#ECTRIMS2022 – ATA188 Still Easing Disability in Progressive MS Patients

The investigational immunotherapy ATA188 continues to ease disability and prevent brain tissue shrinkage in people with progressive forms of multiple sclerosis, according to the data, now reaching up to four years, on patients in an ongoing clinical trial.

People who achieved confirmed disability improvement also showed potential signs of remyelination, or the restoration of the protective myelin sheath around nerve cells that is progressively lost in MS.

These latest findings, from the Phase 1 portion of the EMBOLD trial (NCT03283826) and its open-label extension (OLE), could be confirmed in the trial’s randomized and placebo-controlled Phase 2 part, which is ongoing.

Recommended Reading

April 19, 2022 News by Marta Figueiredo, PhD

Atara Planning Phase 3 Trials of ATA188 in Non-active SPMS, PPMS

ATT188 aims to treat MS by targeting B-cells infected by Epstein-Barr virus

Findings were presented by Samantha Noteboom with the MS Center Amsterdam in the poster, “Long-term disability improvement during EBV-targeted T-cell immunotherapy ATA188 is related to brain volume change and normalised magnetisation transfer ratio in T2 lesions.” The presentation took place at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held last week in Amsterdam and virtually.

“New biomarker imaging data presented at ECTRIMS suggest brain structural changes and potential remyelination may underlie clinical disability improvements observed with ATA188 treatment,” AJ Joshi, MD, chief medical officer for Atara Biotherapeutics, which is developing the immunotherapy, said in a company press release.

A growing body of evidence supports the notion that infection with the Epstein-Barr virus (EBV) can be a leading cause of MS. This common virus, which infects about 90%–95% of all adults at some point, typically lives dormant inside B-cells — immune cells responsible for producing antibodies — after the infection.

In a recent landmark study of 801 U.S. military personnel with MS and previous EBV blood tests, Harvard researchers showed that EBV infection preceded disease onset in virtually all these people, and increased the risk of developing the neurodegenerative disease by 32 times.

Weeks later, a published study by Stanford scientists reported that the antibodies produced in the immune system to fight off EBV accidentally attack a structurally similar brain protein, offering a potential mechanistic link between EBV infection and MS autoimmunity.

Notably, data suggest that T-cells, a type of immune cell that normally acts to control B-cells and prevent autoimmunity, may be unable to exert sufficient control over EBV-infected B-cells.

ATA188, infused intravenously (into the bloodstream), consists of  T-cells from healthy donors that have been modified in the lab to specifically target and kill EBV-infected B-cells. This is expected to reduce the inflammation driving MS, and potentially ease disease outcomes.

The EMBOLD Phase 1/2 trial is testing the safety and effectiveness of ATA188 in adults with secondary progressive (SPMS) and primary progressive MS (PPMS).

In the open-label Phase 1 portion, 24 patients received one of four ATA188 doses (5, 10, 20, or 40 million cells) and were followed for one year. The goal was to determine the optimal dose for the Phase 2 portion, or the dose with the best safety profile and the greatest signs of efficacy.

After completing the one-year trial, 18 patients chose to enroll in its long-term extension and be treated with ATA188 for up to an additional four years.

More progressive MS patients now with confirmed disability improvement

Results reported at ECTRIMS 2021, covering about three years of follow-up, showed that nine patients achieved sustained disability improvements (SDI) — defined as an improvement in the Expanded Disability Status Scale (EDSS) score or a 20% improvement in the timed 25-foot walk test. This reduction in disability progression was experienced during the initial trial by seven patients and in the OLE by two patients.

Seven of these nine people now have confirmed disability improvement (CDI), defined as improving EDSS scores recorded at two consecutive visits, while 13 others  — all part of main trial’s 24 patients — have maintained stable EDSS scores. Four patients experienced confirmed disability progression, the latest presentation reported.

As of September — the cut-off date for the data included in the poster presentation — five patients who achieved CDI and were continuing in the OLE had been followed for up to 46.5 months, or almost four years. Notably, all maintained their CDI status, with a median duration of improvement of 27.5 months.

Of the eight people with stable EDSS scores and still in the trial’s OLE, followed for up to 48.5 months, all remained stable. Their median follow-up times was 41.2 months, or about 3.5 years.

“We are pleased to see a majority of patients experiencing either long term durability of CDI based on EDSS improvement or long-term stability in EDSS, which would also represent a transformational profile relative to the expected natural course of the disease,” Joshi said.

Clinical improvements were continuing to be accompanied by beneficial changes observed on MRI scans, trial researchers reported. Over up to 42 months of follow-up, patients who achieved CDI continue to show evidence of lesser brain atrophy than those not with CDI status.

These patients also had higher magnetic transfer ratio (MTR) scores within brain lesions, which may reflect signs of remyelination, according to Atara. A non-significant trend was also observed for increased myelin density in healthy, non-lesioned brain tissue for patients with CDI.

ATA188 was well-tolerated, with no severe side effects or dose-limiting toxicities observed. No cases of cytokine release syndrome or graft-versus-host disease — two potentially serious immune reactions associated with T-cell therapies — were reported.

The researchers noted that “although encouraging,” these findings need to be confirmed in the placebo-controlled Phase 2 portion of EMBOLD. Top-line data from this second trial part are expected next year.

Atara has reported plans to start Phase 3 trials of ATA188 in people with non-active SPMS and non-active PPMS. If positive, results from these trials are expected to support regulatory applications seeking the therapy’s approval.

Note: The Multiple Sclerosis News Today team is providing in-depth coverage of the ECTRIMS Forum 2022 Oct. 26–28. Go here to see the latest stories from the conference.