The Janssen Pharmaceutical Companies of Johnson & Johnson announced the results from the Phase 3 COLUMBA study, investigating a subcutaneously (SC) administered formulation of DARZALEX®(daratumumab), co-formulated with recombinant human hyaluronidase PH20 (rHuPH20) , in patients with relapsed/refractory multiple myeloma.
Results of COLUMBA
The results showed non-inferior efficacy and pharmacokinetics for the SC administered formulation of DARZALEX compared to intravenous (IV) administration, the only currently approved formulation of DARZALEX.
The COLUMBA Trial was a randomized, open-label, multicenter Phase 3 study including 522 patients with multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease is refractory to both a PI and an IMiD. The study consisted of 3 phases: a screening phase; a treatment phase; and a follow-up phase. Efficacy, pharmacokinetics, immunogenicity, biomarkers and safety were assessed at scheduled times. Follow up continued throughout the study, approximately 18 months after the last participant is randomized or when the sponsor decides to end the study.
The Janssen/J&J primary hypotheses is that the (Overall Response Rate) ORR and maximum Ctrough for Dara SC 1800 milligram (mg) are not inferior to the ORR and maximum Ctrough, respectively, for Dara IV 16 mg per kilogram (mg/kg) in participants with multiple myeloma who have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease is refractory to both a PI and an IMiD
Discussion of Results
Overall this study revealed that the subcutaneous formulation of daratumumab actually resulted in “non-inferior” pharmacokinetics and efficacy compared to the current intravenous formulation, and as quoted by Maria -Victoria Mateos, MD, PhD, COLUMBA primary investigator and Director of the Myeloma Unit at University Hospital of Salamanca-IBSAL, Salamanca, Spain, “importantly offers the potential for a fixed-dose administration, shorter infusion times and a lower rate of infusion-related reactions.” Doctor Mateos continued “Daratumumab IV has provide to be an important medication in the treatment of multiple myeloma, and a new subcutaneous formulation may offer patients a different experience, including a shorter administration time.”
Comment on Noninferiority Trials
This was a noninferiority trial which exist to test whether a new experimental treatment is not unacceptably less efficacious than an active control treatment already in use. With continuous improvements in health technologies, standard care and clinical outcomes, the incremental benefits of newly developed treatments may be only marginal over existing treatments. Sometimes assigning patients to a placebo is unethical. In such circumstances, there has been increasingly emphasis on the use of noninferiority trial designs. They are generally more complex to design, conduct and assess than typical superiority trials.
About DARZALEX® (daratumumab)
DARZALEX® (daratumumab), the first CD38-directed antibody approved anywhere in the world, is the only CD38-directed antibody approved to treat multiple myeloma.D38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease. DARZALEX binds to CD38 and inhibits tumor cell growth causing myeloma cell death. DARZALEX may also have an effect on normal cells. 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. 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.
- November 2015: FDA approval as monotherapy for patients with multiple myeloma who have received 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.
- November 2016: FDA additional approvals 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
- June 2017: FDA 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 & a PI
- May 2018: received approval in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT, making it the first monoclonal antibody approved for newly diagnosed patients with the disease
About Halozyme & ENHNAZE® Drug Delivery Technology
Halozyme, based in San Diego, CA enables the administration of medications with an injection under the skin rather than an infusion into a vein. Their goal is to make the injection of life saving medicines less disruptive to patients via their ENHANZE technology. The Darzalex studies utilized technology.
In August 2012 Janssen Biotech, Inc. entered into a global license and development agreement with Genmab A/S, which granted Janssen an executive license to develop, manufacture and commercialize DARZALEX.
Already sales are identified at $2 billion and according to some projections could hit $7 billion by 2026.