During the
past decade, dramatic advances have been made in understanding the mechanisms
regulating the immune system, its pathological processes and the processes of
immune deviation. As such, it is now recognized that systemic or organ-specific
inflammatory, infectious and autoimmune conditions share basic mechanisms of
initiation, maintenance and progression. By exploiting this knowledge,
Novimmune is working to develop treatments satisfying the, largely unmet, needs
of patients affected by the many diseases within the inflammatory disease
spectrum.
During early
development we will work to understand the benefit risk of our new drug
candidates, to maximize value and justify continued investment in the disease
arena selected. In the later phase of development we will focus on
operationally efficient and cost effective confirmatory trials ensuring our
products will be supported by relevant data enabling their safe and effective
use in medical practice worldwide.
Diabetes
Diabetes is now known to be the end
result of an inflammatory process affecting the beta cells of the pancreas. In
early diabetes, this process is thought to be initiated and propagated by the
effect of Th1-secreted cytokines [e.g. interferon (IFN)] and suppressed by
Th2-secreted anti-inflammatory cytokines [e.g. interleukin(IL)-4, IL-10]. This
led to the hypothesis that diabetes can be prevented using Th2-secreted
cytokines. This hypothesis was examined in various animal models. All these
interventions prevented diabetes, either by a direct effect of the
anti-inflammatory cytokines or via their stimulatory and inhibitory effects on
Th2 and Th1 cells, respectively[1].
Another approach that can skew the
cytokine cascade from a Th1 to a Th2 response is the use of a non-depleting
anti-CD3 antibody. A novel anti-CD3 monoclonal antibody has been shown to
induce IL-4 and IL-10-producing Th2 cells while suppressing IFN-producing Th1
cells. Treatment of NOD mice with this antibody prevents or reverses diabetes.
On the basis of these observations, a randomized controlled trial in patients
with new-onset type 1 diabetes was initiated, results of which demonstrated a
preserved C peptide response and reduced requirement for exogenous insulin[2,3,4].
In 2009, Novimmune will initiate a
phase II-III program exploring the effect of NI 0401, a fully human anti CD3
antibody with an improved dosing regimen relative to other MAbs in current
development, in patients with Type 1 Diabetes.
Inflammatory Bowel Disorders
Inflammatory bowel
disease (IBD) is a chronic inflammation of the intestines that can cause
diarrhea, bleeding, abdominal pain, fever, joint pain and weight loss. It is
estimated that, in the US alone, over one million individuals have IBD and the
number of patients diagnosed with the condition is increasing each year.
Genetic and environmental factors play a role in the disease process. Two main
disease entities, Crohn's
Disease and Ulcerative Colitis are the most common inflammatory bowel
disorders. Although these conditions share common symptoms and are often
misdiagnosed for each other, each disease affects the digestive tract
differently and requires unique treatment.
Crohn's Disease is a chronic
inflammatory disease of the gastrointestinal tract thought to be a result of
the stimulation of a dysfunctional immune response in genetically susceptible
individuals. The resultant intestinal mucosal inflammation involves all layers
of the intestinal wall, frequently leading to debilitating intestinal symptoms as
well as the development of serious complications including intestinal
perforation, abscess formation, bowel obstruction and fistula formation leading
to severe impairment of the quality of life. Approximately 80% of patients will
require surgery within the first 15 years of diagnosis, butsurgical
resection is not curative and patients experience relapses of varying severity
throughout life[5-10].
While introduction of biologic
therapy led to significant improvements in disease management, primary and
secondary treatment failure, as well as contraindications and treatment
limiting side effects, leaves many patients requiring alternative therapy.
Therefore, new agents which can support treatment free maintenance of clinical
remission, reducing complications, hospitalizations, surgery and disease
associated mortality, would significantly improve the treatment of this
condition[11].
In health, the intestinal
mucosa is exposed to a large number of commensal bacteria and food antigens.
Regulatory T lymphocytes (Tregs) are thought to play a critical role in
limiting inflammation in response to these nonpathogenic antigens, and defects
in this T-cell subset have been implicated in the pathogenesis of IBD. In
addition to the T cell transfer model of colitis, multiple murine models have
demonstrated a crucial role for Tregs in the control of intestinal inflammation
and elucidate the mechanisms of their generation, migration, interactions and
function[12-17]. A number of pharmacologic agents have been
shown to promote Treg number or function and may be of benefit for the
treatment of IBD. One of the best characterized is anti-CD3 monoclonal antibody.
Although anti-CD3 exerts some of its effects by deletion or induction of anergy
in pathogenic T cells, anti-CD3 therapy has been shown to promote the
development of adaptive TGF-ß-producing Tregs in a murine model of diabetes, lead
to the accumulation of IL-10-expressing FoxP3- (Tr1) cells in the
small intestine and IL-10-expressing FoxP3+ T cells in the lamina
propria of the colon and result in the production of TGF-ß which may be
responsible for the observed generation of Tregs following therapy[18].
Novimmune has completed a
preliminary clinical trial with NI0401 in patients with Crohns disease, over
80% of whom had failed prior treatment with at least one anti TNF agent.
Results of this study demonstrated a significant treatment effect on endoscopic
response markers and mucosal healing which may result in prolongation of
disease remission. This concept is being tested in a further study currently in
progress.
Acute and Chronic Inflammatory Lung Disorders
Inflammation
in the lung can cause a variety of respiratory disorders leading to acute or
chronic inflammatory lung disease.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are
characterized by local and intense inflammatory responses, with accumulation of
several cell types and soluble mediators in lung epithelium. There are parallel
anti-inflammatory response and lung remodeling, with deposition of collagen
leading to chronic lung fibrosis[19].
Asthma is a complex inflammatory disease of the
lung characterized by airway hyper-responsiveness (AHR), eosinophilic
inflammation, mucus hypersecretion and subepithelial fibrosis. Although multifactorial
in origin, the inflammatory process is believed to be a result of inappropriate
immune responses to common aeroallergens in genetically susceptible
individuals.The initial clinical
presentation varies, most often with intermittent symptoms but sometimes with
constant wheezing, cough, or shortness of breath. Wheezing on expiration is the
classic symptom. Symptoms typically increase with exposure to allergens and
triggers, such as viral upper respiratory infections, pollen, dust mites,
animal dander and environmental irritants (most commonly tobacco smoke).In some
cases, asthma symptoms diminish after childhood[20-22] .
Chronic Obstructive
Pulmonary Disease (COPD) is
characterized by airflow limitation that is not fully reversible. The airflow
limitation is usually progressive and associated with an abnormal inflammatory
response of the lung to noxious particles or gases. COPD is
essentially unknown in children and is rare in younger adults without a history
of alpha1-antitrypsin deficiency. After age 40, however, the
prevalence of COPD increases substantially with aging. In general, risk for
COPD increases with pack-years of smoking or, less often, with ongoing
occupational exposure to inhaled toxins or irritants[23-25].
Although daily symptoms are present in a minority of people with
asthma symptoms in COPD are more likely to be constant and progressive,
reflecting the fact that airway obstruction in COPD is not due to the
reversible airway constriction and inflammation of asthma but rather to structural
changes and mechanical derangements with abnormal elastic recoil. Both
asthma and COPD are associated with inflammatory changes in the airway mucosa.
Airway obstruction in COPD is associated with cellular damage and mucus
hypersecretion with inflammation becoming more prominent in exacerbations of
severe disease. Emphysema is characterized by loss of lung elastic recoil and
loss of alveolar structure resulting from inflammatory cell-mediated damage to
bronchioles, alveolar ducts, and alveoli[23-28]. Advances
in our understanding of the immune-mediated inflammatory mechanisms involved in
the pathogenesis of ALI, ARDS, asthma and COPD have resulted in the development
of novel target-specific biological compounds for the treatment of these
conditions. Novimmune intends to explore the effects of antibodies targeting
Tol receptor 4, RANTES and Interferon induced protein 10 in patients affected
by ALI/ARDS, asthma or COPD.
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