- Both trials met the primary and key secondary
endpoints at the pre-specified interim analysis -
- Data continue to demonstrate transformative
and durable benefit -
- Safety profile consistent with busulfan
conditioning and autologous hematopoietic stem cell transplant
-
Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and CRISPR
Therapeutics (Nasdaq: CRSP) today announced that both pivotal
trials for exagamglogene autotemcel (exa-cel) in patients with
transfusion-dependent beta thalassemia (TDT) or severe sickle cell
disease (SCD) met primary and key secondary endpoints at
pre-specified interim analyses. The results are being presented at
the Annual European Hematology Association (EHA) Congress.
“The updated results from both the TDT and SCD trials are
remarkable and bring the promise of an autologous CRISPR/Cas9
gene-edited cell therapy one-step closer to patients who are
waiting,” said Carmen Bozic, M.D., Executive Vice President, Global
Medicines Development and Medical Affairs, and Chief Medical
Officer at Vertex.
“This analysis confirms the potential of exa-cel to render
patients transfusion-independent or VOC-free, with significant
improvement in their quality of life and physical performance,”
said Franco Locatelli, M.D., Ph.D., Professor of Pediatrics at the
Sapienza University of Rome, Director of the Department of
Pediatric Hematology and Oncology at Bambino Gesù Children’s
Hospital. “This therapy offers the potential of a functional cure
for patients with transfusion-dependent beta thalassemia or severe
sickle cell disease along with a favorable safety profile.”
New Data From Pre-Specified Interim Analyses in exa-cel
Pivotal Trials
Both CLIMB-111 and CLIMB-121 met their primary endpoint and key
secondary endpoint at the pre-specified interim analysis for each
trial. These analyses evaluated the efficacy and safety of exa-cel
in patients with TDT or SCD in the ongoing Phase 3 trials as well
as in the long-term follow up trial CLIMB-131. The data shared are
from 83 patients (48 with TDT and 35 with SCD) dosed with exa-cel
with follow-up up to 43.7 months. All patients treated with exa-cel
demonstrated clinical benefit, and these data continue to
demonstrate the potentially transformative profile of exa-cel.
Efficacy of exa-cel in Patients With Transfusion-Dependent
Beta Thalassemia
Of the 48 patients with TDT who had received exa-cel at the time
of the analysis, more than half (58.3%) have genotypes associated
with severe disease, beta-zero/beta-zero or other beta-zero-like
severe genotypes. At the time of the data cut, 27 TDT patients were
evaluable for the primary and key secondary endpoint.
- 24/27 (88.9%) achieved the primary endpoint of
transfusion-independence for at least 12 consecutive months (TI12)
and the secondary endpoint of transfusion-independence for at least
6 consecutive months (TI6) with a mean weighted hemoglobin of at
least 9 g/dL (95% CI: 70.8%, 97.6%; P<0.0001). Mean duration of
transfusion-independence was 20.5 months with a maximum of 40.7
months.
- Of the 3 patients who did not achieve TI12, one patient has
since stopped transfusions and has been transfusion-free for 2.9
months; the remaining 2 patients have had substantial reductions
(80% and 96%) in transfusion volume from baseline.
- Increases in total hemoglobin occurred early within the first
few months and were maintained over time. In the analysis of all
patients who received exa-cel, mean total hemoglobin was ≥11g/dL at
Month 3 and ≥12g/dL from Month 6 onward with pancellular
distribution of fetal hemoglobin.
- Mean proportion of edited BCL11A alleles was stable over time
in bone marrow and peripheral blood indicating successful permanent
editing in the long-term hematopoietic stem cells.
- Patients also had clinically significant improvements in
patient-reported outcomes.
Efficacy of exa-cel in Patients With Severe Sickle Cell
Disease
Of the 35 patients with SCD who had received exa-cel at the time
of the analysis, 17 patients were evaluable for the primary and key
secondary endpoint at the time of the data cut.
- 16/17 (94.1%) achieved the primary endpoint of freedom from
vaso-occlusive crises (VOCs) for at least 12 consecutive months
(VF12) (95% CI: 71.3%, 99.9%; P=0.0001). Mean duration of VOC-free
was 18.7 months, with a maximum of 36.5 months. 17/17 (100%)
achieved the key secondary endpoint of being free from
hospitalizations related to VOCs for at least 12 consecutive months
(HF12) (95% CI: 80.5%, 100.0%; P<0.0001).
- The one patient who did not achieve VF12 did achieve HF12 and
has a complex set of comorbidities, including a history of chronic
pain.
- One patient who achieved VF12 had a VOC 22.8 months following
exa-cel infusion in the setting of a parvovirus infection. This
patient has since fully recovered from the infection and been
VOC-free.
- Increases in fetal hemoglobin and total hemoglobin occurred
early, within the first few months, and were maintained over time.
In the analysis of all patients who received exa-cel, mean fetal
hemoglobin was more than 30% of total hemoglobin by Month 3 and was
then maintained at approximately 40.0% through follow-up, with
pancellular distribution.
- Mean proportion of edited BCL11A alleles was stable over time
in bone marrow and peripheral blood, indicating successful
permanent editing in the long-term hematopoietic stem cells.
- Patients also had clinically significant improvements in
patient-reported outcomes.
Safety of exa-cel in All Patients
The safety profile of exa-cel was generally consistent with
myeloablative conditioning with busulfan and autologous
hematopoietic stem cell transplant. All patients engrafted
neutrophils and platelets after exa-cel infusion.
As previously reported, two TDT patients had serious adverse
events (SAEs) considered related to exa-cel. One patient had three
SAEs considered related to exa-cel: hemophagocytic
lymphohistiocytosis (HLH), acute respiratory distress syndrome and
headache, and one SAE of idiopathic pneumonia syndrome that was
considered related to both exa-cel and busulfan. All four SAEs
occurred in the context of HLH in the peri-engraftment period and
have resolved. One patient had SAEs of delayed neutrophil
engraftment and thrombocytopenia, both of which were considered
related to exa-cel and busulfan, and both SAEs have resolved. Among
the 35 patients with SCD, there were no SAEs considered related to
exa-cel.
Also as previously reported, one adult patient with SCD
developed pneumonia and respiratory failure following SARS-CoV-2
infection, resulting in death. The investigator assessed the events
as not related to exa-cel. There were no other deaths or
discontinuations, and there have been no malignancies in either
study.
These data will be shared as outlined below:
Abstract S270 will be an oral presentation entitled “Transfusion
Independence and Elimination of Vaso-Occlusive Crises After
Exagamglogene Autotemcel For Transfusion-Dependent Βeta-Thalassemia
and Severe Sickle Cell Disease,” on Sunday, June 11 at 11:30 CEST.
This presentation will include updated pivotal trial data from
patients treated with exa-cel in CLIMB-111 and CLIMB-121 and
followed in CLIMB‑131. This abstract was chosen for the media
briefing program.
In addition, three health economics abstracts from Vertex
have been accepted for poster presentation on Friday, June 9 at
18:00 CEST.
- Abstract P1452 is entitled “Mortality and Clinical
Complications Among Patients With Transfusion-Dependent
Beta-Thalassemia in Italy.”
- Abstract P1447 is entitled “Mortality and Clinical
Complications Among Patients With Sickle Cell Disease With
Recurrent Vaso-Occlusive Crises in Italy.”
- Abstract P1464 is entitled “Clinical Complications Among
Patients With Transfusion-Dependent Beta-Thalassemia in
Germany.”
About exagamglogene autotemcel (exa-cel)
Exa-cel is an investigational, autologous, ex vivo CRISPR/Cas9
gene-edited cell therapy that is being evaluated for patients with
SCD or TDT, in which a patient’s own hematopoietic stem cells are
edited to produce high levels of fetal hemoglobin (HbF; hemoglobin
F) in red blood cells. HbF is the form of the oxygen-carrying
hemoglobin that is naturally present during fetal development,
which then switches to the adult form of hemoglobin after birth.
The elevation of HbF by exa-cel has the potential to reduce or
eliminate painful and debilitating VOCs for patients with SCD and
alleviate transfusion requirements for patients with TDT. Earlier
results from these ongoing trials were published in The New England
Journal of Medicine in January of 2021 and presented at the
American Society of Hematology Annual Congress in 2022.
Exa-cel has been granted Regenerative Medicine Advanced Therapy
(RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease
designations from the U.S. FDA for both TDT and SCD. The FDA has
accepted the Biologics License Applications (BLAs) for exa-cel and
assigned Prescription Drug User Fee Act (PDUFA) action dates of
December 8, 2023, for SCD and March 30, 2024, for TDT.
In the EU, exa-cel has been granted Orphan Drug Designation from
the European Commission, as well as Priority Medicines (PRIME)
designation from the European Medicines Agency (EMA), for both SCD
and TDT. In the U.K., exa-cel has also been granted an Innovation
Passport under the Innovative Licensing and Access Pathway (ILAP)
from the Medicines Healthcare products Regulatory Agency (MHRA). In
Europe, the Marketing Authorization Applications (MAAs) for exa-cel
were submitted in December 2022 and validated by the EMA and MHRA
in January 2023.
About CLIMB-111 and CLIMB-121
The ongoing Phase 1/2/3 open-label trials, CLIMB-111 and
CLIMB-121, are designed to assess the safety and efficacy of a
single dose of exa-cel in patients ages 12 to 35 years with TDT or
with SCD, characterized by recurrent VOCs, respectively. The trials
are now closed for enrollment. Patients will be followed for
approximately two years after exa-cel infusion. Each patient will
be asked to participate in CLIMB-131, a long-term follow-up
trial.
About CLIMB-131
The ongoing long-term, open-label trial, CLIMB-131, is designed
to evaluate the safety and efficacy of exa-cel in patients who
received exa-cel in CLIMB-111, CLIMB-121, CLIMB-141, CLIMB-151 or
CLIMB-161. The trial is designed to follow participants for up to
15 years after exa-cel infusion.
About CLIMB-141 and CLIMB-151
The ongoing Phase 3 open-label trials, CLIMB-141 and CLIMB-151,
are designed to assess the safety and efficacy of a single dose of
exa-cel in patients ages 2 to 11 years with TDT or with SCD,
characterized by recurrent VOCs, respectively. The trials are now
open for enrollment and currently enrolling patients ages 5 to 11
years with the plan to extend to ages 2 to less than 5 years at a
later date. Each trial will enroll approximately 15 patients.
Patients will be followed for approximately two years after
infusion. Each patient will be asked to participate in CLIMB-131, a
long-term follow-up trial.
About CLIMB-161
The ongoing Phase 3b trial, CLIMB-161, is to support expansion
of our manufacturing footprint after initial potential approval and
launch. This trial will enroll approximately 12 patients with
either TDT or with SCD, characterized by recurrent VOCs, ages 12 to
35 years. Patients will be followed for approximately one year
after infusion. Each patient will be asked to participate in
CLIMB-131, a long-term follow-up trial.
About the Gene-Editing Process in These Trials
Patients who enroll in these trials will have their own
hematopoietic stem and progenitor cells collected from peripheral
blood. The patient’s cells will be edited using the CRISPR/Cas9
technology. The edited cells, exa-cel, will then be infused back
into the patient as part of an autologous hematopoietic stem cell
transplant (HSCT), a process which involves a patient being treated
with myeloablative busulfan conditioning. Patients undergoing HSCT
may also encounter side effects (ranging from mild to severe) that
are unrelated to the administration of exa-cel. Patients will
initially be monitored to determine when the edited cells begin to
produce mature blood cells, a process known as engraftment. After
engraftment, patients will continue to be monitored to track the
impact of exa-cel on multiple measures of disease and for
safety.
About the Vertex and CRISPR Collaboration
Vertex and CRISPR Therapeutics entered into a strategic research
collaboration in 2015 focused on the use of CRISPR/Cas9 to discover
and develop potential new treatments aimed at the underlying
genetic causes of human disease. ‑Exa-cel represents the first
potential treatment to emerge from the joint research program.
Under an amended collaboration agreement, Vertex now leads global
development, manufacturing and commercialization of exa-cel and
splits program costs and profits worldwide 60/40 with CRISPR
Therapeutics.
About Vertex
Vertex is a global biotechnology company that invests in
scientific innovation to create transformative medicines for people
with serious diseases. The company has multiple approved medicines
that treat the underlying cause of cystic fibrosis (CF) — a rare,
life-threatening genetic disease — and has several ongoing clinical
and research programs in CF. Beyond CF, Vertex has a robust
clinical pipeline of investigational small molecule, mRNA, cell and
genetic therapies (including gene editing) in other serious
diseases where it has deep insight into causal human biology,
including sickle cell disease, beta thalassemia, APOL1-mediated
kidney disease, acute and neuropathic pain, type 1 diabetes and
alpha-1 antitrypsin deficiency.
Founded in 1989 in Cambridge, Mass., Vertex's global
headquarters is now located in Boston's Innovation District and its
international headquarters is in London. Additionally, the company
has research and development sites and commercial offices in North
America, Europe, Australia and Latin America. Vertex is
consistently recognized as one of the industry's top places to
work, including 13 consecutive years on Science magazine's Top
Employers list and one of Fortune’s 100 Best Companies to Work For.
For company updates and to learn more about Vertex's history of
innovation, visit www.vrtx.com or follow us on Facebook, Twitter,
LinkedIn, YouTube and Instagram.
(VRTX-GEN)
Vertex Special Note Regarding Forward-Looking
Statements
This press release contains forward-looking statements as
defined in the Private Securities Litigation Reform Act of 1995, as
amended, including, without limitation, statements made by Carmen
Bozic, M.D., and Franco Locatelli, M.D., Ph.D., in this press
release, our expectations for the therapeutic value of exa-cel, our
plans and expectations to present updated clinical data for exa-cel
at EHA, our plans for additional abstracts for poster presentation
and publication at EHA, the status of our clinical trials of our
product candidates under development by us and our collaborators,
including activities at the clinical trial sites, the gene-editing
process, patient enrollment and expectations regarding clinical
trial follow-up. While Vertex believes the forward-looking
statements contained in this press release are accurate, these
forward-looking statements represent the company's beliefs only as
of the date of this press release and there are a number of risks
and uncertainties that could cause actual events or results to
differ materially from those expressed or implied by such
forward-looking statements. Those risks and uncertainties include,
among other things, that data from a limited number of patients may
not be indicative of final clinical trial results, that regulatory
authorities may not approve, or approve on a timely basis, the
exa-cel applications, that data from the company's development
programs, including its programs with its collaborators, may not
support registration or further development of its compounds due to
safety, efficacy or other reasons, that internal or external
factors that could delay, divert, or change our plans and
objectives with respect to our exa-cel program, that future
competitive or other market factors may adversely affect the
commercial potential for exa-cel, and other risks listed under the
heading “Risk Factors” in Vertex's most recent annual report and
subsequent quarterly reports filed with the Securities and Exchange
Commission (SEC) and available through the company's website at
www.vrtx.com and on the SEC’s website at www.sec.gov. You should
not place undue reliance on these statements or the scientific data
presented. Vertex disclaims any obligation to update the
information contained in this press release as new information
becomes available.
(CRSP-GEN)
About CRISPR Therapeutics
CRISPR Therapeutics is a leading gene editing company focused on
developing transformative gene-based medicines for serious diseases
using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a
revolutionary gene editing technology that allows for precise,
directed changes to genomic DNA. CRISPR Therapeutics has
established a portfolio of therapeutic programs across a broad
range of disease areas including hemoglobinopathies, oncology,
regenerative medicine and rare diseases. To accelerate and expand
its efforts, CRISPR Therapeutics has established strategic
collaborations with leading companies including Bayer, Vertex
Pharmaceuticals and ViaCyte, Inc. CRISPR Therapeutics AG is
headquartered in Zug, Switzerland, with its wholly-owned U.S.
subsidiary, CRISPR Therapeutics, Inc., and R&D operations in
Boston, Massachusetts and San Francisco, California, and business
offices in London, United Kingdom. For more information, please
visit www.crisprtx.com.
CRISPR THERAPEUTICS® word mark and design are trademarks and
registered trademarks of CRISPR Therapeutics AG. All other
trademarks and registered trademarks are the property of their
respective owners.
CRISPR Therapeutics Forward-Looking Statement
This press release may contain a number of “forward-looking
statements” within the meaning of the Private Securities Litigation
Reform Act of 1995, as amended, including statements made by Carmen
Bozic, M.D., and Franco Locatelli, M.D., Ph.D., in this press
release, as well as statements regarding CRISPR Therapeutics’
expectations about any or all of the following: i) the safety,
efficacy and clinical progress of the ongoing exa-cel clinical
trials, including expectations regarding the clinical data being
presented, the therapeutic value of exa-cel, and our plans to
present the clinical data during the EHA Congress; and (ii) the
therapeutic value, development, and commercial potential of
CRISPR/Cas9 gene editing technologies and therapies. Without
limiting the foregoing, the words “believes,” “anticipates,”
“plans,” “expects” and similar expressions are intended to identify
forward-looking statements. You are cautioned that forward-looking
statements are inherently uncertain. Although CRISPR Therapeutics
believes that such statements are based on reasonable assumptions
within the bounds of its knowledge of its business and operations,
existing and prospective investors are cautioned that
forward-looking statements are inherently uncertain, are neither
promises nor guarantees and not to place undue reliance on such
statements, which speak only as of the date they are made. Actual
performance and results may differ materially from those projected
or suggested in the forward-looking statements due to various risks
and uncertainties. These risks and uncertainties include, among
others: the potential that data from a limited number of patients
may not to be indicative of final or future clinical trial results;
the potential that the exa-cel clinical trial results may not be
favorable or may not support registration or further development;
that future competitive or other market factors may adversely
affect the commercial potential for exa-cel; CRISPR Therapeutics
may not realize the potential benefits of its collaboration with
Vertex; uncertainties regarding the intellectual property
protection for CRISPR Therapeutics’ technology and intellectual
property belonging to third parties; and those risks and
uncertainties described under the heading “Risk Factors” in CRISPR
Therapeutics’ most recent annual report on Form 10-K, quarterly
report on Form 10-Q, and in any other subsequent filings made by
CRISPR Therapeutics with the U.S. Securities and Exchange
Commission, which are available on the SEC's website at
www.sec.gov. CRISPR Therapeutics disclaims any obligation or
undertaking to update or revise any forward-looking statements
contained in this press release, other than to the extent required
by law.
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version on businesswire.com: https://www.businesswire.com/news/home/20230609005104/en/
Vertex Pharmaceuticals Incorporated Investors:
Susie Lisa, +1 617-341-6108 Or Manisha Pai, +1 617-961-1899 Or
Miroslava Minkova, +1 617-341-6135
Media: mediainfo@vrtx.com or U.S.: +1 617-341-6992 or
Heather Nichols: +1 617-839-3607 or International: +44 20 3204
5275
CRISPR Therapeutics Investors: Susan Kim, +1
617-307-7503 susan.kim@crisprtx.com
Media: Rachel Eides, +1-617-315-4493
rachel.eides@crisprtx.com
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