Tafasitamab (MOR208)

Tafasitamab (MOR208, formerly Xmab®5574) is an investigational monoclonal antibody directed against the antigen CD19 which 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), as well as chronic lymphocytic leukemia (CLL).  The main development focus of tafasitamab (MOR208) is on the treatment of patients with relapsed or refractory DLBCL who are ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). There is a particularly high unmet medical need for this patient group. Based on FDA breakthrough therapy designation, MorphoSys aims to develop tafasitamab (MOR208) as a potential new treatment option for these patients.

Proposed Mode of Action

Tafasitamab (MOR208) is an investigational Fc-engineered antibody targeting CD19 and is currently in clinical development for the treatment of patients with certain blood cancer.

Tafasitamab (MOR208) binds to CD19. This antigen is broadly and homogeneously expressed across different B cell-derived blood cancers including diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). According to preclinical findings, 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-derived blood cancers. Focus of development is on patient groups with a high unmet medical need.
These diseases arise from malignant 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. As a consequence of B cells turning malignant, the healthy and functional white blood cells are displaced and/or no longer function properly leading to a heavily weakened immune system.

MorphoSys is currently investigating tafasitamab (MOR208) in two 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, comprising about 40% of all 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 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 BTK 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 inhibitor therapy.

Currently active clinical trials:

• Phase 2 - L-MIND study
• Phase 2/3 - B-MIND study
• Phase 1b - First-MIND study
• Phase 2 - COSMOS study

L-MIND study

L-MIND (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 must not 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.

B-MIND study

The randomized, double-arm, open-label, multicenter phase 2/3 B-MIND (bendamustine - MOR208 in DLBCL) study was initiated in 2016 and is expected to enroll 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 will 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 in agreement with the 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 will be increased to 450.

First-MIND

First-MIND is an open-label, randomized, multicenter phase 1b study to evaluate safety and preliminary efficacy of tafasitamab in addition to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristin, prednison) as well as tafasitamab and lenalidomide in addition to R-CHOP in adult patients with newly diagnosed, previously untreated DLBCL. Patients enrolled in each arm will receive 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.

COSMOS study

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 ASH.

Regulatory Highlights

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 relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (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 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 will co-commercialize tafasitamab (MOR208) in the United States, while Incyte has exclusive commercialization rights outside the United States. On March 3 2020, the agreement received antithrust clearance and thus became effective.

End of December 2019,  MorphoSys submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for tafasitamab (MOR208) for the treatment of adult patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL). The BLA submission is based on the primary analysis data from the L-MIND trial of tafasitamab (MOR208) in combination with lenalidomide in patients with r/r DLBCL. The agency accepted filing of MorphoSys’ BLA end of February and granted priority review for tafasitamab.

In October 2017, based on interim data from the ongoing L-MIND study, the FDA granted breakthrough therapy designation (BTD) for tafasitamab (MOR208) in combination with lenalidomide for the treatment of patients with r/r DLBCL who are not eligible for high-dose chemotherapy and autologous stem cell transplantation.

In 2014, we were granted fast track designation for tafasitamab (MOR208) by the FDA for the treatment of r/r DLBCL. Also in 2014, the FDA as well as the European Commission granted orphan drug designation and orphan medicinal product status respectively for tafasitamab (MOR208) for the indications of DLBCL and CLL/SLL.

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.

Commercial Activities

MorphoSys co-commercializes tafasitamab (MOR208) in the United States together with Incyte under the recently signed 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.