Sustained Disability Improvements Seen at Six
Months Were Maintained at 12 Months with ATA188
Potential Therapeutic Response with ATA188
Supports Role of Epstein-Barr Virus (EBV) in Pathogenesis of MS
Conference Call and Webcast Today, May 26, 2020
at 8:00 a.m. EDT/2:00 p.m. CEST
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 additional safety and efficacy data
from its 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; there was a higher proportion of patients showing
sustained disability improvements with increasing dose, and
sustained disability improvements seen at six months were
maintained at 12 months in all three cohorts that have reached the
12-month time point in the study. The results are featured in a
late-breaking e-poster at the 6th Congress of the European Academy
of Neurology (EAN) virtual meeting, held on May 23-26, 2020.
Though the development of MS likely requires more than a single
causative factor, EBV is the only risk factor identified to date
that appears to be necessary for MS.4 Evidence demonstrates that
100 percent of patients with MS have been exposed to EBV.1-4,7
EBV-infected cells, particularly B memory cells which have become
immortalized with EBV infection, are thought to play an important
role in the immune cascade responsible for both relapsing and
progressive forms of MS. The success of interventions that deplete
all peripheral B cells underscores the importance of these cells in
MS pathophysiology. ATA188 offers a unique approach with the
advantage of selectively targeting EBV-infected B cells and plasma
cells in the circulation and in the central nervous system
(CNS).
“The approach of targeting EBV-infected B cells has led to very
encouraging preliminary results, as ATA188 proved to be safe and
well-tolerated across all four dose cohorts in this Phase 1a
study,” said Lawrence Steinman, MD, Professor of Neurology and
Neurological Sciences, Pediatrics and Genetics, Stanford
University. “These results, along with the observed trend in
sustained disability improvements seen at six months and maintained
at 12 months, highlight the opportunity to advance into the
randomized placebo-controlled study of ATA188 for the treatment of
patients with progressive MS.”
This Phase 1a multicenter, open-label study of ATA188 in
patients with progressive forms of MS was designed to establish
safety and tolerability, to select the recommended dose for the
randomized placebo-controlled Phase 1b study, and to assess
potential efficacy. Patients were treated across four
dose-escalating cohorts (5 x 106, 1 x 107, 2 x 107 and 4 x 107
cells), with six patients each in cohorts 1-3 and seven patients in
cohort 4.
The study found that across the four dose cohorts, ATA188 was
well-tolerated in patients with progressive forms of MS. No
dose-limiting toxicities and no fatal adverse events (AEs) have
been reported. Rhinorrhea (runny nose) is the only
treatment-related event that occurred in more than one subject. No
dose-related safety trends were identified across cohorts.
Additionally, ATA188 infusion shows no clinically meaningful effect
on cytokine levels post-infusion.
Patients in the study were assessed on MS-focused clinical
measures at three-, six- and 12-month time points. Composite scales
of clinical outcome and of sustained disability improvement (SDI)
were evaluated in patients receiving all six doses of ATA188, which
includes cohorts 1-4 at six months (n=24) and cohorts 1-3 at 12
months (n=17). Sustained Disability Improvement is defined as
clinically significant improvement in Expanded Disability Status
Scale (EDSS) or timed 25-foot walk (T25FW) observed on two
consecutive time points.
All patients in cohorts 1-3 of this Phase 1 study showing SDI at
six months, maintained improvement through 12 months. For a patient
to achieve SDI, it was required that they have sustained
improvement on a composite of clinically significant improvement in
EDSS or T25FW, confirmed at consecutive time points. This means
that to achieve SDI at six months, there had to be disability
improvement at three months that was confirmed at six months, and
to achieve SDI at 12 months, there had to be disability improvement
at six months that was confirmed at 12 months. Additionally, a
dose-related increase in the number of patients with SDI was
observed.
Cohorts 1 and 2 each had one patient with SDI at 6 months while
Cohorts 3 and 4 each had two patients with SDI at 6 months. All
patients in Cohorts 1-3 with SDI at six months, maintained SDI at
12 months (Cohort 4 patients have not yet reached the 12-month time
point). Of note, in Cohort 3, a third patient had SDI at 12 months.
EDSS was the main driver of SDI.
A dose-related trend of a higher proportion of patients showing
favorable clinical improvement through a second composite scale,
designed to detect early signals of efficacy, was also observed.
The second composite scale is an a priori classification of patient
outcomes incorporating seven clinically recognized scales for MS
symptoms, function, and disability. Both composite scales suggest a
potential therapeutic response of ATA188 in the treatment of
progressive forms of MS. Based on these results, the cohort 3 dose
was selected for the randomized, placebo-controlled Phase 1b
study.
“Although some treatments may delay disability progression in
progressive MS, there are currently no treatment options in
progressive MS that halt or reverse the progression of disease.
Therapies that either halt disability progression or improve
disability could be very meaningful for MS patients,” said Dr.
Steinman. “If these data are confirmed in a double-blind,
placebo-controlled, randomized study, we could see an evolution in
the treatment paradigm for progressive MS and other forms of this
debilitating disease.”
Atara has now advanced into the Phase 1b double-blind randomized
placebo-controlled study, which has resumed enrollment activities
after a brief COVID-19-related pause. In addition to measuring
disability progression, the study will also evaluate many facets of
the disease, including: cognition and outpatient ambulatory
activity; fatigue, and biological end points in blood and
cerebrospinal fluid/CSF (IgG, synthesis and index, OCBs, product
kinetics); and MRI imaging.
In addition to the clinical data reported at EAN, preclinical
translational data published online at the 2020 Academy of
Neurology (AAN) 72nd Annual Meeting further support the proposed
mechanism of action of ATA188 targeting EBV-infected B cells. These
combined analyses of T cells comprising ATA188 are consistent with
its proposed mechanism of targeting EBV-infected B cells by
recognizing MS-relevant EBV antigens on these cells via defined
T-cell receptors (TCRs).
“The body of evidence supporting the important role of
EBV-infected B cells in the chronic autoimmune pathology of MS
continues to grow, including these encouraging late-breaking Phase
1 data at EAN showing sustained disability improvements in
progressive MS patients treated with ATA188,” said AJ Joshi, MD,
Senior Vice President and Chief Medical Officer of Atara
Biotherapeutics. “We look forward to the continued study of ATA188
in progressive MS, and believe our novel therapeutic approach
targeting the EBV-infected B cell as a propagator of autoimmunity
may help patients with other forms of MS and potentially other
autoimmune conditions where EBV has been implicated, including
lupus, rheumatoid arthritis, and Sj�gren’s syndrome.”
Atara Conference Call and Webcast Information
Atara will hold a conference call at 8:00 a.m. EDT/2:00 p.m.
CEST for analysts and investors to review the data, current disease
and treatment landscape, and Atara’s continued plans for the ATA188
program. The call will include:
- Lawrence Steinman, MD, Professor of Neurology and Neurological
Sciences, Pediatrics and Genetics, Stanford University
- Pascal Touchon, President and Chief Executive Officer, Atara
Biotherapeutics
- Jakob Dupont, MD, Executive Vice President, Global Head of
Research and Development, Atara Biotherapeutics
- AJ Joshi, MD, Senior Vice President and Chief Medical Officer,
Atara Biotherapeutics
Analysts and investors can participate in the conference call by
dialing (888) 540-6216 for domestic callers and (734) 385-2715 for
international callers, using the conference ID 3665248. A live
audio webcast can be accessed by visiting the Investors & Media
– News & Events section of atarabio.com. An archived replay
will be available on the Company's website for 30 days following
the live webcast.
Details of the 2020 EAN Virtual Congress Late-Breaking
Presentation Title: Phase 1 study of the safety and efficacy of
ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted
T-cell immunotherapy to treat progressive forms of multiple
sclerosis Poster #: LB130 Poster Session: EPO400
About Multiple Sclerosis (MS)
MS is a chronic neurological autoimmune disease that affects an
estimated 2.3 million people around the world. Relapsing-remitting
MS (RRMS) is the most common form of MS and is characterized by
episodes of new or worsening signs or symptoms (relapses) followed
by periods of recovery. Despite available disease-modifying
treatments, most individuals with RRMS continue to experience
disease activity and disability progression.
Progressive MS (PMS) is a severe form of the disease with few
therapeutic options. PMS comprises two conditions, both
characterized by persistent progression and worsening of MS
symptoms and physical disability over time. Primary progressive MS
(PPMS) occurs when continuous progressive disease is present at
diagnosis and occurs in approximately 15% of newly diagnosed cases.
Secondary progressive MS (SPMS) initially begins as RRMS and
develops into a progressive form. Up to 80 percent of people with
RRMS will eventually develop SPMS. There is substantial unmet
medical need for new and effective therapies for patients with PPMS
and SPMS. Most treatment options that work well in reducing flares
in RRMS have not been shown to be effective in slowing or reversing
disability in PMS.
About EBV in MS
Two decades of converging epidemiological, histological, and
molecular evidence strongly support the role of EBV infection as a
prerequisite for MS—MS likely does not develop in the absence of
EBV infection.5 While several hypotheses have been proposed to
explain the pathophysiology of EBV in MS, the autoreactive B cell
hypothesis provides unifying principles based on the concept that
defective elimination of EBV-infected autoreactive B cells by CD8+
T cells results in their accumulation in lymphoid structures and
target organs implicated in MS, including the central nervous
system leading to inflammation.6 This aberrant inflammation
eventually leads to demyelination and axon destruction. For
progressive MS, there is a significant unmet need for high-efficacy
neuroprotective therapies that work directly in the central nervous
system, and have the potential to delay, stop, or reverse disease
progression, as well as the accumulation of permanent disability.
It is hypothesized that the depletion of autoreactive EBV-infected
B cells and plasma cells in the central nervous system may address
a key factor involved in the development of progressive MS and
result in clinically meaningful results for patients.
About ATA188
Epstein-Barr Virus (EBV) is associated with a wide range of
hematologic malignancies and solid tumors, as well as certain
autoimmune conditions such as multiple sclerosis (MS). T cells are
a critical component of the body’s immune system and can
selectively target EBV believed to be important in the pathogenesis
of MS.
Off-the-shelf, investigational ATA188, has the potential to
target EBV-infected B cells and plasma cells in the central nervous
system that may catalyze autoimmune responses and MS
pathophysiology.
Atara is advancing a Phase 1 ATA188 clinical study in patients
with progressive MS across clinical sites in the U.S. and
Australia.
For more information about the ATA188 Phase 1 study, please
visit ClinicalTrials.gov (NCT03283826).
About Atara Biotherapeutics, Inc.
Atara Biotherapeutics, Inc. (@Atarabio) is a pioneer in T-cell
immunotherapy leveraging its novel allogeneic EBV T-cell platform
to develop transformative therapies for patients with severe
diseases including solid tumors, hematologic cancers and autoimmune
disease. With our lead program in Phase 3 clinical development,
Atara is the most advanced allogeneic T-cell immunotherapy company
and intends to rapidly deliver off-the-shelf treatments to patients
with high unmet medical need. Our platform leverages the unique
biology of EBV T cells and has the capability to treat a wide range
of EBV-associated diseases, or other severe diseases through
incorporation of engineered CARs (chimeric antigen receptors) or
TCRs (T-cell receptors). Atara is applying this one platform to
create a robust pipeline including: tab-cel® (tabelecleucel) in
Phase 3 development for Epstein-Barr virus-driven post-transplant
lymphoproliferative disease (EBV+ PTLD); ATA188, a T-cell
immunotherapy targeting EBV antigens as a potential treatment for
multiple sclerosis; and multiple next-generation chimeric antigen
receptor T-cell (CAR-T) immunotherapies for both solid tumors and
hematologic malignancies. Improving patients’ lives is our mission
and we will never stop working to bring transformative therapies to
those in need. Atara is headquartered in South San Francisco and
our leading-edge research, development and manufacturing facility
is based in Thousand Oaks, California. For additional information
about the company, please visit atarabio.com and follow us on
Twitter and LinkedIn.
References
1Dobson R, et al. Epstein-Barr-negative MS: a true phenomenon?
Neurol Neuroimmunol Neuroinflamm. 2017;4:1-4.
2Pakpoor J, et al. The risk of developing multiple sclerosis in
individuals seronegative for Epstein-Barr virus: a meta-analysis.
Mult Scler. 2012;19:162-166.
3Ruprecht K. Absence of Epstein-Barr virus seronegativity in a
large cohort of patients with early multiple sclerosis. Presented
at: ECTRIMS; October 10-12, 2018; Berlin, Germany. Abstract
320.
4Abrahamyan S, et al. Complete Epstein-Barr virus seropositivity
in a large cohort of patients with early multiple sclerosis. J
Neurol Neurosurg Psychiatry. 2020 May 5. [Epub ahead of print]
5 Bar-Or A, et al. Epstein-Barr Virus in Multiple Sclerosis:
Theory and Emerging Immunotherapies. Trends Mol Med.
2020;26:296-310.
6 Pender MP. Infection of autoreactive B lymphocytes with EBV,
causing chronic autoimmune diseases. Trends Immunol.
2003;24:584-588.
7 Bar-Or A, et al. Phase 1 Study of the Safety and Efficacy of
ATA188, an Off-the-shelf, Allogeneic Epstein-Barr Virus-targeted
T-cell Immunotherapy to Treat Progressive Forms of Multiple
Sclerosis. Presented at: EAN; May 23-26, 2020; Virtual from Vienna,
Austria. EPO130.
Forward-Looking Statements
This press release contains or may imply "forward-looking
statements" within the meaning of Section 27A of the Securities Act
of 1933 and Section 21E of the Securities Exchange Act of 1934. For
example, forward-looking statements include statements regarding:
the potential safety and efficacy of ATA188; the resumption of
screening and enrollment of patients in Atara’s Phase 1b study of
ATA188; Atara’s ability to successfully advance the development of
ATA188; and the potential for Atara’s therapeutic approach to treat
various specified conditions. Because such statements deal with
future events and are based on Atara Biotherapeutics' current
expectations, they are subject to various risks and uncertainties
and actual results, performance or achievements of Atara
Biotherapeutics could differ materially from those described in or
implied by the statements in this press release. These
forward-looking statements are subject to risks and uncertainties,
including those discussed in Atara Biotherapeutics' filings with
the Securities and Exchange Commission (SEC), including in the
“Risk Factors” and “Management’s Discussion and Analysis of
Financial Condition and Results of Operations” sections of the
Company’s most recently filed periodic reports on Form 10-K and
Form 10-Q and subsequent filings and in the documents incorporated
by reference therein. Except as otherwise required by law, Atara
Biotherapeutics disclaims any intention or obligation to update or
revise any forward-looking statements, which speak only as of the
date hereof, whether as a result of new information, future events
or circumstances or otherwise.
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INVESTOR & MEDIA CONTACTS:
Media Kerry Beth Daly Head, Corporate Communications
Atara Biotherapeutics 516-982-9328 kdaly@atarabio.com
Investors Eric Hyllengren Vice President, Investor
Relations & Finance Atara Biotherapeutics 805-395-9669
ehyllengren@atarabio.com
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