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NicOx
pipeline: product portfolio |
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Beyond naproxcinod and the pre-clinical
candidate, NCX 6560, which are being developed in NicOx’ core
therapeutic areas
of inflammatory and cardio-metabolic 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
(HCT 3012) |
osteoarthritis |
phase
3 |
Core
therapeutic area |
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NCX 6560 |
Dyslipidemia
/ CV Risk |
preclinical |
Core
therapeutic area |
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PF-03187207 |
glaucoma |
phase
2 |
partnered
with Pfizer
Inc |
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TPI
1020 (NCX 1020) |
COPD/asthma |
phase
2 |
partnered
with Topigen
Pharmaceuticals Inc. |
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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 |
pre-clinical |
partnered
with Ferrer Grupo |
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NO-donors
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ophthalmology |
research |
partnered
with Pfizer Inc |
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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
Osteoarthritis - phase 3
Core therapeutic area
NicOx' most advanced product, naproxcinod, is in
phase 3 development for treating the signs and symptoms of
osteoarthritis. The anti-inflammatory agents currently used in the
treatment of osteoarthritis (COX-2 inhibitors and non-selective NSAIDs)
have long been associated with a range of side effects, including
gastrointestinal problems. Furthermore, recent clinical findings have
cast significant doubt on their cardiovascular safety, including their
association with increased blood pressure.
Naproxcinod is a unique nitric oxide-donating
anti-inflammatory and the first of the CINOD class ("COX-Inhibiting
Nitric Oxide Donators"). NicOx aims to develop naproxcinod as a
powerful anti-inflammatory agent with no detrimental effects on blood
pressure and good gastrointestinal tolerability and safety.
Top-line results from the first phase 3 study were
successful. This represents an important step towards NicOx’ goal of
making naproxcinod the drug-of-choice for osteoarthritis patients.
More on
naproxcinod…
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NCX 6560
Cardiometabolic
– Preclinical
Core therapeutic area
In September 2006, NicOx selected NCX 6560 as a new
internal development candidate. NCX 6560 is a nitric oxide-donating
derivative of a commonly used statin drug, which has the potential for
broadened and increased benefit in cardiovascular disease. Statins
represent the most effective and best tolerated drugs for lowering
abnormally raised cholesterol and have consequently become the world’s
best selling class of pharmaceuticals, with combined global sales of
$20.1 billion in 2005.
NCX 6560 has the potential to target
atherosclerosis and endothelial dysfunction through a multi-pathway
approach. The capacity of the nitric oxide-donating moiety to
counteract vascular inflammation and endothelial dysfunction should act
in concert with the cholesterol lowering activity of the statin
portion, to favorably influence the composition, structure and
stability of atherosclerotic plaques.
More
on NCX 6560...
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PF-03187207
Glaucoma - Phase 2
Partnered with Pfizer Inc.
Pfizer Inc has entered into clinical development in
its collaboration with NicOx, initiated in August 2004, which is
focused on the research and development of nitric oxide-donating
derivatives of prostaglandin F2-alpha analogs for the treatment of
glaucoma. In March 2007, Pfizer initiated the first in a series of
planned clinical studies for PF-03187207, the lead candidate selected
for development in November 2005. The initiation of this clinical study
follows the granting of an Investigational New Drug (IND) approval for
the PF-03187207, as a new experimental medicine for the treatement of
glaucoma.
The
first clinical study is a phase 2, dose-finding trial, which is
designed to compare the safety and efficacy of PF-03187207 to
latanoprost, a widely used drug for the treatement of glaucoma. The
trial will be a 28 day, parallel group, randomized and double-masked
study, which is expected to enroll around 150 patients with primary
open angle glaucoma, or ocular hypertension, in one or both eyes. The
primary endpoint of this study will be the change in diurnal
intraocular pressure (IOP, pressure within the eye) at day 28.
Secondary endpoints will include: the change in IOP from baseline at
the study center visits on day 7, 14, 21 and 28, the proportion of
patients at target IOP across all study visits, in addition to safety
evaluations.
Based
on the very promising preclinical results and on the well-known
activities of nitric oxide, PF-03187207 is expected to have an
increased capacity to reduce high IOP. The development of abnormally
high IOP, due to blockage or malfunction of systems controlling the
amount of fluid in the eye, is believed to be one of the principal
causes of glaucoma.
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 IOP,
which is believed to cause progressive vision impairment. The degree of
IOP reduction is believed to be linked to prognosis. 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.
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TPI 1020 (NCX 1020)
Chronic Obstructive Pulmonary Disease
(COPD)/Asthma - Phase 2
Partnered with TOPIGEN Pharmaceuticals
Inc.
TOPIGEN is currently performing a phase 2 clinical
development program initiated in May 2006 for TPI 1020 (formerly NCX
1020) in respiratory disorders. TOPIGEN aims to develop TPI 1020, a
novel respiratory anti-inflammatory licensed from NicOx, as a treatment
for Chronic Obstructive Pulmonary Disease (COPD) and other respiratory
disorders. In November 2007, TOPIGEN dosed the first patients in a
phase 2 proof-of-concept study for TPI 1020 in COPD. This study is
expected to provide the first assessment of TPI 1020’s potential
activity in this disease.
This trial is a 6-week, multi-center, double blind, placebo and
active-controlled study, where about 50 patients with COPD are being
randomly allocated to three arms. Each arm will receive inhaled doses
of TPI 1020 (500μg bid), budesonide (800μg bid), a conventional
corticosteroid commonly used in respiratory disorders, or placebo.
Eligible patients are smokers or ex smokers between 40 and 80 years old
with an established clinical history of mild to moderate COPD, as
defined by the Standards for the Diagnosis and Management of patients
with COPD. The primary outcome measures of the study are the effect of
TPI 1020 and budesonide on the change in sputum neutrophil counts
between baseline and day 42 and the safety and tolerability of inhaled
TPI 1020 in COPD patients.
The initiation of this new trial follows the announcement of promising
top-line results from a phase 2a study in asthmatic smokers, where TPI
1020 showed a good safety and tolerability profile, in addition to
certain anti-inflammatory effects which could be potentially beneficial
in COPD. This trial was a 21-day, multi-center, double blind study in
asthmatic smokers who were randomized to receive repeated and ascending
doses of either inhaled TPI 1020 or budesonide. Previously, preclinical
models of COPD have suggested that TPI 1020 is more effective than
budesonide in protecting against bronchoconstriction and in inhibiting
the infiltration and subsequent activation of neutrophils in the lungs
(neutrophils are immune cells releasing enzymes that destroy lung
tissue).
COPD is characterized by persistent airflow limitation in the lungs and
represents the fourth leading cause of death in the United States. The
cellular mechanisms that are responsible for COPD pathology are not
completely understood. Chronic airflow limitation is believed to be a
consequence of an abnormal recruitment of inflammatory cells such as
neutrophils and is frequently a response to exposure to cigarette
smoke. Smoking is the most important risk factor associated with the
development of COPD.
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NCX 1510 (NLA)
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.
A nasal spray formulation of NCX 1510 is currently in phase 2 clinical
development and is expected to have equivalent efficacy to existing
systemic treatments, in addition to a rapid onset of action.
In June 2004, NCX 1510 reached its primary efficacy endpoint in a phase
2a study in allergic rhinitis. This was a double blind, three way
crossover study (NCX 1510 nasal spray, citerizine tablets and placebo)
involving 36 patients, which was carried out at Lund University in
Sweden. NCX 1510 showed a statistically significant reduction in
symptoms (primary endpoint), which were measured as a lower total
nasal-symptom score, compared to placebo. NCX 1510 also demonstrated
equivalent efficacy to citerizine, the standard systemic treatment.
In February 2005, a second clinical study demonstrated a rapid
onset-of-action of only 5-10 minutes. This trial had a randomized,
crossover-design, in which 12 healthy volunteers received a single
intranasal dose of either NCX 1510, or placebo, followed by histamine
challenge to mimic an allergic reaction. NCX 1510 was found to reduce
the levels of a protein linked to allergic reactions, in a
statistically significant manner compared to placebo, only 5-10 minutes
following administration.
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Nitric oxide-donating antihypertensives
Hypertension - phase 1
Partnered with Merck & Co., Inc.
Following the completion of a fruitful three year
research collaboration, NicOx signed a major exclusive worldwide
license agreement with Merck & Co., Inc., in March 2006. This
new agreement covers the development of nitric-oxide donating
derivatives of several major classes of antihypertensive agents for the
treatment of high blood pressure, complications of hypertension, and
other cardiovascular and related disorders.
The joint research has generated very good results,
particularly in in-vivo validated models of
hypertension, suggesting that NicOx‘ proprietary nitric oxide donation
technology has the potential to improve the blood pressure lowering
activity of antihypertensive agents.
In
July 2007, Merck has initiated the first in a series of planned studies
in the clinical program for the first selected drug candidate. This
first trial is a phase 1, dose-escalating study in healthy volunteers.
The primary objective of this trial is to assess the safety,
tolerability and pharmacokinetics of single oral doses, in order to
select the dose and dosing regimen for further clinical studies. The
start of this clinical development program follows the announcement in
January 2007 of the companies' selection of the first development
candidate and that Merck had started the Good Laboratory Practice (GLP)
compliant toxicology studies needed to submit an exploratory IND for
this compound. Since the beginning of 2007, NicOx will have been
received from Merck a total of €10 million milestone payment. Under the
terms of the agreement, Merck is responsible for the funding and
performance of the development of this compound going forward.
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NCX 1047
Dermatology - Pre-clinical
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 the1950s. 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
Ophthalmology - Research
Partnered with Pfizer Inc
In March 2006, NicOx signed a major new agreement that grants Pfizer
Inc exclusive rights, across the entire field of ophthalmology, to use
NicOx proprietary nitric oxide-donating technology.
Generally eye diseases affect millions of people worldwide and can lead
to impaired vision or total blindness. Many important eye conditions
still have no effective treatment, while improved drugs are needed in
other areas. Furthermore, the aging of the population has led to a
rapidly growing incidence of these conditions in the world’s major
pharmaceutical markets.
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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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