Atara Biotherapeutics‘ cell-based therapy ATA188 is safe and well-tolerated in people with progressive forms of multiple sclerosis (MS), and induces a sustained reduction in disability in a dose-dependent manner, findings from the first part of a Phase 1 clinical trial show.
ATA188 had an acceptable safety and tolerability profile across all four doses tested. But more people on higher doses experienced sustained decreases in disability, and researchers chose the 20 million dose (the second highest dose) for further testing in this trial’s second part.
Patient enrollment for this randomized, placebo-controlled part two is again underway at sites in the U.S. and Australia after a temporary pause in response to the COVID-19 pandemic, the company said in a press release.
The new data were presented at the 2020 European Academy of Neurology (EAN) Congress — which was held virtually due to the pandemic — in the poster “Phase 1 study of the safety and efficacy of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy to treat progressive forms of multiple sclerosis” (EAN registration is needed to access the presentations).
Infection with the Epstein-Barr virus (EBV, a common form of the herpes virus) is increasingly seen as a possible cause of MS, leading B-cells to go rogue and produce antibodies that wrongly attack the protective myelin coating of nerve cells.
ATA188 is designed to help patients get rid of these damaging B-cells, by providing them with T-cells (immune cells with the ability to fight threats) that have been modified to eliminate EBV-infected cells.
The ongoing Phase 1a/1b trial (NCT03283826) is assessing the safety and effectiveness of ATA188 in a near equal mix of patients with either primary progressive MS (PPMS) or secondary progressive disease (SPMS).
It is being conducted in two parts. First, 25 patients were given one of four ATA188 doses — 5 million (5 x 106), 10 million (1 x 107), 20 million (2 x 107), or 40 million (4 x 107) cells — to determine the safest and most effective dose for future testing. The first three dose groups had six patients; in the fourth group, seven patients received the 40 million dose.
Treatment was administered in two cycles, with three ATA188 injections each, with patients evaluated after treatment initiation at three, six, and 12 months. These people could then enter an extension part of the trial, and receive once-a-year ATA188 intravenous (IV) injections for up to four years.
Part one’s main goal was to assess treatment safety and tolerability. Secondary measures include changes in disability scores, assessed with the expanded disability status scale (EDSS) and timed 25 foot walk (T25FW; time taken to safely walk 25 feet).
Results here showed that the treatment was safe and well-tolerated across all four dose groups, with runny nose being the only treatment-related side effect reported in more than one person.
There was no evidence of cytokine release syndrome (a systemic inflammatory response), graft versus host disease (a complication in which healthy cells are attacked by transplanted T-cells), or dose-limiting toxicities.
Potential treatment efficacy was assessed using a composite measure of sustained disability improvement (SDI), defined as clinically significant improvements in either EDSS or T25FW scores. These improvements had to be sustained, meaning that patients needed to show improvements at two consecutive time points.
In other words, a patient had SDI at six months if improvement in disability scores was seen at three months and confirmed at six months. For SDI at one year, patients had to show improvements at month six and confirm them at the 12-month evaluation.
Researchers found that one patient on the 5 million dose, one on the 10 million dose, and two patients on the 20 million dose group achieved SDI at six months, and that all maintained those improvements at one year. A third patient on the 20 million cells per dose also achieved SDI at 12 months.
Two patients on the highest 40 million dose also reached SDI at six months, but 12-month assessments are not yet complete in this group.
Most patients achieved SDI due to clinical improvements in EDSS, researchers reported.
An additional outcome measure, based on several validated MS scales, was used to help categorize outcomes on a range from clinical decline to clinical improvement. Those patients who achieved durable clinical improvements on SDI measures also experienced a clinical improvement using this outcome measure.
With dose increases, more patients again showed clinical improvements on this scale, and fewer of them experienced clinical decline.
“The approach of targeting EBV-infected B cells has led to very encouraging preliminary results, as ATA188 proved to be safe and well-tolerated across all four dose cohorts in this Phase 1a study,” Lawrence Steinman, MD, a professor at Stanford University, said in the release.
“These results, along with the observed trend in sustained disability improvements seen at six months and maintained at 12 months, highlight the opportunity to advance into the randomized placebo-controlled study of ATA188 for the treatment of patients with progressive MS,” Steinman added.
Researchers are now testing the recommended 20 million dose in the trial’s second part, which will randomly assign a new group of adults with progressive MS to ATA188 or a placebo.
Treatment goals here are to continue studying safety and effectiveness, and to establish ATA188’s superiority over a placebo in a number of measures, including disability progression, cognition, fatigue, changes on MRI scans, and biological factors.
“If these data are confirmed in a double-blind, placebo-controlled, randomized study, we could see an evolution in the treatment paradigm for progressive MS and other forms of this debilitating disease,” Steinman said.
“We look forward to the continued study of ATA188 in progressive MS, and believe our novel therapeutic approach targeting the EBV-infected B cell as a propagator of autoimmunity may help patients with other forms of MS,” said AJ Joshi, MD, senior vice president and chief medical officer of Atara Biotherapeutics.
Among other disorders being also considered are “autoimmune conditions where EBV has been implicated, including lupus, rheumatoid arthritis, and Sjögren’s syndrome,” Joshi added.
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