- Collaboration to evaluate the
full-potential of NKTR-214 plus Opdivo (nivolumab) across numerous
tumors, based on promising early data from ongoing Phase 1/2 PIVOT
clinical study
- Establishes a broad joint clinical
development plan combining NKTR-214 with Opdivo and Opdivo plus
Yervoy (ipilimumab) in registration-enabling trials in more than 20
indications across 9 tumors
- Bristol-Myers Squibb to pay Nektar
$1.85 billion upfront, comprised of $1.0 billion in cash and the
purchase of ~8.28 million shares of Nektar stock at $102.60
per share
- Companies to share global profits on
NKTR-214, with Nektar receiving 65% and Bristol-Myers Squibb
35%
- Nektar to book revenue for worldwide
sales of NKTR-214 and retains ability to develop NKTR-214 with
other anti-cancer agents
- Bristol-Myers Squibb obtains exclusive
rights in 20 indications across 9 tumors included in the joint
clinical development plan for a specified time period
Bristol-Myers Squibb Company (NYSE:BMY) and Nektar Therapeutics
(Nasdaq:NKTR) announced today the companies have executed a global
strategic development and commercialization collaboration for
Nektar’s lead immuno-oncology program, NKTR-214. Under the
collaboration, the companies will jointly develop and commercialize
NKTR-214 in combination with Bristol-Myers Squibb’s Opdivo
(nivolumab) and Opdivo plus Yervoy (ipilimumab) in more than 20
indications across 9 tumor types, as well as potential combinations
with other anti-cancer agents from either of the respective
companies and/or third parties.
NKTR-214, a CD122-biased agonist, is an investigational
immuno-stimulatory therapy designed to selectively expand
cancer-fighting T cells and natural killer (NK) cells directly in
the tumor micro-environment and increase PD-1 expression on those
immune cells.
“We are excited to bring our leading capabilities and expertise
in developing cancer therapies together with Nektar’s innovative
science to jointly develop and commercialize NKTR-214 in
combination with Opdivo and Opdivo plus Yervoy,” said Giovanni
Caforio, M.D., Chairman and CEO, Bristol-Myers Squibb.
“Bristol-Myers Squibb has established Opdivo plus Yervoy as the
only approved immunotherapy combination for cancer patients and
built a robust oncology pipeline. With this commitment to the
development of NKTR-214, an investigational therapy designed with a
unique approach to harnessing the full potential of the
interleukin-2 pathway, we now have a third validated I-O mechanism
that has demonstrated a clinical benefit in patients, and holds
significant potential to expand the benefits that these
immuno-oncology agents can bring to patients with cancer.”
Bristol-Myers Squibb and Nektar have agreed to a joint clinical
development plan to evaluate NKTR-214 with Opdivo and Opdivo plus
Yervoy in registration-enabling clinical trials in more than 20
indications in 9 tumor types including melanoma, renal cell
carcinoma, non-small cell lung cancer, bladder and triple negative
breast cancer. Pivotal studies in renal cell carcinoma and melanoma
are expected to be initiated in mid-2018.
“Bristol-Myers Squibb, the global leader in immuno-oncology, is
the ideal collaborator to enable us to establish NKTR-214 as a
backbone immunotherapy in the treatment of cancer,”
said Howard Robin, President & CEO of Nektar. "NKTR-214’s
ability to grow tumor infiltrating lymphocytes (TILs) in
vivo and replenish the immune system is critically important
as many patients battling cancer lack sufficient TIL populations to
benefit from approved checkpoint inhibitor therapies. This
strategic collaboration allows us to very quickly develop NKTR-214
with the leading approved PD-1 immune checkpoint inhibitor in
numerous registrational trials. We look forward to our continued
relationship with Bristol-Myers Squibb as we work together to
advance cancer treatment for patients around the world."
Transaction Terms
Under the terms of the agreement, Bristol-Myers Squibb will make
an upfront cash payment of $1.0 billion and an equity investment of
$850 million (8,284,600 shares of Nektar’s common stock
at $102.60 per share). Bristol-Myers Squibb has agreed to
certain lock-up, standstill and voting provisions on its share
ownership for a period of five years subject to certain specified
exceptions.
Nektar is also eligible to receive an additional $1.78 billion
in milestones, of which $1.43 billion are development and
regulatory milestones and the remainder are sales milestones.
Nektar will book revenue for worldwide sales of NKTR-214 and the
companies will split global profits for NKTR-214 with Nektar
receiving 65% and Bristol-Myers Squibb 35%. Bristol-Myers Squibb
will retain 100% of product revenues for its own medicines. The
parties also will share development costs relative to their
ownership interest of medicines included in the trials. For trials
in the joint clinical development plan that include NKTR-214 with
Opdivo only, the parties will share development costs with 67.5%
allocated to Bristol-Myers Squibb and 32.5% allocated to Nektar.
For trials in the joint clinical development plan that include
NKTR-214 with Opdivo and Yervoy, the parties will share development
costs with 78% allocated to Bristol-Myers Squibb and 22%
allocated to Nektar.
Both Bristol-Myers Squibb and Nektar have agreed for a specified
period of time to not commence development with overlapping
mechanisms of action in the same indications as those included in
the joint clinical development plan. The parties are otherwise free
to develop NKTR-214 with their own pipeline assets and/or any other
third party compounds. Both parties have agreed to initiate
registration-enabling studies in the joint clinical development
plan within 14 months of the effective date of the agreement,
subject to allowable delays.
Both parties will jointly commercialize NKTR-214 on a global
basis. Bristol-Myers Squibb will lead global commercialization
activities for NKTR-214 combinations with Bristol-Myers Squibb
medicines and Nektar will co-commercialize such combinations in the
US, major EU markets and Japan. Nektar will lead global
commercialization activities for NKTR-214 combinations with either
Nektar medicines and/or other third-party medicines.
For Bristol-Myers Squibb, the transactions are expected to be
dilutive in 2018 and 2019 to the company’s non-GAAP EPS by $0.02
and $0.10, respectively. Nektar and Bristol-Myers Squibb currently
expect to complete the transaction during the second quarter of
2018, subject to the expiration or termination of applicable
waiting periods under all applicable US antitrust laws and the
satisfaction of other usual and customary closing conditions.
Further details of the agreement can be found in Nektar’s Form 8-K
filed today with the Securities and Exchange Commission. Sidley
Austin LLP is acting as legal counsel to Nektar for the strategic
collaboration agreement and equity investment.
Nektar and Bristol-Myers Squibb entered into a
clinical collaboration in September of 2016 to evaluate the
potential for the combination of Opdivo and NKTR-214 to
show improved and sustained efficacy and tolerability above the
current standard of care. The Phase 1/2 PIVOT clinical study
is ongoing in over 350 patients with melanoma, kidney, non-small
cell lung cancer, bladder, and triple-negative breast cancers.
Nektar Conference Call with Analysts
& Investors
Nektar will host a conference call and webcast presentation
today, February 14, 2018 at 8:00 a.m. Eastern Time to discuss the
transaction. The call can be accessed by dialing (877) 881-2183
(U.S.) or (970) 315-0453 (international), and entering passcode
2289559. To access the live webcast, or the subsequent archived
recording, visit the Investor Events section of the Nektar website
at http://ir.nektar.com/events-and-presentations/events. The
webcast will be available for replay on Nektar’s website for two
weeks following the call.
About NKTR-214
NKTR-214 is an experimental therapy designed to stimulate
cancer-killing immune cells in the body by targeting CD122 specific
receptors found on the surface of these immune cells, known as CD8+
effector T cells and Natural Killer (NK) cells. Growing these
tumor-infiltrating lymphocytes (TILs) in vivo and replenishing the
immune system is critically important as many patients battling
cancer lack sufficient TIL populations to benefit from approved
checkpoint inhibitor therapies. In preclinical studies, treatment
with NKTR-214 resulted in a rapid expansion of these cells and
mobilization into the tumor micro-environment.1,2 NKTR-214 has an
antibody-like dosing regimen similar to the existing checkpoint
inhibitor class of approved medicines.
Bristol-Myers Squibb &
Immuno-Oncology: Advancing Oncology Research
At Bristol-Myers Squibb, patients are at the center of
everything we do. Our vision for the future of cancer care is
focused on researching and developing transformational
Immuno-Oncology (I-O) medicines for hard-to-treat cancers that
could potentially improve outcomes for these patients.
We are leading the scientific understanding of I-O through our
extensive portfolio of investigational compounds and approved
agents. Our differentiated clinical development program is studying
broad patient populations across more than 50 types of cancers with
14 clinical-stage molecules designed to target different immune
system pathways. Our deep expertise and innovative clinical trial
designs position us to advance I-O/I-O, I-O/chemotherapy,
I-O/targeted therapies and I-O radiation therapies across multiple
tumors and potentially deliver the next wave of therapies with a
sense of urgency. We also continue to pioneer research that will
help facilitate a deeper understanding of the role of immune
biomarkers and how patients’ tumor biology can be used as a guide
for treatment decisions throughout their journey.
We understand making the promise of I-O a reality for the many
patients who may benefit from these therapies requires not only
innovation on our part but also close collaboration with leading
experts in the field. Our partnerships with academia, government,
advocacy and biotech companies support our collective goal of
providing new treatment options to advance the standards of
clinical practice.
About Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint
inhibitor that is designed to uniquely harness the body’s own
immune system to help restore anti-tumor immune response. By
harnessing the body’s own immune system to fight
cancer, Opdivo has become an important treatment option
across multiple cancers.
Opdivo’s leading global development program is based on
Bristol-Myers Squibb’s scientific expertise in the field of
Immuno-Oncology and includes a broad range of clinical trials
across all phases, including Phase 3, in a variety of tumor types.
To date, the Opdivo clinical development program has
enrolled more than 25,000 patients. The Opdivo trials
have contributed to gaining a deeper understanding of the potential
role of biomarkers in patient care, particularly regarding how
patients may benefit from Opdivo across the continuum of
PD-L1 expression.
In July 2014, Opdivo was the first PD-1 immune
checkpoint inhibitor to receive regulatory approval anywhere in the
world. Opdivo is currently approved in more than 60
countries, including the United States, the European Union and
Japan. In October 2015, the
company’s Opdivo and Yervoy combination regimen
was the first Immuno-Oncology combination to receive regulatory
approval for the treatment of metastatic melanoma and is currently
approved in more than 50 countries, including the United States and
the European Union.
About Yervoy
Yervoy is a recombinant, human monoclonal antibody that
binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4).
CTLA-4 is a negative regulator of T-cell
activity. Yervoy binds to CTLA-4 and blocks the
interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of
CTLA-4 has been shown to augment T-cell activation and
proliferation, including the activation and proliferation of tumor
infiltrating T-effector cells. Inhibition of CTLA-4 signaling can
also reduce T-regulatory cell function, which may contribute to a
general increase in T-cell responsiveness, including the anti-tumor
immune response. On March 25, 2011, the U.S. Food and Drug
Administration (FDA) approved Yervoy 3 mg/kg monotherapy
for patients with unresectable or metastatic
melanoma. Yervoy is approved for unresectable or
metastatic melanoma in more than 50 countries. There is a broad,
ongoing development program in place for Yervoy spanning
multiple tumor types.
U.S. FDA-APPROVED INDICATIONS FOR
OPDIVO ®
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 mutation-positive unresectable
or metastatic melanoma. This indication is approved under
accelerated approval based on progression-free survival. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) as a single agent is indicated for the
treatment of patients with BRAF V600 wild-type unresectable or
metastatic melanoma.
OPDIVO® (nivolumab), in combination with
YERVOY® (ipilimumab), is indicated for the treatment of
patients with unresectable or metastatic melanoma. This indication
is approved under accelerated approval based on progression-free
survival. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in the
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with metastatic non-small cell lung cancer (NSCLC) with
progression on or after platinum-based chemotherapy. Patients with
EGFR or ALK genomic tumor aberrations should have disease
progression on FDA-approved therapy for these aberrations prior to
receiving OPDIVO.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with advanced renal cell carcinoma (RCC) who have received
prior anti-angiogenic therapy.
OPDIVO® (nivolumab) is indicated for the treatment of adult
patients with classical Hodgkin lymphoma (cHL) that has relapsed or
progressed after autologous hematopoietic stem cell transplantation
(HSCT) and brentuximab vedotin or after 3 or more lines of systemic
therapy that includes autologous HSCT. This indication is approved
under accelerated approval based on overall response rate.
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with recurrent or metastatic squamous cell carcinoma of
the head and neck (SCCHN) with disease progression on or after
platinum-based therapy.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with locally advanced or metastatic urothelial carcinoma
who have disease progression during or following
platinum-containing chemotherapy or have disease progression within
12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy. This indication is approved under
accelerated approval based on tumor response rate and duration of
response. Continued approval for this indication may be contingent
upon verification and description of clinical benefit in
confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of adult
and pediatric (12 years and older) patients with microsatellite
instability high (MSI-H) or mismatch repair deficient (dMMR)
metastatic colorectal cancer (CRC) that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on
overall response rate and duration of response. Continued approval
for this indication may be contingent upon verification and
description of clinical benefit in confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of
patients with hepatocellular carcinoma (HCC) who have been
previously treated with sorafenib. This indication is approved
under accelerated approval based on tumor response rate and
durability of response. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in the confirmatory trials.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment
of patients with melanoma with involvement of lymph nodes or
metastatic disease who have undergone complete resection.
IMPORTANT SAFETY
INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse
reactions. These immune-mediated reactions may involve any organ
system; however, the most common severe immune-mediated adverse
reactions are enterocolitis, hepatitis, dermatitis (including toxic
epidermal necrolysis), neuropathy, and endocrinopathy. The majority
of these immune-mediated reactions initially manifested during
treatment; however, a minority occurred weeks to months after
discontinuation of YERVOY.
Assess patients for signs and symptoms of enterocolitis,
dermatitis, neuropathy, and endocrinopathy and evaluate clinical
chemistries including liver function tests (LFTs),
adrenocorticotropic hormone (ACTH) level, and thyroid function
tests at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic
high-dose corticosteroid therapy for severe immune-mediated
reactions.
Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated pneumonitis. Fatal cases have
been reported. Monitor patients for signs with radiographic imaging
and for symptoms of pneumonitis. Administer corticosteroids for
Grade 2 or more severe pneumonitis. Permanently discontinue for
Grade 3 or 4 and withhold until resolution for Grade 2. In patients
receiving OPDIVO monotherapy, fatal cases of immune-mediated
pneumonitis have occurred. Immune-mediated pneumonitis occurred in
3.1% (61/1994) of patients. In patients receiving OPDIVO with
YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of
patients.
In Checkmate 205 and 039, pneumonitis, including interstitial
lung disease, occurred in 6.0% (16/266) of patients receiving
OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of
patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).
Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis. Monitor patients for
signs and symptoms of colitis. Administer corticosteroids for Grade
2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO
monotherapy for Grade 2 or 3 and permanently discontinue for Grade
4 or recurrent colitis upon re-initiation of OPDIVO. When
administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2
and permanently discontinue for Grade 3 or 4 or recurrent colitis.
In patients receiving OPDIVO monotherapy, immune-mediated colitis
occurred in 2.9% (58/1994) of patients. In patients receiving
OPDIVO with YERVOY, immune-mediated colitis occurred in 26%
(107/407) of patients including three fatal cases.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal (diarrhea of ≥7 stools above baseline,
fever, ileus, peritoneal signs; Grade 3-5) immune-mediated
enterocolitis occurred in 34 (7%) patients. Across all
YERVOY-treated patients in that study (n=511), 5 (1%) developed
intestinal perforation, 4 (0.8%) died as a result of complications,
and 26 (5%) were hospitalized for severe enterocolitis.
Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis. Monitor patients for
abnormal liver tests prior to and periodically during treatment.
Administer corticosteroids for Grade 2 or greater transaminase
elevations. For patients without HCC, withhold OPDIVO for Grade 2
and permanently discontinue OPDIVO for Grade 3 or 4. For patients
with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT
is within normal limits at baseline and increases to >3 and up
to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and
up to 3 times ULN at baseline and increases to >5 and up to 10
times the ULN, and if AST/ALT is >3 and up to 5 times ULN at
baseline and increases to >8 and up to 10 times the ULN.
Permanently discontinue OPDIVO and administer corticosteroids if
AST or ALT increases to >10 times the ULN or total bilirubin
increases >3 times the ULN. In patients receiving OPDIVO
monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994)
of patients. In patients receiving OPDIVO with YERVOY,
immune-mediated hepatitis occurred in 13% (51/407) of patients.
In Checkmate 040, immune-mediated hepatitis requiring systemic
corticosteroids occurred in 5% (8/154) of patients receiving
OPDIVO.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal hepatotoxicity (AST or ALT elevations
>5x the ULN or total bilirubin elevations >3x the ULN; Grade
3-5) occurred in 8 (2%) patients, with fatal hepatic failure
in 0.2% and hospitalization in 0.4%.
Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal
Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral
motor neuropathy were reported.
Immune-Mediated Endocrinopathies
OPDIVO can cause immune-mediated hypophysitis, immune-mediated
adrenal insufficiency, autoimmune thyroid disorders, and Type 1
diabetes mellitus. Monitor patients for signs and symptoms of
hypophysitis, signs and symptoms of adrenal insufficiency, thyroid
function prior to and periodically during treatment, and
hyperglycemia. Administer hormone replacement as clinically
indicated and corticosteroids for Grade 2 or greater hypophysitis.
Withhold for Grade 2 or 3 and permanently discontinue for Grade 4
hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal
insufficiency. Withhold for Grade 2 and permanently discontinue for
Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement
therapy for hypothyroidism. Initiate medical management for control
of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently
discontinue for Grade 4 hyperglycemia.
In patients receiving OPDIVO monotherapy, hypophysitis occurred
in 0.6% (12/1994) of patients. In patients receiving OPDIVO with
YERVOY, hypophysitis occurred in 9% (36/407) of patients. In
patients receiving OPDIVO monotherapy, adrenal insufficiency
occurred in 1% (20/1994) of patients. In patients receiving OPDIVO
with YERVOY, adrenal insufficiency occurred in 5% (21/407) of
patients. In patients receiving OPDIVO monotherapy, hypothyroidism
or thyroiditis resulting in hypothyroidism occurred in 9%
(171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994)
of patients receiving OPDIVO monotherapy. In patients receiving
OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in
hypothyroidism occurred in 22% (89/407) of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving
OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy,
diabetes occurred in 0.9% (17/1994) of patients. In patients
receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of
patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe to
life-threatening immune-mediated endocrinopathies (requiring
hospitalization, urgent medical intervention, or interfering with
activities of daily living; Grade 3-4) occurred in 9 (1.8%)
patients. All 9 patients had hypopituitarism, and some had
additional concomitant endocrinopathies such as adrenal
insufficiency, hypogonadism, and hypothyroidism. 6 of the 9
patients were hospitalized for severe endocrinopathies.
Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for
elevated serum creatinine prior to and periodically during
treatment. Administer corticosteroids for Grades 2-4 increased
serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently
discontinue for Grade 4 increased serum creatinine. In patients
receiving OPDIVO monotherapy, immune-mediated nephritis and renal
dysfunction occurred in 1.2% (23/1994) of patients. In patients
receiving OPDIVO with YERVOY, immune-mediated nephritis and renal
dysfunction occurred in 2.2% (9/407) of patients.
Immune-Mediated Skin Adverse Reactions and Dermatitis
OPDIVO can cause immune-mediated rash, including Stevens-Johnson
syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases
with fatal outcome. Administer corticosteroids for Grade 3 or 4
rash. Withhold for Grade 3 and permanently discontinue for Grade 4
rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and
refer the patient for specialized care for assessment and
treatment; if confirmed, permanently discontinue. In patients
receiving OPDIVO monotherapy, immune-mediated rash occurred in 9%
(171/1994) of patients. In patients receiving OPDIVO with YERVOY,
immune-mediated rash occurred in 22.6% (92/407) of patients.
In a separate Phase 3 study of YERVOY 3 mg/kg, severe,
life-threatening, or fatal immune-mediated dermatitis (eg,
Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash
complicated by full thickness dermal ulceration, or necrotic,
bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13
(2.5%) patients. 1 (0.2%) patient died as a result of toxic
epidermal necrolysis. 1 additional patient required hospitalization
for severe dermatitis.
Immune-Mediated Encephalitis
OPDIVO can cause immune-mediated encephalitis. Evaluation of
patients with neurologic symptoms may include, but not be limited
to, consultation with a neurologist, brain MRI, and lumbar
puncture. Withhold OPDIVO in patients with new-onset moderate to
severe neurologic signs or symptoms and evaluate to rule out other
causes. If other etiologies are ruled out, administer
corticosteroids and permanently discontinue OPDIVO for
immune-mediated encephalitis. In patients receiving OPDIVO
monotherapy, encephalitis occurred in 0.2% (3/1994) of patients.
Fatal limbic encephalitis occurred in one patient after 7.2 months
of exposure despite discontinuation of OPDIVO and administration of
corticosteroids. Encephalitis occurred in one patient receiving
OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.
Other Immune-Mediated Adverse Reactions
Based on the severity of the adverse reaction, permanently
discontinue or withhold OPDIVO, administer high-dose
corticosteroids, and, if appropriate, initiate hormone-replacement
therapy. Across clinical trials of OPDIVO monotherapy or in
combination with YERVOY, the following clinically significant
immune-mediated adverse reactions, some with fatal outcome,
occurred in <1.0% of patients receiving OPDIVO: myocarditis,
rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and
abducens nerve paresis, demyelination, polymyalgia rheumatica,
autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism,
systemic inflammatory response syndrome, gastritis, duodenitis,
sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), motor dysfunction, vasculitis, and myasthenic
syndrome.
Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been
reported in <1.0% of patients in clinical trials. Discontinue
OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt
or slow the rate of infusion in patients with Grade 1 or 2. In
patients receiving OPDIVO monotherapy, infusion-related reactions
occurred in 6.4% (127/1994) of patients. In patients receiving
OPDIVO with YERVOY, infusion-related reactions occurred in 2.5%
(10/407) of patients.
Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who
received allogeneic HSCT after OPDIVO. Outcomes were evaluated in
17 patients from Checkmate 205 and 039, who underwent allogeneic
HSCT after discontinuing OPDIVO (15 with reduced-intensity
conditioning, 2 with myeloablative conditioning). Thirty-five
percent (6/17) of patients died from complications of allogeneic
HSCT after OPDIVO. Five deaths occurred in the setting of severe or
refractory GVHD. Grade 3 or higher acute GVHD was reported in 29%
(5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of
patients. A steroid-requiring febrile syndrome, without an
identified infectious cause, was reported in 35% (n=6) of patients.
Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic
encephalitis without an identified infectious cause, and Grade 3
(n=1) suspected viral encephalitis. Hepatic veno-occlusive disease
(VOD) occurred in one patient, who received reduced-intensity
conditioned allogeneic HSCT and died of GVHD and multi-organ
failure. Other cases of hepatic VOD after reduced-intensity
conditioned allogeneic HSCT have also been reported in patients
with lymphoma who received a PD-1 receptor blocking antibody before
transplantation. Cases of fatal hyperacute GVHD have also been
reported. These complications may occur despite intervening therapy
between PD-1 blockade and allogeneic HSCT.
Follow patients closely for early evidence of transplant-related
complications such as hyperacute GVHD, severe (Grade 3 to 4) acute
GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other
immune-mediated adverse reactions, and intervene promptly.
Embryo-Fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY can cause
fetal harm when administered to a pregnant woman. Advise pregnant
women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during
treatment with an OPDIVO- or YERVOY- containing regimen and for at
least 5 months after the last dose of OPDIVO.
Lactation
It is not known whether OPDIVO or YERVOY is present in human
milk. Because many drugs, including antibodies, are excreted in
human milk and because of the potential for serious adverse
reactions in nursing infants from an OPDIVO-containing regimen,
advise women to discontinue breastfeeding during treatment. Advise
women to discontinue nursing during treatment with YERVOY and for 3
months following the final dose.
Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of
patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions
occurred in 42% of patients receiving OPDIVO. The most frequent
Grade 3 and 4 adverse drug reactions reported in 2% to <5% of
patients receiving OPDIVO were abdominal pain, hyponatremia,
increased aspartate aminotransferase, and increased lipase. In
Checkmate 066, serious adverse reactions occurred in 36% of
patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions
occurred in 41% of patients receiving OPDIVO. The most frequent
Grade 3 and 4 adverse reactions reported in ≥2% of patients
receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and
diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73%
and 37%), adverse reactions leading to permanent discontinuation
(43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4
adverse reactions (72% and 44%) all occurred more frequently in the
OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313).
The most frequent (≥10%) serious adverse reactions in the OPDIVO
plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea
(13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%).
In Checkmate 017 and 057, serious adverse reactions occurred in 46%
of patients receiving OPDIVO (n=418). The most frequent serious
adverse reactions reported in at least 2% of patients receiving
OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia,
pleural effusion, pneumonitis, and respiratory failure. In
Checkmate 025, serious adverse reactions occurred in 47% of
patients receiving OPDIVO (n=406). The most frequent serious
adverse reactions reported in ≥2% of patients were acute kidney
injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.
In Checkmate 205 and 039, adverse reactions leading to
discontinuation occurred in 7% and dose delays due to adverse
reactions occurred in 34% of patients (n=266). Serious adverse
reactions occurred in 26% of patients. The most frequent serious
adverse reactions reported in ≥1% of patients were pneumonia,
infusion-related reaction, pyrexia, colitis or diarrhea, pleural
effusion, pneumonitis, and rash. Eleven patients died from causes
other than disease progression: 3 from adverse reactions within 30
days of the last OPDIVO dose, 2 from infection 8 to 9 months after
completing OPDIVO, and 6 from complications of allogeneic HSCT. In
Checkmate 141, serious adverse reactions occurred in 49% of
patients receiving OPDIVO (n=236). The most frequent serious
adverse reactions reported in at least 2% of patients receiving
OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory
tract infection, and sepsis. In Checkmate 275, serious adverse
reactions occurred in 54% of patients receiving OPDIVO (n=270). The
most frequent serious adverse reactions reported in at least 2% of
patients receiving OPDIVO were urinary tract infection, sepsis,
diarrhea, small intestine obstruction, and general physical health
deterioration. In Checkmate 040, serious adverse reactions occurred
in 49% of patients (n=154). The most frequent serious adverse
reactions reported in at least 2% of patients were pyrexia,
ascites, back pain, general physical health deterioration,
abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4
adverse reactions occurred in 25% of OPDIVO-treated patients
(n=452). The most frequent Grade 3 and 4 adverse reactions reported
in at least 2% of OPDIVO-treated patients were diarrhea and
increased lipase and amylase. Serious adverse reactions occurred in
18% of OPDIVO-treated patients.
Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%)
reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the
most common adverse reactions (≥20%) reported with OPDIVO (n=206)
vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal
pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In
Checkmate 067, the most common (≥20%) adverse reactions in the
OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%),
diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and
dyspnea (20%). The most common (≥20%) adverse reactions in the
OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%),
and nausea (28%). In Checkmate 017 and 057, the most common adverse
reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue,
musculoskeletal pain, cough, dyspnea, and decreased appetite. In
Checkmate 025, the most common adverse reactions (≥20%) reported in
patients receiving OPDIVO (n=406) vs everolimus (n=397) were
asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28%
vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs
32%), constipation (23% vs 18%), decreased appetite (23% vs 30%),
back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate
205 and 039, the most common adverse reactions (≥20%) reported in
patients receiving OPDIVO (n=266) were upper respiratory tract
infection (44%), fatigue (39%), cough (36%), diarrhea (33%),
pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%)
and pruritus (20%). In Checkmate 141, the most common adverse
reactions (≥10%) in patients receiving OPDIVO (n=236) were cough
and dyspnea at a higher incidence than investigator’s choice. In
Checkmate 275, the most common adverse reactions (≥ 20%) reported
in patients receiving OPDIVO (n=270) were fatigue (46%),
musculoskeletal pain (30%), nausea (22%), and decreased appetite
(22%). In Checkmate 040, the most common adverse reactions (≥20%)
in patients receiving OPDIVO (n=154) were fatigue (38%),
musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%),
diarrhea (27%), rash (26%), cough (23%), and decreased appetite
(22%). In Checkmate 238, the most common adverse reactions (≥20%)
reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated
patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%),
rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28%
vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper
respiratory infection (22% vs 15%), and abdominal pain (21% vs
23%). The most common immune-mediated adverse reactions were rash
(16%), diarrhea/colitis (6%), and hepatitis (3%). The most common
adverse reactions (≥20%) in patients who received OPDIVO as a
single agent were fatigue, rash, musculoskeletal pain, pruritus,
diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased
appetite, back pain, arthralgia, upper respiratory tract infection,
pyrexia, headache, and abdominal pain.
In a separate Phase 3 study of YERVOY 3 mg/kg, the most common
adverse reactions (≥5%) in patients who received YERVOY at
3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%),
rash (29%), and colitis (8%).
Checkmate Trials and Patient Populations
Checkmate 067 – advanced melanoma alone or in
combination with YERVOY; Checkmate 037 and 066 –
advanced melanoma; Checkmate 017 – squamous
non-small cell lung cancer (NSCLC); Checkmate
057 – non-squamous NSCLC; Checkmate 025 –
renal cell carcinoma; Checkmate 205/039 –
classical Hodgkin lymphoma; Checkmate 141 –
squamous cell carcinoma of the head and neck; Checkmate
275 – urothelial carcinoma; Checkmate
040 – hepatocellular carcinoma; CheckMate
238 – adjuvant treatment of melanoma.
Please see U.S. Full Prescribing Information
for OPDIVO and YERVOY, including Boxed
WARNING regarding immune-mediated adverse reactions for
YERVOY.
About the Bristol-Myers Squibb and Ono
Pharmaceutical Co., Ltd. Collaboration
In 2011, through a collaboration agreement with Ono
Pharmaceutical Co., Ltd. (Ono), Bristol-Myers Squibb expanded its
territorial rights to develop and
commercialize Opdivo globally except in Japan, South
Korea and Taiwan, where Ono had retained all rights to the compound
at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further
expanded the companies’ strategic collaboration agreement to
jointly develop and commercialize multiple immunotherapies – as
single agents and combination regimens – for patients with cancer
in Japan, South Korea and Taiwan.
About Bristol-Myers
Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol-Myers Squibb, visit us at BMS.com or
follow us on
LinkedIn, Twitter, YouTube and Facebook.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee
that the collaboration with Nektar will progress as contemplated in
this release or that NKTR-214, alone or in combination with Opdivo
or Opdivo plus Yervoy will receive regulatory approval for the
treatment of cancer. Forward-looking statements in this press
release should be evaluated together with the many uncertainties
that affect Bristol-Myers Squibb's business, particularly those
identified in the cautionary factors discussion in Bristol-Myers
Squibb's Annual Report on Form 10-K for the year ended December 31,
2017 in our Quarterly Reports on Form 10-Q and our Current Reports
on Form 8-K. Bristol-Myers Squibb undertakes no obligation to
publicly update any forward-looking statement, whether as a result
of new information, future events or otherwise.
About Nektar Therapeutics
Nektar Therapeutics is a biopharmaceutical company with a
robust, wholly-owned R&D pipeline of investigational medicines
in oncology, immunology and pain as well as a portfolio of approved
partnered medicines. Nektar is headquartered in San Francisco,
California, with additional operations in Huntsville, Alabama and
Hyderabad, India. Further information about the company and its
drug development programs and capabilities may be found online at
http://www.nektar.com.
Nektar Cautionary Note Regarding Forward-Looking
Statements
This press release contains forward-looking statements which can
be identified by words such as: "anticipate," "intend," "plan,"
"expect," "believe," "should," "may," "will" and similar references
to future periods. Examples of forward-looking statements include,
among others, statements we make regarding the therapeutic
potential of NKTR-214, the therapeutic potential of NKTR-214 in
combination with OPDIVO, the development plans and timing related
to NKTR-214, and the potential of our technology and drug
candidates in our research and development pipeline.
Forward-looking statements are neither historical facts nor
assurances of future performance. Instead, they are based only on
our current beliefs, expectations and assumptions regarding the
future of our business, future plans and strategies, anticipated
events and trends, the economy and other future conditions. Because
forward-looking statements relate to the future, they are subject
to inherent uncertainties, risks and changes in circumstances that
are difficult to predict and many of which are outside of our
control. Our actual results may differ materially from those
indicated in the forward-looking statements. Therefore, you should
not rely on any of these forward-looking statements. Important
factors that could cause our actual results to differ materially
from those indicated in the forward-looking statements include,
among others: (i) our statements regarding the therapeutic
potential of NKTR-214 in combination with Opdivo are based on
findings and observations from ongoing clinical studies and these
finding and observations will evolve over time as more data emerges
from the studies; (ii) NKTR-214 is in early-stage clinical
development and the risk of failure remains high and failure can
unexpectedly occur due to efficacy, safety, economic, commercial or
other unpredictable factors; (iii) the timing of the commencement
or end of clinical trials and the availability of clinical data may
be delayed or unsuccessful due to regulatory delays, slower than
anticipated patient enrollment, manufacturing challenges, changing
standards of care, evolving regulatory requirements, clinical trial
design, clinical outcomes, competitive factors, or delay or failure
in ultimately obtaining regulatory approval in one or more
important markets; (iv) scientific discovery of new medical
breakthroughs is an inherently uncertain process and the future
success of applying our technology platform to potential new drug
candidates (such as NKTR-214) is therefore highly uncertain and
unpredictable and one or more research and development programs
could fail; (v) patents may not issue from our patent applications
for our drug candidates including NKTR-214, patents that have
issued may not be enforceable, or additional intellectual property
licenses from third parties may be required; and (vi) certain other
important risks and uncertainties set forth in our Quarterly Report
on Form 10-Q filed with the Securities and Exchange Commission on
November 8, 2017. Any forward-looking statement made by us in this
press release is based only on information currently available to
us and speaks only as of the date on which it is made. We undertake
no obligation to update any forward-looking statement, whether
written or oral, that may be made from time to time, whether as a
result of new information, future developments or otherwise.
1. Charych, D., et al., Cancer Res. 2013;73(8
Suppl):Abstract nr 482 and Data on file. 2. Hoch U, at al. AACR;
Mol Cancer Ther. 2013;12(11 Suppl):Abstract nr B296.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20180214005660/en/
For Bristol-Myers Squibb:Media:Ken Dominski,
609-252-5251, ken.dominski@bms.comLisa McCormick Lavery,
609-252-7602, lisa.mccormicklavery@bms.comorInvestors:Tim
Power, 609-252-7509, timothy.power@bms.comBill Szablewski,
609-252-5894, william.szablewski@bms.comorFor
Nektar:Investors:Jennifer Ruddock of Nektar
Therapeutics415-482-5585orMedia:Dan Budwick of
1AB973-271-6085dan@1abmedia.comorJennifer Paganelli of Pure
Communications347-658-8290jpaganelli@purecommunications.com
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