CNR, MEDICINA

Inhibition of the receptor p75NTR: a new treatment for inflammation

Based on the discovery of a novel pathogenetic mechanism involving p75NTR receptor, authors demonstrated that p75NTR receptor inhibitors, alone or in association with TrkA receptor activators, reduce inflammatory cytokine production and prospect their use for anti-inflammatory treatment of chronic inflammatory diseases of auto-inflammatory or autoimmune origin.

Patent status

SUBMITTED

Priority Number

RM 2011A000024

Priority Date

24.11.2011

License

EUROPE

Market

TAM – Rheumatoid arthritis is the most common chronic inflammatory disease affecting 1% of women worldwide. In Europe more than 2.3 million individuals have rheumatoid arthritis, generating annual direct and indirect costs of management of over €45 billion per year. The other chronic inflammatory diseases all together represent also a sizeable number of patients. There are over 3 million patients with chronic inflammatory bowel disease in Europe. SAM – 20 to 50% of patients with chronic arthritis, such as rheumatoid arthritis, show persistently active disease despite current available advanced targeted therapies. The number of patients with the other chronic inflammatory diseases refractory to available therapies varies from 100% to 30%, depending on the disease.
SOM – Following completion of the p75NTR trials in rheumatoid arthritis and approval, we foresee the possibility to treat with p75NTR inhibition a percentage of patients with persistently active rheumatoid arthritis ranging from 2% to 5% of the prevalent patients in Europe. This will correspond to approximately 15.000 to 35.000 patients. Available targeted treatments have a market price in Italy ranging from 5.000 to 20.000€/year/patient

Problem

Chronic inflammatory diseases are one of the main causes of death in the world and considered by the World Health Organization as a great threat to human health. In United States the number of patients with chronic inflammatory diseases has been growing persistently for the last 30 years. If we consider only chronic arthritis and joint diseases they affect approximately 350 million people worldwide.
Chronic inflammation is caused by different mechanisms: errors in the innate immune system (i.e. auto-inflammatory diseases) or errors in the adaptive immune system (autoimmune diseases). Whatever the etiology, inflammatory cytokines produced by activated monocytes and other immune and non-immune cells are the common drivers of inflammation in all chronic inflammatory diseases.

Current Technology Limitations

Inflammation is a central feature of many chronic diseases. The specific characteristics of the inflammatory response in each disease differ but all involve activation of inflammatory cells and increased expression of cytokines and chemokines.
Glucocorticoids are compounds currently used for the treatment of a variety of chronic inflammatory diseases as they are potent suppressors of the expression of cytokines and chemokines which drive the inflammatory response. They have a potent anti-inflammatory action but they have severe and systemic side-effects in the medium-long term, including muscle atrophy, osteoporosis with fractures, hypertension, peptic ulcers, diabetes and severe infection. The presence of these side effects is the limiting factor in glucocorticoid therapy and that has driven research and the development of new compounds. New innovative biological agents for blocking and regulating inflammatory cytokine activities have emerged as therapeutic tool for the treatment of chronic inflammatory diseases. They have shown an enormous therapeutic potential. However, cytokines are pleiotropic and their effects are redundant so the blocking of one specific cytokine activity can be compensated by others, whose effects are overlapping. Indeed, despite these treatments, considering patients with chronic arthritis, approximately 50% of patients show persistent inflammatory activity and joint damage accrual associated with increasing medical and social costs. Compared to chemical drugs the costs of biological therapy are high and they have limited shelf half-life and special storage conditions.

Killer Application

Given the unmet medical need and the size of the potential market we believe that development of p75NTR inhibitors in rheumatoid arthritis is the starting application.
Preliminary data in vivo in animals and in patients show absence of significant toxicity and one compound is already being tested in a phase II study in the treatment of patients with Alzheimer’s disease, given its effect on neuron survival (clinical trial.gov number NCT03069014).

Our technology and solutions

The discovery that in chronic inflammatory diseases there is an enhanced expression of the pro Nerve growth Factor (proNGF) receptor, p75NTR, in peripheral blood cells and in inflamed tissues, allowed us to identify p75NTR as a novel therapeutic target in chronic inflammation. Inhibition of p75NTR reduces the activation of inflammatory intracellular pathways resulting in a marked down-regulation of the synthesis of several inflammatory mediators. p75NTR inhibition using specific peptide or non peptide inhibitors or monoclonal antibodies against p75NTR has, in vitro, an anti-inflammatory effect that is potentially achievable in many chronic inflammatory diseases, independently from their complex underlying etiology. Whatever the etiology, inflammatory cytokines produced by activated monocytes and other cells are the drivers of inflammation in all chronic inflammatory diseases.
Because down-stream pathogenic mechanisms of inflammation are commonly shared by chronic inflammatory diseases, recent therapeutic strategies have focused on blocking cytokine activity or their binding to their specific receptors. The same immunological targets are often used for the treatment of conditions apparently distinct from each other. Indeed, cytokine specific inhibitors (e.g. inhibitors of IL-1, IL-6 or TNF) are variably used in the treatment of chronic inflammatory diseases of autoimmune or auto-inflammatory origin. Furthermore, the feasibility and effectiveness of targeting up-stream generalized mechanisms is shown by the recent development of chemical inhibitors of kinases (so called Janus kinases, JAK), involved in intracellular signaling of several cytokine receptors. JAK inhibitors have been developed and recently approved in the treatment of chronic inflammatory diseases.

Advantages

Blocking of p75NTR receptor using non-peptide inhibitors results in a reduced activation of several signal transduction pathways associated with the initiation and progression of inflammation. These pathways control the production of several inflammatory cytokines that plays a major role in maintaining chronic inflammation. Blocking p75NTR triggers cascade events that influence simultaneously the production of different inflammatory cytokines with the final results of dampening the inflammatory response. This up-stream effect of p75NTR on the reduction of several inflammatory cytokines is very important considering the frequently redundant and interchangeable role of inflammatory cytokines. The in vivo studies indicate that the inhibition of p75NTR reduces or even abolish the expression of IL-6, IL-1b and IL-8 in the inflamed joints, rapidly decreasing the swelling and limiting inflammatory infiltrate in the synovia with a reduction of articular cartilage loss. Our invention identifies a novel targetable mechanism of action of chronic inflammation and may therefore fill the unmet need of those patients who do not respond satisfactorily to presently available modern therapies. This neutralization is achievable with monoclonal antibodies or, even better, with small non-peptide inhibitors that can be administered orally.

Roadmap

Animal models of arthritis and other inflammatory diseases to test in additional models the efficacy of small non peptide p75NTR inhibitors.

Comparison of the in vivo effects of small non peptide p75NTR inhibitors and monoclonal antibodies.

Analysis of doses and route of administration of small non peptide p75NTR in collaboration with PharmatrophiX and Prof Frank Longo, Stanford University USA.

Longitudinal studies to define the expression of p75NTR during disease progression and after the use of standard treatments in chronic inflammatory diseases in responder and not responder arthritis patients.

Design a phase II study for the treatment of rheumatoid arthritis patients.

Development stage

European patent granted.

In vitro experiment completed.

Preliminary experiments on animal models of arthritis completed.

Additional experiments on in vivo models of arthritis are underway.

Phase 2 trial for the use of the non peptidic inhibitor of p75NTR in patients with Alzheimer (pharmacokinetics and safety of the molecule already assessed).