Patrizia Ricci, PhD

Small peptide C3-inhibitors for the treatment of paroxysmal nocturnal hemoglobinuria: moving towards the bedside
Pubmed Author Name: 
Ricci P
Original Research Center: 
University of Naples, Italy
Current Position/Title: 
Department of Clinical Medicine and Surgery
2014

PNH is a rare hematological disease characterized by spontaneous destruction of red blood cells (intravascular hemolysis), poor functioning of bone marrow, and thrombosis. Recently, the availability of the complement inhibitor eculizumab has dramatically improved the treatment of PNH. Nevertheless, about half of the patients treated with eculizumab shows a persistence of clinical signs of the disease. We have recently described the reasons underlying the limited efficacy of current anti-complement treatment for PNH. With this proposal we aim to complete the pre-clinical development of a novel complement inhibitor which targets early events in complement activation, the component-3 of the complement cascade.

First Year Report: 

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, which results in severe anemia and contributes to a high risk of clotting. The availability of the anti-C5 complement inhibitor Eculizumab 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 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 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 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 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 (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.

Final Report: 

Paroxysmal Nocturnal Hemoglobinuria (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, which results in severe anemia and contributes to a high risk of clotting. The availability of the anti-C5 complement inhibitor Eculizumab 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.

Several novel anti-complement agents are currently in pre-clinical or clinical development; our project aimed to complete the pre-clinical development of the lead analog of a novel class of peptides targeting the key component of the complement cascade C3. In our hands, Cp40/AMY-101 showed an optimal efficacy in vitro, as well as a favorable toxicology profile in animal studies using non-human primates. In comparison to other anti-complement agents in development, Cp40/AMY-101 anticipates a better efficacy for the treatment of PNH because it should prevent the destruction of red blood cells (hemolysis) occurring via different mechanisms (intravascular hemolysis and extravascular hemolysis), possibly resulting in a substantial benefit for PNH patients. With the completion of the pre-clinical work, Cp40/AMY-101 is currently under investigation in human trials, starting with a phase I study in human volunteers. The further clinical translation program of Cp40/AMY-101 in PNH patients is also supported by another AAMDS grant awarded to Prof. Risitano.

Current Institution: 
University of Naples, Italy