#ECTRIMS2022 – ATA188 Could Be ‘Game Changing’ for Progressive MS

In an early clinical trial, Atara Biotherapeutics’ investigational treatment ATA188 stabilized or eased disability in most people with nonactive, progressive forms of multiple sclerosis (MS) — with those benefits now having been sustained for up to four years.

For MS patients, in whom disability progressively accumulates over time, and for whom few disease-modifying therapies (DMTs) exist, such a treatment could be transformative, AJ Joshi, MD, chief medical officer at Atara, said in an interview with Multiple Sclerosis News Today.

“What we’re looking at is a very transformational benefit,” Joshi said. “If we can actually reverse disability progression in these nonactive patients, that’s really … a game-changing opportunity for patients.”

The treatment’s benefits were observed in the Phase 1 portion of the ongoing EMBOLD Phase 1/2 clinical trial (NCT03283826) and its open-label extension (OLE) study, which enrolled patients with nonactive secondary progressive MS (SPMS) and nonactive primary progressive MS (PPMS).

In the initial trial, a total of 24 patients received ATA188 at doses ranging from 5–40 million cells. ATA188 was administered in two cycles of treatment, each comprised of three intravenous (into-the-vein) infusions given one week apart. 

Participants were monitored for one year following the first infusion, after which 18 patients chose to enroll in the open label extension part. Those patients are continuing to receive ATA188 for up to four years.

‘Extremely uncommon’ disability improvements

Data spanning EMBOLD and the OLE demonstrated that nine of the overall 24 patients achieved sustained disability improvement. This was defined as an improvement in Expanded Disability Status Scale (EDSS) scores or a 20% reduction in the time needed to walk 25 feet — a common test of motor function — recorded in at least two consecutive visits.

EDSS is a scale ranging from 0 to 10 that is commonly used by clinicians to monitor changes in disability among MS patients, with higher scores reflecting more significant disability.

Seven of the patients in this group achieved a clinical outcome called confirmed disability improvement (CDI), defined as improving EDSS scores confirmed at two visits in a row. Another 13 people had stable EDSS scores, meaning no improvement and no progression. The other four experienced confirmed disability progression, or an accumulation of disability.

After up to four years of follow-up, the five patients with CDI who remain in the OLE have maintained their improvements for all subsequent clinic visits, with a median duration of improvement of 27.5 months (or more than two years).

The eight participants with stable EDSS scores still in the OLE also have remained stable for a median of 41.2 months (more than three years). At least one patient experienced disease stabilization for up to 48.5 months — a little over four years.

In EMBOLD, an improvement in EDSS was found when scores lowered at least one point for patients with scores of 3 to 5 at the study’s start, and at least 0.5 points for individuals with EDSS scores of 5.5 to 7.

For people with progressive MS, “an improvement, even a small improvement of half a point or a full point, really means a lot to a patient,” Bridget Bagert, MD, director of the Ochsner Multiple Sclerosis Center, said in the interview.

“For example, EDSS of 6 means a patient can walk a football field (100 meters) with a cane. … They can do it, but not without some sort of unilateral assist in their hand,” Bagert said. “An improvement [to] EDSS of 5.5 means they can do it without the cane.”

“For an individual who is living with multiple sclerosis, that’s huge,” Bagert said. “To put the cane down, to be able to go out, go to the mall, go shopping, or even go to their kid’s football game without a cane. … That’s big stuff, right?”

Function goes up as scores go down, Bagert said.

“If you go further down [to EDSS] 5, it would be two football fields without a cane. These are really very, very significant changes, as you can imagine,” she said.

In the EMBOLD trial, one of the most striking improvements was observed in a progressive MS patient who initially had an EDSS score of 5.5. Just three months after treatment, that patient reached an EDSS score of 3.5, which further dropped to an EDSS of 3 — meaning moderate disability and no difficulty walking — at 30 months of follow-up.

Two additional patients with disability improvement had an EDSS score of 6 at study start and experienced score reductions to 4.5 within about two years of follow-up.

Achieving these gains for a sustained period of time is “extremely uncommon” in this patient group, according to Bagert.

“We don’t see that commonly at all in patients with progressive forms of MS,” she said.

According to Joshi, EMBOLD recruited people with nonactive, progressive forms of MS precisely because those are the patients who could benefit the most from disability improvements.

“The biggest unmet need area is actually addressing disability for patients who have nonactive disease,” Joshi said. But he noted that, even among the therapies available for active disease, “very few have even tried to address disability, and those that do have a modest at best impact on slowing progression.”

To date, Ocrevus (ocrelizumab) remains the only approved treatment for PPMS, and mitoxantrone the only therapy available for nonactive SPMS. But trial results from EMBOLD are looking quite different compared with what was seen for these therapies, the researchers say.

For example, in the ORATORIO Phase 3 trial (NCT01194570), Ocrevus significantly outperformed a placebo at slowing disability progression in people with active and nonactive PPMS. “But everybody was getting worse,” Bagert said.

“That’s the significant difference,” she said. “In [EMBOLD] we have a big chunk of patients who improved and sustained it … and another group that stayed stable, which is also notable.”

The researchers caution that these are still early data for ATA188, and that Phase 3 trials are needed to confirm the findings. However, Bagert noted that this sustained improvement has “never really [been] seen … in progressive MS trials.”

“I hope we’ll continue to see it in the future trials for the sake of our patients,” she added.

In addition to the clinical benefits, patients in EMBOLD who achieved confirmed disability improvement showed evidence of increased magnetization transfer ratios (MTR) on MRI scans.

“MTR is considered to be a measurement of myelin density,” Joshi said. That means that patients with higher MTR scores could be experiencing remyelination, or the repair of the myelin sheath that’s progressively lost in MS.

While EDSS scores are a good indicator of improvements, there is always some subjectivity in such clinical assessments, he noted. “That’s where MTR begins to come in,” as MRI findings like MTR provide the biological basis for the clinical findings and are a good way to support that something’s actually changing for these patients.

How does ATA188 work?

ATA188 was developed based on the increasingly well-established link between MS and the Epstein-Barr virus (EBV), one of the most common viruses in the world.

EBV, as Epstein-Barr is called, lives in a latent state inside B-cells, the immune cells responsible for producing antibodies. To prevent its reactivation, the virus is kept in check by other components of the immune system, namely T-cells, which become programmed to recognize and fight off EBV during the initial infection.

“For most of us who’ve already been infected with EBV, our T-cells completely control the EBV infection. But for an MS patient, T-cells aren’t able to control it,” Joshi said.

ATA188 is comprised of T-cells collected from healthy donors who have been previously infected with EBV. It specifically includes a population of T-cells primed to attack certain proteins found only on EBV-infected cells.

Essentially, the therapy generates “a large population of cells that can eliminate those EBV infected B-cells that have those very specific EBV proteins,” Joshi said. And importantly, “ATA188 is not genetically modified in any way.”

The specificity of the treatment for the infected cells also means ATA188 may be safer than other, genetically modified T-cell therapies, which often are associated with severe side effects.

With some of these modified therapies, intensive care units are ready to receive the patient in case of life-threatening side effects, and patients need to stay close to the facility for about a month in case any adverse events develop later on, Joshi explained.

But with ATA188, after a 5–10 minute into-the-vein infusion, patients remain in the facility to monitor “the vital stats for a couple of hours and they go home. So it’s a very different profile because it’s not genetically engineered,” he said.

And in fact, the potentially serious immune side effects that are commonly seen with modified T-cell therapies — including cytokine release syndrome, seizures, and neurological side effects — have not been observed in the EMBOLD trial.

Future of EBV-targeted therapies

As EMBOLD was progressing, two landmark studies emerged earlier this year, further strengthening the link between EBV and MS. In the first, researchers identified a prior EBV infection in nearly all people who later developed MS, demonstrating that the virus raises the risk of the neurodegenerative disease by about 32 times.

Weeks later, another study found that a process called molecular mimicry — in which the body’s immune system mistakes a protein expressed in the brain with the virus, and erroneously attacks it — could underlie the relationship.

With the emergence of these research studies, both Joshi and Bagert agree the interest in developing EBV-targeted therapies for MS has grown. And, they say, these therapies could become part of MS treatment regimens in years to come.

There has been a “tremendous amount of excitement,” Bagert said. “Understanding EBV to be at the root of MS is definitely going to change where future investments are targeted and future therapeutic developments, especially in progressive MS.”

While no vaccine is yet approved for preventing EBV altogether, clinical trials conducted by the National Institutes of Health and others are underway. These trials “will be very interesting,” according to Bagert, as they may help understand if MS can be prevented by targeting EBV.

As for the development of ATA188 itself, Joshi said it hasn’t necessarily changed in response to these emerging EBV studies — though the attitude around it has.

“I wouldn’t say [the development] has changed because obviously we’ve been out on the forefront of this for several years with this program,” Joshi said. “The main things that are different is there’s been more momentum, more excitement around it, both in the patient community and the physician community.”

As an example, Joshi noted that some companies have been setting up specific divisions “to try to understand how they want to tackle EBV and MS,” he said. “So that entire momentum is really … the biggest difference in the way we look at our program.”

Joshi also explained that EBV-targeted therapies are particularly exciting because they may be effective for patients with all forms of the disease, even when these treatments aren’t started early in the disease course.

“We are focused in on the later stage patients because I don’t think you can forget about them either. These are the people who actually have the disease and who need it the most,” Joshi said. “What’s unique is that these EBV directed therapies may be able to hit it all.”

Thus, although EMBOLD’s findings support ATA188’s development for nonactive progressive MS patients, the company expects the treatment to be similarly effective for individuals with active, relapsing forms of the disease.

“If you think about the pathology of MS, whether it’s active disease or progressive disease, much of it is still driven by the autoimmune cascade that’s caused by some of those EBV infected cells,” Joshi said. “So we would expect [ATA188] to be able to impact both [relapsing and progressive forms of the disease] in a very positive fashion.”

“It is definitely part of the development program” to test ATA188 in relapsing forms of MS, Joshi added.

Meanwhile, Atara is moving forward with ATA188’s development for progressive MS patients.

If we can actually reverse disability progression in these nonactive patients, that’s really … a game-changing opportunity for patients.

Earlier this year, ATA188 earned fast-track designation from the U.S. Food and Drug Administration (FDA) for nonactive SPMS and nonactive PPMS, which aims to speed the clinical development of much-needed treatments for indications like these toward regulatory approval.

While awaiting top-line data from EMBOLD’s Phase 2 portion — which is evaluating ATA188 against a placebo in nonactive progressive forms of MS — the company plans to continue interacting with the FDA under the fast track status to prepare two upcoming Phase 3 trials. One is planned for nonactive SPMS and one for nonactive PPMS patients.

Results from EMBOLD are expected in late 2023 and will continue to inform the development program of ATA188. Atara also is looking to establish partnerships that help advance ATA188 into larger trials and additional indications.

“We’ve had lots of conversations with potential partners as we try to move the program forward, because as you might imagine, as we think about further studies, and eventually Phase 3 trials and other expanded indications and things like relapsing disease — that’s a lot for a small company to handle,” Joshi said.

When asked how he envisions EBV-targeted therapies fitting into the MS treatment landscape in the next 10 years, Joshi said: “I would anticipate, assuming these data continue to come out well, that EBV directed therapies, including ours, would become foundational.”

“We already do some combination therapy today in MS,” Joshi said. “I wouldn’t be surprised [if] eight to 10 years from now … that becomes the de facto standard. And how you mix and match, that’s going to be the interesting part as we all learn together and get more and more information and try to work things out.”

Bagert agrees that combinations of EBV directed therapies with other DMTs could be the future in MS treatment, but also noted there are “very important questions that still need to be sorted.” Namely, a better understanding of the mechanism by which EBV could be leading to MS could greatly influence future directions, she explained.

“So there’s still a lot of research to be done and a lot of exciting areas to to explore,” she said.