Patrizia Ricci, PhD

PNH is a rare hematological disease caused by a defective expression of regulatory proteins on the surface of blood cells, leaving them vulnerable to complement attack. This can lead to premature death of the red blood cells, a process called hemolysis hemolysis: (hi-MOL-uh-suss) The destruction of red blood cells. , which results in severe anemia anemia: (uh-NEE-mee-uh) A condition in which there is a shortage of red blood cells in the bloodstream. This causes a low red blood cell count. Symptoms of anemia are fatigue and tiredness. and contributes to a high risk of clotting. The availability of the anti-C5 complement inhibitor Eculizumab Eculizumab: Eculizumab (Soliris ®) is given as an IV into a vein at the doctor’s office or at a special center. The procedure usually takes about 35 minutes. You will probably get an IV once a week for the first 4 weeks. Starting in the 5th week, you will get a slightly higher dose of Soliris every 2 weeks. … has dramatically improved the treatment of PNH; however, since a substantial proportion of patients continue to show sign and symptoms of the disease, there is a room for improving the current anti-complement treatment of PNH.

To date, clinical translation plans have been started with the fusion protein TT30 only. However, pre-clinical data with other agents seem robust enough to support clinical translation with other second-generation complement inhibitors that, by blocking early phases of complement activation, should result in a better control of both intravascular and extravascular hemolysis in PNH patients. This is the case of compstatin analogs, and in particular of the derivative AMY-101, which has shown in vitro a complete abrogation of intravascular hemolysis of PNH erythrocytes, as well as a full prevention of their C3 opsonization. Combined with the excellent bio-availability and the safety profile demonstrated in non-human primates, these data pave the way for forthcoming human studies.

In our proposal, we aimed to complete the pre-clinical investigation of a novel class of peptides which target the complement system complement system: A group of proteins that move freely in the bloodstream. These proteins support (complement) the work of white blood cells by fighting infections. at the level of C3, the key component of the complement. 

The inhibitors tested are all derivatives of compstatin, an agent that prevents cleavage and activation of the complement protein C3; in particular, our data support a clinical translation with the second generation compstatin analog Cp40 (AMY-101). 

In the first year of our research, we have definitely confirmed the efficacy of Cp40 in an in vitro model of PNH, providing strong evidence that the compound prevents the destruction of red blood cells obtained from PNH patients. We also demonstrated that pharmacological levels of Cp40 were able to prevent the modification of PNH red blood cells (e.g., the decoration with the complement component 3) which usually impair the efficacy of Soliris in a substantial proportion of PNH patients. 

These in vitro data were accompanied by extensive investigations in non-human primates, which ruled out possible side effects, and provided detailed information about the pharmacokinetics and the pharmacodynamics of Cp40 in vivo. Indeed, a single intravenous injection of PEG Cp40 resulted in

a prolonged elimination half-life of >5 days but may potentially affect the plasma plasma: The fluid part of the blood. Plasma is mostly made of water with chemicals in it. These chemicals include proteins, hormones, minerals, and vitamins. levels of C3. Despite faster elimination kinetics, saturating inhibitor concentration could be reached with unmodified Cp40 through repetitive subcutaneous administration. It was important to demonstrate that sustained plasma inhibitor levels could be achieved even with unmodified Cp 40 when ijected subcutaneosly into non-humane primate in a multi-dose regimen (at 12h-intervals). These findings suggest that Cp-40 may prove a valuable option for long-term systemic treatment of PNH patients potentially even allowing for self-administration by the patient via a subcutaneous formulation.

According to our data, the inhibition of the complement cascade using small inhibitory molecules like AMY-101 would be a better strategy to prevent hemolysis and immune cell recognition while being potentially more cost-effective. Our pre-clinical data are almost complete to lead to the design of clinical trials clinical trials: Clinical research is at the heart of all medical advances, identifying new ways to prevent, detect or treat disease. If you have a bone marrow failure disease, you may want to consider taking part in a clinical trial, also called a research study. Understanding Clinical Trials Clinical… for human subjects, including PNH patients. In the meantime, based on the potential benefit of this treatment over current standard therapies for PNH, together with Amyndas (a small biotech Company based in Europe) we have applied for the status of Orphan Drug Orphan Drug: A drug or biologic agent that treats a rare disease or condition. A disease is considered rare if fewer than 200,000 people in the United States have it. to competent authorities. Indeed, without further discussion AMY-101 has been granted AMY-101 with the Orphan Drug Designation for the treatment of Paroxysmal Nocturnal Hemoglobinuria Paroxysmal Nocturnal Hemoglobinuria: (par-uk-SIZ-muhl nok-TURN-uhl hee-muh-gloe-buh-NYOOR-ee-uh) A rare and serious blood disease that causes red blood cells to break apart. Paroxysmal means sudden and irregular. Nocturnal means at night. Hemoglobinuria means hemoglobin in the urine. Hemoglobin is the red part of red blood cells. A… (PNH) in July 2014 by the European Medicines Agency (EMA), and more recently by the U.S. Food and Drug Administration (FDA).

This achievement may be useful to speed the clinical translation of AMY-101, eventually leading to first-in-human studies before the end of 2015; in addition, the Orphan Drug Designation may expedite the clinical development, and possibly a future marketing authorization for PNH patients.