Felzartamab (MOR202)

Felzartamab is a human monoclonal HuCAL anti-CD38 antibody in clinical development for the treatment of autoimmune diseases and multiple myeloma.

Felzartamab (MOR202) is a therapeutic human monoclonal antibody derived from MorphoSys’ HuCAL antibody library and directed against CD38. Felzartamab is currently under clinical investigation in patients with anti-PLA2R antibody-positive membranous nephropathy, a kidney specific autoimmune disease, and in patients with multiple myeloma. In the future, Felzartamab might potentially be evaluated as targeting therapy in additional autoimmune mediated diseases. End of 2017, MorphoSys entered into an exclusive regional licensing agreement with I-Mab Biopharma to develop and commercialize Felzartamab in Greater China.

Therapeutic fields and proposed mode of action
 

Anti-PLA2R Antibody-positive Membranous Nephropathy

Anti-PLA2R antibody-positive Membranous Nephropathy is an immune disease caused by autoantibodies against kidney cells. Membranous nephropathy is the leading cause of nephrotic syndrome in adults. Around 80% of membranous nephropathy (MN) cases are primary with an autoimmune nature, while only 20% are secondary and related to other diseases or exposures. The natural course of MN is variable and unpredictable: 50% of patients diagnosed with primary MN continue to have nephrotic syndrome and 30% of patients may progress to end-stage renal disease over 10 years (Keri, 2019). Moreover, patients with MN remaining nephrotic are at increased risk for thromboembolic and cardiovascular events.  
PLA2R is a membrane glycoprotein expressed in epithelial cells in normal human glomeruli. Under autoimmune pathological condition, the immune system of MN patients reacts against PLA2R by producing specific autoantibodies. Binding of such autoantibodies to PLA2R induces inflammatory processes which can end up in thickening of the glomerular membrane and finally may lead to nephrotic syndrome (see cartoon).
Currently, there is no approved standard treatment for autoantibody-positive MN. The current treatment regimen mainly comprises off-label use of various non-immunosuppressive drugs (e.g. ACE inhibitors or Angiotensin Receptor Blockers, statins and diuretics), conventional immunosuppressive drugs (e.g. cyclophosphamide combined with steroids, calcineurin inhibitors, Mycophenolat-Mofetil) and targeted immunosuppressive drugs (i.e. anti-CD20 antibodies) (Couser WG, 2017; Bomback AS, 2018)

 

Suggested pathogenesis in anti-PLA2R antibody-positive Membranous Nephropathy

Suggested pathogenesis in anti-PLA2R antibody-positive Membranous Nephropathy

Proposed mode of action for Felzartamab in anti-PLA2R antibody-positive MN

Felzartamab specifically binds to the cell surface antigen CD38, a molecule highly expressed on antibody producing B cells like plasma cells and plasmablasts. Binding of Felzartamab induces depletion of such cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). Since depletion of antibody producing cells subsequently should lead to a decrease in antibody titers, treatment with Felzartamab may be potentially beneficial in autoimmune diseases with a causal relationship between autoantibodies and the disease.

Proposed mode of action of Felzartamab

Proposed mode of action of Felzartamab for depleting antibody producing plasma cells.

In MN, a tight correlation of the clinical course of the disease with PLA2R autoantibody titer has been described. High titers and sustained or recurrent positivity for anti-PLA2R antibody titers during therapy emerge as negative predictors for outcome (Bomback AS, 2018). By contrast, a reduction in anti-PLA2R autoantibody levels in serum usually precedes a reduction in proteinuria and increase in serum albumin (Beck LH, 2011; Ruggenenti P, 2015).
The majority of patients presenting with high autoantibody titers are still inadequately treated with anti-CD20 antibodies (Ruggenenti P, 2015; Fervenza FC, 2019), as the main source for these autoantibodies are most probably CD20-negative (but CD38-positive) plasma cells. Plasma cells are described as the B cell subpopulation with the quantitatively highest degree of antibody formation (Bayles I and Milcarek C, 2014; Jackson DA and Elsawa SF, 2015).
In this context, a Felzartamab-induced depletion of plasma cells may potentially provide a viable emerging therapeutic option sparing patients of significant toxicity by conventional immunosuppressive agents and possibly improve outcomes for patients with limited benefit of an anti-CD20 directed therapy

 

Suggested effect of anti-PLA2R antibody depletion in primary MN

Suggested effect of anti-PLA2R antibody depletion in primary MN

Ongoing clinical studies

• Phase Ib/IIa study: Felzartabmab in patients with Anti-PLA2R Antibody-Positive Membranous Nephropathy (aMN) - M-PLACE (MorphoSys)

 Felzartamab is currently under investigation in a phase 1b/2a, open-label, multi-center clinical trial, to assess safety and efficacy of the therapeutic antibody in MN. The clinical trial is conducted at multiple sites in Europe and US and the recruitment is ongoing. For further details please refer to this site.
 

Multiple Myeloma (MM)

Multiple myeloma (MM) causes cancer cells to accumulate in the bone marrow, where they displace and suppress healthy blood progenitor cell populations. MM is also characterized by destructive lytic bone lesions (rounded, punched-out areas of bone), diffuse osteoporosis, bone pain, and the production of abnormal proteins, which accumulate in the urine. Anemia is also present in most multiple myeloma patients at the time of diagnosis and during follow-up. Anemia in multiple myeloma is multifactorial, and is secondary to bone marrow replacement by malignant plasma cells, chronic inflammation, relative erythropoietin deficiency, and vitamin deficiency.

Proposed mode of action of Felzartamab in multiple myeloma

CD38 is one of the most strongly and uniformly expressed antigens on the surface of malignant plasma cells, and is an established diagnostic marker for MM. Binding of Felzartamab to CD38 may result in in antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) mediated killing of cancer cells. 

Proposed Mode of action of Felzartabmab in multiple myeloma

Proposed Mode of action of Felzartabmab in multiple myeloma

Ongoing clinical studies

Phase 1/2a study: Felzartamab in patients with relapsed/refractory multiple myeloma (MorphoSys)

Phase 2 study: MOR202/TJ202 with dexamethasone in patients with relapsed/ refractory multiple myeloma (I-Mab)

Phase 3 study: MOR202/TJ202 with lenalidomide in patients with relapsed/ refractory multiple myeloma (I-Mab)

PHASE 1/2A DOSE ESCALATION STUDY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (MORPHOSYS)

MOR202 is currently under clinical investigation in a phase 1/2a, open-label, multi-center, dose-escalation study conducted in several sites in Germany and Austria. The study is evaluating the safety and preliminary efficacy of MOR202 alone and in combination with the immunomodulatory drugs (IMiDs) pomalidomide and lenalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma. The primary endpoints of the trial are the safety, tolerability and recommended dose of MOR202 alone and in combination with the IMiDs. Secondary outcome measures are pharmacokinetics and preliminary efficacy based on overall response rate, duration of response, time-to-progression, and progression-free survival. The treatment period is completed and the final Clinical Study Report is in preparation.

PHASE 2 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF MOR202/TJ202 COMBINED WITH DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (I-MAB)

The multi-center, single-arm phase 2 study to evaluate the efficacy and safety of MOR202/TJ202 combined with dexamethasone in patients with relapsed or refractory multiple myeloma is conducted by I-Mab Biopharma. The trial enrolls patients in mainland China and Taiwan who received at least 2 prior lines of treatment of which one treatment must include a proteasome inhibitor and an immunomodulator. All patients will receive MOR202/TJ202 and dexamethasone (Dex) in the study. The primary endpoint of the study is overall response rate, secondary outcome measures are amongst others duration of response, time-to-progression, and progression-free survival. The treatment will continue until endpoint events such as intolerance or progressive disease. The study has been designed as a pivotal trial, which, if successful, could lead to a biologics license application (BLA) in Greater China.

PHASE 3 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF MOR202/TJ202 COMBINED WITH LENALIDOMIDE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (I-MAB) 

The randomized, open-label, parallel-controlled, multicenter phase 3 study will be conducted by I-Mab in mainland China and Taiwan to evaluate the efficacy and safety of the combination of MOR202/TJ202 plus lenalidomide (LEN) and dexamethasone (DEX) versus the combination of LEN and DEX in patients with relapsed or refractory multiple myeloma who received at least one prior line of treatment. The primary endpoint is to evaluate the progression-free survival (PFS) comparing the efficacy of MOR202/TJ202 plus LEN/DEX versus LEN/DEX. The study has been designed as a pivotal trial, which, if successful, could lead to a biologics license application (BLA) in Greater China.