Products

Date: 2016-05-23

Type of information: Granting of a Market Authorisation in the EU

Product name: Darzalex®

Compound: daratumumab

Therapeutic area: Cancer - Oncology

Action mechanism:

• monoclonal antibody. Daratumumab is a human CD38 monoclonal antibody with broad-spectrum killing activity. Daratumumab is in clinical development for multiple myeloma. It targets the CD38 molecule which is highly expressed on the surface of multiple myeloma cells and may also have potential in other cancers on which CD38 is expressed, including diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, plasma cell leukemia, acute myeloid leukemia, follicular lymphoma and mantle cell lymphoma. In May, 2013, daratumumab has been granted Breakthrough Therapy Designation from the FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab. With the exception of one study sponsored globally by the French multiple myeloma cooperative group, Intergroupe Francophone du Myelome (IFM), Janssen is the global sponsor of all current and future clinical studies for daratumumab.
• Daratumumab is the second medicine in the Janssen oncology portfolio to receive Breakthrough Therapy Designation, which is intended to expedite the development and review time for a potential new medicine. If approved, daratumumab would be commercialized in the U.S. by Janssen Biotech.

Company: Janssen Research & Development, a J&J company (USA - NJ) Genmab (Denmark)

Disease:

• • patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double refractory to a PI and an IMiD
• • adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy

Latest news:

• The data from the POLLUX study formed the basis, along with data from the CASTOR study, of two regulatory submissions in August; the supplemental Biologics License Application submitted to the FDA and the submission of the variation to the Marketing Authorization to the European Medicines Agency.
• • On May 23, 2016, J&J and Genmab announced that the European Commission (EC) has granted a conditional marketing authorization for first-in-class CD38 antibody Darzalex® (daratumumab) as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. The marketing authorization was based on data from the Phase II study (SIRIUS MMY2002, published in The Lancet in January 2016), the Phase I/II GEN501 monotherapy study (published in The New England Journal of Medicine in August 2015) and data from three additional supportive studies. These studies included heavily pre-treated patients with relapsed and refractory multiple myeloma who had exhausted other approved treatment options and whose disease was progressive at enrolment. Findings from a combined efficacy analysis of the GEN501 and MMY2002 (SIRIUS) trials demonstrated that after a mean follow-up of 14.8 months, the estimated median overall survival (OS) for single-agent daratumumab (16 mg/kg) in these heavily pre-treated patients was 20 months (95 percent Confidence Interval, 15 months to not yet estimable). The overall response rate (ORR) for the combined analysis was 31 percent, and 83 percent of patients achieved stable disease or better. Daratumumab demonstrated a clinically manageable safety profile. The most commonly occurring adverse reactions (in 20 percent or more of patients in three pooled clinical studies) were infusion-related reactions (IRRs), fatigue, pyrexia, cough, nausea, back pain, upper respiratory tract infection, anemia, neutropenia (abnormally low levels of neutrophils, a type of white blood cell) and thrombocytopenia (abnormally low levels of platelets in the blood). In data from three pooled clinical studies including a total of 156 patients, four percent of patients discontinued treatment due to adverse reactions, none of which were considered drug-related. IRRs were reported in approximately half of all patients treated with Darzalex®, the majority of which (91 percent) occurred during the first infusion. Seven percent of patients had an IRR at more than one infusion. Common (?5 percent) symptoms of IRRs included nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnea, and nausea, and these were mild to moderate in severity.2 Severe IRRs (4 percent), including bronchospasm (1.3 percent), hypertension (1.3 percent), and hypoxia, or decreased oxygen supply to the tissues (0.6 percent), were also reported.
• •  On 1 April 2016, the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion,  recommending the granting of a conditional marketing authorisation for Darzalex® (daratumumab) intended for the treatment of relapsed and refractory multiple myeloma. Darzalex® will be available as a 20 mg/ml concentrate for solution for infusion. The most frequently reported adverse reactions were infusion-related reactions, which occurred in 48% of patients. Other frequently reported adverse reactions  were fatigue, pyrexia, cough, nausea, back pain, upper respiratory tract infection, anaemia, neutropenia and thrombocytopenia. The full indication is: "Darzalex® as monotherapy is indicated for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.”
• Darzalex® should be administered by a healthcare professional, in an environment where resuscitation facilities are available.
• • On November 18, 2015, Janssen announced that Health Canada has accepted for review the New Drug Submission (NDS) for daratumumab as a treatment for patients with multiple myeloma. Health Canada will review the submission with advance consideration under the Ministry's Notice of Compliance with Conditions Policy (NOC/c) based on data from the Phase 2 MMY2002 (SIRIUS) monotherapy study.
• The submission for daratumumab is primarily supported by data from the Phase 2 SIRIUS study announced in May 2015, at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO). The submission also is supported with data from other studies, including the multi-centre, two-part open-label Phase 1/2 GEN501 monotherapy study published in The New England Journal of Medicine in August 2015. This study enrolled patients with multiple myeloma who had a relapse after, or had disease that was refractory to, two or more different prior therapies, including IMiDs, PIs, chemotherapy, and autologous stem-cell transplantation. The study showed daratumumab demonstrated a tolerable safety profile and a 36 per cent overall response rate in patients treated with a 16 mg/kg dose, with responses deepening over time.
• The NDS was filed under Health Canada's NOC/c policy. The policy aims to provide access to promising new drugs for patients suffering from serious, life-threatening or severely debilitating diseases, or conditions for which no drug is currently marketed in Canada, or for which a significant increase in efficacy or significant decrease in risk is demonstrated in relation to existing drugs marketed in Canada.
• •  On November 16, 2015, the FDA granted accelerated approval for Darzalex® (daratumumab) to treat patients with multiple myeloma who have received at least three prior treatments. Darzalex® is the first monoclonal antibody approved for treating multiple myeloma. The safety and efficacy of Darzalex® were demonstrated in two open-label studies. In one study of 106 participants receiving Darzalex®, 29 percent of patients experienced a complete or partial reduction in their tumor burden, which lasted for an average of 7.4 months. In the second study of 42 participants receiving Darzalex®, 36 percent had a complete or partial reduction in their tumor burden.
• The most common side effects of Darzalex® were infusion-related reactions, fatigue, nausea, back pain, fever and cough. Darzalex® may also result in low counts of infection-fighting white blood cells (lymphopenia, neutropenia, and leukopenia) or red blood cells (anemia) and low levels of blood platelets (thrombocytopenia).
• Blood banks should be informed that patients are receiving Darzalex® because the drug may interfere with certain tests that are done by blood banks (such as antibody screening) for patients who need a blood transfusion. Women who are pregnant should not use Darzalex, and women planning to become pregnant should use effective contraceptives during and for at least three months after treatment.
• • On September 25, 2015, Janssen Cilag and Genmab announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has granted accelerated assessment to the Marketing Authorization Application (MAA) for daratumumab. The MAA is for daratumumab as a treatment for patients with relapsed and refractory multiple myeloma. The MAA was submitted to the EMA on September 9, 2015 by Janssen-Cilag International. The MAA submission includes data from the Phase II study (Sirius MMY2002) of daratumumab in multiple myeloma patients who have received at least three prior lines of therapy including both a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double refractory to a PI and an IMiD. Safety and efficacy data from the Phase I/II study (GEN501) and safety data from three other studies have also been included in the submission. A regulatory application for daratumumab has also been submitted to the FDA and has been granted Priority Review with a PDUFA date of March 9, 2016.
• •  On September 9, 2015, Janssen-Cilag International announced it has submitted a new Marketing Authorisation Application to the European Medicines Agency (EMA) for daratumumab for the treatment of patients with relapsed and refractory multiple myeloma. The regulatory submission for daratumumab is now pending validation by the EMA and is based on data from the Phase 2 MMY2002 (SIRIUS) monotherapy study, which was presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO), data from the Phase 1/2 GEN501 monotherapy study, which was recently published in The New England Journal of Medicine, and data from three supportive studies.
• For MMY2002, the primary efficacy endpoint was overall response rate (ORR). Ninety-five percent of patients in the study were double refractory to a PI and IMiD. Patients received three or more lines of prior therapy (median of five), including a PI and an IMiD. Daratumumab achieved an ORR of 29 percent in the group of patients who received 16 mg/kg (n=106) as a single-agent therapy, with a well tolerated safety profile.
• The ORR outcomes of MMY2002 are similar to the ORR data in the Phase 1/2 GEN501 study, in which safety was the primary endpoint. Patients enrolled in GEN501 received two or more lines of prior therapy (median four), including a PI and an IMiD, and 64 percent were refractory to both PIs and IMiDs. In this study, daratumumab demonstrated a tolerable safety profile and achieved an ORR of 36 percent (11 partial responses, two very good partial responses and two complete responses) in the group of patients who received 16 mg/kg, with responses improving over time. Median progression-free survival was 5.6 months (95% CI: 4.2, 8.1) and 65 percent (95% CI: 28, 68) of responders remained in remission at 12 months. The OS rate at 12 months was 77 percent (95% CI: 58, 88).
• • On September 4, 2015, Genmab announced that the FDA has granted Priority Review to the Biologics License Application (BLA) for daratumumab. The BLA is for daratumumab as a treatment for patients with multiple myeloma who have received at least three different lines of therapy including both a proteasome inhibitor and an immunomodulatory agent (IMiD) or who are double refractory to a proteasome inhibitor and an IMiD. A rolling BLA submission was started by Genmab's licensing partner, Janssen Biotech, Inc. in June and was completed on July 9, 2015. The FDA aims to complete its review of the daratumumab BLA within six months and has assigned a Prescription Drug User Fee Act (PDUFA) target date of March 9, 2016. The BLA submission includes data from the Phase II study (Sirius MMY2002) of daratumumab in multiple myeloma patients who have received at least three prior lines of therapy including both a PI and an IMiD, or who are double refractory to a PI and an IMiD. However, safety and efficacy data from the Phase I/II study (GEN501) and safety data from three other studies, have also been included in the BLA submission. Daratumumab received a Breakthrough Therapy Designation for this indication from the FDA in May 2013.
• • On July 9, 2015, Genmab announced its licensing partner Janssen Biotech has completed the rolling submission of the Biologics License Application (BLA) to the FDA for daratumumab. The submission is for daratumumab as a treatment for patients with multiple myeloma who have received at least three prior lines of therapy including both a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD. The completion of the submission triggers a milestone payment of $ 15 million to Genmab from Janssen. The milestone was included in Genmab's financial guidance for 2015, which was updated on May 20, 2015.  A request for Priority Review has been submitted by Janssen with this BLA. The FDA will inform Janssen whether a Priority Review has been granted by calendar day 60 of their review starting today. If the FDA grants Priority Review the review period may not exceed 6 months from that date.
• If daratumumab receives FDA approval, Genmab will receive a milestone payment from Janssen of USD 45 million associated with the first commercial sale of the product in the United States. However, it is not possible to precisely predict the timing of a potential marketing approval and first commercial sale; therefore, this milestone has not been included in the 2015 financial guidance at this time.
• • On June 5, 2015, Janssen Research & Development has initiated the rolling submission of its Biologic License Application (BLA) for daratumumab to the FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double refractory to a PI and an IMiD. A rolling submission allows the company to submit portions of the regulatory application to the FDA as they are completed. The regulatory submission for daratumumab will be primarily supported by data from the Phase 2 MMY2002 (SIRIUS) monotherapy study announced in May 2015 at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO), along with additional data from four other studies, including the Phase 1/2 GEN501 monotherapy study
• •  On 11-13 June 2013, the Committee for Orphan Medicinal Products (COMP) has recommended the granting of an orphan designation for daratumumab for treatment of plasma cell myeloma.
• •  On May 1, 2013, Genmab has announced that the FDA has granted Breakthrough Therapy Designation for daratumumab for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and IMiD. .
• •  On April 2, 2013, Genmab has announced that the FDA has granted Fast Track designation for daratumumab. This designation covers patients with multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or are double refractory to a PI and an IMiD.

Patents:

• • On April 4, 2016, MorphoSys announced that it filed a lawsuit in the U.S. District Court of Delaware against Janssen Biotech, and Genmab for patent infringement of U.S. Patent Number 8,263,746. This patent, which is owned by MorphoSys, describes and claims antibodies with particular features that bind to CD38. By its complaint, MorphoSys seeks redress for the infringing manufacture, use and sale of Janssen's and Genmab's daratumumab, an antibody targeting CD38. Janssen and Genmab recently obtained FDA approval on daratumumab and are marketing the product as Darzalex® in the U.S. MorphoSys continues to develop MOR202, its own investigational human antibody to CD38, for the treatment of cancer, including multiple myeloma. Genmab announced that Janssen will in consultation with Genmab determine the appropriate action in response to the complaint.

Submission of marketing authorization application USA : 2015-07-09

Submission of marketing authorization application UE: 2015-09-09

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2015-11-16

UE authorization: 2016-05-23

Favourable opinion UE: 2016-04-01

Favourable opinion USA:

Orphan status USA: 2013-06-05

Orphan status UE: 2013-07-17

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes