Summary:-
- BRIUMVI is the first and only anti-CD20 monoclonal antibody approved for patients with relapsing forms of multiple sclerosis that can be administered in a one-hour infusion twice-a-year following the starting dose
- U.S. Commercial launch expected Q1 2023
- Approval was granted for this indication based on data from the ULTIMATE I & II Phase 3 trials
TG Therapeutics, Inc. (NASDAQ: TGTX) today announced the U.S. Food and Drug Administration (FDA) has approved BRIUMVI™ (ublituximab-xiiy), for the treatment of relapsing forms of multiple sclerosis (RMS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Approval was granted for this indication based on data from the ULTIMATE I & II Phase 3 trials, which demonstrated superiority over teriflunomide in significantly reducing the annualized relapse rate (ARR, the primary endpoint), the number of T1 Gd-enhancing lesions and the number of new or enlarging T2 lesions. Results from the ULTIMATE I & II trials were recently published in August 2022 in The New England Journal of Medicine.
ABOUT Briumvi™ (ublituximab-xiiy)
CD20 monoclonal antibodies for the treatment of multiple sclerosis
- API– Ublituximab-xiiy
- Description– Briumvi is a novel monoclonal antibody that targets a unique epitope on CD20-expressing B-cells. Targeting CD20 using monoclonal antibodies has proven to be an important therapeutic approach for the management of autoimmune disorders, such as RMS. Briumvi is uniquely designed to lack certain sugar molecules normally expressed on the antibody. Removal of these sugar molecules, a process called glycoengineering, allows for efficient B-cell depletion at low doses.
- Indication-BRIUMVI is indicated for the treatment of adults with relapsing forms of multiple sclerosis (RMS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
- Class-Antineoplastics; Biobetters; Immunotherapies; Monoclonal antibodies
- Mechanism of Action-Antibody-dependent cell cytotoxicity; T lymphocyte stimulants
Ublituximab MOA
- Orphan Drug Status-Yes – Neuromyelitis optica; Chronic lymphocytic leukaemia; Non-Hodgkin’s lymphoma; Diffuse large B cell lymphoma; Marginal zone B-cell lymphoma
WARNINGS AND PRECAUTIONS
Infusion Reactions: Briumvi can cause infusion reactions, which can include pyrexia, chills, headache, influenza-like illness, tachycardia, nausea, throat irritation, erythema, and an anaphylactic reaction. In MS clinical trials, the incidence of infusion reactions in Briumvi-treated patients who received infusion reaction-limiting premedication prior to each infusion was 48%, with the highest incidence within 24 hours of the first infusion. 0.6% of Briumvi-treated patients experienced infusion reactions that were serious, some requiring hospitalization.
Observe treated patients for infusion reactions during the infusion and for at least one hour after the completion of the first two infusions unless infusion reaction and/or hypersensitivity has been observed in association with the current or any prior infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion. Administer the recommended pre-medication to reduce the frequency and severity of infusion reactions. If life-threatening, stop the infusion immediately, permanently discontinue Briumvi, and administer appropriate supportive treatment. Less severe infusion reactions may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.
Infections: Serious, life-threatening or fatal, bacterial and viral infections have been reported in Briumvi-treated patients. In MS clinical trials, the overall rate of infections in Briumvi-treated patients was 56% compared to 54% in teriflunomide-treated patients. The rate of serious infections was 5% compared to 3% respectively. There were 3 infection-related deaths in Briumvi-treated patients. The most common infections in Briumvi-treated patients included upper respiratory tract infection (45%) and urinary tract infection (10%). Delay Briumvi administration in patients with an active infection until the infection is resolved.
Consider the potential for increased immunosuppressive effects when initiating Briumvi after immunosuppressive therapy or initiating an immunosuppressive therapy after Briumvi.
Hepatitis B Virus (HBV) Reactivation: HBV reactivation occurred in an MS patient treated with Briumvi in clinical trials. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with Briumvi. Do not start treatment with Briumvi in patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult a liver disease expert before starting and during treatment.
Progressive Multifocal Leukoencephalopathy (PML): Although no cases of PML have occurred in Briumvi-treated MS patients, JCV infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies.
Fetal Risk: Based on data from animal studies, Briumvi may cause fetal harm when administered to a pregnant woman. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies during pregnancy. A pregnancy test is recommended in females of reproductive potential prior to each infusion. Advise females of reproductive potential to use effective contraception during Briumvi treatment and for 6 months after the last dose.
Reduction in Immunoglobulins: As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed. Decrease in immunoglobulin M (IgM) was reported in 0.6% of Briumvi-treated patients compared to none of the patients treated with teriflunomide in RMS clinical trials. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and after discontinuation of therapy until B-cell repletion. Consider discontinuing Briumvi therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.
Most Common Adverse Reactions: The most common adverse reactions in RMS trials (incidence ≥ 10% and >teriflunomide) were upper respiratory tract infections (40%) and infusion reactions (34%).
Lawrence Steinman, MD, Zimmermann Professor of Neurology & Neurological Sciences, and Pediatrics at Stanford University, stated, “Over the past several years we have seen a dramatic shift in the MS treatment landscape towards the use of B-cell therapy, which has shown to be highly effective in reducing relapses in patients. The outcome of the ULTIMATE I & II trials evaluating ublituximab, a novel targeted anti-CD20 agent designed for efficient B-cell depletion that supported this approval, represents an important milestone in the history of MS research as the first Phase 3 study of an anti-CD20 monoclonal antibody in patients with relapsing MS to produce an annualized relapse rate of less than 0.10, which translates to less than 1 relapse in 10 years. This approval is great news for patients living with MS and provides an appealing treatment alternative that can be administered in a one-hour infusion twice-a-year following the starting dose, which I believe is an added benefit to patients.”
“We are pleased to have a new treatment approved for people with relapsing forms of Multiple Sclerosis. MS is an unpredictable disease of the central nervous system that affects each person differently. Since we know that early treatment can minimize disease progression, it is incredibly important for people with MS to have a choice of treatment options to find the one that works best for them,” said Bari Talente, Executive Vice President, Advocacy & Healthcare Access at the National MS Society.
June Halper, MSN, APN-C, MSCN, FAAN, Chief Executive Officer of the Consortium of Multiple Sclerosis Centers has stated, “The approval of BRIUMVI is wonderful news. MS is most frequently diagnosed during the prime of a person’s life when they are just starting a career or beginning a family. The availability of anti-CD20s has launched a new era of high efficacy therapies for multiple sclerosis. The addition of BRIUMVI has added to the hope chest of patients, families, and the MS professional community. As a multi-disciplinary organization centered on the needs of those with MS, we appreciate the increasing array of treatment choices. Congratulations to TG Therapeutics from the CMSC and our leadership.”
ABOUT THE ULTIMATE I & II PHASE 3 TRIALS
ULTIMATE I & II are two randomized, double-blind, double-dummy, parallel group, active comparator-controlled clinical trials of identical design, in patients with RMS treated for 96 weeks. Patients were randomized to receive either BRIUMVI, given as an IV infusion of 150 mg administered in four hours, 450 mg two weeks after the first infusion administered in one hour, and 450 mg every 24 weeks administered in one hour, with oral placebo administered daily; or teriflunomide, the active comparator, given orally as a 14 mg daily dose with IV placebo administered on the same schedule as BRIUMVI. Both studies enrolled patients who had experienced at least one relapse in the previous year, two relapses in the previous two years, or had the presence of a T1 gadolinium (Gd)-enhancing lesion in the previous year. Patients were also required to have an Expanded Disability Status Scale (EDSS) score from 0 to 5.5 at baseline. The ULTIMATE I & II trials enrolled a total of 1,094 patients with RMS across 10 countries. These trials were led by Lawrence Steinman, MD, Zimmermann Professor of Neurology & Neurological Sciences, and Pediatrics at Stanford University.
ABOUT MULTIPLE SCLEROSIS
Relapsing multiple sclerosis (RMS) is a chronic demyelinating disease of the central nervous system (CNS) and includes people with relapsing-remitting multiple sclerosis (RRMS) and people with secondary progressive multiple sclerosis (SPMS) who continue to experience relapses. RRMS is the most common form of multiple sclerosis (MS) and is characterized by episodes of new or worsening signs or symptoms (relapses) followed by periods of recovery. It is estimated that nearly million people are living with MS in the United States and approximately 85% are initially diagnosed with RRMS.The majority of people who are diagnosed with RRMS will eventually transition to SPMS, in which they experience steadily worsening disability over time. Worldwide, more than 2.3 million people have a diagnosis of MS.
ABOUT TG THERAPEUTICS
TG Therapeutics is a biopharmaceutical company focused on the acquisition, development and commercialization of novel treatments for B-cell diseases. In addition to a research pipeline including several investigational medicines, TG has received approval from the U.S. FDA for Briumvi™ (ublituximab-xiiy), for the treatment of adult patients with relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
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