FDA Approves Ublituximab for Relapsing Forms of Multiple Sclerosis

Multiple Sclerosis (MS) is a lifelong inflammatory demyelinating disease of the central nervous system (CNS). Approximately 85% of MS patients have a biphasic disease course marked by alternating episodes of neurological disability and recovery, which is designated as relapsing-remitting MS (RRMS).1,2

In December 2022, the FDA approved BRIUMVI™ (ublituximab-xiiy), a chimeric monoclonal antibody (mAb) labelled for the treatment of relapsing forms of multiple sclerosis (RMS), which includes clinically isolated syndrome, relapsing-remitting disease (RRMS), and active secondary progressive disease, in adults.3 Ublituximab’s administration schedule consists of a Day 1 infusion of 150mg administered over four hours, a Day 15 infusion of 450mg administered over one hour, followed by 450mg infusions every 24 weeks administered over one hour. 

Ublituximab targets a unique epitope on the CD20 antigen and its regulatory nod rides a B-cell therapy wave that has swept the MS treatment landscape in the last few years.4 Monoclonal antibodies that target CD20 expressing B-cells have proven highly effective in reducing relapses in patients, and is also the first-line option for protecting against disability worsening in primary progressive MS.4 Often referred to as B-cell depletion therapy, anti-CD20 mAbs rapidly and profoundly deplete circulating CD20+ B cells. In contrast to other anti-CD20 mAb molecules, ublituximab was glycoengineered to produce higher affinity to FcγRIIIa receptors, yielding greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab and ofatumumab,5, especially in cells with low CD20 expression. 

FDA’s approval was based on the outcome of ULTIMATE 1 and 2 trials (NCT03277261; NCT03277248),6 two identical Phase III randomized, multi-centre, double-blinded, double-dummy active-controlled trials, evaluating a one hour 450mg infusion of ublituximab vs. teriflunomide in patients with RMS. Ublituximab demonstrated superiority over teriflunomide in significantly reducing the annualized relapsed rate (ARR), the number of T1 gadolinium-enhancing lesions and the number of new or enlarging T2 lesions.6 In patients with relapsing MS, ublituximab produced an ARR of less than 0.10, which translates to less than 1 relapse in 10 years.6 The drug also demonstrated a favourable safety and tolerability profile with no unexpected safety signals. 

A summary of the ULTIMATE 1 and 2 baseline demographics, efficacy outcomes and safety findings are described in the table below. 

Ublituximab’s novel mechanism of action, coupled with the convenience of a 1-hour infusion, provides a valuable new treatment option for patients with RMS. Notwithstanding, more evidence is required to compare the benefit of ublituximab with other mAbs currently used for MS (natalizumab, ofatumumab, ocrelizumab and rituximab). 

References

1. Noseworthy JH. Progress in determining the causes and treatment of multiple sclerosis. Nature. 1999;399(6738 Suppl): A40-47. doi:10.1038/399a040
2. Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52(1):61-76. doi:10.1016/j.neuron.2006.09.011
3. 761238s000lbl.pdf. Accessed January 12, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761238s000lbl.pdf
4. Greenfield AL, Hauser SL. B Cell Therapy for Multiple Sclerosis: Entering an Era. Ann Neurol. 2018;83(1):13-26. doi:10.1002/ana.25119
5. Sharman JP, Farber CM, Mahadevan D, et al. Ublituximab (TG‐1101), a novel glycoengineered anti‐CD20 antibody, in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukaemia: results of a phase 2 trial. Br J Haematol. 2017;176(3):412-420. doi:10.1111/bjh.14447
6. Steinman L, Fox E, Hartung HP, et al. Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med. 2022;387(8):704-714. doi:10.1056/NEJMoa2201904