Dipeptidyl peptidase I (cathepsin C)

- a novel target for the treatment of inflammatory diseases

 

UNIZYME Laboratories is a virtual Danish biotech company focused on design and development of novel small molecule inhibitors of dipeptidyl peptidase I (DPPI; also known as cathepsin C) for treatment of inflammatory diseases.

 

DPPI is an activator of neutrophil elastase (NE), cathepsin G (catG) and proteinase 3 (Pr3) known to be involved in a vast variety of inflammatory condition and a validated drug target for a number of chronic diseases with components of neutrophil inflammation, such as COPD, cystic fibrosis, alpha-1 antitrypsin deficiency, rheumatoid arthritis and gout.

 

 

 

 

The proteases are synthesized and activated by DPPI in the bone marrow. Inhibitors of DPPI reduce levels of inflammatory proteases and are likely to be useful for treatment of protease-driven inflammatory diseases.

 

Unizyme has developed an oral available candidate drug XPZ-35, which has a PK profile that supports a once-daily oral dosing regime. Oral administration of XPZ-35 dosing from 0.2 mg/kg/day has a clear dose dependent effect on NE, CatG and Pr3 activity in both bone marrow and circulating neutrophils in an inhaled LPS challenge mouse PD model.

 

The next step in the XPZ-35 development process is GMP batch production and two species tox analysis prior to entering phase 1 clinical testing. IPR for XPZ-35 and the backup program has priority date September 2013.

 

Unizyme has demonstrated significant effect in the collagen antibody-induced arthritis (CAIA) mouse model for rheumatoid arthritis with the DPPI inhibitor tool compound XPZ-01. There is also compelling data that supports DPPI as an attractive drug target in chronic lung diseases with components of neutrophil inflammation – examples are:

  • Animal in vivo data have provided evidence of the collateral involvement of NE, CatG and Pr3 in cigarette smoke induced tissue damage and emphysema 
  • The DPPI inhibitor tool compound MOTP, prevents the development of emphysema following 32 weeks smoke exposure in a COPD animal model
  • Lack of elastase reduces inflammation, mucus hypersecretion, and emphysema in mice with cystic fibrosis-like lung disease 
  • Clinical stable patients with either alpha-1 antitrypsin deficiency or usual COPD with chronic bronchitis has elevated Pr3 activity in sputum and Pr3 activity is greater during exacerbations than in stable state
 

For further information, please contact John Pedersen.

 

March 2015