Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in
allogeneic cellular medicines for inflammatory diseases, announced
today it has resubmitted to the U.S. Food and Drug Administration
(FDA) its Biologics License Application (BLA) for approval of
remestemcel-L in the treatment of children with steroid-refractory
acute graft versus host disease (SR-aGVHD).
Survival outcomes have not improved over the
past two decades for the most severe forms of SR-aGVHD, a
life-threatening complication of an allogeneic bone marrow
transplant following treatment for blood cancers and other
conditions.1-3 The lack of any approved treatments for children
under 12 means that there is an urgent need for a therapy that
improves the dismal survival outcomes. If remestemcel-L receives
FDA approval, it will be the first allogeneic “off-the-shelf”
cellular medicine to be approved in the United States, and the
first therapy for children under 12 years old with SR-aGVHD.
The resubmission contains substantial new
information as required by FDA in the Complete Response Letter
(CRL) received in September 2020 to the BLA for remestemcel-L.
Mesoblast has maintained an active dialogue with FDA since
receiving the CRL and in October 2022 provided a high-level
synopsis of the substantial new information under its
Investigational New Drug (IND) application for remestemcel-L. FDA
granted remestemcel-L Fast Track designation, a process to
facilitate the development and expedited review of therapies for
serious conditions that fill unmet medical needs, and Priority
Review designation, which is given to drugs that treat a serious
condition and provide a significant improvement in safety or
effectiveness over existing treatments. The BLA resubmission will
have a review period up to six months from filing upon acceptance
by FDA.
Mesoblast has responded to the CRL and the
further guidance it has received from the FDA and has generated and
provided new data and analyses in the resubmission which we believe
provide substantial evidence of remestemcel-L's effectiveness in
pediatric SR-aGVHD. Specifically, the resubmission contains the
following:
- new long-term
survival data of children enrolled in the Phase 3 trial showing
durability of treatment effect through at least four years,
- new data showing
remestemcel-L’s treatment benefit in high-risk disease activity and
on survival in propensity-matched studies of children in the Phase
3 trial and controls stratified by validated biomarkers for
high-risk disease,
- new analyses of data
obtained prospectively showing that the validated potency assay
which was in place and used to release product for the 54-patient
Phase 3 clinical trial measures a key product attribute which
reflects the primary mechanism of action of remestemcel-L in
children with SR-aGVHD, correlates with the product’s in vivo
bioactivity, and predicts overall survival outcomes,
- new analyses of data
obtained prospectively relating manufacturing changes during
product development prior to Phase 3 to progressive increases in
potency and to improved survival outcomes in larger studies of
remestemcel-L under expanded access in children with SR-aGVHD,
- new data showing
that the validated potency assay has low variability and can
adequately demonstrate manufacturing consistency and
reproducibility, and
- establishment of a new specification
for release of commercial product based on extensive clinical data
which provides assurance that future batches of remestemcel-L will
have attributes supportive of expected survival outcomes.
“There is an urgent need for a therapy that
improves the dismal survival outcome in children with SR-aGVHD”
said Dr. Silviu Itescu, Chief Executive of Mesoblast. “Our team has
worked tirelessly over the past two years to provide a
comprehensive response to the FDA. We are grateful for the agency’s
active dialogue and constructive feedback that will ensure a high
bar is met in terms of product consistency and predictability of
clinical outcomes.”
About Steroid-Refractory Acute Graft
Versus Host Disease Survival outcomes have not improved
over the past two decades for children or adults with the most
severe forms of SR-aGVHD.1-3 The lack of any approved treatments
for children under 12 means thatthere is an urgent need for a
therapy that improves the dismal survival outcomes in children.
Acute GVHD occurs in approximately 50% of
patients who receive an allogeneic bone marrow transplant (BMT).
Over 30,000 patients worldwide undergo an allogeneic BMT annually,
primarily during treatment for blood cancers, including about 20%
in pediatric patients.4,5 SR-aGVHD is associated with mortality as
high as 90% and significant extended hospital stay costs.6,7 There
are currently no FDA-approved treatments in the US for children
under 12 with SR-aGVHD.
About Remestemcel-L Mesoblast’s
lead product candidate, Remestemcel-L, is an investigational
therapy comprising culture expanded mesenchymal stromal cells
derived from the bone marrow of an unrelated donor. It is
administered to patients in a series of intravenous infusions.
Remestemcel-L is believed to have immunomodulatory properties to
counteract the inflammatory processes that are implicated in
SR-aGVHD by down-regulating the production of pro-inflammatory
cytokines, increasing production of anti-inflammatory cytokines,
and enabling recruitment of naturally occurring anti-inflammatory
cells to involved tissues.
The original BLA submission contained clinical
outcomes of 309 children with SR-aGVHD treated with remestemcel-L
showing consistent treatment responses and survival across three
separate trials. The data were reviewed by the agency’s panel of
the Oncologic Drugs Advisory Committee (ODAC) which voted in favor
9:1 that the available data support the efficacy of remestemcel-L
in pediatric patients with SR-aGVHD.
The BLA resubmission now contains additional
clinical and biomarker data, including from a propensity-matched
study of children with high-risk disease, based on the validated
MAP biomarker score, comparing outcomes in 25 children from
Mesoblast’s Phase 3 trial and 27 control children treated with
various biologics, including ruxolitinib, from the Mount Sinai
Acute GvHD International Consortium (MAGIC) database. The study
showed that 67% of high-risk children treated with remestemcel
responded positively to treatment within 28 days and were alive
after 180 days compared to just 10% in both categories in the MAGIC
group.
The BLA resubmission also contains results of a
4-year survival study performed by the Center for International
Blood and Marrow Transplant Research (CIBMTR) on 51 evaluable
patients with SR-aGVHD who were enrolled in the Phase 3 trial. The
results demonstrated durability of the early day 180 survival
benefits, with 63% survival at 1 year and 51% at 2 years in a group
of children with predominantly grade C/D disease (89%) and with
expected 2 year survival of just 25-38% using best available
therapy.1,8-9
About Mesoblast Mesoblast is a
world leader in developing allogeneic (off-the-shelf) cellular
medicines for the treatment of severe and life-threatening
inflammatory conditions. The Company has leveraged its proprietary
mesenchymal lineage cell therapy technology platform to establish a
broad portfolio of late-stage product candidates which respond to
severe inflammation by releasing anti-inflammatory factors that
counter and modulate multiple effector arms of the immune system,
resulting in significant reduction of the damaging inflammatory
process.
Mesoblast has a strong and extensive global
intellectual property portfolio with protection extending through
to at least 2041 in all major markets. The Company’s proprietary
manufacturing processes yield industrial-scale, cryopreserved,
off-the-shelf, cellular medicines. These cell therapies, with
defined pharmaceutical release criteria, are planned to be readily
available to patients worldwide.
Mesoblast is developing product candidates for
distinct indications based on its remestemcel-L and
rexlemestrocel-L allogeneic stromal cell technology platforms.
Remestemcel-L is being developed for inflammatory diseases in
children and adults including steroid refractory acute graft versus
host disease, biologic-resistant inflammatory bowel disease, and
acute respiratory distress syndrome. Rexlemestrocel-L is in
development for advanced chronic heart failure and chronic low back
pain. Two products have been commercialized in Japan and Europe by
Mesoblast’s licensees, and the Company has established commercial
partnerships in Europe and China for certain Phase 3 assets.
Mesoblast has locations in Australia, the United
States and Singapore and is listed on the Australian Securities
Exchange (MSB) and on the Nasdaq (MESO). For more information,
please see www.mesoblast.com, LinkedIn: Mesoblast Limited and
Twitter: @Mesoblast
References / Footnotes
- Rashidi A et al. Outcomes and
predictors of response in steroid-refractory acute
graft-versus-host disease: single-center results from a cohort of
203 patients. Biol Blood Bone Marrow Transplant 2019;
25(11):2297-2302.
- Berger M, Pessolano R, Carraro F,
Saglio F, Vassallo E, Fagioli F. Steroid-refractory acute
graft-versus-host disease graded III-IV in pediatric patients. A
mono-institutional experience with a long-term follow-up. Pediatric
Transplantation. 2020; 24(7):e13806
- Biavasco F, Ihorst G, Wasch R, Wehr
C, Bertz H, Finke J, Zeiser R. Therapy response of
glucocorticoid-refractory acute GVHD of the lower intestinal tract.
Bone Marrow Transplantation. 2022
- Niederwieser D, Baldomero H, Szer
J. (2016) Hematopoietic stem cell transplantation activity
worldwide in 2012 and a SWOT analysis of the Worldwide Network for
Blood and Marrow Transplantation Group including the global
survey.
- HRSA Transplant Activity Report,
CIBMTR, 2019
- Westin, J., Saliba, RM., Lima, M.
(2011) Steroid-refractory acute GVHD: predictors and outcomes.
Advances in Hematology.
- Axt L, Naumann A, Toennies J (2019)
Retrospective single center analysis of outcome, risk factors and
therapy in steroid refractory graft-versus-host disease after
allogeneic hematopoietic cell transplantation. Bone Marrow
Transplantation.
- MacMillan ML et al. Pediatric acute
GVHD: clinical phenotype and response to upfront steroids. Bone
Marrow Transplant 2020; 55(1): 165-171
- Zeiser R et al. Ruxolitinib for
Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J
Med 2020;382:1800-10.
Forward-Looking StatementsThis
press release includes forward-looking statements that relate to
future events or our future financial performance and involve known
and unknown risks, uncertainties and other factors that may cause
our actual results, levels of activity, performance or achievements
to differ materially from any future results, levels of activity,
performance or achievements expressed or implied by these
forward-looking statements. We make such forward-looking statements
pursuant to the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995 and other federal securities laws.
Forward-looking statements should not be read as a guarantee of
future performance or results, and actual results may differ from
the results anticipated in these forward-looking statements, and
the differences may be material and adverse. Forward-looking
statements include, but are not limited to, statements about: the
initiation, timing, progress and results of Mesoblast’s preclinical
and clinical studies, and Mesoblast’s research and development
programs; Mesoblast’s ability to advance product candidates into,
enroll and successfully complete, clinical studies, including
multi-national clinical trials; Mesoblast’s ability to advance its
manufacturing capabilities; the timing or likelihood of regulatory
filings and approvals (including BLA resubmission), manufacturing
activities and product marketing activities, if any; the
commercialization of Mesoblast’s product candidates, if approved;
regulatory or public perceptions and market acceptance surrounding
the use of stem-cell based therapies; the potential for Mesoblast’s
product candidates, if any are approved, to be withdrawn from the
market due to patient adverse events or deaths; the potential
benefits of strategic collaboration agreements and Mesoblast’s
ability to enter into and maintain established strategic
collaborations; Mesoblast’s ability to establish and maintain
intellectual property on its product candidates and Mesoblast’s
ability to successfully defend these in cases of alleged
infringement; the scope of protection Mesoblast is able to
establish and maintain for intellectual property rights covering
its product candidates and technology; estimates of Mesoblast’s
expenses, future revenues, capital requirements and its needs for
additional financing; Mesoblast’s financial performance;
developments relating to Mesoblast’s competitors and industry; and
the pricing and reimbursement of Mesoblast’s product candidates, if
approved. You should read this press release together with our risk
factors, in our most recently filed reports with the SEC or on our
website. Uncertainties and risks that may cause Mesoblast’s actual
results, performance or achievements to be materially different
from those which may be expressed or implied by such statements,
and accordingly, you should not place undue reliance on these
forward-looking statements. We do not undertake any obligations to
publicly update or revise any forward-looking statements, whether
as a result of new information, future developments or
otherwise.
Release authorized by the Chief Executive.
For more information, please contact:
Corporate Communications / Investors |
Media |
Paul Hughes |
BlueDot Media |
T: +61 3 9639 6036 |
Steve Dabkowski |
E: investors@mesoblast.com |
T: +61 419 880 486 |
|
E: steve@bluedot.net.au |
|
|
|
Rubenstein |
|
Tali Mackay |
|
E: tmackay@rubenstein.com |
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