Background

Infection with Epstein-Barr virus (EBV) is a necessary risk factor for the development of multiple sclerosis (MS) [Abrahamyan S et al. JNNP 2020; Pakpoor J, et al. Mult Scler 2012]. ATA188 – an off-the-shelf, allogeneic EBV-targeted T-cell immunotherapy – is being evaluated in a two-part Phase I, multicenter study in adults with progressive forms of MS (PMS; NCT03283826). Part 1 of the study (open-label, single-arm sequential dose escalation) indicates ATA188 is well tolerated, with a higher proportion of patients (pts) showing sustained disability improvement with increasing dose [Pender MP et al. EAN 2020]. These data need to be confirmed in a well-designed randomized, double-blind, placebo-controlled study (DBPCS).

Objectives

Part 2 is a DBPCS designed to further characterize ATA188 safety/tolerability, product kinetics, as well as to assess the impact of treatment on clinical endpoints and biological markers of MS compared to placebo.

Methods

This trial will utilize an adaptive study design. Potential adaptations include considerations in dose, sample size, and endpoints.

Results

In this DBPCS, 36 pts will be randomized to receive ATA188 or placebo; up to 36 additional pts (72 total) may be added if needed. Based on part 1 results, the first 18 pts in part 2 will be randomized to receive ATA188 Cohort 3 dose (2.0x10⁷cells) or placebo. Different doses of ATA188 may be explored in additional pts. In year 1, pts will receive two treatment cycles, ATA188 or placebo. In year 2, pts in the placebo arm will cross over to receive two cycles of ATA188; pts in the ATA188 arm will receive one cycle of ATA188 followed by one cycle of placebo. Pts completing year 2 will be eligible for a 3-year open-label extension, receiving ATA188 once a year.

Eligible pts are those with a current diagnosis of PMS (primary or secondary), EBV seropositivity, age 18–55 years, and an expanded disability status scale (EDSS) score of 3.0–6.5 at screening. Key exclusion criteria include evidence of clinical relapse or radiological activity within the 2 years prior to screening. Pts in part 1 are not eligible for part 2.

Endpoints include: incidence of adverse events; change from baseline in cerebrospinal fluid (CSF) immunoglobulin G index; change from baseline in clinical disability per EDSS, Timed 25-Foot Walk, and/or 9HPT; ambulatory activity monitoring; cervical spinal cord volume and whole brain volume on magnetic resonance imaging (MRI); the number of gadolinium-enhancing and new or enlarging T2 lesions on brain MRI scans. Exploratory endpoints include assessment of potential biomarkers such as oligoclonal bands in CSF, persistence of ATA188, and cytokine profiling in blood and CSF compartments.

Conclusions

Part 2, the randomized, placebo-controlled portion of this phase 1 study, is now enrolling pts with the objective of evaluating the safety/tolerability, product kinetics and biological and clinical effect of ATA188 on PMS.