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 an investigational drug that has not yet been approved by any regulatory authorities. The safety and efficacy of Felzartamab are currently evaluated in patients with glomerulonephritis, precisely anti-PLA2R antibody-positive membranous nephropathy, an autoimmune renal disease. In the future, Felzartamab might potentially be evaluated as targeting therapy in additional autoimmune mediated diseases.

Therapeutic fields and proposed mode of action
 

Glomerulonephritis is a group of renal disorders that cause damage to the glomeruli, the filtration units of the kidney, hindering their ability to carry out their essential functions.  It is a common cause of end stage renal disease (Sim et al. 2019). Patients living with end stage renal disease are burdened by the need for lifelong dialysis and/or transplantation. Dialysis is typically required three times weekly for 4 hours per session (National Kidney Foundation, 2020); it carries an increased risk of infection (Wakasugi, 2012), and is associated with 44% mortality at 5 years (Nordio, 2012). Moreover, autoimmunity is unequivocally regarded as the predominant pathogenic process underlying most forms of Glomerulonephritis (Couser, 2014). The ongoing presence of autoantibodies can precipitate recurrence of disease after transplantation, increasing the risk of graft failure (Passerini, 2019; Ponticelli, 2010). Although some patients do not progress to end stage renal disease, they are at an increased risk for life-threatening thrombotic events including deep venous thrombosis, renal vein thrombosis, and pulmonary embolism (Mirrakhimov, 2014).

The manifestations of glomerular diseases  are also associated with significantly impaired Quality of life including physical and mental health, fatigue, sleep impairment and anxiety (Canetta, 2019; Murphy, 2020).

Membranous Nephropathy

Membranous Nephropathy (MN) is a leading cause of nephrotic syndrome in adults worldwide (Couser, 2017). Nephrotic syndrome refers mainly to the presence of heavy proteinuria (loss of protein greater than 3.5 g/day), low serum albumin and marked edema (Couser 2017; Trujillo, 2019). The natural course of MN is variable and unpredictable. Although 30-40% of patients may experience spontaneous remission, 30% of patients experience persistent proteinuria with long-term preservation of renal function, and another 30%–50% progress to renal failure within 10-15 years (Trujillo, 2019; Heaf, 1999, Troyanov, 2004). Even if patients with nephrotic syndrome do not progress to renal failure, they have an increased risk of life-threatening thromboembolic and cardiovascular events, and are subject to infections (Wagoner, 1983; Heaf, 1999; Lee, 2016).
In the United States, the incidence of Membranous Nephropathy is estimated at 1.2 per 100,000; about 3,000 adults newly diagnosed every year (Mc Gorgan, 2011). Around 80% of Membranous Nephropathy cases are primary and mediated by autoantibodies, while 20% are secondary to other diseases. The age of onset is typically 50-60 years old (Couser, 2017).

Phospholipase A2 receptor (PLA2R) antibody positive MN makes up to 85% of all primary Membranous Nephropathy (Trujillo, 2019, Pozdizk, 2018, Couser 2017). PLA2R is a membrane glycoprotein expressed on epithelial cells in glomeruli. In PLA2R antibody-positive MN, patients’ immune system reacts against PLA2R by producing specific autoantibodies. The immune complexes formed by the binding of these autoantibodies to PLA2R induces inflammation, which leads to thickening of the glomerular membrane and cause nephrotic syndrome in 80% of the patients with MN (Couser 2017; Trujillo, 2019; Pozdizk, 2018) (figure 1).

Currently, there is no approved standard treatment for Membranous Nephropathy. The KDIGO guidelines – a global nonprofit organization developing and implementing evidence-based clinical practice guidelines in kidney disease - recommend using criteria such as anti-PLA2R antibody titer and proteinuria to stratify patients by risk and determine course of treatment. The current treatment regimen mainly comprises various non-immunosuppressive drugs (eg ACE inhibitors or Angiotensin receptor blockers, statins, and diuretics), conventional immunosuppressive drugs (e.g. cyclophosphamide combined with steroids, calcineurin inhibitors, mycophenolat-Mofetil) and off-label use of B-cell depleting agents (e.g. anti-CD20 antibodies) (KDIGO 2020; Ronco, 2021).

 

Figure 1: Pathogenesis in anti-PLA2R antibody-positive Membranous Nephropathy.

Figure 1: Pathogenesis in anti-PLA2R antibody-positive Membranous Nephropathy.

Role of plasma cells and proposed mode of action for Felzartamab in anti-PLA2R antibody-positive MN

B-cells provide immunity, and have a key role in autoimmunity, by differentiating into antibody-secreting plasma cells. This differentiation is associated with a change of cell markers. Earlier B-cell stages expressed CD20 marker at their cell surface, while CD38 molecule is highly expressed on differentiated B-cells called plasmablasts and short/long lived-plasma cells. CD38-positive plasma cells are the main source of autoantibodies in autoimmune diseases as they produce quantitatively more autoantibodies than CD20-positive B cells (Bayles, 2014; Jackson, 2015, Halliley, 2016)

Figure 2: B-cell differentiation and antibody production in autoimmune diseases.

Figure 2: B-cell differentiation and antibody production in autoimmune diseases.

Felzartamab specifically binds to the cell surface antigen CD38. Binding of Felzartamab to CD38-positive plasma cells facilitates the depletion of such cells via two modes of action: i) antibody-dependent cell-mediated cytotoxicity (ADCC) in which the plasma cells are lysed by Natural killer (NK) cells, and ii) antibody-dependent cell-mediated phagocytosis (ADCP) in which the macrophages clear away the plasma cells  (Endell, 2012; Boxhammer, 2015; Raab, 2020). Since the depletion of antibody producing cells should subsequently 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 (Figure 2).

Figure 3: Proposed mode of action of Felzartamab (MOR202) for depleting antibody producing plasma cells.

Figure 3: Proposed mode of action of Felzartamab (MOR202) for depleting antibody producing plasma cells.

In Membranous Nephropathy, long-lived plasma cells drive pathogenic antibody production, contributing to functional damage to the glomeruli (Rodrigues, 2017; Ruggenenti, 2015). A tight correlation has been described between the clinical course of the disease and PLA2R pathogenic autoantibody titer. Patients with a higher anti-PLA2R autoantibody titer have more severe disease and a longer time to disease remission (Pozdzik, 2018; van de Logt, 2019). High titers and sustained or recurrent positivity for anti-PLA2R antibody titers during therapy emerge as negative predictors for outcome (Bomback 2018; Ruggenenti, 2015). By contrast, a reduction in anti-PLA2R autoantibody levels is predictive of future likelihood of remission of proteinuria (Dahan, 2017; Ruggenenti, 2015). It precedes a reduction in proteinuria and increase in serum albumin (Beck, 2011; Ruggenenti, 2015). Patients presenting with high autoantibody titers are treated with anti-CD20 antibodies (Ruggenent, 2015; Fervenza et al., 2019). However, anti-CD20 therapeutic approaches target only activated B-cells that produce less autoantibodies, and leave C20-negative/CD38-positive long-lived plasma cells, which maintains the autoimmunity.  As a result, up to 40% of patients failed to respond to anti-CD20 therapies (Bomback, 2018, Couser 2017). 

In this context, a Felzartamab-induced depletion of the main source of pathogenic antibodies, ie the 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.

 

Ongoing clinical studies in Membranous Nephropathy

Phase 1b/2a study: Felzartamab in patients with Anti-PLA2R Antibody-Positive Membranous Nephropathy (aMN) - M-PLACE study (MorphoSys)

Felzartamab is currently under investigation in a phase Ib/IIa, 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, US, and Asia-Pacific (APAC) countries, and the recruitment is ongoing. For further details please refer to the following site:

https://clinicaltrials.gov/ct2/show/NCT04145440?term=MOR202&draw=2&rank=1.

• Phase 2a study: Felzartamab in patients with Anti-PLA2R Antibody-Positive Membranous Nephropathy (aMN) - NewPLACE study (MorphoSys)

Felzartamab is currently also under investigation in a phase IIa, open-label, 2-arm multi-center clinical trial, to assess PK/PD, safety and efficacy of the therapeutic antibody in MN. The clinical trial is conducted at multiple sites in Europe and APAC and the recruitment is ongoing. For further details please refer to the following site:

https://clinicaltrials.gov/ct2/show/NCT04733040?term=NewPlace&draw=2&rank=1

 

 

Multiple Myeloma (MM)

Multiple myeloma (MM) is subtype of blood cancer that originates in plasma cells. The malignant cells accumulate in the bone marrow, where they displace and suppress healthy blood progenitor cell populations (Kyle, 2009; Rawstron, 1998). Multiple myeloma 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 (Dispenzieri, 2005; Kyle, 2003). 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 (Baz, 2004; Bouchnita, 2016).

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 Multiple myeloma (Jeong, 2012; Flores-Montero, 2016). 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 (Raab, 2020). 

Figure 4: Proposed Mode of action of Felzartamab in multiple myeloma

Figure 4: Proposed Mode of action of Felzartamab in multiple myeloma

Ongoing clinical studies

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

MOR202 was investigated in a phase 1/2a, open-label, multi-center, dose-escalation study conducted in several sites in Germany and Austria. The study evaluated 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 final Clinical Study Report has been submitted.

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 leanalidomide 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.

 

References

  1. Bayles I, et al. Plasma Cell Formation, Secretion, and Persistence: The Short and the Long of It. Critical Reviews in Immunology. 2014;34(6):481–99.
  2. Baz R, et al. Prevalence of vitamin B12 deficiency in patients with plasma cell dyscrasias: a retrospective review. Cancer. 2004; 101(4):790-795.
  3. Beck LH Jr, et al. Rituximab-Induced Depletion of Anti-PLA 2 R Autoantibodies Predicts Response in Membranous Nephropathy. Journal of the American Society of Nephrology. 2011;22(8):1543–50.
  4. Bomback AS, et al. Membranous Nephropathy: Approaches to Treatment. American Journal of Nephrology. 2018;47(1):30–42.
  5. Bouchnita A, et al. Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis. Am J Hematol. 2016;91(4):371-378.

  6. Boxhammer R, et al. MOR202, a Human Anti-CD38 Monoclonal Antibody, Mediates Potent Tumoricidal Activity In Vivo and Shows Synergistic Efficacy in Combination with Different Antineoplastic Compounds. ASH annual meeting. 2015;3015

  7. Canetta PA, et al. Health-related quality of life in glomerular disease. Kidney Int. 2019;95(5):1209-1224.

  8. Couser WG, et al. The etiology of glomerulonephritis: roles of infection and autoimmunity. Kidney Int. 2014;86(5):905-914.

  9. Couser WG. Primary Membranous Nephropathy. Clinical Journal of the American Society of Nephrology. 2017;12(6):983–97.

  10. Dahan K, et al. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up. Journal of the American Society of Nephrology. 2017;28(1):348-58.

  11. Dispenzieri A, et al. Multiple myeloma: clinical features and indications for therapy. Best Pract Res Clin Haematol. 2005;18(4):553-568.

  12. Endell J, et al. The Activity of MOR202, a Fully Human Anti-CD38 Antibody, Is Complemented by ADCP and Is Synergistically Enhanced by Lenalidomide in Vitro and in Vivo. Blood. 2012;120(21):4018–4018.

  13. Fervenza FC, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. New England Journal of Medicine. 2019;381(1): 36-46.

  14. Flores-Montero J, et al. Immunophenotype of normal vs. myeloma plasma cells: Toward antibody panel specifications for MRD detection in multiple myeloma. Cytometry B Clin Cytom. 2016;90(1):61-72

  15. Halliley JL et al. Long-Lived Plasma Cells Are Contained within the CD19−CD38hiCD138+ Subset in Human Bone Marrow. Immunity. 2015;43(1):132–145.

  16. Heaf J, et al. The Epidemiology and Prognosis of Glomerulonephritis in Denmark 1985–1997. Nephrology Dialysis Transplantation. 1999;14(8):1889-1897.

  17. Jackson DA and Elsawa SF. Factors Regulating Immunoglobulin Production by Normal and Disease-Associated Plasma Cells. Biomolecules. 2015;5(1):20–40.

  18. Jeong TD, et al. Simplified flow cytometric immunophenotyping panel for multiple myeloma, CD56/CD19/CD138(CD38)/CD45, to differentiate neoplastic myeloma cells from reactive plasma cells. Korean J Hematol. 2012;47(4):260-266

  19. KDIGO Clinical Practice Guideline on Glomerular Diseases; June 2020. Available at: https://kdigo.org/wp-content/uploads/2017/02/KDIGO-GN-GL-Public-Review-Draft_1-June-2020.pdf

  20. Kyle RA, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78(1):21-33.

  21. Kyle RA, et al. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23(1):3-9.

  22. Lee T, et al. Patients with Primary Membranous Nephropathy Are at High Risk of Cardiovascular Events. Kidney International. 2016;89(5):1111–1118.

  23. Mirrakhimov A, et al. Primary Nephrotic Syndrome in Adults as a risk Factor for Pulmonary Embolism: An up-to-Date Review of the Literature. International Journal of Nephrology. 2014;2014:916760

  24. Murphy SL, et al. Longitudinal Changes in Health-Related Quality of Life in Primary Glomerular Disease: Results From the CureGN Study. Kidney Int Rep. 2020;5(10):1679-1689.

  25. National Kidney Foundation. Hemodialysis - Definition, procedure, and types. Available at https://www.kidney.org/atoz/content/hemodialysis. Accessed May 2021.

  26. Nordio M, et al. Survival in patients treated by long-term dialysis compared with the general population. Am J Kidney Dis. 2012;59(6):819-828.

  27. Passerini P, et al. Membranous Nephropathy (MN) Recurrence After Renal Transplantation. Front Immunol. 2019;10:1326.

  28. Ponticelli C, et al. Posttransplant recurrence of primary glomerulonephritis. Clin J Am Soc Nephrol. 2010;5(12):2363-2372.

  29. Pozdzik A, et al. Membranous Nephropathy and Anti-Podocytes Antibodies: Implications for the Diagnostic Workup and Disease Management. BioMed Research International. 2018:1–19.

  30. Raab MS, et al. MOR202, a Novel Anti-CD38 Monoclonal Antibody, in Patients with Relapsed or Refractory Multiple Myeloma: A First-in-Human, Multicentre, Phase 1–2a Trial. The Lancet Haematology. 2020;7(5):e381–e394.

  31. Rawstron AC, et al. B-lymphocyte suppression in multiple myeloma is a reversible phenomenon specific to normal B-cell progenitors and plasma cell precursors. Br J Haematol. 1998;100(1):176-183.

  32. Rodrigues JC, et al. IgA Nephropathy. Clin J Am Soc Nephrol. 2017;12(4):677-686

  33. Ronco P, et al. Advances in Membranous Nephropathy. Journal of Clinical Medicine. 2021;10(4): 607.

  34. Ruggenenti P, et al. Anti-Phospholipase A 2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy. Journal of the American Society of Nephrology. 2015;26(10):2545–58.

  35. Sim JJ, et al. End-Stage Renal Disease and Mortality Outcomes Across Different Glomerulonephropathies in a Large Diverse US Population. Mayo Clin Proc. 2018;93(2):167-178.

  36. Troyanov S, et al. Idiopathic Membranous Nephropathy: Definition and Relevance of a Partial Remission. Kidney International. 2004;66(3):1199–1205.

  37. Trujillo H and Praga M. Membranous Nephropathy: An Update. Portuguese Journal of Nephrology & Hypertension. 2019;33(1): 19-27.

  38. Van de Logt AE, et al. The Anti-PLA2R Antibody in Membranous Nephropathy: What We Know and What Remains a Decade after Its Discovery. Kidney International. 96(6): 1292–1302.

  39. Wagoner RD, et al. Renal Vein Thrombosis in Idiopathic Membranous Glomerulopathy and Nephrotic Syndrome: Incidence and Significance. Kidney International. 1983;23(2): 368–374.

  40. Wakasugi M, et al. High mortality rate of infectious diseases in dialysis patients: a comparison with the general population in Japan. Ther Apher Dial. 2012;16(3):226-231.

  41. Wyatt J, et al. IgA Nephropathy. N Engl J Med. 2013;368:2402-2414

  42. Wetmore JB, et al. The incidence, prevalence, and outcomes of glomerulonephritis derived from a large retrospective analysis. Kidney Int. 2016;90(4):853-860.