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| REGN > SEC Filings for REGN > Form 10-Q on 5-Nov-2008 | All Recent SEC Filings |
5-Nov-2008
Quarterly Report
We believe that our ability to develop product candidates is enhanced by the
application of our technology platforms. Our discovery platforms are designed to
identify specific genes of therapeutic interest for a particular disease or cell
type and validate targets through high-throughput production of mammalian
models. Our human monoclonal antibody technology (VelocImmune®) and cell line
expression technologies may then be utilized to design and produce new product
candidates directed against the disease target. Based on the VelocImmuneplatform
which we believe, in conjunction with our other proprietary technologies, can
accelerate the development of fully human monoclonal antibodies, we moved our
first antibody product candidate (REGN88) into clinical trials in the fourth
quarter of 2007. We plan to file an Investigational New Drug Application (IND)
for an antibody to Delta-like ligand-4 (Dll4) by the end of 2008. We plan to
file an IND for a third antibody product candidate shortly thereafter, and to
advance an average of two to three antibody product candidates into clinical
development each year. We continue to invest in the development of enabling
technologies to assist in our efforts to identify, develop, and commercialize
new product candidates.
Commercial Product:
ARCALYST® (rilonacept) - Cryopyrin-Associated Periodic Syndromes (CAPS)
In February 2008, we received marketing approval from the U.S. Food and Drug
Administration (FDA) for ARCALYSTŇ (rilonacept) Injection for Subcutaneous Use
for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including
Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome
(MWS) in adults and children 12 and older. In March 2008, ARCALYST became
available for prescription in the United States and we began making shipments to
our distributors and transitioning the patients who participated in the CAPS
pivotal study from clinical study drug to commercial supplies. This transition
has been mostly completed and we currently project shipments of ARCALYST to our
distributors to total approximately $10 million in 2008. During the third
quarter and first nine months of 2008, we shipped $4.3 million and $6.7 million,
respectively, of ARCALYST to our distributors. In July 2008, we submitted a
Marketing Authorization Application (MAA) to the European Medicines Agency
(EMEA) for ARCALYST for the treatment of CAPS in the European Union.
ARCALYST is a protein-based product designed to bind the interleukin-1
(called IL-1) cytokine and prevent its interaction with cell surface receptors.
ARCALYST is the only therapy approved in the United States for patients with
CAPS, a group of rare, inherited, auto-inflammatory conditions characterized by
life-long, recurrent symptoms of rash, fever/chills, joint pain, eye
redness/pain, and fatigue. Intermittent, disruptive exacerbations or flares can
be triggered at any time by exposure to cooling temperatures, stress, exercise,
or other unknown stimuli. CAPS is caused by a range of mutations in the gene
NLRP3 (formerly known as CIAS1) which encodes a protein named cryopyrin. In
addition to FCAS and MWS, CAPS includes Neonatal Onset Multisystem Inflammatory
Disease (NOMID). ARCALYST has not been studied for the treatment of NOMID.
Late-Stage Clinical Programs:
Below is a summary of the status of our late-stage clinical candidates:
1. Aflibercept (VEGF Trap) - Oncology
Aflibercept is a protein-based product candidate designed to bind all forms
of Vascular Endothelial Growth Factor-A (called VEGF-A, also known as Vascular
Permeability Factor or VPF) and the related Placental Growth Factor (called
PlGF), and prevent their interaction with cell surface receptors. VEGF-A (and to
a less validated degree, PlGF) is required for the growth of new blood vessels
(a process known as angiogenesis) that are needed for tumors to grow and is a
potent regulator of vascular permeability and leakage.
Aflibercept is being developed in cancer indications in collaboration with
sanofi-aventis. We and sanofi-aventis currently are enrolling patients in four
Phase 3 trials that combine aflibercept with standard chemotherapy regimens. One
trial is evaluating aflibercept as a 2ndline treatment for metastatic colorectal
cancer (the VELOUR study) in combination with FOLFIRI (folinic acid
(leucovorin), 5-fluorouracil, and irinotecan). A second trial is evaluating
aflibercept as a 1st line treatment for metastatic pancreatic cancer in
combination with gemcitabine (the VANILLA study). A third trial is evaluating
aflibercept as a 1st line treatment for metastatic androgen independent prostate
cancer in combination with docetaxel/prednisone (the VENICE study). The fourth
trial is evaluating aflibercept as a 2nd line treatment for metastatic non-small
cell lung cancer in combination with docetaxel (the VITAL study). All four
trials are studying the current standard of chemotherapy care for the cancer
being studied with and without aflibercept. In addition, a Phase 2 study of
aflibercept in 1st-line metastatic colorectal cancer in combination with folinic
acid (leucovirin), 5-fluorouracil, and oxaliplatin is expected to begin by the
end of 2008.
Aflibercept is also being studied in a Phase 2 single-agent study in advanced
ovarian cancer (AOC) patients with symptomatic malignant ascites (SMA). This
trial is more than 90% enrolled and patients continue to be enrolled in the
study. A separate non-blinded single-agent aflibercept study in 16 AOC patients
with SMA has been completed and the results are currently being evaluated. In
2004, the FDA granted Fast Track designation to aflibercept for the treatment of
SMA.
Sanofi-aventis has also expanded the aflibercept development program to
Japan, where they are conducting Phase 1 safety and tolerability studies in
combination with standard chemotherapies in patients with advanced solid
malignancies.
In addition, multiple exploratory studies are currently underway or scheduled
to begin that are being or will be conducted in conjunction with the National
Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) evaluating
aflibercept as a single agent or in combination with chemotherapy regimens in a
variety of cancer indications. At the 2008 annual meeting of the American
Society of Clinical Oncology (ASCO), investigators reported preliminary results
of an NCI-sponsored study of single-agent aflibercept in 48 patients with either
relapsed or first recurrence temozolomide-resistant glioblastoma multiforme or
anaplastic glioma. As assessed by the investigators, responses were achieved in
50% of patients with anaplastic glioma
and 30% of patients with glioblastoma. As assessed by an independent
radiological reading center, preliminary data indicates that responses were
achieved in approximately 30% of patients with anaplastic glioma and 22% of
patients with glioblastoma. Grade 3 adverse events in this study included
fatigue, hypertension, hand-foot syndrome, lymphopenia, thrombosis, and
proteinuria.
In September 2008, at the 2008 ASCO Breast Cancer Symposium, investigators
reported the results of a small, exploratory NCI-sponsored study in 21 patients
with poor prognostic characteristics (i.e., tumors resistant to anthracyclines
and/or taxanes and a majority with metastatic visceral disease). In this trial,
single-agent aflibercept had a confirmed partial response rate, as assessed by
the investigators, of 5% (with a 95% Confidence Interval of 0-24%), a median
progression free survival (PFS) of 2.7 months, and a median overall survival
(OS) of 10.8 months. There were no unexpected safety concerns in this small
study. The investigators reported that there were two cases of congestive heart
failure in patients at high risk.
Aflibercept Collaboration with the sanofi-aventis Group
In September 2003, we entered into a collaboration agreement with Aventis
Pharmaceuticals, Inc. (predecessor to sanofi-aventis U.S.) to collaborate on the
development and commercialization of aflibercept in all countries other than
Japan, where we retained the exclusive right to develop and commercialize
aflibercept. In January 2005, we and sanofi-aventis amended the collaboration
agreement to exclude, from the scope of the collaboration, the development and
commercialization of aflibercept for intraocular delivery to the eye. In
December 2005, we and sanofi-aventis amended our collaboration agreement to
expand the territory in which the companies are collaborating on the development
of aflibercept to include Japan. Under the collaboration agreement, as amended,
we and sanofi-aventis will share co-promotion rights and profits on sales, if
any, of aflibercept outside of Japan for disease indications included in our
collaboration. In Japan, we are entitled to a royalty of approximately 35% on
annual sales of aflibercept, subject to certain potential adjustments. We may
also receive up to $400.0 million in milestone payments upon receipt of
specified marketing approvals. This total includes up to $360.0 million in
milestone payments related to receipt of marketing approvals for up to eight
aflibercept oncology and other indications in the United States or the European
Union. Another $40.0 million of milestone payments relate to receipt of
marketing approvals for up to five oncology indications in Japan.
Under the aflibercept collaboration agreement, as amended, agreed upon
worldwide development expenses incurred by both companies during the term of the
agreement will be funded by sanofi-aventis. If the collaboration becomes
profitable, we will be obligated to reimburse sanofi-aventis for 50% of
aflibercept development expenses in accordance with a formula based on the
amount of development expenses and our share of the collaboration profits and
Japan royalties, or at a faster rate at our option.
2. VEGF Trap - Eye Diseases
VEGF Trap-Eye is a form of the VEGF Trap that has been purified and
formulated with excipients and at concentrations suitable for direct injection
into the eye. We and Bayer HealthCare are currently testing VEGF Trap-Eye in a
Phase 3 program in patients with the
neovascular form of Age-related Macular Degeneration (wet AMD). We and Bayer
HealthCare are also developing VEGF Trap-Eye in diabetic macular edema (DME) and
plan to initiate a Phase 2 study in patients with DME in early 2009.
The Phase 3 trials in wet AMD, known as VIEW 1 and VIEW 2 (VEGF Trap:
Investigation of Efficacy and Safety in Wet age-related macular degeneration),
are comparing VEGF Trap-Eye and ranibizumab (Lucentis®, a registered trademark
of Genetech, Inc.), an anti-angiogenic agent approved for use in wet AMD. VIEW 1
is being conducted in North America and VIEW 2 is being conducted in Europe,
Asia Pacific, Japan and Latin America. The VIEW 1 and VIEW 2 trials are both
evaluating dosing intervals of four and eight weeks for VEGF Trap-Eye compared
with ranibizumab dosed according to its U.S. label every four weeks over the
first year. As needed dosing (PRN) with both agents will be evaluated in the
second year of the studies.
In August 2008, we and Bayer HealthCare AG announced the preliminary results
of a Phase 2 study in wet AMD which demonstrated that patients treated with the
VEGF Trap-Eye achieved durable improvements in visual acuity and retinal
thickness for up to one year in wet AMD. In September 2008, the complete results
of this study, including additional data on reductions in the active choroidal
neovascularization lesion size, were reported at the 2008 annual meeting of the
Retina Society in Scottsdale, Arizona.
In this double-masked Phase 2 trial, patients were initially treated with
either fixed monthly or quarterly dosing for 12 weeks and then continued to
receive treatment for another 40 weeks on a PRN dosing schedule. Patients
receiving monthly doses of VEGF Trap-Eye of either 2.0 or 0.5 milligrams
(mg) for 12 weeks followed by PRN dosing achieved mean improvements in visual
acuity versus baseline of 9.0 letters (p<0.0001 versus baseline) and 5.4 letters
(p<0.085 versus baseline), respectively, at the end of one year. The proportion
of patients with vision of 20/40 or better (part of the legal minimum
requirement for an unrestricted driver's license in the U.S.) increased from 23%
at baseline to 45% at week 52 in patients initially treated with 2.0 mg monthly
and from 16% at baseline to 47% at week 52 in patients initially treated with
0.5 mg monthly.
Patients receiving monthly doses of VEGF Trap-Eye of either 2.0 or 0.5 mg for
12 weeks followed by PRN dosing also achieved mean decreases in retinal
thickness versus baseline of 143 microns (p<0.0001 versus baseline) and 125
microns (p<0.0001 versus baseline) at week 52, respectively.
During the week 12 to week 52 PRN dosing period, patients initially dosed on
a 2.0 mg monthly schedule received, on average, only 1.6 additional injections
and those initially dosed on a 0.5 mg monthly schedule received, on average, 2.5
additional injections.
While PRN dosing following a fixed quarterly dosing regimen (with dosing at
baseline and week 12) also yielded improvements in visual acuity and retinal
thickness versus baseline at week 52, the results generally were not as robust
as those obtained with initial fixed monthly dosing.
In this Phase 2 study, treatment with VEGF Trap-Eye was also associated with
a reduction in the size of the total active choroidal neovascular membrane
(CNV), the active lesion that is the
underlying cause of vision loss in patients with wet AMD. Patients initially
receiving either a 2.0 mg or 0.5 mg monthly fixed dose of VEGF Trap-Eye for
12 weeks followed by PRN dosing experienced statistically significant 3.41 mm2
and 1.42 mm2 reductions in mean CNV size at 48 weeks (the final one-year
analysis endpoint from the independent reading center) versus baseline,
respectively. Patients in the 2.0 mg monthly cohort also achieved a
statistically significant 1.75 mm2 reduction in total lesion size. A reduction
in total lesion size was not seen in the cohort initially dosed with 0.5 mg
monthly.
VEGF Trap-Eye was generally well tolerated and there were no reported
drug-related serious adverse events. There was one reported case of
culture-negative endophthalmitis/uveitis in the study eye, which was deemed not
to be drug-related. The most commonly reported adverse events were those
typically associated with intravitreal injections.
VEGF-A both stimulates angiogenesis and increases vascular permeability. It
has been shown in preclinical studies to be a major pathogenic factor in both
wet AMD and diabetic retinopathy, and it is believed to be involved in other
medical problems affecting the eyes. Wet AMD and diabetic retinopathy (which
includes DME) are two of the leading causes of adult blindness in the developed
world. In both conditions, severe visual loss is caused by a combination of
retinal edema and neovascular proliferation.
Collaboration with Bayer HealthCare
In October 2006, we entered into a collaboration agreement with Bayer
HealthCare for the global development and commercialization outside the United
States of VEGF Trap-Eye. Under the agreement, we and Bayer HealthCare will
collaborate on, and share the costs of, the development of VEGF Trap-Eye through
an integrated global plan that encompasses wet AMD, diabetic eye diseases, and
other diseases and disorders. Bayer HealthCare will market VEGF Trap-Eye outside
the United States, where the companies will share equally in profits from any
future sales of VEGF Trap-Eye. If VEGF Trap-Eye is granted marketing
authorization in a major market country outside the United States, we will be
obligated to reimburse Bayer HealthCare for 50% of the development costs that it
has incurred under the agreement from our share of the collaboration profits.
Within the United States, we retain exclusive commercialization rights to VEGF
Trap-Eye and are entitled to all profits from any such sales. We received an
up-front payment of $75.0 million from Bayer HealthCare. In 2007, we received a
$20.0 million milestone payment from Bayer HealthCare following dosing of the
first patient in the Phase 3 study of VEGF Trap-Eye in wet AMD, and can earn up
to $90.0 million in additional development and regulatory milestones related to
the development of VEGF Trap-Eye and marketing approvals in major market
countries outside the United States. We can also earn up to $135.0 million in
sales milestones if total annual sales of VEGF Trap-Eye outside the United
States achieve certain specified levels starting at $200.0 million.
3. ARCALYST® (rilonacept) - Inflammatory Diseases
We are evaluating ARCALYST in a number of diseases and disorders, in addition
to CAPS, where IL-1 may play an important role. In September 2008, we announced
the results of a Phase 2 study which evaluated the efficacy and safety of
ARCALYST versus placebo in the prevention of gout flares induced by the
initiation of urate-lowering drug therapy that is used to control
gout. In this 83-patient, double-blind, placebo-controlled study, the mean
number of flares per patient over the first 12 weeks of urate-lowering therapy
was 0.79 with placebo and 0.15 with rilonacept (p=0.0011), an 81% reduction.
This was the primary endpoint of the study. All secondary endpoints also were
met with statistical significance.
In the first 12 weeks of treatment, 45.2% of patients treated with placebo
experienced a gout flare and, of those, 47.4% had more than one flare. Among
patients treated with ARCALYST® (rilonacept), only 14.6% experienced a gout
flare (p=0.0037 versus placebo) and none had more than one flare. Injection-site
reaction was the most commonly reported adverse event with ARCALYST treatment
and no serious drug-related adverse events were reported.
Gout is characterized by high blood levels of uric acid, a bodily waste
product normally excreted by the kidneys. The uric acid can form crystals in the
joints of the toes, ankles, knees, wrists, fingers, and elbows. Chronic
treatment with uric acid-lowering medicines, such as allopurinol, is prescribed
to eliminate the uric acid crystals and prevent reformation. During the first
months of allopurinol therapy, while uric acid blood levels are being reduced,
the break up of the uric acid crystals can result in stimulation of inflammatory
mediators, including IL-1, resulting in acute flares of joint pain and
inflammation. These painful flares generally persist for at least five days.
We plan to initiate a Phase 3 clinical development program with ARCALYST in
the first half of 2009 both for the prevention of gout flares in patients
initiating urate-lowering drug therapy and in acute gout. We are also planning
to evaluate ARCALYST in other indications in which IL-1 may play a role.
Under a March 2003 collaboration agreement with Novartis Pharma AG, we retain
the right to elect to collaborate in the future development and
commercialization of a Novartis IL-1 antibody which is in clinical development.
Following completion of Phase 2 development and submission to us of a written
report on the Novartis IL-1 antibody, we have the right, in consideration for an
opt-in payment, to elect to co-develop and co-commercialize the Novartis IL-1
antibody in North America. If we elect to exercise this right, we are
responsible for paying 45% of post-election North American development costs for
the antibody product. In return, we are entitled to co-promote the Novartis IL-1
antibody, and to receive 45% of net profits on sales of the antibody product, in
North America. Under certain circumstances, we are also entitled to receive
royalties on sales of the Novartis IL-1 antibody in Europe.
Under the collaboration agreement, Novartis has the right to elect to
collaborate in the development and commercialization of a second generation IL-1
Trap following completion of its Phase 2 development, should we decide to
clinically develop such a second generation product candidate. Novartis does not
have any rights or options with respect to ARCALYST.
Antibody Research Technologies and Development Program:
One way that a cell communicates with other cells is by releasing specific
signaling proteins, either locally or into the bloodstream. These proteins have
distinct functions, and are classified into different "families" of molecules,
such as peptide hormones, growth factors, and cytokines. All of these secreted
(or signaling) proteins travel to and are recognized by another set of
proteins, called "receptors," which reside on the surface of responding cells.
These secreted proteins impact many critical cellular and biological processes,
causing diverse effects ranging from the regulation of growth of particular cell
types, to inflammation mediated by white blood cells. Secreted proteins can at
times be overactive and thus result in a variety of diseases. In these disease
settings, blocking the action of secreted proteins can have clinical benefit.
Regeneron scientists have developed two different technologies to design
protein therapeutics to block the action of specific secreted proteins. The
first technology, termed the "Trap" technology, was used to generate our first
approved product, ARCALYST® (rilonacept) for the treatment of CAPS, and our
current clinical pipeline, including aflibercept, VEGF Trap-Eye, and ARCALYST in
other indications. These novel "Traps" are composed of fusions between two
distinct receptor components and the constant region of an antibody molecule
called the "Fc region", resulting in high affinity product candidates.
Regeneron scientists also have discovered and developed a new technology for
designing protein therapeutics that facilitates the discovery and production of
fully human monoclonal antibodies. We call our technology VelocImmune and, as
described below, we believe that it is an improved way of generating a wide
variety of high affinity, therapeutic, fully human monoclonal antibodies.
VelocImmune® (Human Monoclonal Antibodies)
We have developed a novel mouse technology platform, called VelocImmune, for
producing fully human monoclonal antibodies. The VelocImmune mouse platform was
generated by exploiting our VelociGene® technology platform (see below), in a
process in which six megabases of mouse immune gene loci were replaced, or
"humanized," with corresponding human immune gene loci. The VelocImmune mice can
be used to generate efficiently fully human monoclonal antibodies to targets of
therapeutic interest. VelocImmune and our related technologies offer the
potential to increase the speed and efficiency through which human monoclonal
antibody therapeutics may be discovered and validated, thereby improving the
overall efficiency of our early stage drug development activities. We are
utilizing the VelocImmune technology to produce our next generation of drug
candidates for preclinical development, and are exploring possible additional
licensing arrangements with third parties related to VelocImmune and related
technologies.
Antibody Collaboration with sanofi-aventis
In November 2007, we and sanofi-aventis entered into a global, strategic
collaboration to discover, develop, and commercialize fully human monoclonal
antibodies. The first therapeutic antibody to enter clinical development under
the collaboration is REGN88, an antibody to the interleukin-6 receptor (IL-6R),
that is being evaluated in rheumatoid arthritis. The second is expected to be an
antibody to Delta-like ligand-4 (Dll4), for which we plan to file an IND by the
end of 2008. We plan to file an IND for a third therapeutic antibody shortly
thereafter and to advance an average of two to three antibody candidates into
clinical development each year.
The collaboration is governed by a Discovery and Preclinical Development
Agreement and a License and Collaboration Agreement. We received a
non-refundable, up-front payment of $85.0
million from sanofi-aventis under the discovery agreement. In addition, sanofi-aventis is funding up to $475.0 million of our research for identifying and validating potential drug discovery targets and developing fully human monoclonal antibodies against these targets through December 31, 2012. . . .
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