NORTH CHICAGO, Ill.,
June 24, 2019 /PRNewswire/
-- AbbVie (NYSE: ABBV), a research-based global
biopharmaceutical company, today announced that the U.S. Food and
Drug Administration (FDA) has lifted the partial clinical hold
placed on CANOVA (M13-494), a Phase 3 trial evaluating venetoclax
(VENCLEXTA® OR VENCLYXTO®) for the
investigational treatment of relapsed/refractory multiple myeloma.
The CANOVA trial evaluates venetoclax in combination with
dexamethasone versus pomalidomide in combination with
dexamethasone in patients with relapsed/refractory multiple myeloma
positive for the translocation (11;14) abnormality. The t(11;14)
genetic biomarker is among the most common and routinely tested
genetic abnormalities in patients with multiple
myeloma.1
The FDA removed the partial clinical hold based upon agreement
on revisions to the CANOVA study protocol, including new risk
mitigation measures, protocol-specified guidelines and updated
futility criteria. Enrollment in the CANOVA trial may resume as
determined by each participant site based on the approved
protocol.
All other clinical trials evaluating venetoclax in patients with
multiple myeloma remain on partial clinical hold while next steps
continue to be evaluated with the agency. The partial clinical hold
does not impact any of the approved indications for venetoclax,
such as chronic lymphocytic leukemia (CLL) or acute myeloid
leukemia (AML). AbbVie remains confident in the benefit/risk
profile of venetoclax in those approved indications.
"We are pleased to move forward with the CANOVA study which,
with the t(11;14) biomarker test, can help identify patients who
may respond better to treatment and add clarity for physicians when
choosing a therapy, if approved," said Mohamed Zaki, M.D., Ph.D., global head of
hematology development, AbbVie. "We are working closely with
regulatory authorities worldwide to continue our efforts to
understand the potential of venetoclax for patients with multiple
myeloma while continuing to advance research in patients with the
t(11;14) genetic abnormality."
Results from the Phase 3 BELLINI trial evaluating patients with
relapsed/refractory multiple myeloma were presented at the 24th
European Hematology Association (EHA) Annual Congress during the
late-breaking oral presentation session on Sunday, June 16. Additional data will be
presented at a future congress or published in a medical
journal.2
In March 2019, AbbVie announced
the FDA placed a partial clinical hold on all trials
evaluating venetoclax for the investigational treatment of multiple
myeloma, following a review of data from the Phase 3 BELLINI trial
of venetoclax with bortezomib and dexamethasone (Ven + Vd) versus
placebo (placebo + Vd) in patients with relapsed/refractory
multiple myeloma, in which a higher proportion of deaths (41/194
(21%)) was observed in the venetoclax arm compared to the control
arm of the trial (11/97 (11%) — overall survival hazard ratio (HR)
2.027, 95% confidence interval (CI): [1.042, 3.945]). Progressive
disease was the most common cause (45%) of death. The rates of
serious adverse events (AEs) (48% vs 50%) and serious infections
(28% vs 27%) were comparable between arms.2
Venetoclax is not approved by any regulatory authority, in any
country for the treatment of multiple myeloma.
Despite the availability of multiple myeloma therapies, there is
no optimal treatment sequence.3 Nearly all multiple
myeloma patients eventually relapse, which is associated with poor
outcomes, and each remission is typically shorter than the previous
one.4 Patients with multiple myeloma have an average
life expectancy of approximately five to six years after
diagnosis.5 It is the second most common blood cancer
with nearly 140,000 cases expected to be diagnosed worldwide this
year.6,7
Venetoclax 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.
About CANOVA
CANOVA is a Phase 3, multicenter, randomized, open label study of
either venetoclax or pomalidomide in combination with dexamethasone
in patients with t(11;14)-positive relapsed/refractory multiple
myeloma.8
About BELLINI
BELLINI is a multicenter, randomized,
double blind study of either venetoclax or placebo in combination
with bortezomib and dexamethasone in patients with
relapsed/refractory multiple myeloma who have received 1 to 3 prior
lines of therapy and are sensitive or naïve to proteasome
inhibitors. The study included 291 patients with 194 in the
venetoclax arm and 97 in the placebo
arm.9
The BELLINI trial met its primary endpoint of improved
progression-free survival (PFS) (22.4 months vs. 11.5 months,
[hazard ratio=0.63, p=0.01]), with a median follow-up of 18.7
months, and demonstrated statistically significant improvement in
overall response rate (ORR) (82% vs. 68%, p<0.01) and very good
partial or better response (59% vs. 36%, p<0.01) in the
venetoclax arm compared to the control arm. Median overall survival
was not reached (HR 2.027, 95% CI (1.042,
3.945)).2
Safety analyses showed the majority of deaths in the venetoclax
arm were related to infection and progressive disease. There were
52 deaths in the study population, 41 (21%) in the venetoclax arm
and 11 (12%) in the placebo arm, with progressive disease the most
common cause (45%). The rates of serious AEs (48% vs 50%) and
serious infections (28% vs 27%) were comparable between
arms.2
About VENCLEXTA®/VENCLYXTO®
(venetoclax)
VENCLEXTA®/VENCLYXTO® (venetoclax) is a
first-in-class medicine that selectively binds and inhibits the
B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2
prevents cancer cells from undergoing their natural death or
self-destruction process, called apoptosis. VENCLEXTA/VENCLYXTO
targets the BCL-2 protein and works to help restore the process of
apoptosis.10
VENCLEXTA/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 and to
studying venetoclax in clinical trials across several blood and
other cancers.
VENCLEXTA/VENCLYXTO is approved in more than 50 countries,
including the U.S. Venetoclax is not approved by any
regulatory authority, in any country for the treatment of multiple
myeloma. AbbVie, in collaboration with Roche, is currently working
with regulatory agencies around the world to bring this medicine to
additional eligible patients in need.
Uses and Important
VENCLEXTA® (venetoclax) U.S. Safety
Information10
Uses
VENCLEXTA is a prescription medicine used:
- to treat adults with chronic lymphocytic leukemia (CLL) or
small lymphocytic lymphoma (SLL), with or without 17p deletion, who
have received at least one prior treatment.
- in combination with azacitidine, or decitabine, or low-dose
cytarabine to treat adults with newly-diagnosed acute myeloid
leukemia (AML) who:
-
- are 75 years of age or older, or
- have other medical conditions that prevent the use of standard
chemotherapy.
It is not known if VENCLEXTA is safe and effective in
children.
Important Safety Information
What is the most important information I should know about
VENCLEXTA?
VENCLEXTA can cause serious side effects, including:
Tumor lysis syndrome (TLS). TLS is caused by the
fast breakdown of cancer cells. TLS can cause kidney failure, the
need for dialysis treatment, and may lead to death. Your
healthcare provider will do tests to check your risk of getting TLS
before you start taking VENCLEXTA. You will receive other medicines
before starting and during treatment with VENCLEXTA to help reduce
your risk of TLS. You may also need to receive intravenous (IV)
fluids into your vein. Your healthcare provider will do blood tests
to check for TLS when you first start treatment and during
treatment with VENCLEXTA.
It is important to keep your appointments for blood tests.
Tell your healthcare provider right away if you have any symptoms
of TLS during treatment with VENCLEXTA, including fever, chills,
nausea, vomiting, confusion, shortness of breath, seizures,
irregular heartbeat, dark or cloudy urine, unusual tiredness, or
muscle or joint pain.
Drink plenty of water when taking VENCLEXTA to help reduce
your risk of getting TLS.
Drink 6 to 8 glasses (about 56 ounces total) of water each day,
starting 2 days before your first dose, on the day of your first
dose of VENCLEXTA, and each time your dose is increased.
Your healthcare provider may delay, decrease your dose, or stop
treatment with VENCLEXTA if you have side effects.
Who should not take VENCLEXTA?
Certain medicines must not be taken when you first start
taking VENCLEXTA and while your dose is being slowly increased
because of the risk of increased TLS.
- Tell your healthcare provider about all the medicines you
take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements. VENCLEXTA and other
medicines may affect each other, causing serious side effects.
- Do not start new medicines during treatment with VENCLEXTA
without first talking with your healthcare provider.
Before taking VENCLEXTA, tell your healthcare provider about
all of your medical conditions, including if you:
- have kidney problems.
- have problems with your body salts or electrolytes, such as
potassium, phosphorus, or calcium.
- have a history of high uric acid levels in your blood or
gout.
- are scheduled to receive a vaccine. You should not receive a
"live vaccine" before, during, or after treatment with VENCLEXTA,
until your healthcare provider tells you it is okay. If you are not
sure about the type of immunization or vaccine, ask your healthcare
provider. These vaccines may not be safe or may not work as well
during treatment with VENCLEXTA.
- are pregnant or plan to become pregnant. VENCLEXTA may harm
your unborn baby. If you are able to become pregnant, your
healthcare provider should do a pregnancy test before you start
treatment with VENCLEXTA, and you should use effective birth
control during treatment and for 30 days after the last dose of
VENCLEXTA. If you become pregnant or think you are pregnant, tell
your healthcare provider right away.
- are breastfeeding or plan to breastfeed. It is not known if
VENCLEXTA passes into your breast milk. Do not breastfeed during
treatment with VENCLEXTA.
What should I avoid while taking VENCLEXTA?
You should
not drink grapefruit juice or eat
grapefruit, Seville oranges (often used in marmalades),
or starfruit while you are taking VENCLEXTA. These products
may increase the amount of VENCLEXTA in your blood.
What are the possible side effects of VENCLEXTA?
VENCLEXTA can cause serious side effects, including:
- Low white blood cell counts (neutropenia). Low
white blood cell counts are common with VENCLEXTA, but can also be
severe. Your healthcare provider will do blood tests to check your
blood counts during treatment with VENCLEXTA.
- Infections. Death and serious infections such as
pneumonia and blood infection (sepsis) have happened during
treatment with VENCLEXTA. Your healthcare provider will closely
monitor and treat you right away if you have a fever or any signs
of infection during treatment with VENCLEXTA.
Tell your healthcare provider right away if you have a fever or
any signs of an infection during treatment with VENCLEXTA.
The most common side effects of VENCLEXTA when used in
combination with obinutuzumab or rituximab or alone in people with
CLL or SLL include low white blood cell counts; low
platelet counts; low red blood cell counts; diarrhea; nausea; upper
respiratory tract infection; cough; muscle and joint pain;
tiredness; and swelling of your arms, legs, hands, and feet.
The most common side effects of VENCLEXTA in combination with
azacitidine or decitabine or low-dose cytarabine in people with AML
include low white blood cell counts; nausea; diarrhea; low
platelet counts; constipation; fever with low white blood cell
counts; low red blood cell counts; infection in blood; rash;
dizziness; low blood pressure; fever; swelling of your arms, legs,
hands, and feet; vomiting; tiredness; shortness of breath;
bleeding; infection in lung; stomach (abdominal) pain; pain in
muscles or back; cough; and sore throat.
VENCLEXTA may cause fertility problems in males. This may
affect your ability to father a child. Talk to your healthcare
provider if you have concerns about fertility.
These are not all the possible side effects of VENCLEXTA. For
more information, ask your healthcare provider or pharmacist.
You are encouraged to report negative side effects of
prescription drugs to the FDA.
Visit http://www.fda.gov/medwatch or call
1-800-FDA-1088.
If you cannot afford your medication,
contact: www.pparx.org for assistance.
The full U.S. prescribing information, including Medication
Guide, for VENCLEXTA can be found here. Globally,
prescribing information varies; refer to the individual country
product label for complete information.
Use and Important
VENCLYXTO® (venetoclax) EU Safety
Information11
VENCLYXTO (venetoclax) Indication
Venclyxto in combination with rituximab is indicated for
the treatment of adult patients with chronic
lymphocytic leukaemia(CLL) who have received at least one
prior therapy.
Venclyxto monotherapy is indicated 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, or
- in the absence of 17p deletion or TP53 mutation
in adult patients who have failed both chemo immunotherapy and
a B-cell receptor pathway inhibitor.
Important VENCLYXTO (venetoclax) EU Safety
Information
Contraindications
Hypersensitivity to the active
substance or to any of the excipients is contraindicated.
Concomitant use of strong CYP3A inhibitors at initiation and during
the dose-titration phase due to increased risk for tumor lysis
syndrome (TLS). Concomitant use of preparations containing
St. John's wort as VENCLYXTO
efficacy may be reduced.
Special Warnings & Precautions for Use
Tumor lysis
syndrome (TLS), including fatal events, has occurred in patients
with previously treated CLL with high tumor 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, monitoring, and management for TLS.
Neutropenia (grade 3 or 4) has been reported and complete blood
counts should be monitored throughout the treatment period. Serious
infections including events of sepsis with fatal outcome have been
reported. Supportive measures including antimicrobials for any
signs of infection should be considered.
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 in patients receiving venetoclax
in the combination study with rituximab were neutropenia, diarrhea,
and upper respiratory tract infection. In the monotherapy studies,
the most common adverse reactions were neutropenia/neutrophil count
decreased, diarrhea, nausea, anemia, fatigue, and upper respiratory
tract infection.
The most frequently occurring serious adverse reactions
(>=2%) in patients receiving venetoclax in combination with
rituximab or as monotherapy were pneumonia, febrile neutropenia and
TLS.
Discontinuation due to adverse reactions occurred in 16% of
patients receiving venetoclax plus rituximab and 9% receiving
venetoclax monotherapy. Dosage adjustments due to adverse reactions
occurred in 15% of patients receiving venetoclax plus rituximab and
2% receiving venetoclax monotherapy. Dose interruptions occurred in
71% of patients treated with the combination of venetoclax and
rituximab.
Specific Populations
Patients with reduced renal
function (CrCl <80 mL/min) may require more intensive
prophylaxis and monitoring to reduce the risk of TLS. Safety in
patients with severe renal impairment (CrCl <30 mL/min) or on
dialysis has not been established, and a recommended dose for these
patients has not been determined. VENCLYXTO should be administered
to patients with severe renal impairment only if the benefit
outweighs the risk and patients should be monitored closely for
signs of toxicity due to increased risk of TLS.
VENCLYXTO may cause embryo-fetal harm when administered to a
pregnant woman. 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://www.abbvie.com/oncology.
About AbbVie
AbbVie is a global, research and development-based
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, LinkedIn or Instagram.
Forward-Looking Statements
Some statements in this news release are, or may be considered,
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, competition from
other products, challenges to intellectual property, 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," of AbbVie's 2018 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.
1 Anderson, K. C. (2014). Multiple
myeloma: NCCN clinical practice guidelines in oncology (NCCN
Guidelines®).
2 Kumar, et al. EHA 2019 Abstract #LBA2601.
3 Costello, C., & Mikhael, J. R. (2018).
Therapy sequencing strategies in multiple myeloma: Who, what and
why? Future Oncology, 14(2), 95-99.
4 Myeloma UK. Infopack for relapsed and/or
refractory myeloma patients.
https://www.myeloma.org.uk/wp-content/uploads/2018/03/Myeloma-UK-Infopack-for-relapsed_refractory-myeloma-patients.pdf
[ONLINE] Accessed June 14, 2019.
5 SEER Cancer Stat Facts: Myeloma. National Cancer
Institute. Bethesda,
MD, https://seer.cancer.gov/statfacts/html/mulmy.html.
[ONLINE] Accessed, June 14, 2019.
6 Kazandjian D. Multiple myeloma epidemiology and
survival, a unique malignancy. Semin Oncol. 2016;
43(6): 676-681.
7 Cowan AJ, Allen C, Barac A, et al. Global burden
of multiple myeloma: a systematic analysis for the global burden of
disease study 2016. JAMA Oncol. 2018; 4(9): 1221-1227.
8 Clinicaltrials.gov (2018). NCT 03539744: A
Study of Venetoclax and Dexamethasone Compared With Pomalidomide
and Dexamethasone in Subjects With Relapsed or Refractory Multiple
Myeloma (CANOVA). Accessed June 14,
2019.
9 Clinicaltrials.gov (2018). NCT02755597: A study
evaluating venetoclax (ABT-199) in multiple myeloma subjects who
are receiving bortezomib and dexamethasone as standard therapy.
Accessed March 2019.
10 VENCLEXTA (venetoclax) [Package
Insert]. North Chicago, IL.:
AbbVie Inc.
11 Summary of Product Characteristics for VENCLYXTO
(venetoclax). Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co.
KG.
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