MOR208

MOR208 is a humanized monoclonal antibody directed against CD19 in clinical development for the treatment of B cell malignancies.

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 an important factor 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 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 MOR208 as a new treatment option for these patients.

 

Mode of action

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

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.

The constant Fc region of the antibody has been engineered to enhance the response of the body’s immune system against cancer cells. This Fc-enhancement of MOR208 has been shown to lead to a substantial potentiation of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).
 

CD19-expression on B cells

CD19 is expressed very broadly and early on B cells. Therefore it provides an ideal target for the treatment of B cell malignancies.

 

MACROPHAGE NATURAL KILLER CELL ENGINEERED FC-PORTION MOR208 CD19 TUMOR CELL ADCP ADCC DIRECT CYTOTOXICITY

The therapeutic field: B cell malignancies

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 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 dismal. 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 medical need for this patient group after discontinuation of a prior BTK inhibitor therapy.

 

L-MIND study

L-MIND (lenalidomide - MOR208 in DLBCL) is a phase 2 single-arm, open-label, multicenter study of 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 overall 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 MOR208. End of 2017, the enrollment was completed, follow-up and analysis of patients is currently ongoing.

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 approximately 330 patients in up to 180 centers in Europe, Asia Pacific (APAC) and the USA. , The trial will enroll 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 MOR208 plus bendamustine vs. the rituximab plus bendamustine combination, was successfully 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).

COSMOS study

The COSMOS-Study (CLL patients assessed for ORR & Safety in MOR208 Study) is a single-arm, open-label, multicenter combination trial of 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 safetry of the drug combinations.

 

Regulatory Highlights

In October 2017, based on interim data from the ongoing L-MIND study, the FDA granted breakthrough therapy designation (BTD) for 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 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 MOR208 for the indications of DLBCL and CLL/SLL.

In June 2010, MorphoSys AG and the 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.

 

Commercial Activities

In the event that MOR208 receives regulatory approval, MorphoSys intends to pursue an own commercialization strategy for MOR208. Therefore, MorphoSys intends to begin the setup of commercial capabilities in 2018.