The phase 1a multicenter, open-label study of ATA188 in patients with progressive forms of MS was designed to establish safety and tolerability, to select the recommended dose for the randomized placebo-controlled Phase 1b study, and to assess potential efficacy. Patients were treated across four dose-escalating cohorts (5 x 10, 1 x 10, 2 x 10 and 4 x 10 cells), with six patients each in cohorts 1-3 and seven patients in cohort 4.
Patients in the study were assessed on MS-focused clinical measures at three-, six- and 12-month time points. Composite scales of clinical outcome and of sustained disability improvement (SDI) were evaluated in patients receiving all six doses of ATA188, which includes cohorts 1-4 at six months (n=24) and cohorts 1-3 at 12 months (n=17). Sustained Disability Improvement is defined as clinically significant improvement in Expanded Disability Status Scale (EDSS) or timed 25-foot walk (T25FW) observed on two consecutive time points.
The study found that across the four dose cohorts, ATA188 was well-tolerated in patients with progressive forms of MS. No dose-limiting toxicities and no fatal adverse events (AEs) have been reported. Rhinorrhea (runny nose) is the only treatment-related event that occurred in more than one subject. No dose-related safety trends were identified across cohorts. Additionally, ATA188 infusion shows no clinically meaningful effect on cytokine levels post-infusion.
All patients in cohorts 1-3 of this Phase 1 study showing SDI at six months, maintained improvement through 12 months. For a patient to achieve SDI, it was required that they have sustained improvement on a composite of clinically significant improvement in EDSS or T25FW, confirmed at consecutive time points. This means that to achieve SDI at six months, there had to be disability improvement at three months that was confirmed at six months, and to achieve SDI at 12 months, there had to be disability improvement at six months that was confirmed at 12 months. Additionally, a dose-related increase in the number of patients with SDI was observed.
Cohorts 1 and 2 each had one patient with SDI at 6 months while Cohorts 3 and 4 each had two patients with SDI at 6 months. All patients in Cohorts 1-3 with SDI at six months, maintained SDI at 12 months (Cohort 4 patients have not yet reached the 12-month time point). Of note, in Cohort 3, a third patient had SDI at 12 months. EDSS was the main driver of SDI.
A dose-related trend of a higher proportion of patients showing favorable clinical improvement through a second composite scale, designed to detect early signals of efficacy, was also observed. The second composite scale is an a priori classification of patient outcomes incorporating seven clinically recognized scales for MS symptoms, function, and disability. Both composite scales suggest a potential therapeutic response of ATA188 in the treatment of progressive forms of MS.
Based on these results, the cohort 3 dose was selected for the randomized, placebo-controlled Phase 1b study. Atara has now advanced into the Phase 1b double-blind randomized placebo-controlled study, which has resumed enrollment activities after a brief redacted-related pause. In addition to measuring disability progression, the study will also evaluate many facets of the disease, including: cognition and outpatient ambulatory activity; fatigue, and biological end points in blood and cerebrospinal fluid/CSF (IgG, synthesis and index, OCBs, product kinetics); and MRI imaging.
In addition to the clinical data reported at EAN, preclinical translational data published online at the 2020 Academy of Neurology (AAN) 72nd Annual Meeting further support the proposed mechanism of action of ATA188 targeting EBV-infected B cells. These combined analyses of T cells comprising ATA188 are consistent with its proposed mechanism of targeting EBV-infected B cells by recognizing MS-relevant EBV antigens on these cells via defined T-cell receptors (TCRs).