Genmab A/S Profile
Genmab A/S (Genmab) operates as an international biotechnology company. The company creates and develops innovative antibody therapeutics.
The company’s pipeline of novel antibody-based product candidates for the treatment of solid tumors and hematological cancers is designed to address unmet medical needs and improve treatment outcomes for cancer patients. The company’s pipeline includes bispecific T-cell engagers, next-generation immune checkpoint modulators, effector function enhanced antibodies and antibody-drug conjugates. The company has nine proprietary product candidates, where it is responsible for at least 50% of development, in clinical development.
The company’s most advanced products are tisotumab vedotin and epcoritamab. Tisotumab vedotin, marketed as Tivdak, is being developed in collaboration with Seagen. Tivdak was granted accelerated approval by the FDA for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Tivdak is the first and only FDA approved ADC in this indication. Epcoritamab is being developed in collaboration with AbbVie. In September 2022, the company submitted a BLA for SC epcoritamab to the FDA, which was subsequently accepted with Priority Review in November 2022 with a target action date of May 21, 2023. In December 2022 the company submitted a JNDA to the MHLW. AbbVie submitted an MAA to the EMA in October 2022, which was validated that same month. In addition to the company’s marketed products and clinical product candidates, it has multiple in-house and partnered pre-clinical programs.
In addition to the company’s own pipeline of product candidates, its innovation and proprietary technology platforms are applied in the pipelines of global pharmaceutical and biotechnology companies. These companies are running clinical development programs with antibodies created by Genmab or created using the company’s proprietary DuoBody bispecific antibody technology platform. The programs run from Phase 1 development to approved medicines. The five approved medicines created by Genmab or that incorporate Genmab’s innovation are daratumumab, marketed by Janssen as DARZALEX (intravenous (IV) formulation) and DARZALEX FASPRO or DARZALEX SC (SC formulation), approved in the U.S., Europe, Japan and certain other territories for the treatment of certain indications of multiple myeloma (MM) and light-chain (AL) amyloidosis; amivantamab, marketed in the U.S., Europe and certain other territories as RYBREVANT for the treatment of certain adult patients with locally-advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations; teclistamab, marketed in the U.S. and Europe as TECVAYLI for certain indications of MM; SC ofatumumab, marketed in the U.S., Europe, Japan and certain other territories as Kesimpta by Novartis for the treatment of relapsing multiple sclerosis (RMS); teprotumumab, marketed in the U.S. as TEPEZZA by Horizon for the treatment of thyroid eye disease (TED). In addition, in December 2022 and January 2023, Janssen submitted a BLA to the FDA and a marketing authorization application (MAA) to the European Medical Agency (EMA), respectively, for an additional DuoBody-based product, talquetamab, for the treatment of relapsed or refractory (R/R) MM.
The company’s portfolio includes four proprietary antibody technology platforms, such as its DuoBody platform, which can be used for the creation and development of bispecific antibodies; its HexaBody platform, which can be used to increase the potential potency of antibodies through hexamerization; its DuoHexaBody platform, which enhances the potential potency of bispecific antibodies through hexamerization; and its HexElect platform, which combines two HexaBody molecules to maximize potential potency while minimizing potential toxicity by more selective binding to desired target cells. Antibody products created with these technologies may be used in a wide variety of indications, including cancer and autoimmune, central nervous system and infectious diseases.
Products and Product Candidates
Daratumumab (DARZALEX)
Daratumumab (marketed as DARZALEX for IV administration and as DARZALEX FASPRO in the United States and as DARZALEX SC in Europe for SC administration) is a human monoclonal antibody that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of MM cells and is also expressed by AL amyloidosis plasma cells. Genmab used technology licensed from Medarex to generate the CD38 antibody. Daratumumab is being developed by Janssen, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, under an exclusive worldwide license from Genmab to develop, manufacture and commercialize daratumumab. Daratumumab is approved in a large number of territories for the treatment of adult patients with certain MM indications and is the only approved therapy in the U.S., Europe, and Japan for the treatment of adult patients with AL amyloidosis.
Development Status
Beyond the labeled indications, Janssen is conducting additional clinical trials for daratumumab, including multiple Phase III trials for the treatment of various stages of MM, including smoldering MM (SMM), frontline MM and R/R MM, with daratumumab alone or in combination with other therapies, including Janssen’s DuoBody-based teclistamab and talquetamab. The majority of these Phase III trials are utilizing the SC formulation of daratumumab.
Key Ongoing Trials
Janssen’s comprehensive clinical development program for daratumumab also includes the following ongoing clinical trials:
Daratumumab for High Risk SMM
Janssen is conducting clinical trials to assess whether earlier treatment with daratumumab could be used for patients with high-risk SMM to delay progression to MM, compared with active monitoring. The Phase II randomized, multicenter, open-label CENTAURUS (SMM2001) trial is assessing three dose schedules of daratumumab for the treatment of patients with high-risk or intermediate-risk SMM who had a confirmed diagnosis of high-risk or intermediate-risk SMM for <5 years.
Janssen used CENTAURUS data to set the dose schedule for the Phase III randomized, open-label, multicenter AQUILA (SMM3001) trial, which is designed to assess the efficacy of daratumumab by SC injection in delaying the progression from SMM to MM in high-risk SMM patients. The trial completed enrollment in May 2019.
Daratumumab for Frontline Treatment for Transplant Eligible Patients
Janssen is conducting the following Phase III trials for frontline treatment of transplant eligible MM patients:
The Phase III PERSEUS (MMY3014) trial is evaluating the SC formulation of daratumumab in combination with bortezomib, lenalidomide and dexamethasone (VRd) compared to VRd alone in approximately 690 participants with previously untreated MM. The PERSEUS trial completed enrollment in November 2019.
The Phase III randomized, open-label AURIGA (MMY3021) trial is evaluating SC daratumumab in combination with lenalidomide as maintenance treatment in patients with newly diagnosed MM who are minimal residual disease (MRD) positive after frontline ASCT and have no prior anti-CD38 exposure, compared with maintenance treatment by lenalidomide alone.
Daratumumab for Frontline Treatment for Non-Transplant Eligible Patients
Janssen is conducting the following Phase III trial for frontline treatment of non-transplant eligible MM patients:
The Phase III CEPHEUS (MMY3019) trial is evaluating the SC formulation of daratumumab in combination with bortezomib, lenalidomide and dexamethasone, or VRd, compared to VRd alone in patients with frontline MM for whom hematopoietic stem cell transplant is not planned as initial therapy. The CEPHEUS trial completed enrollment in September 2019.
Amivantamab
In July 2012, Genmab entered into a collaboration with Janssen to create and develop bispecific antibodies using Genmab’s DuoBody technology platform. One of these, amivantamab, is a fully human bispecific antibody that targets epidermal growth factor receptor (EGFR) and cMet, two validated cancer targets. The two antibody libraries used to produce amivantamab were both generated by Genmab. In collaboration with Janssen, the antibody pair used to create amivantamab was selected. Janssen is responsible for the development and commercialization of amivantamab.
In 2021, Janssen received approvals in the U.S., Europe and other markets for amivantamab as RYBREVANT for the treatment of certain adult patients with NSCLC with EGFR exon 20 insertion mutations. These were the first regulatory approvals for a therapy that was created using Genmab’s proprietary DuoBody bispecific technology platform.
Key Ongoing Trials in NSCLC
Janssen’s clinical development program for amivantamab also includes the following ongoing Phase III clinical trials:
The Phase III PAPILLON trial is a randomized, open-label trial of the combination of amivantamab and carboplatin-pemetrexed therapy compared with carboplatin-pemetrexed alone in patients with EGFR exon 20 insertion mutated locally advanced or metastatic NSCLC.
The Phase III MARIPOSA trial is a randomized trial of amivantamab and lazertinib combination therapy versus osimertinib versus lazertinib as first-line treatment in patients with EGFR-mutated locally advanced or metastatic NSCLC.
The Phase III MARIPOSA-2 trial is a randomized, open-label trial of amivantamab and lazertinib in combination with platinum-based chemotherapy compared with platinum-based chemotherapy alone in patients with EGFR-mutated locally advanced or metastatic NSCLC after osimertinib failure.
The Phase II PALOMA-2 trial is a non-randomized parallel cohort study of subcutaneous (SC) amivantamab in multiple regimens in patients with advanced or metastatic solid tumors, including EGFR-mutated NSCLC.
The Phase III PALOMA-3 trial is an open-label randomized trial of lazertinib with SC amivantamab administered via manual injection compared with IV amivantamab or amivantamab SC on body delivery system in patients with EGFR-mutated advanced or metastatic NSCLC after progression on osimertinib and chemotherapy.
A Phase I/II open-label platform study to evaluate the safety and efficacy of multiple amivantamab-based therapeutic combinations in patients with advanced, unresectable lung cancer.
Additional Trials of Interest
Phase Ib PALOMA trial to assess the safety and pharmacokinetics of the SC formulation of amivantamab in advanced solid malignancies.
Phase I/II open-label trial of amivantamab monotherapy and in addition to standard-of-care chemotherapy in patients with advanced or metastatic colorectal cancer.
Phase II open-label trial of amivantamab in patients with previously treated advanced or metastatic gastric or esophageal cancer.
Phase II open-label study is evaluating the safety, efficacy and pharmacokinetics of amivantamab monotherapy in patients with previously treated advanced hepatocellular carcinoma.
Teclistamab
In July 2012, Genmab entered into a collaboration with Janssen to create and develop bispecific antibodies using Genmab’s DuoBody technology platform. One of the products subsequently created, discovered and developed by Janssen is teclistamab, a bispecific antibody that targets CD3, which is expressed on T-cells and B-cell maturation antigen (BCMA), which is expressed on mature B lymphocytes.
In August 2022, Janssen received conditional marketing authorization from the European Commission for subcutaneously administered teclistamab as TECVAYLI as monotherapy for the treatment of adult patients with relapsed and refractory MM. Patients must have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and a CD38 antibody and have demonstrated disease progression on the last therapy. In October 2022, Janssen received FDA approval of teclistamab for the treatment of adult patients with R/R MM, who previously received four or more prior lines of therapy, including a proteasome inhibitor, immunomodulatory drug and anti-CD38 monoclonal antibody. Teclistamab is the second therapy created using Genmab’s proprietary DuoBody bispecific technology platform to receive regulatory approval.
Key Ongoing Trials
Janssen’s clinical development program for teclistamab also includes the following ongoing Phase III clinical trials:
The Phase III MajesTEC-3 trial is a randomized trial comparing teclistamab in combination with SC daratumumab versus SC daratumumab, pomalidomide, and dexamethasone or SC daratumumab, bortezomib, and dexamethasone in patients with R/R MM.
The Phase III MajesTEC-4 trial is a trial of teclistamab in combination with lenalidomide versus lenalidomide alone in participants with newly diagnosed MM as maintenance therapy following autologous stem cell transplantation.
The Phase III MajesTEC-7 trial is comparing teclistamab in combination with SC daratumumab and lenalidomide versus SC daratumumab, lenalidomide, and dexamethasone in patients with newly diagnosed MM who are either ineligible or not intended for autologous stem cell transplant as initial therapy.
The Phase III MajesTEC-9 trial is a randomized trial comparing teclistamab monotherapy versus pomalidomide, bortezomib, dexamethasone or carfilzomib, dexamethasone in patients with R/R MM who have received 1 to 3 prior lines of therapy, including an anti-CD38 monoclonal antibody and lenalidomide.
Additional Trials of Interest
Phase Ib RedirecTT-1 trial is a dose escalation trial of daratumumab, talquetamab and teclistamab in patients with relapsed or refractory (R/R) MM.
Phase Ib TRIMM-3 trial is a dose escalation trial of teclistamab or talquetamab in combination with a PD-1 inhibitor for the treatment of patients with R/R MM.
Ofatumumab
Ofatumumab is a human monoclonal antibody that targets an epitope on the CD20 molecule encompassing parts of the small and large extracellular loops. Genmab used technology licensed from Medarex to generate the CD20 antibody.
Ofatumumab, marketed as Kesimpta, is approved in territories, including the U.S., Europe, and Japan for the treatment of certain adult patients with Reference Member State (RMS). Ofatumumab is the first B-cell therapy that can be self-administered by patients at home or anywhere using the Sensoready autoinjector pen, once monthly after starting therapy. Ofatumumab is being developed and marketed worldwide by Novartis under a license agreement between Genmab and Novartis.
Key Ongoing Trials
Novartis’ clinical development program for ofatumumab also includes the following ongoing Phase III clinical trials:
The Phase III OLIKOS trial is a single arm trial evaluating the continued efficacy, safety and tolerability of ofatumumab in patients with RMS who are transitioning from a CD20 monoclonal antibody therapy.
The Phase III ALITHIOS trial is evaluating the long-term safety, tolerability and effectiveness of ofatumumab in patients with RMS. The purpose of this trial is to collect long-term safety, tolerability, effectiveness and health outcomes data in eligible subjects who have participated in a Novartis ofatumumab clinical MS trial.
The Phase III ARTIOS trial is an open-label trial to evaluate the effectiveness of treatment with ofatumumab in patients transitioning from commonly used oral MS therapies —fingolimod or dimethyl fumarate — due to breakthrough disease.
The Phase III STHENOS trial is an open-label, rater-blind randomized multi-center parallel-arm active-comparator trial to assess the efficacy and tolerability of ofatumumab 20mg SC monthly versus first line physician’s choice standard of care disease modifying therapy in the treatment of newly diagnosed RMS.
The Phase III NEOS trial is a two-year, randomized, three-arm, double-blind, non-inferiority trial comparing the efficacy and safety of ofatumumab and Siponimod versus fingolimod in pediatric patients with MS followed by an open-label extension.
Teprotumumab
Teprotumumab, approved by the U.S. FDA under the trade name TEPEZZA, is a human monoclonal antibody that targets the Insulin-like Growth Factor 1 Receptor (IGF-1R), a well-validated target. Genmab used technology licensed from Medarex to generate the IGF-1R antibody. The antibody was created by Genmab under a collaboration with Roche and development and commercialization of the product is being conducted by Horizon Therapeutics plc (Horizon) under a sublicense from Roche.
Tisotumab Vedotin
Tisotumab vedotin is an antibody-drug conjugate (ADC) created to tissue factor (TF), a protein involved in tumor signaling and angiogenesis. TF is a transmembrane protein that is the main physiological initiator of coagulation and is involved in angiogenesis, cell adhesion, motility and cell survival. TF is expressed on many solid tumors, including cervical, ovarian, pancreatic, prostate and bladder tumors. The presence of TF is associated with poor prognosis. Based on its high expression on many solid tumors and its rapid internalization, TF is a suitable target for an ADC approach. Tisotumab vedotin combines the company’s human mAb that binds to TF and Seagen’s ADC technology that utilizes a cleavable linker and the cytotoxic drug monomethyl auristatin E. The company used technology licensed from Medarex to generate the TF antibody forming part of tisotumab vedotin. ADCs are mAbs that are linked to cytotoxic or cell-killing agents. Seagen’s ADC technology utilizes mAbs that internalize within target cells after binding to a specified cell-surface receptor. The company is developing tisotumab vedotin in collaboration with Seagen.
In September 2021, the FDA granted Genmab and Seagen accelerated approval for tisotumab vedotin as Tivdak, the first and only approved ADC for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Tisotumab vedotin was approved under the FDA’s Accelerated Approval Program based on tumor response and the durability of the response. The approval was based on the innovaTV 204 trial in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen.
Ongoing Trials
In collaboration with Seagen, the company is evaluating tisotumab vedotin for the treatment of cervical cancer and other solid tumors in three clinical trials: innovaTV 205, innovaTV 207 and innovaTV 301.
innovaTV 205 is a Phase I/II trial of tisotumab vedotin as monotherapy or in combination with other therapies in subjects with recurrent or stage IVB cervical cancer. Interim data of tisotumab vedotin in combination with pembrolizumab in patients with recurrent or metastatic cervical cancer who have not received prior systemic therapy was presented in an oral session at the American Society of Clinical Oncology 2022 Annual Meeting in June 2022. The trial is ongoing.
The innovaTV 207 trial is a Phase II trial to assess the activity, safety and tolerability of tisotumab vedotin for the treatment of selected solid tumors. Preliminary data from the squamous cell carcinoma of the head and neck cohort of the trial was presented at the American Society for Radiation Oncology (ASTRO) 2022 Multidisciplinary Head and Neck Cancers Symposium in February 2022. The trial is recruiting.
The first Phase III trial of tisotumab vedotin, innovaTV 301, was announced in January 2021. The open-label, randomized, global trial of tisotumab vedotin versus chemotherapy is enrolling patients with recurrent or metastatic cervical cancer who have received one or two prior lines of systemic therapy for their recurrent or metastatic disease. This global trial is sponsored by Seagen in collaboration with Genmab, European Network of Gynaecological Oncological Trial Groups and the Gynecologic Oncology Group. The trial is designed to confirm the potential of tisotumab vedotin as monotherapy for patients with metastatic and/or recurrent cervical cancer. The trial is recruiting.
Epcoritamab
Epcoritamab is a proprietary bispecific antibody therapeutic candidate created using the company’s proprietary DuoBody technology. Epcoritamab is designed to target CD3, which is expressed on all T-cell subtypes and is part of the T-cell receptor, and CD20, a clinically well-validated therapeutic target. CD20 is expressed in a majority of B-cell malignancies, including CLL, DLBCL, FL and mantle cell lymphoma (MCL). The company used technology licensed from Medarex to generate the CD20 antibody forming part of epcoritamab. In a number of laboratory models, epcoritamab has shown high potency in killing CD20+ tumors and induced potent tumor cell lysis across a panel of B-cell tumor lines. In March 2022, the FDA granted orphan-drug designation to epcoritamab for the treatment of FL. The company is developing epcoritamab in collaboration with AbbVie.
Epcoritamab for the Treatment of B-cell Malignancies
In September 2022 and December 2022, respectively, Genmab submitted a Biologics License Application (BLA) to the FDA and an Japan New Drug Application (JNDA) to the Ministry of Health, Labor and Welfare (MHLW) for SC epcoritamab for the treatment of patients with R/R large B-cell lymphoma (LBCL) after two or more lines of systemic therapy. In October 2022 AbbVie submitted an MAA to the EMA for SC epcoritamab for the treatment of patients with R/R DLBCL after two or more lines of systemic therapy. The EMA validated for review the MAA in October 2022 and in November 2022 the FDA accepted for Priority Review the BLA with a target action date of May 21, 2023. The submissions were supported by results from the LBCL cohort of the pivotal Phase II EPCORE NHL-1 open-label, multi-center trial evaluating the safety and preliminary efficacy of epcoritamab in patients with relapsed, progressive or refractory CD20+ mature B-NHL, including DLBCL. Data from this trial was presented as part of a late-breaking oral presentation selected for the Presidential Symposium at the European Hematology Association Annual Congress in June 2022.
Ongoing Trials
Along with its collaboration partner, AbbVie, the company is evaluating SC epcoritamab for the treatment of B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL), FL and chronic lymphocytic leukemia (CLL) in multiple clinical trials. Additional trials, including Phase III trials, are expected. In addition to EPCORE NHL-1, ongoing and announced trials include:
EPCORE NHL-2 is a Phase Ib/II open-label trial to assess the safety and preliminary efficacy of epcoritamab in combination with other agents in patients with B-cell non-Hodgkin lymphoma (NHL). The trial is recruiting.
EPCORE NHL-3 is a Phase I/II trial to evaluate the safety and preliminary efficacy of epcoritamab in Japanese patients with R/R B-cell NHL. The trial is recruiting.
EPCORE NHL-4 is a Phase Ib/II open-label trial to evaluate the safety and preliminary efficacy of epcoritamab as monotherapy or combined with standard of care therapies in Chinese patients with B-cell NHL. The trial is recruiting.
EPCORE NHL-5 is a Phase Ib/II open-label trial to evaluate the safety and tolerability of epcoritamab in combination with anti-neoplastic agents in patients with NHL. The trial is recruiting.
EPCORE NHL-6 is a Phase II open-label trial to evaluate the safety of epcoritamab monotherapy in subjects with R/R DLBCL and FL grade 1-3a when administered in the outpatient setting. The trial is recruiting.
EPCORE DLBCL-1 was the first Phase III trial of epcoritamab. The purpose of the open-label, randomized, multi-center trial is to evaluate the efficacy of epcoritamab compared to investigator's choice of chemotherapy in patients with R/R DLBCL who have failed or are ineligible for autologous stem cell transplantation (ASCT). The trial is recruiting.
A new Phase III trial, EPCORE DLBCL-2, will be a randomized, open-label trial to evaluate the safety and efficacy of epcoritamab in combination with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) compared to R-CHOP in patients with newly diagnosed DLBCL. The trial is recruiting.
A new Phase II trial, EPCORE DLBCL-3, will be an open-label, multicenter, global trial evaluating the efficacy and safety of epcoritamab monotherapy and epcoritamab plus lenalidomide as first-line therapy for elderly patients with DLBCL who are deemed anthracycline ineligible. The trial is anticipated to start in February 2023.
EPCORE FL-1 is a Phase III, open-label trial to evaluate the safety and efficacy of epcoritamab in combination with rituximab and lenalidomide (R2) compared to R2 in patients with R/R FL. The trial is recruiting.
EPCORE CLL-1, is a Phase I/II open-label, multi-center safety and efficacy trial of epcoritamab in R/R CLL and Richter’s Syndrome. The trial includes two parts, a dose escalation Phase (Phase Ib) and an expansion Phase (Phase II). Preliminary results in Richter’s Syndrome were presented at The American Society of Hematology (ASH) Annual Meeting in December 2022. The trial is recruiting.
EPCORE Peds-1 is a single arm, open-label Phase Ib trial of epcoritamab in pediatric patients with R/R aggressive mature B-cell neoplasms. The trial is recruiting.
An expanded access program for eligible patients is also available. This program is designed to provide access to epcoritamab prior to approval by the local regulatory agency.
DuoBody-PD-L1x4-1BB (GEN1046/BNT311)
DuoBody-PD-L1x4-1BB is a proprietary bispecific antibody designed to target PD-L1 and 4-1BB. PD-L1 is a validated target that is expressed on tumor cells. 4-1BB is a trans-membrane receptor belonging to the tumor necrosis factor (TNF) receptor super-family and is expressed predominantly on activated T-cells. In pre-clinical settings, DuoBody-PD-L1x4-1BB promoted conditional T-cell activation in a tumor-specific manner by simultaneous activation and release of the key inhibitory brake. Pre-clinical trials also indicated a release of T-cell inhibition through the PD-1/PD-L1 axis, including in the absence of 4-1BB, strong co-stimulation via the agonistic activity of 4-1BB and T-cell clonal expansion. The company is developing DuoBody-PD-L1x4-1BB for the treatment of solid cancers in collaboration with BioNTech SE (BioNTech) using its proprietary DuoBody technology platform and PD-L1 antibody and BioNTech’s 4-1BB antibody.
A Phase I/II trial of DuoBody-PD-L1x4-1BB for the treatment of malignant solid tumors was initiated in May 2019 with the first expansion cohort initiated in the first quarter of 2020. Preliminary clinical data was presented at the Society for Immunotherapy of Cancer (SITC) Annual Meeting in November 2020. The anticipated enrollment for this trial is 752 patients and the trial is recruiting. A Phase II trial of DuoBody-PD-L1x4-1BB was initiated in November 2021. The multicenter, randomized, open-label trial is evaluating DuoBody-PD-L1x4-1BB as monotherapy and in combination with pembrolizumab as treatment for patients with R/R metastatic non-small-cell lung cancer (NSCLC) after treatment with standard of care therapy with an immune checkpoint inhibitor. The trial is recruiting.
DuoBody-CD40x4-1BB (GEN1042/BNT312)
DuoBody-CD40x4-1BB is a proprietary bispecific antibody designed to conditionally activate both CD40-expressing antigen-presenting cells and 4-1BB-expressing T-cells using an inert DuoBody format. In pre-clinical settings, as presented at the European Association for Cancer Immunotherapy Annual Meeting in May 2019, the CD40- and 4-1BB-specific Fab arms of DuoBody-CD40x4-1BB bound to primary human CD40-expressing CD20+ B cells and activated 4-1BB-expressing CD3+ T cells.
The company is developing DuoBody-CD40x4-1BB for the treatment of solid cancers in collaboration with BioNTech using Genmab’s proprietary DuoBody technology platform and BioNTech’s CD40 and 4-1BB antibodies. The first patient was dosed in the first-in-human Phase I/II trial of DuoBody-CD40x4-1BB for the treatment of malignant solid tumors in September 2019. Preliminary dose-escalation data was presented at the SITC Annual Meeting in November 2021. In September 2021 the trial was updated to include multiple expansion cohorts in combination and in additional indications. Safety and preliminary anti-tumor activity data in HNSCC patients treated with chemotherapy, pembrolizumab and DuoBody-CD40x4-1BB was presented at the European Society for Medical Oncology Immuno-Oncology Annual Congress in December 2022. The trial is recruiting. A Phase I/II randomized, open-label trial to evaluate the safety and clinical activity of DuoBody-CD40x4-1BB in combination with radiotherapy with or without pembrolizumab was announced in August 2022 and is not yet recruiting.
HexaBody-CD27 (GEN1053/BNT313)
HexaBody-CD27 is a novel CD27 antibody with an IgG Fc domain engineered to induce CD27 agonist activity independently of FcgammaR-bearing cells. In November 2022, in pre-clinical trials in vitro and in vivo, HexaBody-CD27 increased T-cell activation, proliferation, cytokine secretion, and cytotoxic activity.
The company is developing HexaBody-CD27 for the treatment of solid cancers in collaboration with BioNTech, using Genmab’s proprietary HexaBody technology platform. In May 2022, the IND application and first CTA were submitted for HexaBody-CD27. The first patient was dosed in the first-in-human Phase I/II trial of HexaBody-CD27 for the treatment of patients with malignant solid tumors in November 2022. The trial is recruiting.
GEN1056 (BNT322)
GEN1056 is an antibody product being co-developed by Genmab and BioNTech for the treatment of solid tumors and for use in combination with other products. The first CTA was submitted for GEN1056 in July 2022. A first-in-human Phase I trial of GEN1056 in patients with advanced solid tumors was initiated in November 2022.
DuoHexaBody-CD37 (GEN3009)
DuoHexaBody-CD37 is a bispecific IgG1, created with the company’s propriety DuoHexaBody technology platform that targets two non-overlapping CD37 epitopes. CD37 is a tetraspanin membrane protein abundantly expressed on normal and malignant B cells and represents a promising target for the treatment of B-cell malignancies. With DuoHexaBody-CD37 the company intended to generate CD37-specific antibodies with superior complement-dependent cytotoxicity (CDC) activity. In March 2020, the company initiated a Phase I/II clinical trial of DuoHexaBody-CD37 for the treatment of hematologic malignancies. In December 2021 an arm was added to the trial investigating DuoHexaBody-CD37 in combination with epcoritamab. The trial is recruiting. In June 2022 AbbVie decided to discontinue co-development of DuoHexaBody-CD37. Upon expiry of the 180-day notice period on December 24, 2022, Genmab became solely responsible for the further development of DuoHexaBody-CD37, with low-single digit royalty payments payable by Genmab to AbbVie, up to an agreed maximum total royalty amount, based on future sales of the product, if any.
HexaBody-CD38 (GEN3014)
HexaBody-CD38 is a novel human CD38 monoclonal antibody product incorporating the company’s HexaBody technology. In June 2019, Genmab entered into an exclusive worldwide license and option agreement with Janssen to develop and commercialize HexaBody-CD38. The company submitted an IND to the FDA for HexaBody-CD38 in October 2020. In March 2021, the company initiated a Phase I/II clinical trial of HexaBody-CD38 for the treatment of hematologic malignancies. Preliminary dose-escalation results from the trial were presented at the ASH Annual Meeting in December 2022. Dose-escalation results show HexaBody-CD38 had a tolerable safety profile and clinical activity in patients with R/R MM, including patients with prior exposure to an anti-CD38 antibody. The trial is recruiting. As of December 2022, this study included an arm comparing HexaBody-CD38 to daratumumab in anti-CD38 monoclonal antibody-naïve R/R MM patients.
DuoBody-CD3xB7H4 (GEN1047)
DuoBody-CD3xB7H4 is a bispecific antibody created with the company’s proprietary DuoBody technology platform. B7H4 is an immune checkpoint protein expressed on malignant cells in various solid cancers, including breast, ovarian and lung cancer. The first pre-clinical presentation of DuoBody-CD3xB7H4 was made at the SITC Annual Meeting in November 2021. In pre-clinical trials, DuoBody-CD3xB7H4 induced T-cell mediated cytotoxicity of B7H4-positive tumor cells. DuoBody-CD3xB7H4 is being developed as a therapeutic agent for the treatment of solid cancer indications known to express B7H4. The company submitted an IND to the FDA for DuoBody-CD3xB7H4 in July 2021. In January 2022 the first patient was dosed in the first-in-human Phase I/II clinical trial of DuoBody-CD3xB7H4 for the treatment of solid tumors. The trial is recruiting.
Partnered Candidates
The company’s collaboration partners have multiple product candidates in clinical development through collaboration agreements with it. These include three bispecific antibodies being developed by Janssen using the company’s proprietary DuoBody technology, which are being tested to treat NSCLC, other solid tumors and certain MM indications. Additional products are being developed in collaboration with Bristol-Myers Squibb (BMS), ADC Therapeutics, Lundbeck, Provention Bio, Global Blood Therapeutics (owned by Pfizer) and Novo Nordisk.
Technology Platforms
DuoBody Platform
The DuoBody platform is the company’s innovative proprietary platform for the discovery and development of bispecific antibodies. Bispecific antibodies bind to two different epitopes (or docking sites) either on the same, or on different targets (also known as dual-targeting). Bispecific antibodies generated with the company’s DuoBody platform can be used for the development of therapeutics for diseases, such as cancer, hemophilia and autoimmune, infectious, cardiovascular and central nervous system diseases. Based on a proof-of-concept study, the company’s DuoBody platform generates bispecific antibodies via a versatile and broadly applicable process that is easily performed at high throughput, at standard bench, as well as on a commercial manufacturing scale. The company uses the DuoBody platform to create its own bispecific antibody programs and it actively seeks collaboration partners interested in developing antibody therapeutics using its DuoBody technology. The company has a number of commercial collaboration partners for the DuoBody technology, including Janssen, BioNTech, AbbVie and Novo Nordisk.
A number of the company’s proprietary bispecific antibodies created with the DuoBody technology are in clinical development. In addition, Janssen has progressed a number of product candidates into clinical development through the company’s DuoBody collaboration, including amivantamab, which has been approved in the U.S., Europe and certain other markets, teclistamab, which has been approved in the U.S. and Europe, and talquetamab, for which Janssen submitted a BLA to the FDA in December 2022 and an MAA to the EMA in January 2023.
HexaBody Platform
The company’s HexaBody platform is a proprietary technology that is designed to increase the potency of antibodies. The HexaBody platform is designed to build on natural biology to strengthen the natural killing ability of antibodies while retaining regular structure and specificity. The HexaBody technology allows for the creation of potentially potent therapeutics by inducing antibody hexamer formation (clusters of six antibodies) after binding to their target antigen on the cell surface. The company has used the HexaBody platform to generate antibodies with an enhanced complement-mediated killing design, allowing antibodies with limited or absent killing capacity to be transformed into potent, cytotoxic antibodies. In addition to complement-mediated killing, the clustering of membrane receptors by the HexaBody platform may lead to subsequent outside-in signaling. The HexaBody technology creates opportunities to explore new product candidates, to repurpose drug candidates unsuccessful in previous clinical trials due to insufficient potency and may provide a useful strategy in product life cycle management.
The company’s HexaBody-based products in clinical development are HexaBody-CD38, for which it entered into an exclusive license and option agreement with Janssen, and HexaBody-CD27, which the company is co-developing with BioNTech. The investigational new drug (IND) for HexaBody-CD38 was submitted to the FDA in October 2020 and the first patient was dosed with HexaBody-CD38 in March 2021. The IND for HexaBody-CD27 was submitted in May 2022 and the first patient was dosed with HexaBody-CD27 in November 2022.
DuoHexaBody Platform
The DuoHexaBody platform is a novel proprietary technology that combines the dual targeting design of the company’s DuoBody technology with the potential enhanced potency of its HexaBody technology, creating bispecific antibodies with a target-mediated enhanced hexamerization design. DuoHexaBody-CD37 is the company’s only proprietary bispecific antibody created with DuoHexaBody technology. An IND for DuoHexaBody-CD37 was submitted to the FDA in November 2019 and the first patient was treated with DuoHexaBody-CD37 in March 2020.
HexElect Platform
The HexElect platform is a novel proprietary technology that combines two different HexaBody molecules in order to selectively hit only those cells that express both targets by making the activity of complexes of HexaBody molecules dependent on their binding to two different targets on the same cell. The HexElect platform maximizes potency while minimizing potential toxicity, potentially leading to more potent and safer products.
Manufacturing
The company has no involvement with the manufacturing process for its approved products in development with collaboration partners, DARZALEX, RYBREVANT and TECVAYLI, which are handled by Janssen; Kesimpta, handled by Novartis; and TEPEZZA, handled by Horizon, under the applicable agreements. The company’s partners, Seagen and AbbVie, are responsible for the manufacturing processes for tisotumab vedotin and epcoritamab, respectively, under the applicable agreements.
The majority of the drug products required for the company’s clinical trials and pre-clinical trials are manufactured by Lonza.
Product and Technology Collaborations
Collaborations for Marketed Products
Janssen Daratumumab License and Development Agreement
In August 2012, the company entered into a global license, development and commercialization agreement with Janssen, granting Janssen an exclusive, sublicensable license to certain of its patents, know-how and materials, owned by or licensed to it, to research, develop, make, offer and sell worldwide certain licensed products containing the human mAb denoted ‘daratumumab’, also known as HuMax-CD38 and DARZALEX. With respect to the licensed technology, the company has given up the ability to develop or commercialize other products with affinity to the CD38 antigen target.
Novartis Ofatumumab Collaboration
In December 2006, the company entered into a co-development and collaboration agreement with GlaxoSmithKline (GSK), pursuant to which GSK obtained exclusive, worldwide rights to develop and commercialize ofatumumab. This agreement was subsequently amended in 2010. In 2015, GSK transferred the ofatumumab collaboration for oncology and autoimmune diseases to Novartis. Novartis is responsible for the development and commercialization of ofatumumab in all potential indications. Novartis is investigating an SC formulation of ofatumumab for the treatment of RMS and has obtained approval for this indication in the U.S., Europe, and Japan, among other territories.
In August 2020, the FDA approved the use of ofatumumab, marketed as Kesimpta injection for SC use, for the treatment of RMS in adults, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. In March 2021, Kesimpta was approved by the European Commission in adults with active disease defined by clinical or imaging features. Kesimpta was also approved in Japan in March 2021 and is approved in over 60 countries.
Roche / Horizon Teprotumumab Collaboration
In 2001, Genmab entered a collaboration with Roche to develop human antibodies to disease targets identified by Roche. In 2002, this alliance was expanded, and Roche made an equity investment in Genmab. Under the agreement, Genmab will receive milestones, as well as royalty payments on successful products and, in certain circumstances, Genmab could obtain rights to develop products based on disease targets identified by Roche. Teprotumumab was created by Genmab under the collaboration with Roche, and development and commercialization of the product, which was approved in 2020 by the FDA, as TEPEZZA, for the treatment of thyroid eye disease (TED), is being conducted by Horizon under a license from Roche.
Janssen DuoBody Collaboration (Amivantamab and Teclistamab)
In July 2012, Genmab entered into a collaboration with Janssen to create and develop bispecific antibodies using the company’s DuoBody platform. Under this original agreement, Janssen had the right to use the DuoBody technology to create panels of bispecific antibodies (up to 10 DuoBody programs) to multiple disease target combinations.
Under the terms of a December 2013 amendment, Janssen was entitled to work on up to 10 additional programs. Janssen has exercised 14 licenses under this collaboration, not all of which are active, and no further options remain for use by Janssen. Of these, amivantamab and teclistamab are the first products created using the DuoBody technology platform to receive regulatory approval.
In May 2021, Janssen received approval from the FDA for amivantamab, marketed as RYBREVANT, for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Amivantamab has also been approved in the EU and other markets.
In August 2022, Janssen received conditional marketing authorization from the European Commission for subcutaneously administered teclistamab, marketed as TECVAYLI, as monotherapy for the treatment of adult patients with relapsed and refractory MM. Patients must have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy. In October 2022, Janssen received FDA approval of teclistamab for the treatment of adult patients with R/R MM, who previously received four or more prior lines of therapy, including a proteasome inhibitor, immunomodulatory drug and anti-CD38 monoclonal antibody.
Certain Collaborations for Proprietary Product Candidates
AbbVie Collaboration Agreement
In June 2020, the company entered into a Collaboration and License Agreement with AbbVie Inc. (AbbVie) to jointly develop and commercialize three of its early-stage investigational bispecific antibody product candidates, epcoritamab (DuoBody-CD3xCD20), DuoHexaBody-CD37 and DuoBody-CD3x5T4. In addition, under the agreement, the company agreed with AbbVie to enter into a discovery research collaboration for future differentiated antibody therapeutics for cancer.
For epcoritamab, the company shares commercial responsibilities with AbbVie in the United States and Japan, while AbbVie is responsible for global commercialization outside of the United States and Japan. Subject to certain requirements, the company has an option to co-commercialize these products, along with AbbVie, outside of the United States and Japan.
The company and AbbVie grant to each other co-exclusive licenses to use certain intellectual property that is necessary for or directly related to the development, manufacture or commercialization of the compounds being developed under the agreement and the resulting licensed products.
In September 2021 the company, along with AbbVie, decided that the data did not support the further development of DuoBody-CD3x5T4. In June 2022 AbbVie decided to discontinue co-development of DuoHexaBody-CD37. Upon expiry of the 180-day notice period on December 24, 2022, Genmab became solely responsible for the further development of DuoHexaBody-CD37, with low-single digit royalty payments payable by Genmab to AbbVie, up to an agreed maximum total royalty amount, based on future sales of the product, if any.
Seagen Tisotumab Vedotin Collaboration
In October 2011, the company entered into a license and collaboration agreement with Seagen that granted it rights to utilize Seagen’s ADC technology with its HuMax-TF antibody in return for milestone payments and royalties. The company also granted Seagen a right to exercise a co-development and co-commercialization option at the end of Phase I clinical development for tisotumab vedotin. In August 2017, Seagen exercised this option to co-develop and co-commercialize tisotumab vedotin with the company. In October 2020, Genmab and Seagen entered into a joint commercialization agreement. Genmab is co-promoting tisotumab vedotin, marketed as Tivdak, in the United States, and the company will lead commercial operational activities and record sales in Japan, while Seagen will lead operational commercial activities in the United States, Europe and China. The companies will continue the practice of joint decision-making on the worldwide development and commercialization strategy for tisotumab vedotin. In September 2021 tisotumab vedotin received accelerated approval from the FDA as Tivdak, for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. In September 2022 Seagen and Zai Lab announced an exclusive collaboration and license agreement for the development and commercialization of Tivdak in mainland China, Hong Kong, Macau and Taiwan. Based on the company’s agreement with Seagen, all upfront, milestone payments and royalties have been and will continue to be shared 50:50 with Genmab.
BioNTech Collaboration
In May 2015, the company entered into an agreement with BioNTech to jointly research, develop and commercialize bispecific antibody products using its DuoBody technology platform and antibodies. Under the terms of the agreement, BioNTech provides proprietary antibodies against key immunomodulatory targets, while the company provides proprietary antibodies and access to its DuoBody technology platform.
In July 2022, the company expanded this collaboration. Under the expansion, the companies will jointly develop and commercialize, subject to regulatory approval, monospecific antibodies leveraging Genmab’s proprietary HexaBody technology platform.
Genmab and BioNTech have four product candidates in clinical development: DuoBody-PD-L1x4-1BB, DuoBody-CD40x4-1BB, HexaBody-CD27 and GEN1056.
Certain Other Collaborations, Agreements and Enabling Technologies
Medarex UltiMAb System License
In 1999, the company entered into a license agreement with Medarex, a wholly owned subsidiary of BMS, pursuant to which the company received access to the UltiMAb technology, the KM Mouse technology and the right to obtain antibody-exclusive licenses for an unlimited number of antigens and own the worldwide development and commercialization rights to antibody products targeting such antigens. In addition, Medarex granted the company antigen-exclusive licenses in exchange for Genmab shares that are fully paid-up subject to, in case the products have been generated in the KM Mouse, pass-through of milestones and royalties payable by Medarex under its own license of the KM Mouse technology. The company’s principal obligation under this agreement is to make milestone and royalty payments in connection with any such antibody-exclusive licenses or in connection with use of the KM Mouse technology under this agreement. The company used technology licensed from Medarex to generate daratumumab, ofatumumab, tisotumab forming part of tisotumab vedotin, the CD20 antibody forming part of epcoritamab (DuoBody-CD3xCD20), and certain of its other product candidates. Based on the type of license and technology used in their development, product candidates that are subject to future payment obligations under this license agreement include ofatumumab, epcoritamab (DuoBody-CD3xCD20), amivantamab (DuoBody-cMetxEGFR) and Lu AF82422, but do not include daratumumab, tisotumab vedotin and HexaBody-CD38.
Janssen HexaBody-CD38 Collaboration
In June 2019, the company entered into an exclusive worldwide license and option agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize HexaBody-CD38, a next-generation human CD38 monoclonal antibody (mAb) product incorporating the company’s proprietary HexaBody technology. Under the terms of the agreement, the company has agreed to collaborate exclusively with Janssen on HexaBody-CD38 and to fund research and development activities until completion of clinical proof-of-concept studies in MM and DLBCL. The IND for HexaBody-CD38 was submitted to the FDA in October 2020. The first patient was dosed with HexaBody-CD38 in March 2021.
Other Collaborations and Agreements
The company has other active collaborations and agreements with a number of companies, including Janssen, ADC Therapeutics, BMS, Lundbeck, Amgen Inc. (Amgen), Immatics, Novo Nordisk, and CureVac AG (CureVac) to create, develop and/or commercialize antibody candidates and/or license certain of the company’s product candidates and use of its technology platforms.
The company also licenses technologies from a number of other companies that it uses or has used to contribute to the antibody products in its pipeline. Key technologies include Seagen’s ADC technologies, the OmniAb transgenic mouse and rat platforms from Open Monoclonal Technology, Inc., certain transgenic mouse technologies from Medarex, the rabbit antibody platform from MAB Discovery GmbH and certain expression systems used by Lonza for production of the company’s product candidates.
The company also licenses certain targets disclosed and developed from Immatics’ XPRESIDENT targets and T-cell receptor technology as part of a research collaboration and exclusive license agreement with Immatics to discover and develop next-generation bispecific immunotherapies to target multiple cancer indications.
Business Strategy
The key elements of the company’s strategy are to actively advance and expand its proprietary product pipeline; strengthen its product portfolio with strategic collaborations and potential acquisitions; leverage its proprietary technology platforms; build its translational research capabilities; and build its commercialization capabilities.
Intellectual Property
As of December 31, 2022, the company held more than 2,450 patents and patent applications, including more than 74 issued U.S. patents and more than 135 U.S. patent applications. All of the company’s issued patents and patent applications are projected to expire between 2023 and 2043.
With respect to daratumumab, the company has issued patents and pending patent applications in numerous jurisdictions, including patents issued in the United States, Europe and Japan. The company’s issued U.S., European and Japanese patents covering the composition of matter for daratumumab do not begin to expire until March 2026. In addition, the company has patent term extensions (PTE) and supplementary protection certificates (SPC) covering the composition of matter for daratumumab which provide protection beyond March 2026. In addition to its key composition of matter patents for daratumumab, the company and Janssen have issued patents and pending patent applications in numerous jurisdictions and for specific formulations, indications and combination therapies that may offer additional protection. With respect to ofatumumab, the company has issued patents and pending patent applications in numerous jurisdictions, including in the United States, Europe and Japan. The company’s issued U.S., European and Japanese patents covering the composition of matter for ofatumumab do not begin to expire until October 2023, with the U.S. composition of matter patent extended to May 2031. Novartis has issued patents and pending patent applications in numerous jurisdictions that may offer additional protection. With respect to tisotumab vedotin, the company has issued patents and pending patent applications in numerous jurisdictions, including the United States, Europe and Japan. The company’s issued U.S., European and Japanese patents covering the composition of matter for tisotumab vedotin do not begin to expire until June 2031. In addition to its key composition of matter patents for tisotumab vedotin, the company has issued patents and pending patent applications in numerous jurisdictions relating to specific formulations, indications and combination therapies that may offer additional protection.
Trademarks
As of January 3, 2023, the company and/or its subsidiaries owned approximately 311 trademark registrations and applications, hereof 14 U.S. trademark registrations, including Genmab; the Y-shaped Genmab logo; Genmab in combination with the Y-shaped Genmab logo; KYSO; HuMax; DuoBody; DuoBody in combination with the DuoBody logo; HexaBody; HexaBody in combination with the HexaBody logo; DuoHexaBody and HexElect. Tivdak is a trademark of Seagen Inc. (Seagen). EPCORE is a trademark of AbbVie Biotechnology Ltd. Arzerra is a trademark of Novartis Pharma AG. Kesimpta is a trademark of Novartis Pharma AG or its affiliates. DARZALEX, DARZALEX FASPRO RYBREVANT and TECVAYLI are trademarks of Johnson & Johnson. TEPEZZA is a trademark of Horizon Therapeutics Ireland DAC.
Government Regulation
Any products manufactured or distributed by the company or its collaboration partners pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product.
History
Genmab A/S was founded in 1999.
