Atara Planning Phase 3 Trials of ATA188 in Non-active SPMS, PPMS
Atara Biotherapeutics plans to launch two Phase 3 clinical trials of its investigational immunotherapy ATA188 in people with non-active, progressive forms of multiple sclerosis (MS).
Whether efforts for these trials will go forward, however, depends on positive results from an interim analysis of the Phase 2 portion of the EMBOLD trial (NCT03283826), expected in the coming months. Interim findings will also inform the optimal size needed for EMBOLD — currently enrolling progressive MS patients at U.S. and Australian sites — to meet its goals.
Atara’s plans for ATA188, along with results from EMBOLD’s Phase 1 part, were detailed in a company investor presentation.
In MS, the body’s immune system wrongly recognizes myelin — the fatty protective sheath around nerve fibers — as foreign, mounting an immune attack against it. This leads to progressive myelin loss and nerve cell death.
While the disease is thought to be caused by a combination of genetic and environmental factors, a growing body of evidence points to Epstein-Barr virus (EBV) infection as its leading cause.
Mostly known for causing infectious mononucleosis, or mono, EBV infects about 95% of the adult population at some point in life. After infection — which can go unnoticed by most people — the virus lingers in the body in a dormant form inside B-cells, a type of immune cell involved in the abnormal immune attacks that drive neurodegeneration in MS.
Notably, compelling evidence of a cause-and-effect relationship between EBV and MS was provided early this year in a study that analyzed more than two decades of data covering over 10 million U.S. military members.
Infection with EBV, but not other viruses, was found to both precede and be necessary for MS development, increasing the risk of the disease by 32 times — the strongest link yet.
A separate study, published just weeks later, showed that this link may be due to structural similarities between an EBV protein and certain brain proteins. While fighting off the virus, antibodies produced by B-cells against EBV may accidentally bind to these proteins in the brain, triggering immune attacks that damage nerve cells.
As such, therapies aiming to clear EBV from the body could help lessen MS symptoms.
Infused directly into the bloodstream, ATA188 is made of T-cells — immune cells with the ability to fight infections and other threats — modified to target and kill EBV-infected B-cells. To be more scalable and efficient, the therapy uses T-cells collected from healthy donors instead of the patients themselves.
ATA188 received fast track designation from the U.S. Food and Drug Administration as a potential treatment of both non-active primary and secondary progressive MS (PPMS and SPMS). This designation is expected to speed the therapy’s clinical development and regulatory review.
The two-part, Phase 1/2 EMBOLD trial is evaluating ATA188’s safety and effectiveness in adults with non-active PPMS and SPMS. Of note, there is currently no approved treatment for people with non-active SPMS.
In its Phase 1 part, 24 patients were given one of four escalating doses of ATA188 and followed for one year to determine the best dose for further testing in the study’s placebo-controlled Phase 2 part.
Among those completing the one-year assessment, 18 chose to enroll in its open-label extension (OLE) phase, in which they are receiving one ATA188 infusion every year for up to four years.
Previously reported results showed a dose-response effect for ATA188, with patients given the two highest doses (20 and 40 million T-cells) being more likely to achieve clinical improvements at one year.
Notably, these improvements were associated with a significant increase in magnetization transfer ratio (MTR) — an MRI biomarker considered to reflect myelin density — indicating fewer lesions and potential remyelination, or myelin repair.
Newly presented data, concerning up to 3.5 years of follow-up, indicated that 20 (83.3%) of the 24 patients experienced a sustained stabilization (13 patients) or improvement (seven patients) meaning a lessening in their functional disability, as assessed with the Expanded Disability Status Scale (EDSS).
Some of these improvements reflected the return of previously lost functions, such as the ability to walk unaided or for longer distances, suggesting a reversal of disease progression, Atara reported.
The therapy was found to be generally safe and well-tolerated across all doses.
Up to 80 PPMS and SPMS patients with evidence of past or current EBV infection are currently being enrolled in EMBOLD’s Phase 2 part. They will be randomly assigned to two cycles of either the optimal dose of ATA188 or a placebo.
After one year of follow-up, patients in the placebo group will receive two cycles of ATA188, while those originally assigned to the therapy will be given one cycle of the therapy and one cycle of placebo, according to the trial’s NCT document.
After these two years, Phase 2 participants may choose to enroll in an open-label extension study, and be treated once a year for up to three years.
Atara now plans to conduct a formal interim analysis of both safety and efficacy data, with the main goal being reductions in the EDSS scores, indicating less disability, at six months. The company noted Phase 1 trial data suggested that EDSS reductions at six months strongly predict sustained improvements at one year.
Other efficacy measures and biomarkers, such as MTR, will also be analyzed.
Interim results will be used to determine the number of trial participants needed to achieve enough statistical power to detect significant differences between ATA188 and a placebo. While Atara expects to meet the target enrollment of 80 patients soon after the interim analysis, findings may indicate a need to enroll more patients.
These data will also help to inform the design of two parallel, global Phase 3 trials: one in people with non-active PPMS and another in non-active PPMS patients. If positive, results from these trials are expected to support future submissions of regulatory applications seeking the therapy’s approval.
Atara is also planning Phase 2 trials of ATA188 in other MS patient populations, including clinically isolated syndrome, relapsing-remitting MS, and active progressive MS.
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