Development stage: Phase II

Development of recombinant human Angiotensin Converting Enzyme 2 (rhACE2) for the therapy of various diseases with an imbalance of the Renin Angiotensin System.

APN01 - Recombinant human soluble Angiotensin Converting Enzyme 2

APN01 is a recombinant, well soluble, highly glycosylated form of human Angiotensin Converting Enzyme 2 (rhACE2). This ACE2 enhancement therapy targets imbalances of the Renin Angiotensin System (RAS), accompanied by insufficient natural ACE2 activity and pathologic elevation of the RAS effector peptide Angiotensin II. An activated and imbalanced RAS plays an important role in various pathologic conditions such as respiratory, cardiovascular, renal and hepatic diseases as well as cancer.
 
Within 4 years only, APN01 was advanced until end of clinical Phase I. In January 2010, Apeiron signed a licensing agreement with GlaxoSmithKline, granting an exclusive, worldwide license to APN01, amounting to a total potential deal volume of approx. € 230 million (excluding royalties on sales, see press release in our News section). The initial focus of clinical development by GSK is the treatment of Acute Lung Injury where GSK is currently conducting a multi-center phase II trial in the US and Canada.

 

Literature about ACE2 (APN01)

ACE2 review 

Hamming I et al. The emerging role of ACE2 in physiology and disease. J Pathol 212: 1-11 (2007) 

ACE2 and ARDS

G Santacruz JF et al. Update in ARDS management: recent randomized controlled trials that changed our practice. Cleve Clin J Med. 73, 217 (2006)

Rubenfeld GD et al., Incidence and Outcomes of Acute Lung Injury. New England Journal of Medicine 16:1685 (2005)

Imai, Y. et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436, 112-116 (2005).

Kuba, K. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 11, 875-879 (2005).

Kuba K, Penninger J et al. Angiotensin-converting enzyme 2 in lung diseases. Curr Opin Pharmacol. 6, 271-6 (2006)

Imai Y, Kuba K, Penninger J. The renin-angiotensin system in acute respiratory distress syndrome. Drug Discovery Today: Disease Mechanisms: Immuno-disorders and autoimmunity Vol. 3, No. 2 (2006)  

ACE2 and cardiovascular disease 

Crackower, M.A. et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417, 822-828 (2002)

Danilczyk, U. & Penninger, J.M. Angiotensin-converting enzyme II in the heart and the kidney. Circ Res 98, 463-471 (2006)

Sarkissian SD et al. ACE2: A novel therapeutic target for cardiovascular diseases. Progress in Biophysics and Molecular Biology 91, 163-98 (2006)

Ferrario CM. Angiotensin-Converting Enzyme 2 and Angiotensin-(1-7): An Evolving Story in Cardiovascular Regulation. Hypertension 47: 515-521 (2006)

Burrell LM et al. Myocardial infarction increases ACE2 expression in rat and humans. European Heart Journal 26: 369-375 (2005) Goulter A et al. ACE2 gene expression is up-regulated in the human failing heart. BMC Medicine 2:19 (2004)

Huentelman M et al. Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE2 in rats. Exp Physiol 90.5, 783-790 (2005)

Yamamoto, K. et al. Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II. Hypertension 47, 718-726 (2006)  

ACE2 and kidney disease 

Ingelfinger, J.R. ACE2: a new target for prevention of diabetic nephropathy? J Am Soc Nephrol 17, 2957-2959 (2006)

Danilczyk, U. & Penninger, J.M. Angiotensin-converting enzyme II in the heart and the kidney. Circ Res 98, 463-471 (2006)

Ye, M. et al. Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: implications for albuminuria in diabetes. J Am Soc Nephrol 17, 3067-3075 (2006)

Soler MJ et al. ACE2 inhibition worsens glomular injury associated with increased ACE expression in streptozotocin-induced diabetic mice. Kidney International advance online publication, 20 June 2007

Reich H et al. Glomerular and Tubular Expression of ACE2 in Type 2 Diabetic Patients with Diabetic Nephropathy, submitted.  

APN01 publications based on Apeiron's work 

Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice. Hepatology 2009

Targeting the Degradation of Angiotensin II With Recombinant Angiotensin-Convertng Enzyme 2. Prevention of Angiotensin II-Dependent Hypertension. Hypertension 2009

Human recombinant angiotensin converting enzyme 2 reduces the progression of diabetic nephropathy. Diabetes 2010

Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets. Crit Care Med 2009

Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction Circulation. 2010