Experimental therapy against EBV performs well

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frodo
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Experimental therapy against EBV performs well

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Atara Biotherapeutics Announces All Progressive Multiple Sclerosis Patients with Sustained Disability Improvement at Six Months Confirmed Improvement at 12 Months in the Phase 1a Study of ATA188

https://www.wallstreet-online.de/nachri ... ata188/all

Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a pioneer in T-cell immunotherapy leveraging its novel allogeneic EBV T-cell platform to develop treatments for patients with severe diseases, including solid tumors, hematologic cancers and autoimmune disease, today announced the presentation of data from the first part of the ongoing Phase 1 study of ATA188 for the treatment of progressive forms of multiple sclerosis (MS). ATA188 is an off-the-shelf, allogeneic EBV-specific T-cell immunotherapy. These data demonstrate that ATA188 was well-tolerated across all four dose cohorts; patients who achieved sustained disability improvements at any timepoint maintained it at all future timepoints and a higher proportion of patients showed sustained disability improvements (SDI) with increasing dose. The results are featured in an e-poster at MSVirtual2020: 8th Joint ACTRIMS-ECTRIMS Meeting, held September 11-13, 2020.

“It is very encouraging to see that patients receiving ATA188 who achieved sustained disability improvement at any time point maintained it at all future time points and tended to also show improvements in fatigue and physical function at 12 months,” said Jakob Dupont, Global Head, Research and Development. “These results together with a favorable safety profile highlight the potential of ATA188 for patients with progressive MS and reinforce our excitement around advancing the randomized placebo-controlled portion of the study which is currently enrolling.”
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Re: Experimental therapy against EBV performs well

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They have a recruiting study of ATA188 in progressive MS on clinicaltrials.gov.

https://clinicaltrials.gov/ct2/show/NCT03283826
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Re: Experimental therapy against EBV performs well

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Here's a presentation on ATA188 from ECTRIMS 2020.

https://d1io3yog0oux5.cloudfront.net/_5 ... inal-1.pdf
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Re: Experimental therapy against EBV performs well

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News on ATA188 from Atara's quarterly earnings report.
https://www.fool.com/earnings/call-tran ... rnings-ca/

Turning now to our exciting program ATA188 for multiple sclerosis. As most of us know, progressive MS patients remain underserved with current treatment options. Unfortunately, a continued decline of their disease is expected in progressive MS. The current treatment options offer a modest efficacy benefit at best, only delayed progression -- only delaying progression by a few months. We believe there is tremendous opportunity to develop a transformative therapy to help these patients in need. We have seen early but encouraging data with ATA188.

Recall, that we presented an important 12 months Phase 1a data for ATA188 at the Joint ACTRIMS-ECTRIMS Meeting held in September of 2020. These data demonstrated that ATA188 was well tolerated across all four dose cohorts, no dose limiting toxicities and no fatal adverse events have been reported. The safety profile has remained consistent with previously reported data. Importantly, a meaningful number of patients across all four dose cohorts achieved sustained disability improvement or SDI, with a greater proportion demonstrating SDI at higher doses, particularly 42% of patients had SDI in the two highest dose cohorts, namely Cohorts 3 and 4.

And once patients achieved SDI at any time point, they maintained it at all future time points. Sustained disability improvement is rare in this patient population and the fact that we have a number of progressive MS patients with this evidence of benefit is very encouraging.

Data from the open label extension or OLE part of the study with redosing at 12 months showed that the three patients enrolled in OLE that had SDI 12 months all maintained SDI 15 months, including one patient evaluated 15 months and 18 months who maintained SDI at both time points. A fourth patient achieved SDI during the OLE at 24 months. We will present additional data on larger numbers of OLE patients periodically over the next 12 months.

We also presented at ACTRIMS-ECTRIMS preclinical translational data that further support the proposed mechanism of action of ATA188 which is to target EBV infected B cells and plasma cells in multiple sclerosis. These analyses of the ATA188 T-cells reveals that there is a high specificity of these T-cells defined by their T-cell receptors to EBV antigens known to be expressed in multiple sclerosis. Looking ahead, we will present an e-poster with additional data from the OLE and all four cohorts of European Charcot Foundation 28th Annual Meeting to be held very soon, November 15th to 19th 2020.

With respect to the double-blind randomized placebo control trial, we enrolled the first patient in June of 2020 and the study enrollment is progressing well. Giving encouraging clinical results to date in the ATA188 studies and the significant unmet medical need in progressive MS, we are now increasing investment in the ATA188 program. We are expanding the size of the RCT to at least 64 patients changing the primary endpoint of the study to disability improvements and maintaining biological endpoints to create more opportunity to generate meaningful clinical data and to deliver value. The design allows for the addition of the cohort 4 dose if desired.

In addition to measuring disability progression, the study will evaluate other facets of disease including cognition, outpatient ambulatory activity level and fatigue, biomarkers and blood and CSF and MRI imaging. We have submitted material to the FDA, that includes the Phase 1a data, the planned updated design of the RCT study, and potential opportunities for expedited development of ATA188 for MS patients. We look forward to receiving the agency feedback by the end of this year.
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Re: Experimental therapy against EBV performs well

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Atara Bio's view on EBV in MS.

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Re: Experimental therapy against EBV performs well

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I think that Atara Bio's concept falls short on a number of points.

First, I do not think that the B cell is the main carrier of EBV into the CNS, but that herpes strains can enter the CNS from the mucosa of the oro / naso pharynx via the Virchow Robin space.

Second, I think that EBV has a much greater role in the development of MS, namely through the transactivation of HERV, which triggers true autoimmunity.

Third, I think that in an evolutionary sense but also in the MS cascade, B and T cells are the last stage of immune protection. Many things have happened before.

T cells will certainly precede but not necessarily trigger a B cell response. The latter depends on the idiotypic regulatory network and the type of epitopes created (Ab3s hyper-immunization).

Only at the very end do we see things like epitope spreading and immortalized EBV B cells shedding superoxide and cell apoptosis, the real underlying reason for progression.

It should further be noted here that the B cell problem is not unique to MS but is more common than just in MS.

What we see in the above figure of Atara Bio is a rather narrow view of the matter, nevertheless it does get to the heart of progression and developments to stop progression seem quite hopeful.

The figure also shows the tonsils, that is part of the nasopharynx, where the bad EBV B cells originate. I think that is correct and is completely in line with my own view on the origins of MS. See also Annex I of the document on Theoretical Immunology and Chronic Disease that you find here viewtopic.php?f=1&t=15188&start=900#p260052
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