEDA study demonstrated that the addition of subcutaneous daratumumab to the triplet regimen cyclophosphamide (Cytoxan), bortezomib (Velcade), plus dexamethasone (Ozurdex), also known as CyBorD, was superior to CyBorD alone. The regimen induced deeper and more rapid hematologic responses, as well as improved the clinical outcomes of patients with AL amyloidosis with an acceptable safety profile.2

The primary end point of the study was overall hematologic complete response (CR) rate in the intent-to-treat population, which was 53% for the daratumumab regimen versus 18% with CyBorD alone (OR, 5.1; 95% CI, 3.2-8.2; P <.0001).

Major organ deterioration progression-free survival (MOD-PFS) was improved with the combination regimen, and organ responses were substantially higher in newly diagnosed patients. MOD-PFS favored the daratumumab regimen, which was a secondary end point (HR, 0.58; 95% CI, 0.37-0.93; P =.0230). Other secondary end points included organ response rate, time to hematologic response, survival, and safety.

The 6-month organ response rate was nearly doubled in the daratumumab arm compared with the control, in which the rates were 42% versus 22% for cardiac and 54% versus 27% for renal, respectively. The overall hematologic response rate was 92% with the daratumumab regimen versus 77% with CyBorD alone, with very good partial responses (VGPRs) or better observed in 79% and 49% of patients, respectively. The median time to ≥VGPR/CR was 17 out of 60 days for the daratumumab arm compared with 25 out of85 days for CyBorD alone.

According to the results presented at the European Hematology Association (EHA) Annual Congress, there were no new safety concerns when daratumumab was added to CyBorD. The rate of discontinuation due to treatment-emergent adverse events (TEAEs) in 4% of both treatment arms, while 56 total deaths occurred in the study, 29 from the combination arm versus 27 in the control.

The most common TEAEs of grade 3/4 were lymphopenia in 13% of the combination arm versus 10% in the control arm, pneumonia in 8% versus 4%, diarrhea in 6% versus 4%, congestive cardiac failure in 6% versus 5%, neutropenia in 5% versus 3%, syncope in 5% versus 6%, and peripheral edema in 3% versus 6%. In addition, 7% of patients had systemic administration-related reactions with the combination regimen, which were all grades 1/2 and occurred most frequently in the first infusion.

The application will be reviewed under the FDA Real-Time Oncology Review (RTOR) program that allows for select applications to be reviewed prior to formally submitting the complete application for the drug. While selection to the RTOR program does not guarantee that the drug will be FDA approved. The process aims to explore a more efficient review process that can ensure treatments are available as early as possible for patients.1


1. Janssen submits application seeking US FDA approval of Darzalex faspro (daratumumab and hyaluronidase-fihj) for the treatment of patients with light chain (AL) amyloidosis. News Release. Janssen. September 10, 2020. Accessed September 11, 2020. https://bit.ly/33lp6QI

2. Kastritis E, Palladini G, Minnema MC, et al. Subcutaneous daratumumab + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study Presented at: the 25th Annual European Hematology Congress: Virtual. June 11-21, 2020. Abstract #LB2604

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