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NicOx
pipeline: product portfolio |
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Beyond naproxcinod, NCX 6560 and NCX 116 which are being developed in NicOx’s core
therapeutic areas of inflammatory, cardiometabolic and ophthalmology disorders, the
company has a broader pipeline of molecules in other therapeutic areas,
many of which are the subject of partnership agreements :
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Compound |
Therapeutic
area |
Phase |
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Naproxcinod
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relief of the signs and symptoms of osteoarthritis |
MAA validated |
Core
therapeutic area |
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NCX 6560 |
reduction of major cardiac events in CHD patients |
phase
1 |
Core
therapeutic area |
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NCX 116 (PF-03187207) |
glaucoma |
phase
2 |
Core
therapeutic area Partnered with Bausch + Lomb |
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NCX 1020 (TPI 1020) |
respiratory
disorders |
phase
2 |
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NCX 1510 |
allergic
rhinitis |
phase
2 |
partnered
with
Orexo AB |
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NO-antihypertensives |
hypertension |
phase 1 |
partnered
with Merck & Co., Inc. |
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NCX 1047 |
dermatology |
preclinical |
partnered
with Ferrer Grupo |
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NO-donors
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ophthalmology |
research |
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NO-donors |
cardiometabolic |
research |
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NO-donors |
inflammation
pain |
research |
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click
on the name of a compound for more information |
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Naproxcinod
Signs
and symptoms of Osteoarthritis – MAA validated in Jan. 2010 – Complete Response Letter received from FDA in July 2010.
Core therapeutic area
NicOx's
most advanced investigational drug, naproxcinod, has successfully
completed a regulatory phase 3 program in patients with osteoarthritis
of the knee and hip. Anti-inflammatory agents currently used in the
treatment of osteoarthritis (traditional NSAIDs and COX-2 inhibitors)
have long been associated with a range of side effects, including
gastrointestinal problems. Furthermore, clinical findings continue to
cast significant doubt on their cardiovascular safety, including their
association with increased blood pressure.
Naproxcinod is a
unique nitric oxide-donating anti-inflammatory compound and the first
CINOD (Cyclooxygenase-Inhibiting Nitric Oxide Donator) in late-phase
development. NicOx aims to demonstrate that naproxcinod is an
anti-inflammatory agent with no detrimental effect on blood pressure
and good gastrointestinal tolerability and safety.
NicOx has
completed a regulatory phase 3 program for naproxcinod in patients with
OA of the knee (the 301 and 302 studies) and hip (the 303 study), with
all three studies achieving highly statistically significant results on
all three co-primary efficacy endpoints. The naproxcinod Marketing Authorization
Application (MAA) submitted by NicOx in December 2009 is currently
under review by the European Medicines Agency (EMA). In
July 2010, the US Food and Drug Administration (FDA) provided a Complete Response Letter to the New Drug
Application (NDA) for naproxcinod stating that it does not approve the
naproxcinod application. NicOx plans to discuss the Complete Response Letter and potential next steps as early as possible with the FDA. More on
naproxcinod…
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NCX 6560
Cardiometabolic
– Phase 1
Core therapeutic area
In
November 2009, NicOx announced that a phase 1b, first-in-man study for
NCX 6560, versus placebo and Lipitor® (atorvastatin), had met its
primary and secondary objectives. The top-line results demonstrated
very good safety and tolerability for all the tested doses of NCX 6560,
as well as the expected cholesterol lowering profile. NCX 6560 is an
innovative nitric oxide (NO)-donating HMG-CoA Reductase Inhibitor,
which has the potential to be developed as a new treatment to further
reduce the risk of major adverse cardiac events (MACEs) in Coronary
Heart Disease (CHD) patients.
More
on NCX 6560...
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NCX 116
Glaucoma
- Phase 2 Partnered with Bausch + Lomb
Core therapeutic area In
March 2010, NicOx and Bausch + Lomb, a leading eye health company,
entered into a licensing agreement which grants Bausch + Lomb exclusive
worldwide rights to develop and commercialize NCX 116 (previously PF
03187207), a nitric oxide donating prostaglandin F2-alpha analog. It
is estimated that over 3 million people in the United States suffer
from glaucoma and 120,000 are believed to have lost their vision as a
result of the disease. Current drug therapy is focused on reducing
intraocular pressure (IOP), which is believed to cause progressive
vision impairment. The degree of IOP reduction is believed to be linked
to prognosis (i.e. the greater the reduction in IOP the slower the
progression towards vision loss and eventually blindness).
Xalatan®
(latanoprost) is a proprietary Pfizer product and the leader in
worldwide glaucoma sales, with approximately $1.6 billion of franchise
sales in 2007. However, despite recent advances in glaucoma treatment,
research shows that around 10% of patients who receive proper care
still experience vision loss, demonstrating the strong necessity for
improved drugs.
In
2008, NicOx announced the results of two dose-ranging phase 2 studies
conducted with NCX 116 in glaucoma
patients, in the United States and in Japan. These studies were designed to
compare the safety and efficacy of several doses of NCX 116
to
Xalatan® and enrolled an overall number of 327 patients with primary
open angle glaucoma or ocular hypertension.
On
the primary endpoint of both studies at 28 days, the highest doses of NCX 116 showed an improvement over Xalatan® 0.005% of up to 12%, in
terms of the reduction in diurnal IOP compared to baseline, although
this did not reach statistical significance. NCX 116 appeared to be
safe and well tolerated, with adverse events being mild.
In
both the Japanese and U.S. studies, NCX 116
showed a 20% greater
reduction in IOP at 20 hours post-dose compared to Xalatan® 0.005%,
which reached statistical significance in the U.S. study, suggesting a
more sustained IOP lowering effect. |
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NCX 1020 (ex TPI 1020)
Respiratory
disorders - Phase 2
NCX 1020 is a novel anti-inflammatory
drug-candidate for respiratory
indications. In
January 2010, NicOx and TOPIGEN Pharmaceuticals Inc. have mutually
terminated their collaboration for NCX 1020, as a result of the
acquisition of TOPIGEN by Pharmaxis. Following
two phase 2a studies that were conducted by TOPIGEN with NCX 1020 in
patients with asthma and COPD, NicOx and TOPIGEN had recently been in
active discussions to explore potential new opportunities for the
development of NCX 1020 in a variety of respiratory indications. As a
result of the strategic review of Pharmaxis and TOPIGEN’s development
pipeline, they have decided not to move forward with the development of
NCX 1020. In December 2008, the results of a phase 2a study in 61
patients with Chronic Obstructive Pulmonary Disease (COPD) were
announced. COPD is a very prevalent respiratory disorder characterized
by persistent airflow limitation in the lungs. COPD is very difficult
to treat and there are no drugs available that can slow the progressive
decline in lung function.
In the phase 2a study, NCX 1020 showed good overall safety and
tolerability, although its activity profile was not significantly
different from budesonide, a conventional corticosteroid commonly used
in respiratory disorders. Nevertheless, NCX 1020 did show a numerical
reduction in the sputum neutrophil count in the airways between
baseline and day 42, as compared to budesonide which increased them
(p=0.095). Neutrophils are inflammatory cells which are directly
implicated in the pathology of COPD.
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NCX 1510
Allergic
rhinitis - Phase 2
Partnered with Orexo AB
NCX 1510 is a nitric oxide-donating drug candidate
for the treatment of allergic rhinitis, an extremely common allergic
reaction which leads to inflammation of the nasal membrane and
associated symptoms such as sneezing or a blocked nose.
This
partnership has not resulted in significant developments and
accordingly NicOx and Orexo AB are currently considering alternatives
for its termination.
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Nitric oxide-donating antihypertensives
Hypertension
- phase 1b
Partnered with Merck & Co., Inc.
In the United States, nearly one person in three
suffers from hypertension (high blood pressure). This chronic disorder
is a leading cause of mortality and morbidity, as it increases the risk
of stroke, heart failure, cardiovascular disease and renal disease. It
is estimated that more than 190 million people suffer from high blood
pressure in the seven leading pharmaceutical markets, and researchers
have predicted that there will be a relative increase of 24% in the
prevalence of hypertension in developed countries from 2000 to 2025,
due to an aging population and the increased rate of diabetes and
obesity. The global market for antihypertensive drugs totaled $53.1
billion in 2007, which represents the largest indication for
prescription pharmaceuticals worldwide.
Despite the numerous different classes of
antihypertensive therapies available to physicians, less than one third
of treated patients are believed to achieve established blood pressure
goals, highlighting the pressing need for new drugs. NicOx and Merck
& Co., Inc. are collaborating on the development of new
antihypertensive drugs using NicOx’ proprietary nitric-oxide donating
technology, which has the potential to meet this need.
Merck
& Co., Inc. is conducting a program, with the objective of
selecting a nitric oxide-donating candidate to advance into phase 2
clinical development. This program includes several compounds, being
evaluated in clinical trials involving healthy subjects and individuals
with mild to moderate hypertension.
Endothelial nitric oxide is believed to play an
important role in the regulation of blood pressure. Very promising
preclinical results were presented in 2006 at the American Heart
Association for a prototype compound, a nitric oxide-donating
derivative of a commonly used antihypertensive drug. These results
suggest that NicOx’ proprietary technology has the potential to improve
the blood pressure lowering activity of existing antihypertensive
agents.
The clinical program for developing new nitric
oxide-donating antihypertensive drugs is being funded and managed by
Merck & Co., Inc., following the signature of the companies’
2006 exclusive worldwide agreement.
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NCX 1047
Dermatology
- Preclinical
Partnered with Grupo Ferrer Internacional,
S.A.
NicOx is collaborating with Ferrer to develop novel
nitric
oxide-donating anti-inflammatory drugs for treating a range of skin
disorders, such as Atopic Dermatitis, Psoriasis and Seborrheic
Dermatitis.
In May 2006 NicOx and Ferrer selected NCX 1047 as
the development
candidate in their dermatology collaboration. The selection of NCX 1047
marks the successful completion of the partners’ research program,
announced in September 2005, to identify a novel, high potency, nitric
oxide-donating anti-inflammatory drug, for use in dermatology, with the
potential for an improved risk-benefit ratio in humans.
In October 2007, NicOx and Ferrer presented
clinical and preclinical
results at the 21st World Congress of Dermatology, in Buenos Aires,
Argentina. These included phase 1 results for NCX 1022, a prototype
compound, showing the potential for improved safety and tolerability
and preclinical results for a novel, high potency, nitric
oxide-donating anti-inflammatory suggesting it could have enhanced
anti-inflammatory activity over current dermatology products.
Topical anti-inflammatory drugs such as
corticosteroids have been the
mainstay for treating a range of skin disorders since the first use of
hydrocortisone in the 1950s. However, they are associated with local
tolerability issues, including thinning of the skin which can be
permanent and disfiguring in some cases. These drawbacks typically
require doctors to review patients frequently, limit the duration of
treatment and the area to which the cream is applied. These local skin
problems have been linked to the propensity of topical corticosteroids
to reduce dermal blood flow, which can be visualized as a blanching of
the skin.
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Nitric
oxide-donating compounds
Diabetic
retinopathy and Glaucoma -
Research
Diabetic
retinopathy causes 12,000 to 24,000 new cases of blindness each year in
the United
States
and represents the leading cause of blindness among adults aged 20 to
74 years.
In the US,
40-45% of adults diagnosed with diabetes have some degree of diabetic
retinopathy, which corresponds to 4.1 million adults (2004).
Diabetic
retinopathy is retina damage due to diabetes. High blood sugar can
damage
ocular blood vessels, causing them to become blocked or leak fluid.
Frequently
a swelling of the retina or a build-up of protein deposits on the
retina can be
involved in the disease. In some cases there is a development of new,
abnormal
vessels, which can break and bleed into the center of the eye, inducing
blindness. In addition to prevention through the management of blood
sugar
levels, the most established treatment for diabetic retinopathy is
laser
surgery.
NicOx
and Pfizer have collaborated on various research projects to identify
new compounds for the potential treatment of diabetic retinopathy and
glaucoma. Under the new agreement signed between both companies in
August 2009, NicOx has regained rights to a number of novel,
research-stage, nitric oxide-donating compounds for the potential
treatment of these ophthalmology disorders. The compounds targeting
diabetic retinopathy have produced positive results in a variety of
models showing their potential benefit for the treatment of this
prevalent eye disease.
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Nitric
oxide-donating compounds
Cardiometabolic
- Research
Clinical studies have established that the widely
used lipid-lowering drugs commonly referred to as statins reduce the
incidence of coronary heart disease or other serious events such as
stroke when given over an extended period of time. NicOx has modified
the chemical structure of well established statins to enhance the
beneficial effects of nitric oxide.
The new compounds, while maintaining lipid lowering
properties, show marked NO-mediated effects in predictive models of
cardiovascular disorders such as myocardial infarction or peripheral
vascular diseases, with an activity superior to that of reference
compounds. Thus, nitric oxide-donating derivatives of atorvastatin or
pravastatin, for instance, represent an attractive generation of drugs
for the treatment of atherosclerosis and other cardiometabolic
disorders.
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Nitric
oxide-donating compounds
Inflammation
& Pain - Research
Previous research efforts have clearly demonstrated
the value of nitric oxide-donation in enhancing anti-inflammatory
properties of commonly used drugs, e.g. NSAIDs or glucocorticoids.
Given the interesting clinical results obtained with the most advanced
compound, naproxcinod, an additional effort is ongoing to identify
other NO-donating NSAIDs (CINODs) which can combine effective
anti-inflammatory properties with gastrointestinal and cardiovascular
safety.
Moreover, nitric oxide has been found to enhance
the effects of gabapentin, which has become a reference drug for the
treatment of neuropathic pain. Thus, a prototypic compound NCX 8001 is
effective in models of neuropathic pain with a profile superior to that
of gabapentin. These data have been of stimulus to focus
further on the potential of nitric oxide-donating drugs for
the treatment of neuropathic pain, an area of still high medical need.
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