Atara Biotherapeutics

Author Of 2 Presentations

Clinical Trials Poster Presentation

P0226 - Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive forms of multiple sclerosis (ID 1635)

Speakers
Presentation Number
P0226
Presentation Topic
Clinical Trials

Abstract

Background

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]. Early experience with autologous EBV-specific T-cell adoptive immunotherapy proved safe and may offer clinical benefit [Pender MP et al. JCI Insight 2018].

Objectives

This Phase I study evaluated the safety and potential efficacy of off-the-shelf, allogeneic EBV-targeted T-cell therapy (ATA188) in adults with progressive forms of MS (NCT03283826).

Methods

In part 1, four cohorts received escalating doses of ATA188 to determine the recommended part 2 dose (RP2D). Patients (pts) were followed for 1-year and given the option to participate in a 4-year open label extension (OLE) at the RP2D (cohort 3 dose). In addition to safety, sustained disability improvement (SDI) was assessed, defined as improvement in Expanded Disability Status Scale (EDSS) or Timed 25-Foot Walk (T25FW) at ≥2 consecutive time points [Pender MP et al. EAN 2020; LB130]. Other measures evaluated include Fatigue Severity Scale (FSS), 12-item MS Walking Scale (MSWS-12), MS Impact Scale-29 (physical; MSIS-29), and whole brain volume (via magnetic resonance imaging [MRI]). As of August 2020, we expect 12-month (m) data for all 4 cohorts, which marks the end of the dose finding portion of this study, will be available for presentation.

Results

As of April 2020, 25 pts had received ≥1 dose of ATA188. No grade >3 events, dose-limiting toxicities, cytokine release syndrome, graft vs host disease, or infusion reactions were observed. Two treatment-emergent serious adverse events were reported: muscle spasticity (grade 2; not treatment related) and MS relapse (grade 3; possibly treatment related). Efficacy endpoints were assessed in cohorts 1–4 (n=24) at 6m and in cohorts 1–3 (n=17) at 12m. Six pts met SDI criteria at 6m and 5 pts met it at 12m, which was driven by EDSS in all but 2 pts at both 6 and 12m. At both timepoints, a higher proportion of pts showed SDI with increasing dose. In cohorts 1–3, all pts with SDI at 6m maintained it through 12m. Pts with SDI (vs those without) tended to have greater improvements in FSS, MSWS-12, and MSIS-29 (physical) scores, as well as less reduction in whole brain volume on MRI, from baseline to 12m. As of June 2020, OLE data from the 15m timepoint were available for 4 pts; 3 had SDI at 6m and 12m which was maintained at 15m.

Conclusions

Preliminary data indicate ATA188 is well tolerated. A higher proportion of pts showed sustained disability improvement (SDI) with increasing dose. Pts who achieved SDI at any timepoint maintained it at all future timepoints and tended to show improvements in fatigue, physical function, and MRI whole brain volume at 12m. Based on these data, part 2 of the study (randomized placebo-controlled portion) has been initiated using the cohort 3 dose.

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Clinical Trials Poster Presentation

P0227 - Phase I, multicenter, two-part study of ATA188, an open-label, dose-escalation and double-blind, placebo-controlled dose-expansion study (ID 1691)

Speakers
Presentation Number
P0227
Presentation Topic
Clinical Trials

Abstract

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.

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