[Monoclonal antibodies at the forefront of health care economic analyses]. / Les anticorps monoclonaux à l'aune de l'économie de la santé - Les accords de l'industrie pharmaceutique.

Therapeutic antibodies have been used for several decades and their associated market (project numbers, approvals…) continues to grow. Remarkably, a new threshold was crossed in the early 2010's to make this decade the decade of immunotherapy. Over the past 10 years, 62 antibodies have been approved, the number of annual transactions between stakeholders has increased to more than 300 (three times more in 2018 than in 2009). The revolution of immunotherapy in cancer treatment and the recent use of antibodies as first-line treatment are the major turning points in oncology. Thus, the last three years alone represent two thirds of the most important deals of the decade involving immunotherapies. Immunotherapy is currently experiencing a golden age that has resulted in many successes, especially in France where biotechnology companies and large pharmaceutical companies have achieved impressive therapeutic and financial results.

TITLE: Les anticorps monoclonaux à l'aune de l'économie de la santé - Les accords de l'industrie pharmaceutique. ABSTRACT: Bien que les anticorps thérapeutiques existent depuis maintenant plusieurs décennies et que le marché associé (nombre de projets en développement, nombre d'anticorps mis sur le marché…) soit en croissance, un palier a été franchi au début des années 2010 pour faire de cette décennie celle de l'immunothérapie. Pendant ces 10 dernières années, 62 anticorps ont obtenu une autorisation de mise sur le marché et le nombre d'accords (acquisitions, participations, partenariats) annuels entre les différents acteurs a dépassé la barre des 300 (avec trois fois plus d'accords en 2018 qu'en 2009). La révolution de l'immunothérapie dans le traitement des cancers et la récente utilisation d'anticorps en première ligne thérapeutique dans celui-ci sont les tournants majeurs de l'oncologie. Les trois dernières années (2016-2019) regroupent d'ailleurs à elles seules les deux tiers des plus importants accords de la décennie impliquant des immunothérapies. L'immunothérapie connaît donc actuellement un âge d'or qui se traduit par de nombreuses success stories, notamment en France, où sociétés de biotechnologie et big pharma présentent des résultats très positifs au plan tant thérapeutique que financier.

Role of the French rescue teams in Diquini Hospital: Port-au-Prince, January 2010.

On January 12, 2010, Port-au-Prince, Haiti, was shattered by a violent earthquake that killed or injured thousands of its citizens. Local emergency services became overwhelmed and international assistance was required. French relief teams were deployed to assist local hospitals in caring for the victims. The medical care activity of the team at Diquini Hospital from January 17-26 was analyzed. Priority was given to surgery, leading to the creation of a pre- and post-operative area and a medical care unit. Special attention was required for infection prevention, pain relief, minor surgery, and pre-surgery triage. The continual influx of accompanied victims necessitated the creation of a receiving area. In spite of the assistance from several foreign surgical teams, some patients had to be evacuated to French or American facilities, particularly children, patients with spinal cord injuries, and those needing intensive care. Analysis of the actions undertaken highlights the importance of well-prepared and flexible medical teams and the ability to provide local and regional anesthesia, including the necessary medical supplies and equipment. Medical care activity, especially post-surgical care, was a predominant, ongoing need. The ability to provide medical care required organization and cooperation among local health care providers and other relief workers.

IRC-083927 is a new tubulin binder that inhibits growth of human tumor cells resistant to standard tubulin-binding agents.

Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for drug efflux pumps (P-glycoprotein) and/or by the acquisition of point mutations in tubulin residues important for drug-tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic imidazole derivative IRC-083927, which inhibits the tubulin polymerization by a binding to the colchicine site. IRC-083927 inhibits in vitro cell growth of human cancer cell lines in the low nanomolar range. More interesting, it remains highly active against cell lines resistant to microtubule-interacting agents (taxanes, Vinca alkaloids, or epothilones). Such resistances are due to the presence of efflux pumps (NCI-H69/LX4 resistant to navelbine and paclitaxel) and/or the presence of mutations on beta-tubulin and on alpha-tubulin and beta-tubulin (A549.EpoB40/A549.EpoB480 resistant to epothilone B or paclitaxel). IRC-083927 displayed cell cycle arrest in G(2)-M phase in tumor cells, including in the drug-resistant cells. In addition, IRC-083927 inhibited endothelial cell proliferation in vitro and vessel formation in the low nanomolar range supporting an antiangiogenic behavior. Finally, chronic oral treatment with IRC-083927 (5 mg/kg) inhibits the growth of two human tumor xenografts in nude mice (C33-A, human cervical cancer and MDA-MB-231, human hormone-independent breast cancer). Together, the antitumor effects induced by IRC-083927 on tumor models resistant to tubulin agents support further investigations to fully evaluate its potential for the treatment of advanced cancers, particularly those resistant to current clinically available drugs.

Novel dual inhibitors of calpain and lipid peroxidation.

A series of molecules with dual inhibitory activities on calpain and lipid peroxidation were synthesized. These hybrid compounds were built on the calpain pharmacophore 2-hydroxytetrahydrofuran linked to a set of antioxidants via a l-leucine linker. Compound 7, the most potent in cellular calpain and lipid peroxidation inhibitions, provided effective protection against glial cell death induced by maitotoxin.

Accuracy of single measurements of pregnancy-associated plasma protein-A, human chorionic gonadotropin and progesterone in the diagnosis of early pregnancy failure.

BACKGROUND: Circulating human chorionic gonadotropin (hCG) and progesterone are commonly used as markers of abnormal pregnancies. Previous studies have shown that pregnancy-associated plasma protein-A (PAPP-A) was also depressed in extrauterine pregnancies (EUP). Previously, PAPP-A was measured with polyclonal antibodies which were later shown to recognise also the pro-form of major basic protein (pro-MBP). OBJECTIVE: To evaluate the clinical usefulness of PAPP-A measurements in early pregnancy. STUDY DESIGN: Circulating PAPP-A, hCG and progesterone were measured in patients with EUP (n=68), abnormal intrauterine pregnancies (abIUP, n=31) and normal intrauterine pregnancies (nIUP, n=72). Gestational age was 30-70 days from the last menstruation. RESULTS: For PAPP-A and hCG, a steep increase was observed from day 30 after last menstrual period onwards, this increase being much less important for abIUP and EUP. The values of PAPP-A and hCG were significantly decreased in abIUP and EUP, from 42 days after LMP onwards. There were no significant differences between abIUP and EUP. Progesterone concentration does not vary with amenorrhoea and was significantly lower in abIUP and EUP. Values in abIUP were significantly (P=0.02) lower compared with EUP for amenorrhoea above 42 days. ROC curves were constructed for amenorrhoea above 42 days. For a specificity of 99%, the sensitivity of PAPP-A, hCG and progesterone were 64.5, 93.3 and 76%, respectively. The threshold values were 14.3mIU/l, 10,400IU/l and 10.1ng/ml for PAPP-A, hCG and progesterone. CONCLUSION: We confirm the decrease of PAPP-A concentrations in pregnancy failure, but hCG and progesterone remain the best clinical tools.