- First oral presentation of full Phase 2 trial results with
overall response rate (ORR), inclusive of complete and partial
remission rates(1)
- Results also presented from a separate investigational
Phase 1b study in CLL/small lymphocytic leukemia (SLL) patients
receiving venetoclax in combination with rituximab after at least
one prior therapy(2)
NORTH CHICAGO, Illinois,
June 23, 2017 /PRNewswire/
-- AbbVie (NYSE: ABBV), a global biopharmaceutical company,
today announced the presentation of results from the pivotal Phase
2 study of VENCLYXTO™ (venetoclax), a first-in-class oral B-cell
lymphoma-2 (BCL-2) inhibitor. VENCLYXTO monotherapy responses in
158 patients with relapsed/refractory chronic lymphocytic leukemia
(CLL) and 17p deletion showed that 77 percent (95% confidence
interval [CI]: 69.9, 83.5) achieved an overall response rate (ORR =
complete remission [CR] + complete remission with incomplete marrow
recovery [Cri] + partial remission [PR] + nodular partial remission
[nPR]) (primary endpoint),1 18 percent achieved a
complete remission (CR +CRi) (secondary endpoint), 53 percent
achieved a partial remission (PR), 6 percent achieved an
nPR,3 and 27 percent achieved blood minimal residual
disease (MRD) negativity, as measured by flow cytometry
(exploratory endpoint).1 These results, which were based
on an investigator assessment, will be presented in an oral session
on Sunday, June 25, at the
22nd European Hematology Association (EHA) Annual
Congress in Madrid.
VENCLYXTO monotherapy was granted conditional marketing
authorization in the EU for the treatment of CLL in the presence of
17p deletion or TP53 mutation in adult patients who are unsuitable
for or have failed a B-cell receptor pathway inhibitor; and for the
treatment of CLL in the absence of 17p deletion or TP53 mutation in
adult patients who have failed both chemoimmunotherapy and a B-cell
receptor pathway inhibitor.3 VENCLYXTO is being
developed by AbbVie and Roche. It is jointly commercialized by
AbbVie and Genentech, a member of the Roche Group, in the U.S. and
by AbbVie outside of the U.S.
"These response rates associated with venetoclax treatment in
patients with CLL and 17p deletion who relapsed or were refractory
to prior treatments were evaluated in one of the two pivotal
studies that were included in the EU summary of product
characteristics for VENCLYXTO for use in this patient population,"
said Prof. Dr. Stephan Stilgenbauer
of the Department of Internal Medicine at Ulm University in
Germany, who will present the
study results at the EHA Annual Congress. "In addition, we are
encouraged by the results of the secondary and exploratory
endpoints included in this Phase 2 trial."
Design and Results of Pivotal Phase 2 Study Presented at EHA
Congress
In the pivotal Phase 2 study, patients with
relapsed/refractory CLL harboring 17p deletion received VENCLYXTO
400 mg daily following a four to five-week dose titration phase
until they experienced progressive disease or discontinued due to
other reasons.1 Assessment of minimal residual disease
(MRD) in peripheral blood was performed with the first clinical
assessment of complete remission (CR) or partial remission (PR)
with nodes less than 2 cm and then every 12 weeks until MRD
negativity.1 This means fewer than one CLL cell in
10,000 leukocytes (white blood cells) could be
detected.4 A total of 158 study participants had
received a median of two prior therapies, and 11 percent had
previously received a B-cell receptor signaling
inhibitor.1 The median age of study participants was 67
years, and the median duration of VENCLYXTO therapy was 16.7 months
(range: 0-34.4).1
An initial analysis of results from 107 patients by an
independent review committee showed that VENCLYXTO resulted in an
overall response rate (ORR = CR + CRi + PR +nPR) of 79 percent (95%
confidence interval [CI]: 70.5, 86.6), a CR +CRi rate of 7 percent,
a PR rate of 69 percent, and an nPR rate of 3 percent.3
Subsequently, 51 additional patients were enrolled in a safety
expansion cohort.1 Results of the full study cohort of
158 patients showed the investigator-assessed ORR was 77 percent
(95% CI: 69.9, 83.5),1 the CR +CRi rate was 18 percent,
the PR rate was 53 percent, and the nPR rate was 6
percent.3 Among 18 patients who had received prior BCR
inhibitor treatment, the ORR was 61 percent and the CR rate was 11
percent.1 Among the full trial cohort of 158 patients,
27 percent demonstrated MRD negativity (exploratory endpoint) in
peripheral blood by flow cytometry.1 A total of 101
patients were evaluable for blood MRD by flow
cytometry.1 Progression-free survival (PFS) and overall
survival (OS) (secondary endpoints) over 24 months were estimated
to be 52 percent and 72 percent, respectively.1
In the study, the most commonly reported adverse events were
neutropenia (42 percent), nausea (37 percent), diarrhea (37
percent), anemia (24 percent) and fatigue (22 percent).1
The most common grade 3-4 adverse events were neutropenia (39
percent), thrombocytopenia (15 percent) and anemia (14 percent).
Infection rate (77 percent all grades, 22 percent grade 3-4) and
spectrum were consistent with the underlying
disease.1 The rate of laboratory tumor lysis
syndrome (TLS) was 5 percent, with no cases of clinical
TLS.1
Phase 1b Venetoclax Data Presented at EHA Congress
Results from an ongoing Phase 1b investigational study of
venetoclax were also presented at the EHA Congress. This
open-label, multicenter study is evaluating the safety and
tolerability of venetoclax in combination with rituximab in
patients with relapsed CLL/small lymphocytic leukemia
(SLL).5 The primary objectives of this study are to
assess the safety profile, determine the maximum tolerated dose,
and establish the recommended Phase 2 dose of venetoclax when
administered in combination with rituximab.5
This analysis evaluated responses in 49 patients with
previously-treated CLL/SLL who were treated with venetoclax and
rituximab therapy.2 Patients who achieved CR or MRD
negativity could stop therapy and remain on the study. Patients who
manifested progressive disease (per iWCLL criteria) while off
therapy could re-initiate venetoclax and subsequent rituximab
therapy. A total of 21 patients discontinued the study.2
A total of 12 had progressive disease while on therapy (five with
Richter's transformation and seven with CLL
progression).2 The other nine patients either withdrew
consent (five), failed to report for follow-up evaluations (one),
discontinued due to adverse events related to venetoclax (one with
tumor lysis syndrome and one with worsening peripheral neuropathy)
or discontinued due to adverse events considered not related to
therapy (one).2 A total of 16 patients stopped
venetoclax per protocol.2
In the Phase 1b study, the most commonly reported adverse events
were upper respiratory tract infection, neutropenia and mild GI
issues. Grade 3-4 adverse events were reported for 37 patients (76
percent); the most common were neutropenia (53 percent),
thrombocytopenia (16 percent) and anemia (14
percent).2
As of April 5, 2017, the ORR was
86 percent. 51 percent of patients had achieved an
investigator-assessed CR/CRi, 35 percent had achieved PR/nPR, and
59 percent had achieved MRD negativity.2
"We are encouraged by the early results from this Phase 1b study
of continuous venetoclax in patients with relapsed/refractory
CLL/SLL and in those who received venetoclax in combination with
rituximab," said Gary Gordon, M.D.,
Ph.D., vice president, oncology clinical development, AbbVie. "We
remain committed to developing and delivering therapies that
address unmet needs in certain patients with CLL."
About VENCLYXTO™ (venetoclax)
VENCLYXTO™
(venetoclax), an oral B-cell lymphoma-2 (BCL-2) inhibitor, is
indicated for the treatment of chronic lymphocytic leukaemia (CLL)
in the presence of 17p deletion or TP53 mutation in adult patients
who are unsuitable for or have failed a B-cell receptor pathway
inhibitor; and for the treatment of CLL in the absence of 17p
deletion or TP53 mutation in adult patients who have failed both
chemoimmunotherapy and a B-cell receptor pathway
inhibitor.3 It is also being evaluated for the treatment
of patients with various blood cancer
types.3,6,7,8,9 The
BCL-2 protein prevents apoptosis (programmed cell death) of some
cells, including lymphocytes, and can be overexpressed in CLL
cells.3 VENCLYXTO, which is given once-daily, is
designed to selectively inhibit the function of the BCL-2
protein.3
VENCLYXTO is being developed by AbbVie and Roche. It is jointly
commercialized by AbbVie and Genentech, a member of the Roche
Group, in the U.S. and by AbbVie outside of the U.S. Together, the
companies are committed to BCL-2 research with venetoclax, which is
currently being evaluated in Phase 3 clinical trials for the
treatment of relapsed/refractory CLL and frontline CLL, along with
studies in several other cancers.
Venetoclax is currently approved in several countries in
Europe, as well as in Argentina, Australia, Mexico, Puerto
Rico, Israel, USA, and Canada. AbbVie, in
collaboration with Roche and Genentech, is currently working with
regulatory agencies around the world to bring this medicine to
eligible patients in need.
Important VENCLYXTO (venetoclax) EU Safety
Information
Contraindications
Hypersensitivity to the active substance or to any of the
excipients. Concomitant use of strong CYP3A inhibitors at
initiation and during the dose-titration phase. Concomitant use of
preparations containing St. John's
wort.
Special Warnings & Precautions for Use
Tumour
lysis syndrome (TLS), including fatal events, has occurred in
patients with previously treated CLL with high tumour burden when
treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the
initial 5-week dose-titration phase. Changes in electrolytes
consistent with TLS that require prompt management can occur as
early as 6 to 8 hours following the first dose of VENCLYXTO and at
each dose increase. Patients should be assessed for risk and should
receive appropriate prophylaxis for TLS. Blood chemistries
should be monitored and abnormalities managed promptly. More
intensive measures (including IV hydration, frequent monitoring and
hospitalization) should be employed as overall risk increases.
Neutropenia (grade 3 or 4) has been reported and complete blood
counts should be monitored throughout the treatment
period.
Live vaccines should not be administered during treatment or
thereafter until B-cell recovery.
Drug Interactions
CYP3A inhibitors may increase
VENCLYXTO plasma concentrations. At initiation and dose-titration
phase: Strong CYP3A inhibitors are contraindicated due to increased
risk for TLS and moderate CYP3A inhibitors should be
avoided. If moderate CYP3A inhibitors must be used, physicians
should refer to the SmPC for dose adjustment recommendations. At
steady daily dose: If moderate or strong CYP3A inhibitors must be
used, physicians should refer to the SmPC for dose adjustment
recommendations.
Avoid concomitant use of P-gp and BCRP inhibitors at initiation
and during the dose titration phase. CYP3A4 inducers may decrease
VENCLYXTO plasma concentrations.
Avoid coadministration with strong or moderate CYP3A
inducers. These agents may decrease venetoclax plasma
concentrations.
Co-administration of bile acid sequestrants with VENCLYXTO is
not recommended as this may reduce the absorption of VENCLYXTO.
Adverse Reactions
The most commonly occurring adverse
reactions (>=20%) of any grade were neutropenia/neutrophil count
decreased, diarrhoea, nausea, anemia, upper respiratory tract
infection, fatigue, hyperphosphatemia, vomiting and
constipation.
The most frequently occurring adverse reactions (>=2%) were
pneumonia, febrile neutropenia and TLS.
Discontinuations due to adverse reactions occurred in 9.1% of
patients and dosage adjustments due to adverse reactions occurred
in 11.8% of patients.
Specific Populations
VENCLYXTO may cause embryo-fetal harm when administered to a
pregnant woman. Advise females of reproductive potential to avoid
pregnancy during treatment. Advise nursing women to discontinue
breastfeeding during treatment.
This is not a complete summary of all safety
information. See VENCLYXTO full summary of product
characteristics (SmPC) at www.ema.europa.eu.
Globally, prescribing information varies; refer to the individual
country product label for complete information.
About AbbVie in Oncology
At AbbVie, we strive to
discover and develop medicines that deliver transformational
improvements in cancer treatment by uniquely combining our deep
knowledge in core areas of biology with cutting-edge technologies,
and by working together with our partners – scientists, clinical
experts, industry peers, advocates, and patients. We remain focused
on delivering these transformative advances in treatment across
some of the most debilitating and widespread cancers. We are also
committed to exploring solutions to help patients obtain access to
our cancer medicines. With the acquisitions of Pharmacyclics
in 2015 and Stemcentrx in 2016, our research and development
efforts, and through collaborations, AbbVie's oncology portfolio
now consists of marketed medicines and a pipeline containing
multiple new molecules being evaluated worldwide in more than 200
clinical trials and more than 20 different tumor types. For more
information, please visit http://abbvieoncology.com.
About AbbVie
AbbVie is a global, research-driven
biopharmaceutical company committed to developing innovative
advanced therapies for some of the world's most complex and
critical conditions. The company's mission is to use its expertise,
dedicated people and unique approach to innovation to markedly
improve treatments across four primary therapeutic areas:
immunology, oncology, virology and neuroscience. In more than
75 countries, AbbVie employees are working every day to advance
health solutions for people around the world. For more information
about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on
Twitter, Facebook or LinkedIn.
AbbVie Forward-Looking Statements
Some statements in
this news release may be forward-looking statements for purposes of
the Private Securities Litigation Reform Act of 1995. The words
"believe," "expect," "anticipate," "project" and similar
expressions, among others, generally identify forward-looking
statements. AbbVie cautions that these forward-looking statements
are subject to risks and uncertainties that may cause actual
results to differ materially from those indicated in the
forward-looking statements. Such risks and uncertainties include,
but are not limited to, challenges to intellectual property,
competition from other products, difficulties inherent in the
research and development process, adverse litigation or government
action, and changes to laws and regulations applicable to our
industry.
Additional information about the economic, competitive,
governmental, technological and other factors that may affect
AbbVie's operations is set forth in Item 1A, "Risk Factors," in
AbbVie's 2016 Annual Report on Form 10-K, which has been filed with
the Securities and Exchange Commission. AbbVie undertakes no
obligation to release publicly any revisions to forward-looking
statements as a result of subsequent events or developments, except
as required by law.
References
_______________________________
1 Stilgenbauer S,
et al. Venetoclax in relapsed/refractory chronic lymphocytic
leukemia (CLL) with 17p deletion: outcome and minimal residual
disease from the full population of the pivotal M13-982 trial.
Presented at the 2017 European Hematology Association Congress,
June 25, 2017.
2 Anderson MA, et al. Durability of responses on
continuous therapy and following drug cessation in deep responders
with venetoclax and rituximab. Poster at the 2017 European
Hematology Association Congress, June 23,
2017.
3 Summary of Product Characteristics for VENCLYXTO,
December 2016.
4 EMA (2014) Guidelines on the use of MRD endpoint in
CLL. Accessed June 2017.
5 Clinicaltrials.gov. NCT01682616: A Phase 1b Study
Evaluating the Safety and Tolerability of ABT-199 in Combination
With Rituximab in Subjects With Relapsed Chronic
Lymphocytic Leukemia and Small Lymphocytic Lymphoma. Accessed
June 2017.
6 Clinicaltrials.gov. NCT01994837: A Phase 2 Study of
ABT-199 in subjects with Acute Myelogenous Leukemia (AML). Accessed
October 2016.
7 Clinicaltrials.gov. NCT01794520: Study evaluating
ABT-199 in subjects with relapsed or refractory Multiple Myeloma.
Accessed October 2016.
8 Clinicaltrials.gov. NCT01328626: A Phase 1 study
evaluating the safety and pharmacokinetics of ABT-199 in subjects
with relapsed or refractory Chronic Lymphocytic Leukemia and
Non-Hodgkin Lymphoma. Accessed October
2016.
9 Clinicaltrials.gov. NCT01889186: A study of the
efficacy of ABT-199 in subjects with relapsed or refractory chronic
lymphocytic leukemia with the 17p deletion. Accessed October 2016.