FR104, an immunomodulator, Phase 1 clinical trial completed, Effi-7, a monoclonal antibody in preclinical phase

  • Between 3% and 5% of the world’s population suffer from AID and associated pathologies, 10% to 20% of whom could benefit from better control of the immune balance/system(?).
  • The prevalence of AID is higher in women, occurring 5 to 10 times more frequently than in men (due to the important role of sexual hormones in the occurrence of AID).
  • Rheumatoid arthritis and autoimmune diabetes (type 1, insulin-dependent) are frequent systemic diseases. It is found in 1,000 to 4,000 patients per population of 100,000, and 200 to 300 patients per 100,000.
  • The prevalence of celiac disease is estimated to be 100 to 200 patients per each 100,000 population.
  • Systemic lupus erythematous, scleroderma and dermatopolymyositis are much rarer diseases, with a prevalence of 15 to 50 per 100,000 population, 20 per 100,000 population and between 5 and 10 per 100,000 population, respectively.
  • Therapeutics with better efficacy, an increase in life expectancy, and a reduction in mortality rate for the most severe AID, have meant that the global prevalence for this group of diseases has decreased to 5 – 10 %.

The market of autoimmune diseases includes several breakthrough products with sales figures often over several billions of euros.

AutoImmune Diseases (AID)

Under normal circumstances, the immune system is designed to defend the body against infectious diseases, while hosting its own healthy cells and related tissues. An AID occurs when the self-tolerance mechanisms become defective, allowing autoreactive lymphocytes to attack certain areas of the body. The immune system then becomes pathogenic, inducing tissue or cell damage. These diseases evolve chronically throughout life, with phases of relapses and remissions. Co-stimulatory signals are necessary to enable the harmful T-cell activation to continue.

There are currently more than 80 AID, the most common being rheumatoid arthritis, colitis, multiple sclerosis, psoriasis, diabetes mellitus type 1 and lupus erythematous. In western countries, AID are the primary cause of disability in young adults.

AID may be divided into two classes: organ or tissue-specific AID (for example, autoimmune thyroiditis, myasthenia, pemphygus, etc.) and non-organ specific AID, also called systemic diseases. AID are multifactorial (genetic, endocrine, environmental factors).

The occurrence of AID makes this group of diseases a major health issue, similar to cardiovascular disease or cancer. Autoimmune diseases are chronic, affect young patients and require long term treatments.
Each AID has its own specific treatment regimen with treatment indications strictly symptomatic, anti-inflammatory, immunosuppressive and/or substitutive. The most widely used therapies include corticoids, immunosuppressors and immunomodulators. The use of such chronic treatments is limited, however, due to treatment intolerance and frequent therapeutic escape.

The global market of transplantation

In 2015, it was estimated at $4.3 billion. In 2017, major sales forecasts should be focused on the five first products on a market with high prices and in highly specialized centers.

Transplantation

In the case of organ transplantation, the immune system attacks agents that it considers to be foreign. In bone marrow transplant, immunocompetent cells in the graft recognize alloantigenes of the host as foreign and fight them. This causes Graft Versus Host Disease (GVHD). Alloreactivity (antigenes from a person of the same species but with a different gene and tissue structure) remains a major barrier to organ and tissue transplantation, as immunological rejections trigger a graft loss if no immunosuppressor treatment is delivered.

Transplantation in humans has a relatively short history, spanning just over 50 years. The first successful human kidney transplant was performed in 1954 between identical twin brothers. Since then, the development of new, effective immunosuppressive drugs, coupled with advances in immunology, surgical techniques, donor selection and postoperative care have all contributed to improved outcomes for solid organ transplants, which has now become an established treatment for definitive organ failure of the kidney, pancreas, liver, heart or lung.

A major pharmacological advance has been the discovery of the antiproliferative agent azathioprine, which, combined with corticosteroids and anti-lymphocyte immunoglobulins (ALS) in the 1960s, opened allotransplanation to the clinic.

In 1983, after the launch of the first calcineurin inhibitor (CNI) cyclosporin, graft survival rates improved sufficiently to enable a widespread clinical application of transplantation. In the 1980s, cyclosporin combined with corticosteroids and azathiprine proved to be the most effective drug regimen.

In recent years, a variety of new immunosuppressant medications have been approved, widening the scope of existing therapeutic options. Nevertheless, all current protocols require the patient to take immunosuppression medication on a daily basis and for the rest of his or her life in order to minimize the risk of chronic rejection, which can take months or years to manifest clinically. For example, in 15 years, the six-year survival rate of renal transplant has increased from 66% to 80%.

While for renal transplant, kidney graft survival has improved meaningfully, the rate of graft failure due to a chronic rejection and to nephrotoxicity of immunosuppressors (5% per year) has not improved over this timeframe. Thus, there remains a major medical need for new approaches.