Further results of the 2 phase 3 studies are expected to be completed and presented in detail in first half of 2021, with a BLA submission to follow.
Lawrence Steinman, MD
TG Therapeutics today announced the topline results from its pair of phase 3 studies, ULTIMATE I and II (NCT03277261; NCT03277248), which displayed that its investigational glycoengineered anti-CD20 monoclonal antibody, ublituximab, achieved both primary end points in the treatment of patients with multiple sclerosis (MS).1
All told, ublituximab was compared to 14-mg teriflunomide (Aubagio; Sanofi-Genzyme) in this patient population over a 96-week study course, and the data show that treatment with ublituximab was associated with a statistically significant reduction in annualized relapse rate (ARR; P <.005 for both trials). The relative reduction in ARR was 60% in ULTIMATE I and 50% in ULTIMATE II, with both studies displaying ARRs of <0.10.
Further results of the 2 studies, including safety and secondary end points, are expected to be completed and presented in detail at an upcoming medical meeting, with TG Therapeutics noting a target timeline in the first half of 2021.
“B-cell targeted therapy with anti-CD20 monoclonal antibodies has dramatically shifted the treatment paradigm for patients with MS and has shown to be very effective in reducing relapses in patients,” global study chair Lawrence Steinman, MD, Zimmermann Professor of Neurology and Neurological Sciences, and Pediatrics, Stanford University, said in a statement. “I am pleased to see such positive results from this important trial exploring a 1-hour infusion of ublituximab every 6 months and believe, if approved, the unique attributes of ublituximab, particularly that it has been glycoengineered for enhanced antibody-dependent cellular cytotoxicity, may offer benefits to patients in the RMS treatment paradigm.”
As Steinman alludes to, ublituximab was assessed for safety and efficacy when administered in a dose of 450 mg in a 1-hour infusion twice yearly, following a single 4-hour infusion on day 1 (administered at 150 mg).
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Both ULTIMATE studies were conducted as part of a Special Protocol Assessment (SPA) agreement with the FDA. The secondary end points included the total number of T1 gadolinium-enhancing lesions, the total number of new and/or enlarging T2 hyperintense lesions, and time-to-confirmed disability progression (CDP). The trials enrolled a total of 1094 patients with relapsing disease from 10 countries.
The full and detailed data from these studies are anticipated to be used in support of a biologics license application (BLA) submission for ublituximab in relapsing MS sometime mid-2021.
“MS is a chronic demyelinating disease where having a variety of treatment options within the same class has shown to be important for patients. I look forward to the full data from the ULTIMATE studies to further understand the potential of ublituximab in MS,” Steinman said.
In May 2020, TG Therapeutics announced the publication of the phase 2 study results for the investigational agent, which showed that in a population of 48 patients, it was generally well tolerated across all cohorts including those patients receiving the 1-hour infusion of the 450-mg dose. Patients in that study received 3 ublituximab infusions in 6 dosing cohorts (150 mg over 1-4 hours on day 1, followed by 450 mg to 600 mg over 1–3 hours on day 15 and at week 24).2,3
At week 48, the ARR was 0.07. Additionally, the responder rate was 100%, and the median peripheral B-cell depletion was >99% from baseline through week 4, reductions which were sustained at weeks 24 and 48. At both of those time points, no patients had new or persisting gadolinium-enhancing lesions on any MRI scans, equating to a 100% reduction from baseline (P = .003).3
Safety data were also available from all 48 patients in the phase 2 study and demonstrated that no patients discontinued due to a drug-related adverse event (AE). One grade 3 AE, fatigue, was considered possibly related to study treatment, but no serious infections were reported, and no deaths occurred. The most common ublituximab-related AE was infusion-related reactions (58%) all of which were deemed grade 1 or 2, including for those patients receiving the 450-mg dose in 1 hour.2
If eventually approved, ublituximab would join a pair of anti-CD20 agents, ocrelizumab (Ocrevus; Genentech) and ofatumumab (Kesimpta; Novartis) as the only available members of the drug class. In a recent NeurologyLive Peer Exchange discussion, Scott D. Newsome, DO, of the Johns Hopkins Multiple Sclerosis and Transverse Myelitis Centers, explained the value of these agents as potential first-line therapies for patients with MS.
“At least short-term, and probably intermediate-term, we know that the B-cell depleting therapies do a much better job in suppressing the inflammatory disease activity,” Newsome said. “That includes relapses, Gd+ lesions, and T2 lesions. They’re compelling enough for me to think about using the B-cell depleting therapies as a first-line.”