ADC-1004: Protection against ischemia reperfusion injury

Ischemia reperfusion (I/R) injury is a serious complication after e.g. acute myocardial infarction (AMI) treated with PCI, stroke, and transplantation.
ADC-1004 is a C5a receptor (C5aR) antagonist developed to prevent I/R injury. The drug candidate significantly reduced infarct size in a clinical-like porcine model of AMI. In the clinic, ADC-1004 is expected to reduce mortality, incidence of heart failure, and incidence of malignant arrhythmias, thus contributing to increased lifespan and improved quality of life for millions of patients. Currently no treatment is available to reduce I/R injury.

Alligator Bioscience is seeking partnership with pharmaceutical and biotech companies for the development and commercialization of the program.


Ischemia Reperfusion Injury 

I/R injury refers to damage that occurs when blood flow returns to tissue after a period of ischemia. The absence of oxygen and nutrients creates a situation in which restoration of circulation paradoxically results in inflammation and additional damage and complications, rather than normal function. The injury manifests within minutes after reperfusion and is often associated with microvascular obstruction resulting in incomplete reperfusion (no-reflow). Other clinical manifestations are arrhythmias, myocardial stunning, and increased infarct size. 


Mechanism and Advantage

Neutrophils are particularly important contributors to I/R injury and microvascular obstruction due to their massive accumulation and release of enzymes and radicals.Complement activation is an early event in I/R injury resulting in rapid elevation of local C5a at the ischemic site. 
By blocking the activation of neutrophils, ADC-1004 effectively prevents I/R injury resulting in reduced infarct size and reduced microvascular obstruction. Compared to other candidates in development for I/R injury ADC-1004 targets the C5aR that is available in abundance on neutrophils in circulation.

Convincing Large Animal PoC

ADC-1004 significantly reduced infarct size by 21% in a closed chest AMI model in pigs.
Infarct size is composed of tissue damage both from the ischemia per se and in addition damage due to ischemia reperfusion (I/R) injury. ADC-1004 reduced the major part of the damage caused by I/R injury and had also effects on microvascular obstruction.



Medical Need and Market Potentials

Because of its general mechanism, the drug candidate is expected to have potential in many conditions for which I/R injury is a risk, including AMI, stroke and transplantation.
Myocardial infarction is one of the most common death-causing diseases, affecting more than 2 million people every year. Major resources are invested in this area and the efforts are resulting in decreased mortality. Still, the incidence and mortality rates are far too high, and disabilities from acute heart conditions are severe. A drug that effectively addresses the devastating consequences of a myocardial infarction would not only decrease mortality, but also improve quality of life for millions of patients and decrease the cost to society. Sales for such drug are estimated to exceed $1 billion.

In transplantation, the number of patients in need of a new organ (e.g. lung or heart) far exceed the number of organs available for transplantation. We believe that ADC-1004 has the potential to both increase the number of high-quality organs for transplantation, as well as the clinical outcome of the transplantation.

Scientific References

E. Gustafsson, et al., " Directed evolution of chemotaxis inhibitory protein of Staphylococcus aureus generates biologically functional variants with reduced interaction with human antibodies " Protein Eng. Des. Sel.. 23(2), 91 (2009)

E. Gustafsson, et al., "Purification of truncated and mutated chemotaxis Inhibitory Protein of Staphylococcus aureus-an anti-inflammatory protein" Protein Expr. Purif. 63(2), 95 (2009)

I/R injury is an important contributor to
organ damage.

ADC-1004
Description: 
Optimized anti-inflammatory protein
9.5 kD

Mechanism: 
C5a receptor (C5aR) antagonist.

Effect: 
Inhibits neutrophil activation and migration

Science: 
The involvement of C5a in I/R injury is well supported by animal and human data

Indications: 
Ischemia reperfusion (I/R) injury in e.g. AMI, stroke and transplantation

Edge: 
Block of C5aR on neutrophils in circulation allows for an effective treatment before reperfusion

Status: 
PoC in porcine AMI, rat stroke, and porcine lung transplantation model
IND in 2012

Production:
Expressed in E.coli

IP:
ADC-1004 is protected by patent and patent applications in all markets of commercial interest. Projected expiration 2029

Potential: 
Addressing a high medical need in several diseases. No treatment is currently available for  I/R injury
Market potential >1 billion USD (AMI)