Investigational Drug Targeting Epstein-Barr Virus Shows Promise for Progressive MS


Atara Biotherapeutics’ allogeneic EBV-targeted T-cell therapy, ATA188, is well-tolerated in phase 1, with a dose identified for the randomized placebo-controlled portion of the study.

Amit Bar-Or, MD, the Melissa and Paul Anderson President's Distinguished Professor of Neurology, Perelman School of Medicine, University of Pennsylvania.

Amit Bar-Or, MD

Preliminary phase 1 safety data (NCT03283826) on the investigational off-the-shelf, allogeneic Epstein-Barr virus (EBV)-targeted T-cell therapy ATA188 (Atara Biotherapeutics) suggest that the agent is well tolerated in adult individuals with progressive forms of multiple sclerosis (MS).

The data include those patients dosed up to April 2020 (n = 25), each of which received ≥1 dose of ATA188. Ultimately, there were no events worse than grade 3 reported. In total, 2 treatment-emergent serious adverse events (AEs) were noted: a grade 2 incidence of muscle spasticity, which was not related to therapy, and a grade 3 incidence of MS relapse, which was considered possibly related to treatment.

The data were presented at MS Virtual 2020, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, by Amit Bar-Or, MD, the Melissa and Paul Anderson President's Distinguished Professor of Neurology, Perelman School of Medicine, University of Pennsylvania.

“It was very well-tolerated, and the good news is that we are not seeing that even with the longer-term dosing of patients with these cells going out to 21 months, 24 months, we're not seeing augmentation of safety issues,” Jakob Dupont, MD, executive vice president, and head of global research and development, Atara Biotherapeutics, told NeurologyLive. “One of the aspects of ATA188 is that it's a very specific treatment. These T cells are really directed against only EBV-expressing infected cells, and so we don't have a lot of off-target toxicity because of that.”

READ MORE: Progressive and Relapsing-Remitting Multiple Sclerosis Share Similar Fatigue Severity

As well as the generally low-grade AEs that were observed, there were no dose-limiting toxicities, cytokine release syndrome, graft-versus-host disease, or infusion reactions reported. “With a lot of cell therapies, whether it's CAR-T or whatever it may be, you can see neurological symptoms, you can see cytokine release syndrome and so forth, and we really don't see those types of effects with our treatment because, again, the specificity of our EBV T cells. They're not directed against the patient's own self-antigens, if you will,” Dupont noted.

The first part of this included 4 cohorts of patients who received escalating doses to determine the recommended dose for the second part of the study. The participants were followed for 1 year, and then given the option to participate in a 4-year open-label extension (OLE) at the recommended dose, which was determined by Cohort 3.

In addition to the safety measures, sustained disability improvement (SDI)—defined as improvement in Expanded Disability Status Scale (EDSS) or Timed 25-Foot Walk (T25FW) at 2 or more consecutive time points—was assessed, as well as Fatigue Severity Scale (FSS), 12-item MS Walking Scale (MSWS-12), MS Impact Scale-29 (physical; MSIS-29), and whole-brain volume. The efficacy end points were assessed in all 4 cohorts (n = 24) at the 6-month mark, and in the first 3 cohorts (n = 17) at 12 months.

A higher proportion of patients who were treated with ATA188 showed sustained disability improvement (SDI) with an increasing dose. At 6 months, 6 patients met SDI criteria, and at 12 months, 5 patients did so. This was driven by EDSS score in all but 2 patients at both time points. In cohorts 1, 2, and 3, every patient with SDI at the 6-month time point maintained that status through 12 months.

Additionally, those who achieved SDI at any time point maintained it at all future time points and tended to show improvements in fatigue, physical function, and MRI whole brain volume at 1 year. As of June 2020, OLE data from the 15-month time point were available for 4 individuals: 3 had SDI at 6 and 12 months that was maintained to that point.

“We are encouraged by what we’re seeing in the clinical trial because when we get into Cohort 3, we are seeing sustained disability improvement in these patients…this isn’t just 1 point in time where we’re seeing a patient doing better today,” Dupont said.

For more coverage from MS 2020, click here.

Pender M, Hodgkinson S, Broadley S. Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive forms of multiple sclerosis. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0226.
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