Daratumumab
| Daratumumab | ||
|---|---|---|
| Mass / length primary structure | 145391.67 g / mol | |
| Identifier | ||
| External IDs |
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| Drug information | ||
| ATC code | L01 XC24 | |
| DrugBank | DB09331 | |
| Drug class | Monoclonal Antibodies , Antineoplastic Agents | |
Daratumumab (trade name Darzalex ; manufacturer Janssen-Cilag ) is a human monoclonal antibody ( IgG1 κ ) and is used as a medicinal substance for the treatment of malignant haematological diseases. The recombinant protein is produced by CHO cells .
pharmacology
Pharmacodynamics
Daratumumab binds specifically to the surface protein CD38 , which is particularly overexpressed by myeloma cells . The expression of CD38 on stem cells is low or not pronounced. CD38 is involved in various processes (cell adhesion, signal transduction pathways ) that influence the cell proliferation of malignant cells. Daratumumab inhibits its effects by binding to CD38 and induces apoptosis via direct and indirect mechanisms . The apoptosis-inducing effects include Fc -mediated effects, immune-mediated tumor cell lysis by complement- and antibody-dependent cytotoxicity and antibody-mediated phagocytosis .
Daratumumab provokes cytolysis of other cell types that express CD38. A decline in myeloid suppressor cells and NK cells are described. In contrast, the number of T lymphocytes ( CD4 - / CD8 -positive) and the total number of lymphocytes in the peripheral blood and bone marrow increase.
Pharmacokinetics
The terminal plasma half-life is about 9 days at the start of therapy and increases with repeated administration. After repeated administration, an increase is estimated at around 18 days. A steady state state is reached after about 5 months with 4-weekly application. The placental barrier can be crossed.
application areas
Daratumumab is used as monotherapy in multiple myeloma when other treatment options ( proteasome inhibitors , immunomodulators ) have been ineffective.
In combination with bortezomib , melphalan and prednisone , it is indicated for the treatment of adult patients with newly diagnosed multiple myeloma for whom an autologous stem cell transplant is not possible.
Daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone is also indicated for the treatment of multiple myeloma in adults who have received at least one therapy.
Daratumumab is intravenously administered , with the dosing with 16 mg / kg KG takes place and repeatedly in accordance with the regimen is administered.
effectiveness
The following efficacy data are currently available based on two open studies (phase I / II study GEN5012, phase II study SIRIUS; 148 patients with relapsed and refractory multiple myeloma) (as of March 2019):
- Overall response rate: 31% (8.8% very good response)
- complete response: 4 patients
- stringent complete response: 3 patients
- Disease non-progression: 83%
- Estimated mean overall survival: 20.1 months (median follow-up: 20.7 months)
Side effects
The undesirable effects observed were fatigue , nasal congestion , irritation of the mucous membranes of the mouth and throat, laryngeal edema , cough, dyspnoea , shivering and nausea , in particular during the first infusion . To avoid these side effects, the prior administration ( premedication ) of antihistamines , antipyretics and glucocorticoids is recommended. Other possible side effects are thrombocytopenia , neutropenia , anemia , infectious diseases , pneumonia , pulmonary edema , pyrexia and atrial fibrillation .
Because daratumumab can cross the placental barrier, it affects fetal development of the immune system and bone marrow. Therefore, strict contraceptive measures should be observed during treatment and for 3 months after completing daratumumab therapy.
Admission
In the USA, accelerated approval by the FDA took place in 2015 . Daratumumab was launched in Germany in June 2016.
Early benefit assessment
In Germany, since 2011, newly approved drugs with new active ingredients must be subjected to an " early benefit assessment " by the Federal Joint Committee (G-BA) in accordance with Section 35a SGB V if the pharmaceutical manufacturer wants to achieve a higher sales price than just the fixed amount . Only if there is an additional benefit can the pharmaceutical manufacturer negotiate a price with the umbrella association of statutory health insurance companies. The dossier evaluations, on the basis of which the G-BA makes its decisions, are created by the Institute for Quality and Efficiency in Health Care (IQWiG) .
For the treatment of adults with multiple myeloma who have already received at least one therapy, daratumumab in combination with lenalidomide and dexamethasone or with bortezomib and dexamethasone was compared with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. According to the G-BA decision, there is an indication of a considerable added benefit compared to this ACT. For adults with relapsed and refractory multiple myeloma who had already been treated with a proteasome inhibitor and an immunomodulator and who showed disease progression during the last therapy, daratumumab as a monotherapy was compared with a patient-specific therapy as prescribed by the doctor, particularly depending on the previous therapies as well as the extent and duration of the response and taking into account the approval of the respective medicinal product. According to the G-BA decision, an additional benefit compared to the comparator therapy has not been proven for these patients.
In another indication (patients with newly diagnosed multiple myeloma for whom autologous stem cell transplantation is not suitable) daratumumab in combination with bortezomib, melphalan and prednisone was compared with a combination therapy as directed by the doctor. According to the G-BA decision, there is an indication of a considerable additional benefit here.
swell
- Janssen, Pharmaceutical Information: DARZALEX® 20 mg / ml, concentrate for solution for infusion (Dec. 2018).
- Pharmaceutical newspaper , online: Drug profile: Daratumumab (accessed on March 10, 2019)
- Entry to Daratumumab in DrugBank the University of Alberta , accessed on March 10 of 2019.
Web links
- FDA Approved Drug Products - Biologic License Application (BLA): 761036
- European Public Assessment Reports (EPAR) on daratumumab
Individual evidence
- ↑ A17-40 Daratumumab (multiple myeloma) - Benefit assessment according to Section 35a SGB V ; Accessed April 6, 2020.
- ↑ A18-03 Daratumumab (multiple myeloma) - Addendum to Commission A17-40 ; Accessed April 6, 2020.
- ↑ Benefit assessment procedure for the active ingredient daratumumab (limit of € 50 million: multiple myeloma, monotherapy; new area of application: multiple myeloma, at least 1 previous therapy, combination with lenalidomide and dexamethasone or bortezomib and dexamethasone) ; Accessed April 6, 2020.
- ↑ A18-66 Daratumumab (multiple myeloma) - Benefit assessment according to Section 35a SGB V ; Accessed April 6, 2020.
- ↑ A19-16 Daratumumab (multiple myeloma) - Addendum to Commission A18-66 ; Accessed April 6, 2020.
- ↑ Benefit assessment procedure for the active ingredient daratumumab (new area of application: multiple myeloma, first-line, stem cell transplantation unsuitable, combination with bortezomib, melphalan and prednisone) ; Accessed April 6, 2020.
