ATA188 for multiple sclerosis
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What is ATA188 for MS?
ATA188 is a cell-based therapy that’s being investigated as a potential disease-modifying treatment for progressive forms of multiple sclerosis (MS). It aims to treat MS forms such as nonactive primary progressive MS (PPMS) and nonactive secondary progressive MSÂ (SPMS).
The treatment earned fast-track designation from the U.S. Food and Drug Administration in 2022 for these two indications, which is expected to accelerate its development via more frequent meetings with the regulatory agency.
It is being developed by Atara Biotherapeutics, which also announced plans to test ATA188 in relapsing forms of MS and potentially in other autoimmune diseases.
Therapy snapshot
| Treatment name: | ATA188 |
| Administration: | Tested in MS in infusion formulation |
| Clinical testing: | Previously tested in a Phase 2 trial in nonactive PPMS and SPMS; two Phase 3 trials upcoming |
How does ATA188 work in MS?
MS is a neurodegenerative disorder characterized by the immune system mistakenly attacking the myelin sheath, a protective coating that surrounds nerve fibers. Without this protective sheath, nerve cells cannot send electrical signals as efficiently, leading to a range of symptoms.
The Epstein-Barr virus (EBV) has emerged as a leading cause of MS, with a prior infection preceding virtually all cases of the neurodegenerative disease. A common virus, EBV is mostly known for causing infectious mononucleosis, or mono, but most infections don’t cause any symptoms.
The mechanisms underlying the link between EBV and MS are still being worked out, but one possibility is that the body’s immune system mistakes the virus with a protein found in the brain. This is believed to spark an erroneous attack against it, causing damage to the nervous system.
After the active infection, the virus lives in a latent state inside B-cells, the immune cells that produce antibodies. It’s kept in check by other components of the immune system, such as T-cells. However, T-cells from MS patients seem to be less able to prevent EBV reactivation.
ATA188 is a cell-based therapy designed to destroy EBV-infected B-cells in MS patients, which then would potentially slow or halt disease progression.
It is made of immune T-cells obtained from healthy donors who have previously been infected with EBV. It specifically includes a population of T-cells primed to recognize certain EBV proteins, which are able to launch an immune attack against infected cells.
The specificity of the treatment for EBV-infected cells suggests ATA188 may be safer than genetically modified T-cell therapies, which often are associated with severe side effects.
How will ATA188 be administered in MS?
ATA188 is an off-the-shelf therapy administered via intravenous (into-the-vein) infusions typically lasting 5–10 minutes. In MS clinical trials, the treatment has been tested at doses ranging from 5–40 million T-cells; the 20-million dose was deemed optimal for further testing.
The therapy was administered in two cycles, each consisting of three weekly infusions followed by 20 days of follow-up. Participants then received yearly injections for up to four years.
ATA188 in MS clinical trials
Phase 1 trial of ATA190
Atara conducted an initial Phase 1 clinical trial (ACTRN12615000422527) in Australia to test its autologous immunotherapy ATA190 in people with PPMS and SPMS. The product was similar to ATA188, but the cells used were collected from patients rather than healthy volunteers.
A total of 10 individuals received the full course of treatment, consisting of four escalating doses. The doses started with 5 million cells, then 10 million, 15 million, and 20 million cells, each given one week apart.
The treatment was well-tolerated and led to improvements in neurological function and quality of life. Participants also saw a reduction in fatigue and other symptoms, and fewer self-reactive antibodies were found in their spinal fluid. Three patients also experienced a lessening in disability, defined as a reduction in Expanded Disability Status Scale (EDSS) scores.
The findings helped establish EBV as a promising target for treating progressive forms of MS. But after promising data from ATA188 were released, the company decided to deprioritize the development of ATA190 and focus its efforts on the donor-derived product.
EMBOLD Phase 1 part
ATA188 is being investigated in the ongoing Phase 1/2 EMBOLD trial (NCT03283826), which enrolled adults with nonactive PPMS and nonactive SPMS at sites in the U.S., Australia, and Canada.
In EMBOLD’s first part, a total of 24 participants received one of four ATA188 doses — 5 million, 10 million, 20 million, or 40 million cells — given in two treatment cycles. The goal was to determine the optimal dose for the Phase 2 portion. That would be 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 a long-term extension part, in which all are receiving annual treatment with the 20 million dose for up to four years.
Data spanning EMBOLD and its extension showed that nine of 24 participants achieved a sustained disability improvement, defined as an improvement in EDSS scores or a 20% reduction in the time needed to walk 25 feet, recorded in at least two consecutive study visits.
Seven patients experienced EDSS improvements confirmed at two visits in a row — called a confirmed disability improvement or CDI — and another 13 people had stable EDSS scores. The remaining four participants experienced confirmed disability progression.
After nearly four years of follow-up, the five people with CDI who remained in the trial were found to have maintained their improvements for all subsequent clinic visits. Meanwhile, the eight people with stable EDSS who were still in the trial remained at that status quo.
Participants who achieved CDI after one year also had evidence of reduced brain atrophy and signs of remyelination (a restoration of the lost myelin sheath) compared with those who failed to achieve CDI.
Ongoing EMBOLD Phase 2 part
EMBOLD’s ongoing Phase 2 part is now investigating ATA188 in 80 patients with nonactive PPMS and SPMS who had contracted EBV.
Participants were randomly assigned to receive ATA188 or a placebo for one year, after which patients in the placebo group will receive two cycles of ATA188. Those originally assigned to the therapy will be given one cycle of the therapy and one cycle of the placebo.
Those who complete the two years of treatment will enter an open-label extension portion and receive ATA188 for up to three more years.
Results from the Phase 2 portion are expected in late 2023. According to the company, data from the first 34 participants with six months of follow-up, and the first 15 who were followed for one year were not yet sufficient to to draw conclusions about ATA188’s benefits.
Atara also has announced plans to start two parallel Phase 3 trials that are expected to support regulatory applications seeking ATA188’s approval. One trial will involve people with nonactive PPMS while the other will enroll nonactive SPMS patients.
Common side effects of ATA188
ATA188 has been well-tolerated in MS clinical trials, with no safety concerns identified. Runny nose was the only treatment-related side effect reported in more than one person.
No cases of cytokine release syndrome or graft versus host disease, two serious immune responses that are sometimes observed with T-cell therapies, have been observed with ATA188.
Multiple Sclerosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about ATA188 in MS
ATA188 was an investigational therapy for multiple sclerosis (MS) whose development was stopped. The therapy was designed to kill immune B-cells infected with the Epstein-Barr virus (EBV), a leading risk factor of MS. This was expected to slow or even halt MS progression, but clinical findings failed to support that idea.
ATA188 failed to show significant benefits over a placebo in a Phase 2 clinical trial involving people with nonactive progressive forms of multiple sclerosis (MS). For that reason, its development was discontinued, and it’s very unlikely that the therapy will ever be approved by the U.S. Food and Drug Administration for MS.
Clinical trials of ATA188 excluded patients who were pregnant or breastfeeding, so it was not known if the treatment could be safely used during pregnancy.
Multiple sclerosis can manifest differently in each patient, so individual responses to treatment may vary. In a Phase 1 clinical trial, disability improvements were evident in some patients as early as six months [here, here] after starting ATA188 treatment, but no benefits were observed in the subsequent Phase 2 trial.
Neither hair loss nor weight gain were reported as ATA188 side effects in multiple sclerosis clinical trials. Patients who experience these or other unexpected reactions to any medication should speak with their healthcare team.
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