J&J’s Darzalex Subcutaneous Formulation Approved by European Commission: First CD38-Targeted Subcutaneous Therapy for Multiple Myeloma with 3–5 Minute Administration

June 05, 2020 News /BioValleyBIOON/ -- The European Commission (EC) has recently approved Johnson & Johnson’s (JNJ) blockbuster multiple myeloma drug Darzalex (Zhaoke®, generic name: daratumumab) subcutaneous (SC) formulation for the treatment of adult patients with multiple myeloma (MM). This approval covers all currently approved therapeutic indications for the intravenous (IV) formulation of Darzalex, including first-line treatment and treatment of relapsed/refractory disease.

Darzalex SCAdministered via subcutaneous injection at a fixed dose,Takes only 3-5 minutes to complete. AndIV PreparationsAdministered via intravenous infusion, typically requiringTime-consuming for several hoursThe approval of the subcutaneous (SC) formulation marks a significant milestone, which will help positively transform the lives of patients with multiple myeloma (MM) who rely on Darzalex therapy. Patients currently receiving the intravenous (IV) formulation have the option to switch to the SC formulation.

It is worth noting that Darzalex SC formulation is the only subcutaneous CD38-targeting antibody drug approved by regulatory authorities for the treatment of MM. In the United States, the Darzalex SC formulation was approved this May under the brand name Darzalex Faspro (daratumumab and hyaluronidase-fihj). This drug has beenFDAApproved for four regimens covering five therapeutic indications, including for newDiagnosisMM patients, MM patients ineligible for transplantation, and relapsed or refractory MM patients.

Clinical data demonstrate that, compared with the intravenous (IV) formulation of Darzalex, the subcutaneous (SC) formulation of Darzalex provides consistent efficacy and pharmacokinetics, a similar safety profile, a significant reduction in administration time (from several hours to 3–5 minutes), and a two-thirds reduction in the incidence of systemic administration-related reactions (ARRs) (13% vs. 44%).

This approval is based on the efficacy and safety data from the Phase III clinical study COLUMBA (MMY3012) and the Phase II clinical study PLEIADES (MMY2040).

—COLUMBA is a randomized, open-label study conducted in patients with multiple myeloma (MM) who had previously received at least three prior lines of therapy (including proteasome inhibitors [PIs] and immunomodulatory drugs [IMiDs]) or were refractory to both PIs and IMiDs, comparing the non-inferiority of Darzalex SC versus Darzalex IV formulation as monotherapy.

The results demonstrated non-inferiority of Darzalex SC formulation to Darzalex IV formulation in terms of efficacy (overall response rate: 41% vs. 37%; ratio=1.11, 95% CI: 0.89–1.37) and pharmacokinetics (daratumumab trough concentration [Ctrough]: 499 mg/mL vs. 463 mg/mL; ratio=108%, 90% CI: 90%–122%), while offering shorter administration time (5 minutes vs. >3 hours) and a lower incidence of systemic administration-related reactions (ARRs) (13% vs. 34%).

—In the pooled safety population of 490 patients receiving Darzalex SC formulation as monotherapy or in combination therapy, the incidence rate of ARR was 11%. The safety profile of Darzalex IV formulation was similar to that of Darzalex SC formulation in other aspects.

—The Phase II PLEIADES study evaluated the efficacy and safety of Darzalex SC formulation in combination therapy. In newDiagnosisThe efficacy of the Darzalex SC formulation in combination with bortezomib, melphalan, and prednisone (D-VMP) has been demonstrated in patients with multiple myeloma (MM) who are ineligible for transplantation. Furthermore, the efficacy of the Darzalex SC formulation in combination with lenalidomide and dexamethasone (D-Rd) has also been demonstrated in patients with relapsed or refractory MM who have previously received one prior line of therapy.

In China, Darzalex® (daratumumab) was approved for marketing in October 2019. This medication is indicated as monotherapy for adult patients with relapsed and refractory multiple myeloma, specifically those who have previously received treatments including proteasome inhibitors and immunomodulatory agents and experienced disease progression during their last therapy. As the first CD38 monoclonal antibody targeted therapy approved in China, this innovative regimen holds promise for redefining the treatment landscape of multiple myeloma domestically.

Darzalex is the first CD38-mediated, cytolytic antibody drug approved globally, with broad-spectrum killing activity. It can target and bind to the CD38 molecule, a transmembrane extracellular enzyme highly expressed on the surface of multiple myeloma cells and various solid tumor cells. By inducing rapid death of tumor cells 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 throughApoptosis(apoptosis). In addition, Darzalex has also been shown to targetTumorImmunosuppressive cells in the microenvironment thereby exhibit immunomodulatory activity.

Darzalex was first approved for marketing in November 2015, with sales reaching $2.998 billion in 2019. Currently, the drug has been approved in many countries worldwide for first-line, second-line, and multi-line treatment of multiple myeloma (MM). The specific approved indications vary by country, including: (1) In November 2015, as a monotherapy for adult patients with MM who have previously received at least three therapies (including a proteasome inhibitor [PI] and an immunomodulatory agent [IMiD]) or who are double-refractory to PIs and IMiDs; (2) In November 2016, in combination with lenalidomide and dexamethasone, or in combination with bortezomib and dexamethasone, for adult patients with MM who have previously received at least one therapy; (3) In June 2017, in combination with pomalidomide and dexamethasone, for adult patients with MM who have previously received at least two therapies (including lenalidomide and a PI); (4) In May 2018, in combination with bortezomib, melphalan, and prednisone, for patients ineligible for autologousStem Cellsadult patients with newly diagnosed multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT); this approval makes Darzalex the first approved therapy for newly diagnosed MMMonoclonal Antibody Drugs(5) In June 2019, in combination with lenalidomide and dexamethasone, for adult patients with newly diagnosed multiple myeloma (MM) who are ineligible for autologous stem cell transplantation (ASCT). (6) In September 2019, in combination with bortezomib, thalidomide, and dexamethasone, for adult patients with newly diagnosed MM who are eligible for ASCT. This approval made Darzalex the first biologic agent approved for use in patients with newly diagnosed MM who are eligible for ASCT.

In February 2019, a split-dose regimen of Darzalex was also approved in the United StatesFDAApproved. This regimen will allow healthcare professionals to make choices as needed when treating MM patients, changing the initial intravenous infusion of Darzalex from a single one-time infusion to split intravenous infusions over two consecutive days. (Bioon.com)

Original Source: Subcutaneous formulation of J&J's Darzalex OK'd in Europe