Jeffrey Bennett, MD, PhD

Making transformative progress in the treatment of rare diseases can be challenging. But as we improve our understanding of the etiology of these diseases, we’re uncovering critical biological drivers that can be targeted through therapeutic intervention to deliver improvements in patient care.

One powerful example of this is in neuromyelitis optica spectrum disorder (NMOSD), a rare autoimmune disease caused by autoimmunity attacks against astrocytes in the central nervous system (CNS).

 This inflammation leads to severe attacks of nervous system dysfunction that can result in serious, wide-ranging physical impairments and permanent disability.

Inflammatory attacks in NMOSD are triggered by anti-aquaporin-4 antibodies (anti-AQP4-IgG), proteins that bind primarily to astrocytes in the CNS, causing an immune response that destroys the astrocytes. These antibodies, which are present in roughly 90% of people with NMOSD, are produced in part by mature B cells in the body (known as plasmablasts).

Research into the mechanisms that underlie NMOSD pathophysiology has identified that B cells play a key role in driving disease activity. In particular, studies have indicated that certain B-cell populations are increased in NMOSD patients.

 These B-cell populations bear a common cell surface lineage marker, CD19. Therefore, depletion of CD19 B cells might offer a therapeutic avenue for reducing NMOSD attacks and improving patient outcomes.

The N-MOmentum clinical trial (NCT02200770) was conducted to evaluate the anti-CD19 B-cell-depleting humanized monoclonal antibody UPLIZNA® (inebilizumab-cdon), which was approved by the U.S. Food and Drug Administration for adults with NMOSD who are anti-AQP4-IgG positive.

 The monoclonal antibody binds directly to CD19 on the surface of B cells, targeting B cells from early development through to the stage of antibody secretion. Antibody secreting plasmablasts and plasma cells are not directly targeted by current anti-CD20 B-cell-depleting therapeutics.

The N-MOmentum trial provided important insights about the impact of B cell depletion on the clinical effects of NMOSD. Importantly, depleting B cells in study participants was associated with improved outcomes.

 At six months, participants with lower B-cell counts had improved clinical and imaging metrics of disease activity. 89% of AQP4-antibody positive participants were attack free after 28 weeks of treatment with UPLIZNA.

 In addition, lower B-cell levels measured at the end of the trial’s randomized control period were predictive of stable, deep depletion during the long-term, open-label period, resulting in a 97% reduction in annualized attack rate (AAR) after 2.5 years of treatment.

Ultimately, the findings from this study provide useful insights about the clinical and radiologic benefits of managing NMOSD with anti-CD19 B-cell depletion as well as help to sharpen our understanding of the fundamental biology of this rare disease.

 The result has enhanced optimism for the long-term outlook for NMOSD patients as regular monitoring of B-cell counts may be a useful approach to guide patient care over time as a strategy to reduce NMOSD attacks and their associated damage.

Bennett JL, O’Connor KC, Bar-Or A, et al. B lymphocytes in neuromyelitis optica. 

. 2015;2(3):e104. doi:10.1212/NXI.0000000000000104

Ajmera MR, Boscoe A, Mauskopf J, Candrilli SD, Levy M. Evaluation of comorbidities and health care resource use among patients with highly active neuromyelitis optica. 

Prain K, Woodhall M, Vincent A et al. AQP4 Antibody Assay Sensitivity Comparison in the Era of the 2015 Diagnostic Criteria for NMOSD. 

Hyun JW, Jeong IH, Joung A, Kim SH, Kim HJ. Evaluation of the 2015 diagnostic criteria for neuromyelitis optica spectrum disorder. 

. 2016;86(19):1772-1779. doi:10.1212/WNL.0000000000002655.

Kowarik, MC et al. CNS Aquaporin-4-specific B cells connect with multiple B-cell compartments in neuromyelitis optica spectrum disorder. 

Forsthuber TG, Cimbora DM, Ratchford JN, Katz E, Stüve O. B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets. 

. 2018;11:1-13. doi:10.1177/1756286418761697

UPLIZNA (inebilizumab-cdon) [prescribing information] Horizon.

Bennett JL, Atkas O, Smith M, Rees WA, Katz E and Cree B. Extent of B-cell depletion is associated with disease activity reduction in neuromyelitis optica spectrum disorder: results from the N-MOmentum study. Poster presented at 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. (ECTRIMS 2021); October 2021; Virtual.

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INDICATION AND IMPORTANT SAFETY INFORMATION

UPLIZNA (inebilizumab-cdon) is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

UPLIZNA is contraindicated in patients with:

A history of life-threatening infusion reaction to UPLIZNA

 UPLIZNA can cause infusion reactions, which can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash, or other symptoms. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions. Administer pre-medication with a corticosteroid, an antihistamine, and an anti-pyretic.

 The most common infections reported by UPLIZNA-treated patients in the randomized and open-label periods included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%), and influenza (7%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.

Increased immunosuppressive effects are possible if combining UPLIZNA with another immunosuppressive therapy.

The risk of Hepatitis B Virus (HBV) reactivation has been observed with other B-cell-depleting antibodies. Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer to patients with active hepatitis.

Although no confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell-depleting antibodies and other therapies that affect immune competence. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation.

Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA.

Vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation, until B-cell repletion.

There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment. Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with UPLIZNA until B-cell repletion especially in patients with opportunistic or recurrent infections.

May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping UPLIZNA.

The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were urinary tract infection and arthralgia.

Blocking B Cells may be the Key to Controlling NMOSD Over Time

"The data shows that the early behavior of B-cell depletion in patients with NMOSD was similar to what was observed in the long-term throughout the study. This depletion could be related to clinical metrics of disease activity, as well as MRI metrics of disease activity.”

37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)

, October 13-15, new data were presented from the N-MOmentum trial (NCT), the study that led to the approval of inebiluzumab (Uplizna; Horizon Therapeutics). To date, inebilizumab remains the only FDA-approved anti-CD19 B-cell depleting humanized monoclonal antibody for the treatment of patients with anti-aquaporin-4 (AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD).

At the end of the 28-week randomized, placebo-controlled period of the trial, all participants saw significant treatment effect, and those whose B-cell counts were less than 4 cells/µL had reduced rates of annualized relapse rate (ARR; rate ratio, 0.4) and new/enlarging lesions (0.36) than those with B-cell counts greater than 4 cells/µL.

®,study author Jeffrey Bennett, MD, PhD, professor of neurology, University of Colorado, discussed the clinical significance of the data, including the take-home messages clinicians should understand.

New data reinforce the relationship between B-cell depletion and improved outcomes in people receiving UPLIZNA (inebilizumab) for neuromyelitis optica spectrum disorder (NMOSD). News release. Horizon Therapeutics. October 13, 2021. Accessed October 21, 2021. https://ir.horizontherapeutics.com/news-releases/news-release-details/new-data-reinforce-relationship-between-b-cell-depletion-and

Videos

The professor of neurology at the University of Colorado provided insight on the data that reinforced the relationship between B-cell depletion and improved outcomes using inebilizumab (Uplizna; Horizon Therapeutics). [WATCH TIME: 2 minutes]

Jeffrey Bennett, MD, PhD

Articles

Blocking B Cells may be the Key to Controlling NMOSD Over Time

B-Cell Depletion and Long-Term Outcomes in NMOSD With Inebilizumab: Jeffrey Bennett, MD, PhD

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