-
83% of patients achieved
complete remission (CR) or CR with incomplete blood count recovery
within 3 months of treatment with CTL019; consistent with interim
ELIANA data
-
Data evaluating 63 patients
demonstrate relapse-free survival and probability of survival in a
majority of patients at six months
-
Advances in CTL019 and ELIANA
result from global CAR-T cell therapy collaboration with the
University of Pennsylvania
-
CTL019 is manufactured using
cryopreserved leukapheresis which, in the ELIANA trial, enabled the
treatment of patients in 25 sites across four continents
Basel, June 23, 2017
- Novartis today announced updated results
from the ELIANA clinical trial demonstrating CTL019
(tisagenlecleucel) remission rates are maintained at six months in
relapsed/refractory (r/r) pediatric and young adult patients with
B-cell acute lymphoblastic leukemia (ALL). These data from this
pivotal trial of CTL019 show that 83% (52 of 63; 95% confidence
interval [CI]: 71%-91%) of patients achieved complete remission
(CR) or CR with incomplete blood count recovery within three months
of infusion. No minimal residual disease (MRD) was detected among
responding patients[1]. MRD, which measures the elimination of
residual disease in the blood and bone marrow at the molecular
level following treatment, is important because it may be an
indicator of potential relapse[2]. Results from this study of
CTL019 - an investigational chimeric antigen receptor T cell
(CAR-T) therapy - will be presented at the European Hematology
Association (EHA) Annual Meeting (Abstract #S476; Saturday, June
24, 4:00 PM CEST).
The ELIANA study also showed that the relapse-free
probability was 75% (95% CI, 57%-87%; median duration of response
not reached) at six months and 64% (95% CI, 42%-79%) at 12 months
among responders. In addition, the probability of survival was 89%
(95% CI, 77%-94%) at six months and 79% (95% CI, 63%-89%) at 12
months. The median time from infusion to data cutoff was 8.8
months[1].
"The updated CTL019 ELIANA data illustrating early
observed response rates that have held steady over six months' time
are exciting findings. Durability is an important measure for
children and young adults with relapsed or refractory B-cell ALL,
and we are truly encouraged by the results of this study," said
lead investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny
Professor of Pediatrics at the Perelman School of Medicine at the
University of Pennsylvania (Penn), and Director of the Cancer
Immunotherapy Frontier Program at the Children's Hospital of
Philadelphia (CHOP).
Forty-seven percent of patients in ELIANA
experienced grade 3 or 4 cytokine release syndrome (CRS), a known
complication of the investigational therapy that may occur when the
engineered cells become activated in the patient's body. CRS was
managed globally using prior site education on implementation of
the CRS treatment algorithm. There were no deaths due to refractory
CRS and no incidents of cerebral edema were reported. Fifteen
percent of patients experienced grade 3 neurologic events, with no
grade 4 events seen[1].
The ELIANA trial enrolled 88 patients. Of the 88,
16 patients discontinued before infusion and the majority
(nine patients) did so due to rapid progression of their disease or
deterioration in their clinical status. This reflects the
acute and progressive nature of this disease. Of the 16 patients
who weren't infused, seven were a result of insufficiently
formulated CAR-T cell product. Additionally, five infused patients
had not reached three-month follow-up and four patients were
pending infusion at the time of data cutoff.
"These positive, updated ELIANA data help us
better understand the ability for CTL019 to maintain durable
responses in r/r ALL," said Vas Narasimhan, MD, Global Head of Drug
Development and Chief Medical Officer, Novartis. "The results,
including relapse-free survival findings at six and 12 months,
reaffirm our confidence in CTL019 to potentially become an
effective treatment for pediatric and young adult patients with r/r
ALL in need of more options."
ELIANA (NCT02435849) is the first pediatric global
CAR-T cell therapy registration trial, with study enrollment having
occurred across 25 centers in the US, Canada, EU, Australia and
Japan. The single-arm, open-label, multicenter Phase II study
included patients aged three to 23 years who were primary
refractory, refractory to chemotherapy after their first relapse,
relapsed after second line therapy or ineligible for an allogeneic
stem cell transplant (SCT). Patients in the trial received a median
of three prior lines of therapy and 59% of patients had a prior
SCT.
CTL019 was first developed by Penn and uses the
4-1BB costimulatory domain to enhance cellular responses. In 2012,
Novartis and Penn entered into a global collaboration to further
research, develop and then commercialize CAR-T cell therapies,
including CTL019, for the investigational treatment of cancers.
Additional CTL019 data at
EHA
A pooled data analysis from two multicenter trials of CTL019 in
pediatric and young adult patients with r/r B-cell ALL, including
ELIANA and ENSIGN (NCT02228096), will also be highlighted in a
presentation at the meeting. This research is aimed to identify any
new safety issues with CTL019 as a result of its use in multicenter
trials, which included 25 sites across 11 countries. Study authors
concluded that there were no new safety issues and that CRS and
neurologic events were effectively managed. Prolonged follow-up
will be required to determine the long-term safety of B-cell
aplasia (Abstract #P517; Saturday, June 24, 5:30 PM CEST).
An oral presentation will feature pooled analyses
from two multicenter trials of CTL019 in pediatric and young adult
patients with r/r B-cell ALL, including ELIANA and ENSIGN,
observing response analysis and impact of intrinsic/extrinsic and
manufacturing factors on CTL019 expansion and persistence (Abstract
#S477; Saturday, June 24, 4:15 PM CEST).
Novartis will also present an encore of results
from its global, pivotal multi-center Phase II JULIET study
(NCT02445248; Abstract #LB2604, June 25, 12:00 PM CEST), evaluating
CTL019 in adults with r/r diffuse large-b-cell lymphoma (DLBCL).
CTL019 was granted Priority Review from the FDA
earlier this year in the treatment of r/r pediatric and young adult
patients with B-cell ALL, and Novartis plans to file with the
European Medicines Agency (EMA) later in 2017. The investigational
therapy received PRIME (PRIority MEdicines) designation from the
EMA in 2016. The FDA also granted Breakthrough Therapy designation
to CTL019 for the treatment of adult patients with r/r DLBCL, whose
disease has progressed on or after two or more prior therapies.
About CTL019
Manufacturing
Novartis leukapheresis process using cryopreservation allowed for
manufacturing and treatment of patients from around the world.
Cryopreserved leukapheresis gives physicians the flexibility to
schedule apheresis at a time that is in the best interest of their
patients. Novartis commercial manufacturing for CTL019 continues to
build on its experience in its Morris Plains, New Jersey facility,
which has already manufactured CTL019 for hundreds of patients in
global clinical trials. Novartis believes that experience is
important in cell therapy manufacturing, and the experience gained
at the Morris Plains, New Jersey facility will be a foundation for
commercial manufacturing of CAR-T therapies. Novartis has made and
continues to make investments in manufacturing.
About CAR-T and
CTL019
CAR-T is different from typical small molecule or biologic
therapies because it is manufactured for each individual patient
using their own cells. During the treatment process, T cells are
drawn from a patient's blood and reprogrammed in the laboratory to
create T cells that are genetically coded to hunt the patient's
cancer cells and other B-cells expressing a particular antigen. In
March 2017, Novartis announced that the FDA granted Priority Review
for the company's Biologics License Application for CTL019 in the
treatment of r/r pediatric and young adult patients with B-cell
ALL.
Because CTL019 is an investigational therapy, the
safety and efficacy profile has not yet been established. Access to
investigational therapies is available only through carefully
controlled and monitored clinical trials. These trials are designed
to better understand the potential benefits and risks of the
therapy. Because of the uncertainty of clinical trials, there is no
guarantee that CTL019 will ever be commercially available anywhere
in the world.
About ALL
Acute lymphoblastic leukemia makes up approximately 25% of cancer
diagnoses among children under 15 years old and is the most common
childhood cancer in the US[3]. Patients with r/r ALL have limited
treatment options, and the chance of survival for children with the
disease who relapse or fail to attain remission is between 16% to
30.1%[4].
Disclaimer
The foregoing release contains forward-looking statements that can
be identified by words such as "investigational," "will,"
"exciting," "encouraged," "confidence," "potentially," "aimed,"
"Priority Review," "plans," "later in 2017," "PRIME designation,"
"Breakthrough Therapy designation," "to build," "believes,"
"continues," "yet," or similar terms, or by express or implied
discussions regarding potential marketing approvals for CTL019, or
regarding potential future revenues from CTL019. You should not
place undue reliance on these statements. Such forward-looking
statements are based on the current beliefs and expectations of
management regarding future events, and are subject to significant
known and unknown risks and uncertainties. Should one or more of
these risks or uncertainties materialize, or should underlying
assumptions prove incorrect, actual results may vary materially
from those set forth in the forward-looking statements. There can
be no guarantee that CTL019 will be submitted or approved for sale
in any market, or at any particular time. Nor can there be any
guarantee that CTL019 will be commercially successful in the
future. In particular, management's expectations regarding CTL019
could be affected by, among other things, the uncertainties
inherent in research and development, including clinical trial
results and additional analysis of existing clinical data;
regulatory actions or delays or government regulation generally;
the company's ability to obtain or maintain proprietary
intellectual property protection; general economic and industry
conditions; global trends toward health care cost containment,
including ongoing pricing and reimbursement pressures; safety,
quality or manufacturing issues, and other risks and factors
referred to in Novartis AG's current Form 20-F on file with
the US Securities and Exchange Commission. Novartis is providing
the information in this press release as of this date and does not
undertake any obligation to update any forward-looking statements
contained in this press release as a result of new information,
future events or otherwise.
About Novartis
Novartis provides innovative healthcare solutions that address the
evolving needs of patients and societies. Headquartered in Basel,
Switzerland, Novartis offers a diversified portfolio to best meet
these needs: innovative medicines, cost-saving generic and
biosimilar pharmaceuticals and eye care. Novartis has leading
positions globally in each of these areas. In 2016, the Group
achieved net sales of USD 48.5 billion, while R&D throughout
the Group amounted to approximately USD 9.0 billion. Novartis Group
companies employ approximately 118,000 full-time-equivalent
associates. Novartis products are sold in approximately 155
countries around the world. For more information, please visit
http://www.novartis.com.
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References
[1] Buechner, Jochen Et Al. Global Registration Trial Of Efficacy
And Safety Of Ctl019 In Pediatric And Young Adult Patients With
Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (All):
Update To The Interim Analysis. June 24, 4:00 Pm CEST. European
Hematology Association: Abstract S476.
[2] Campana, Dario. Minimal Residual Disease in Acute Lymphoblastic
Leukemia. Seminars in hematology 46.1 (2009):
100-106. PMC. Web. 22 May 2017.
[3] Howlader, N., Noone, A. M., Krapcho, M, et al. SEER Cancer
Statistics Review, 1975-2010. National Cancer Institute, April
2013; Section 28.9 (12).
http://www.seer.cancer.gov/csr/1975_2010/results_merged/sect_28_childhood_cancer.pdf.
Accessed June 2017.
[4] Satwani, Prkash, Sather, Harland, Ozkaynak, Fevzi, et al.
Allogeneic Bone Marrow Transplantation in First Remission for
Children with Ultra-high-risk Features of Acute Lymphoblastic
Leukemia: A Children's Oncology Group Study Report." Biology of
Blood and Marrow Transplantation 13.2 (2007): 218-27.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731715/. Accessed
June 2017.
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