Tafasitamab (MOR208) is a humanized FC-modified CD19 targeting immunotherapy in clinical development for the treatment of B cell malignancies. CD19 is broadly expressed on the surface of B cells. It is therefore considered as a potential target for the treatment of B cell malignancies, such as non-Hodgkin’s lymphoma (NHL), including diffuse large B cell lymphoma (DLBCL), indolent lymphomas like follicular lymphoma (FL) and marginal zone lymphomas (MZL), as well as chronic lymphocytic leukemia (CLL). The main development focus of tafasitamab (MOR208) is on the treatment of patients with DLBCL. In January 2020, MorphoSys and Incyte entered into a collaboration and licensing agreement to further develop and commercialize tafasitamab globally. Following accelerated approval by the U.S. Food and Drug Administration in July 2020, Tafasitamab is being co-commercialized by MorphoSys and Incyte in the United States. Incyte has exclusive commercialization rights outside the United States. Tafasitamab, combined with Lenalidomide, has been approved, under accelerated approval, in US for adult patients with relapsed/refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplantation (ASCT). In August 2021, Health Canada and the European Commission and in October 2021, MHRA granted conditional Marketing Authorization for Minjuvi® (tafasitamab) in combination with Lenalidomide for the same indication (for details see Regulatory Highlights). There is a high-unmet medical need for this patient group.
What is Tafasitamab?
Proposed Mode of Action
Tafasitamab (MOR208) is a therapeutical Fc-modified antibody targeting CD19 and is currently in clinical development for the treatment of patients with B cell malignancies.
Tafasitamab (MOR208) binds to CD19. This antigen is broadly and homogeneously expressed across different B cell malignancies including diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). CD19 is able to enhance B cell receptor (BCR) signaling, which is important for B cell survival. Therefore, CD19 is considered a potential therapeutic target for drugs aimed at treating B cell-related lymphomas and leukemias.
CD19-EXPRESSION ON B CELLS
The therapeutic field: B cell malignancies
Tafasitamab (MOR208) is currently in clinical development in various B cell malignancies. Focus of development is on patient populations with a high unmet medical need.
These diseases arise from B lymphocytes (or B cells) that are normally part of the body’s immune system which, in a healthy organism, play an important role as they produce antibodies against invaders such as viruses and bacteria. When B cells turn malignant, they displace the healthy and functional white blood cells leading to an impaired and heavily weakened immune system.
MorphoSys is currently investigating tafasitamab (MOR208) in four types of B-cell malignancies:
Diffuse large B cell lymphoma (DLBCL): DLBCL is the most common type of non-Hodgkin’s lymphoma in adults worldwide, accounting for ~40% of NHL cases . Although this disease is prevalent mainly in the elderly, it can occur at any age. It is a very aggressive disease that affects the B cells of the immune system and 30-40% of all patients do not respond to initial therapy or relapse thereafter. There is a high unmet medical need for novel treatments for these patients, since current options are limited and the prognosis for these patients is poor. In particular, patients who have failed initial therapies and who are ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), are in need for more therapeutic options.
Chronic lymphocytic leukemia (CLL): CLL is the most common form of leukemia in adults. In CLL, B cells have become malignant and multiply uncontrolled in the blood. These leukemia cells displace functional B lymphocytes and other blood cells, resulting in a weakening of the immune system and a significantly higher susceptibility to infections. Today, patients are increasingly being treated with a new class of drugs called Bruton‘s Tyrosine Kinase (BTK) inhibitors and B-cell leukemia/lymphoma-2 (BCL-2) inhibitors. However, for those patients who do not respond or no longer respond to this treatment, options are limited. This results in a high unmet medical need for this patient group after discontinuation of a prior BTK/bcl-2 inhibitor therapy.
Follicular lymphoma (FL) and Marginal Zone Lymphoma (MZL): FL and MZL are the most common indolent NHL subtypes and account for approximately 20% to 25% and 7% of adult NHL cases, respectively (Swerdlow et al 2016). Both subtypes are considered incurable and have a variable clinical course, with options for management ranging from active surveillance for asymptomatic patients to chemo-immunotherapy, immunotherapy, or treatment with targeted agents for those with symptomatic disease. Patients usually respond to initial therapy but typically relapse over time. There is no standard treatment approach for patients with relapsed indolent NHLs such as FL or MZL and these patients are treated similarly despite being distinct entities (Dreyling et al 2016, Zucca et al 2020). However, despite improvements in treatment options for R/R FL and MZL, there is a high medical need for additional treatment options with improved outcomes and better safety profiles.
Currently active clinical trials:
LMIND (lenalidomide - MOR208 in DLBCL) is a Phase 2 single-arm, open-label, multicenter study of tafasitamab (MOR208) in combination with lenalidomide in approximately 80 patients with relapsed or refractory DLBCL after at least one, but no more than three prior lines of therapy, including an anti-CD20 targeting therapy (e.g. rituximab). Patients were not allowed to be candidates for high-dose chemotherapy and autologous stem cell transplantation. The study's primary endpoint is objective response rate (ORR). Secondary outcome measures include duration of response (DoR), progression-free survival (PFS) and overall survival (OS), as well as an evaluation of the drug combination's safety and pharmacokinetic parameters of tafasitamab (MOR208). The data from the primary analysis of L-MIND were presented in June 2019. Updated data with a median follow up of 35 months was published in July 2021 confirming the data of the primary analysis (Duell et al 2021).
The randomized, double-arm, open-label, multicenter phase 2/3 B-MIND (bendamustine - MOR208 in DLBCL) study was initiated in 2016 and enrolled patients in up to 180 centers in Europe, Asia Pacific (APAC) and the USA. The trial enrolls patients with relapsed or refractory DLBCL, who have previously been treated with at least one and not more than three prior lines of therapy, including one anti-CD20 targeting therapy (e.g. the antibody rituximab). Patients must not be eligible for high-dose chemotherapy and autologous stem cell transplantation. The phase 2 safety evaluation part of the study to assess the safety and tolerability of tafasitamab (MOR208) plus bendamustine vs. the rituximab plus bendamustine combination was completed in mid-2017. In June 2017, the study was transitioned into the pivotal phase 3 part. The primary endpoint of the study is progression-free survival (PFS). Secondary outcome measures include objective response rate (ORR), duration of response (DoR), overall survival (OS), disease control rate (DCR), time to progression (TTP) as well as an evaluation of patients' quality of life (QoL). In Q1 2019, MorphoSys has implemented an amendment of the B-MIND study after consultation with FDA, which adds a biomarker-based co-primary endpoint to the original study protocol. In November 2019, B-MIND passed a futulity analysis. Based on the recommendation from an independent data monitoring committee, the number of patients in the study was increased to 450.
The MINDway Study is an open-label, multi-centre, phase Ib trial of tafasitamab combined with lenalidomide (LEN) to evaluate the safety and pharmacokinetics (PK) of a modified tafasitamab dosing regimen in adult patients with R/R DLBCL.
The realMIND study is a multicenter, observational study that will collect data on treatments and outcomes for patients in the US with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) who are starting second- or third-line therapy and are not receiving autologous stem cell transplant. Primary objective of the study is to describe treatment patterns of patients with R/R-DLBCL starting second- or third-line therapy and not receiving HD-ASCT in the US. Secondary objectives include description of physician-reported clinical outcomes (effectiveness and safety), patient-reported health related quality of life and healthcare resource utilization. Subgroup analyses by race and ethnicity category are planned for primary and secondary outcomes.
firstMIND is a Phase Ib, open-label, randomized study to assess safety and preliminary efficacy of Tafasitamab in addition to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristin, prednison) or Tafasitamab plus Lenalidomide in addition to R-CHOP in patients with newly diagnosed Diffuse Large B-Cell Lymphoma (DLBCL). Patients enrolled received six cycles of treatment. The primary endpoint is the incidence and severity of treatment-emergent adverse events (AEs), key secondary endpoints are objective response rate (ORR) and PET-negative complete response (CR) rate at the end of treatment. Preliminary data from the First-MIND study presented at scientific meetings in 2020 and 2021 indicated that tafasitamab plus lenalidomide in combination with R-CHOP did not show unexpected toxicities and that adding tafasitamab plus lenalidomide to R-CHOP did not impair the dosing of R-CHOP.
frontMIND is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial designed to compare the efficacy and safety of the humanized monoclonal anti CD19 antibody tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP in previously untreated, high-intermediate and high-risk patients with newly-diagnosed DLBCL. Primary endpoint of the study is progression-free survival (PFS) as assessed by the investigator using the Lugano Response Criteria for Malignant Lymphoma. Secondary endpoints include event-free survival (EFS), overall survival (OS) and metabolic complete response (CR) and overall response rate (ORR)).
The InMIND Study is a Phase 3 double-blind, placebo-controlled, randomized study designed to investigate whether tafasitamab and lenalidomide as an add-on to rituximab provides improved clinical benefit compared with lenalidomide as an add-on to rituximab in patients with R/R follicular lymphoma (FL) Grade 1 to 3a or R/R marginal zone lymphoma (MZL). Primary endpoint of the study is progression-free survival (PFS) in patients with FL. Secondary endpoints include PFS in patients with FL and MZL, complete (CR) and overall response (ORR), duration of response (DoR) and minimal residual disease negativity rate. The InMIND study is sponsored by Incyte.
The COSMOS-Study (CLL patients assessed for ORR & Safety in MOR208 Study) is a single-arm, open-label, multicenter phase 2 combination trial of tafasitamab (MOR208) with either idelalisib or venetoclax in adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Patient enrolled must have been refractory or shown relapse or intolerance to a prior, most recent, therapy with a Bruton's Tyrosine Kinase (BTK) inhibitor (e.g. ibrutinib). The study primarily evaluates the safety of the drug combinations. In 2019, MorphoSys presented data of the primary analysis of the COSMOS trial at the Annual ASH Meeting.
The topMIND Study is a single-arm, open-label, Phase 1b/2a, multicenter basket study evaluating safety, PK, and efficacy of tafasitamab and parsaclisib in patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL or chronic lymphocytic leukemia (CLL). Primary objectives of the study are safety, tolerability, and dose-limiting toxicities of the combination of tafasitamab + parsaclisib and its efficacy. Secondary objectives are PK of tafasitamab and its immunogenicity when administered in combination with parsaclisib. The topMIND study is sponsored by Incyte.
On August 19, 2021, Health Canada (HC) and on October 8th 2021, Medicines and Healthcare Products Regulatory Agency (MHRA),UK granted Incyte MorphoSys’ development and commercialization partner for tafasitamab, a Notice of Compliance with conditions for Minjuvi® (tafasitamab), a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody, in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, who are not eligible for autologous stem cell transplant (ASCT). Just a few days later after HC approval, on August 26, the European Commission (EC) granted conditional marketing authorization for Minjuvi® (tafasitamab) in combination with lenalidomide, followed by Minjuvi monotherapy, for the treatment of adult patients with r/r DLBCL who are not eligible for ASCT. The EC Decision follows the positive opinion received from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in June 2021 recommending the conditional marketing authorization of Minjuvi.
On July 31, 2020, Monjuvi® (tafasitamab-cxix) received accelerated approval in the United States from the Food and Drug Administration (FDA) in combination with lenalidomide for the treatment of adult patients with r/r DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for ASCT. Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial(s). The most common adverse reactions (≥ 20%) were neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite.
In November 2020, MorphoSys and Incyte announced a clinical collaboration agreement with Xencor to investigate the combination of tafasitamab, lenalidomide and plamotamab – a tumor-targeted bispecific antibody from Xencor with both a CD20*- binding domain and a cytotoxic T-cell (CD3*) binding domain – in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), first-line DLBCL and relapsed or refractory follicular lymphoma (FL).
In January 2020, MorphoSys AG and Incyte Corporation signed a collaboration and license agreement for the global development and commercialization of tafasitamab (MOR208). Under the agreement, MorphoSys and Incyte co-commercialize tafasitamab (MOR208) in the United States, while Incyte has exclusive commercialization rights outside the United States.
In June 2010, MorphoSys AG and Xencor, Inc. signed a worldwide exclusive license agreement for the antibody. The agreement provided MorphoSys with an exclusive worldwide license to Xmab®5574, which was subsequently renamed MOR208. In Q1 2019 tafasitamab has been accepted as International Non-proprietary Name (INN) for MOR208.
MorphoSys co-commercializes tafasitamab (MOR208) in the United States together with Incyte under the collaboration and license agreement with Incyte. MorphoSys will determine the marketing strategy in the U.S. In preparation, MorphoSys founded its commercial entity MorphoSys US Inc. located in Boston in July 2018 and since then has successfully set up the required commercial capabilities in the U.S. Outside of the United States, Incyte has exclusive commercialization rights.
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