ATA188, Atara Biotherapeutics’ investigative T-cell immunotherapy, is safe, well tolerated, and able to ease disability and improve exercise capacity in patients with progressive forms of multiple sclerosis (MS), according to one-year data from a Phase 1 trial and its long-term extension study.
Findings also showed that, after one year, patients experiencing lesser disability were also more likely to feel less fatigued and have better physical function, and to show greater brain volume assessed by MRI.
According to a press release, one-year trial data and updated findings from its extension study, as well as additional findings on ATA188’s mechanism of action will be presented in several e-posters during the MSVirtual2020 meeting set for Sept. 11–13.
ATA188, a cell-based therapy, is designed to counter the harmful effects of Epstein-Barr virus (EBV). This common type of herpes virus is thought to cause immune B-cells to go awry and start producing antibodies that wrongly attack the myelin sheath that protects nerve endings, causing MS.
To counter this, ATA188 uses called T-cells, an immune cell that normally defends the body from viruses and bacteria, to specifically destroy EBV-infected B-cells. Instead of being isolated from each MS patient, T-cells used in ATA188 are obtained from healthy donors (off-the-shelf therapy), and modified to target and kill infected B-cells.
The safety, tolerability, and preliminary efficacy of ATA188 are currently being investigated in a two-part Phase 1 trial (NCT03283826) enrolling adults with primary and secondary progressive MS (PPMS and SPMS).
During the study’s first part, 25 patients were assigned to one of four intravenous doses of ATA188 containing either 5, 10, 20, or 40 million modified T-cells to assess dose which could be the most effective and safest for future studies.
In addition to safety and tolerability, investigators also evaluated patients’ ability to reach sustained disability improvement (SDI) in this part of the study. To attain SDI, patients must have had improvements in their expanded disability status scale (EDSS) scores or in their timed 25-foot walk (T25W) test at two or more consecutive time-points during the trial (three, six, and 12 months).
Earlier data from this first part showed ATA188 was safe and well tolerated at all four dose levels, and not associated with cases of cytokine release syndrome (overactivation of the immune system) or graft versus host disease (in which transplanted T-cells start attacking patients’ healthy cells).
Investigators also found that six of the 25 patients dosed in this first part attained SDI at six months post-treatment — one on the 5 million dose, one on the 10 million dose, two on the 20 million dose, and two on the 40 million dose — meaning they met both EDSS and T25W criteria at three and six months. Four on the lower doses maintained SDI at 12 months, and one at the 20 million dose reached SDI at the one-year mark.
However, at the time of these analyses, one-year data on those treated at the highest ATA188 dose were not yet available.
In one of the e-posters (#P0226) to be presented at MSVirtual2020, “Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive forms of multiple sclerosis,” the company will present for one-year data from all dose groups.
These results confirm that six patients met SDI criteria at six months, and that five met it at 12 months. Data also showed that those who achieved SDI were more likely to experience less fatigue, and have better physical function and greater brain volume than those who did not reach SDI after one year.
After completing this part’s one year of treatment, patients were invited to enroll in a long-term extension study to continue treatment for an additional four years.
Data covering 15 months of follow-up (through June 2020) were available for four patients. Three had achieved SDI at six and 12 months, and all maintained it at month 15. Further trial data will be presented at the meeting.
Based on the results so far, ATA188 at its second highest dose (20 million cells) will be used for the trial’s second part. Here, patients will be randomly assigned to intravenous infusions of either the experimental cell-based therapy or a placebo.
For its second part, the Phase 1 trial is enrolling eligible progressive MS patients (with evidence of past, or possibly current, EBV infection) at sites in the U.S. and Australia; information is available here.
In another e-poster (#P0227) — “Phase I, multicenter, two-part study of ATA188, an open-label, dose-escalation and double-blind, placebo-controlled dose-expansion study” — the company shares details of the design of this second part of the study, which has already started enrolling participants.
According to Atara, the trial has an adaptive design, allowing investigators to make changes thought helpful to the study’s sample size, treatment doses, and clinical endpoints.
To start, 36 patients will be randomly divided between the treatment and placebo groups. This may be extended to another 36, for a total of 72 participants, if needed. Those who participated in the study’s first part are not be eligible for this second part.
Over the first year, patients will receive two treatment cycles of either ATA188 or a placebo. In the second year, those originally assigned to the placebo group will switch and receive two cycles of ATA188, while those originally given the investigative therapy will now get one cycle of ATA188 followed by a placebo cycle.
Those completing these two study years will have the option to continue treatment with ATA188 for another year in an open-label extension study.
The main goals of this second trial portion include continuing to evaluate ATA188’s safety and tolerability, its effects on EDSS and T25FW scores, and on the immunoglobulin G (IgG) index — a measure of immune system health. Treatment effects on several neurological parameters assessed by MRI, including brain volume and the presence of new or enlarging MS lesions, will also be evaluated.
In a third e-poster (#P0084) — “Gene expression profiling and TCR diversity of ATA188, an off-the-shelf, allogeneic EBV-targeted T-cell immunotherapy for progressive MS” — the company will present new data on ATA188’s mechanism of action.
Using a series of molecular and genetic assays, investigators analyzed the genetic signature of the modified T-cells making up ATA188. They discovered that, despite being obtained from different donors, the set of genes switched on or off in these cells were identical.
They also discovered these cells became active in response to EBV-specific antigens (molecules that can trigger an immune response), switching on a series of signaling pathways that enabled them to target and destroy other cells containing these antigens.
“These data are consistent with the proposed mechanism of action of ATA188 targeting EBV infected B cells by recognizing EBV antigens,” the researchers wrote in the abstract.
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