ATA188 Shows Sustained Benefit in Progressive MS in Phase 1 Extension Study

Douglas Arnold, MD

Updated results from the small, open-label extension (OLE) portion of the phase 1 study of ATA188 in progressive multiple sclerosis (MS) suggest that the therapy has a sustained clinical benefit over 39 months based on magnetization transfer ratio (MTR), while being safe and tolerable.^1,2

In total, 7 of the 8 patients enrolled in the OLE achieved sustained disease improvement (SDI) that was steady at all measured time points, with most SDI driven by improvement on Expanded Disability Status Scale (EDSS) scores. For those with sustained EDSS improvement (n = 7), the MTR for unenhancing T2 lesions was improved at 6 months (P = .0796) and significant improvement at 12 months (P = .0213) compared with those without sustained EDSS improvement (n = 15). Overall, trends supported a correlation between increase in MTR signal and improvement in EDSS score as early as 6 months.¹

"In progressive MS, our usual yardstick is less disability compared to the alternative, but in this study, not only did the disability slow down—it did more than just stop, it improved. People had improvement in clinical function," study investigator Bridget A. Bagert, MD, MPH, director, Ochsner Multiple Sclerosis Center, told NeurologyLive. "What [the MTR data] mean, we think, is that there may be some remyelination going on—there are objective data to suggest this—in these patients, who, also in this study, clinically improved. These 2 data points taken together are interesting and exciting. It's very early, of course, and it needs to be replicated in a randomized controlled trial, obviously, but it's definitely notable."

The data were presented by Douglas Arnold, MD, neurologist, Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, at the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), October 13-15. The phase 2 portion of the study investigating the allogeneic T-cell immunotherapy, titled EMBOLD (NCT03283826), is currently ongoing and enrolling patients, with planned interim analysis in 2022.²

“When a patient reaches a certain level of advanced disability, it is rare for them to naturally revert, and any improvement that is sustained would not be expected from the natural history of the disease,” said Mark Freedman, MD, professor of neurology, University of Ottawa, said in a statement.² “With progressive MS, spontaneous remyelination without therapeutic intervention is unlikely, highlighting the impact that these MTR data provide suggesting remyelination may be driving the prolonged sustained EDSS improvement.”

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Lead author Amit Bar-Or, MD, FRCPC, director, Center for Neuroinflammation and Neurotherapeutic, and chief, Multiple Sclerosis Division, Penn Medicine, and colleagues also suggest that there may be evidence of a potential remyelination effect based on the increases in MTR from baseline at 12 months that were associated with EDSS scores. “Compared to baseline, MTR at 12 months for unenhanced T2 lesions and normal-appearing brain tissue in patients with sustained EDSS improvement increased (median change of 0.134 and 0.082, respectively), whereas MTR in those patients without sustained EDSS improvement remained unchanged (median change of –0.030 and 0.005, respectively),” Bar-Or et al wrote.

MTR for unenhancing T2 lesions showed a correlation with EDSS at 6 months (n = 21; ρ = –0.4180; P = .0594) and at 12 months (n = 23; ρ = –0.3539; P = .1062). For those with normal-appearing brain tissue, the correlation results at 6 months and 12 months were as follows: 6 months (n = 20): ρ = –0.2473 (P = .2932); 12 months (n = 22): ρ = –0.1027 (P = .6491).

“There is growing robust evidence that EBV-infected B cells and plasma cells play a critical role in the pathogenesis of multiple sclerosis,” AJ Joshi, MD, chief medical officer, Atara, said in a statement.² “These data on ATA188 in progressive MS, the population with highest unmet need, underscore the potential to halt or reverse disability progression by precisely targeting what may be a root cause of MS. Importantly, an increase in MTR imaging signal suggestive of remyelination was seen in patients that achieved sustained EDSS improvement which may provide a potential biological basis for the clinical improvements observed with ATA188 treatment.”

Of the 24 patients who received ATA188 treatment and for whom efficacy was evaluated in the initial 12-month period, 18 chose to participate in the OLE and were followed for up to 39 months, with a data cutoff of August 2021. Efficacy data from the 12-month dose-escalation portion of the trial were previously reported at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021. At the time those data were presented, Jakob Dupont, MD, MA, head of global research and executive vice president, Atara Biotherapeutics, expressed his excitement for the treatment to NeurologyLive, noting that the improvements are “unheard of in this patient population."

"By definition, progressive MS... gets worse and worse over time. So, moving the clock back and seeing physical improvement, as we are in our early clinical experience, is quite notable,” Dupont said.

Of the 9 patients who achieved SDI, 7 did so in the initial 12-month period while the remaining 2 achieved SDI in the OLE phase. In total, 1 patient with secondary progressive MS who had achieved SDI experienced a nontreatment-related relapse at 18 months, approximately 6 months after their last ATA188 dose. This patient elected to discontinue the study.

A relationship between dose-escalation and increasing clinical response was observed, with the majority of the patients that achieved SDI (n = 7; 77.7%) receiving the 2 highest doses either initially or in the OLE, while 2 patients (22.2%) received the 2 lower doses. Eight patients that achieved SDI participated in the OLE, with a median time of maintained SDI of 18 months (range 0.03–27.0).

With regard to safety, as of August 2021, including the OLE period, no fatal adverse events, grade 3 or higher events, dose-limiting toxicities, cytokine release syndrome, or graft versus host disease were observed.

“The updated open-label extension results in patients with progressive MS treated with ATA188 showed a sustained disease improvement in 9 of 24 evaluable subjects, and these subjects had evidence of improved MTR suggestive of possible remyelination, particularly in chronic T2 lesions,” Arnold concluded the poster presentation.¹

For more coverage of ECTRIMS 2021, click here.

REFERENCES
1. Bar-Or A, Pender MP, Hodgkinson SJ, et al. Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosis. Presented at ECTRIMS Congress; October 13-15, 2021; Poster P638.
2. Atara Biotherapeutics Presents New Magnetization Transfer Ratio Imaging Data and Two-Year Clinical Data from the Open Label Extension of ATA188 for Progressive Multiple Sclerosis at ECTRIMS 2021. News release. Atara Bio. October 13, 2021. Accessed October 13, 2021. https://www.businesswire.com/news/home/20211013005398/en/Atara-Biotherapeutics-Presents-New-Magnetization-Transfer-Ratio-Imaging-Data-and-Two-Year-Clinical-Data-from-the-Open-Label-Extension-of-ATA188-for-Progressive-Multiple-Sclerosis-at-ECTRIMS-2021