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KDDF-201212-02 Development of the CETP inhibitor CKD-519 for the treatment of dyslipidemia(Cardiovascular Diseases, Chemical) [2015-07-07]

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Ongoing Project
Section Lead
Generation
Lead
Optimization
Preclinical Phase I Phase II Phase III

Development and Market Objectives

CKD-519 is developed by CKD Pharmaceutical Corp, is a CETP inhibitor that finished pre-clinical and is waiting for IND approval. It increases in-vivo HDL-C levels, subsequently slowing the progression of atherosclerosis and decreasing overall cardiovascular risks through the inhibition of CETP.
 

Unmet Medical Need & Target Patients

The ability to increase HDL-C levels via the inhibition of CETP can reduce the residual risks of cardiovascular diseases (CVDs).
 
CVDs are responsible for over 17.3 million deaths per year and remain the leading cause of deaths worldwide. Dyslipidemia features prominently as one of the major determinants of CVD risk.
 
Over the past two decades, pharmacological prevention strategies for atherosclerotic CVDs have focused on reducing levels of low-density lipoprotein cholesterol (LDL-C). In practice, however, full compliance with statin therapy and the achievement of current LDL-C goals corresponds to only a ~30% risk reduction for major cardiovascular events, leaving a ~70% residual risk.


 

 
A promising alternative target is HDL-C. Genetic and epidemiologic data support the hypothesis that pharmacological intervention to raise HDL-C can translate into significant reductions in cardiovascular events in dyslipidemic patients.
 
Cholesterol ester transfer protein (CETP) is responsible for the transfer of neutral lipids (cholesteryl ester and triglyceride) between HDLs and apoB-containing lipoproteins (VLDL & LDL).
 
Generally, physician satisfaction is the lowest with high-density lipoprotein cholesterol (HDL-C)-raising treatment, as this lipid type exhibits uncontrolled levels for the highest reported proportion of patients (at around 30%) in the 7 major pharmaceutical markets.
 
The current treatments available for increasing HDL-C include nicotinic acid (+30%) and fibrates (+20%), both of which are unsatisfactory. In addition, nicotinic acids cause adverse effects (including flushing) which limit adherence.
 
In contrast, CETP inhibition with anacetrapib or evacetrapib raises HDL-C levels by approximately 138% while decreasing LDL cholesterol (LDL-C) levels by approximately 40%. Physicians have reported that the ability to raise HDL-C levels using antidyslipidemics is their greatest need in the treatment of dyslipidemia.
 
Cholesterol ester transport protein inhibitors represent a novel class of antidyslipidemics with the potential to provide significant opportunities in the dyslipidemic market.
 

Status

GLP toxicity study and ADME study was finished in 4Q, 2013 and there is no significant findings in oral GLP_Tox.
Human Phase I clinical study will be initiated at 2Q, 2014 after approval of IND.
 
(1) Pharmacology
CKD-519 has shown remarkable efficacy in elevating HDL-C levels, inhibiting CETP in a dyslipidemic animal model, as well as a panel of normolipidemic animal models:
 

  • In vitro (CETPi) IC50 = 2.3 nM

In vivo efficacy (po, qd)

 

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Anti-atherosclerotic effects of CKD-519 in rabbit
In a diet-induced atherosclerosis rabbit model (10/30/60 mg/kg, po, 12 wks), CKD-519 significantly reduced the extent of aortic lesions. These results strongly underline the firm potential for CKD-519 to be developed for the effective treatment of atherosclerotic cardiovascular disease.




Comparison of aortic lesions in control and CKD-519-treated rabbit

 

(2) Pharmacokinetics

 

CKD-519 is a low clearance compound that exhibits long half-life values in tested species. Oral administration of CKD-519 resulted in sufficient exposure for maximal efficacy. The candidate is projected to be an once-a-day drug in human.

 
 

      Excellent microsomal stability and without detectable gender or species bias
No detectable inhibitory effects toward CYP isozymes up to ~10 uM concentrations

 

 

(3) Toxicology and Safety Pharmacology
     No inhibitory effects against alternate lipid transfer proteins (including LCAT, MTTP, PLTP)
     No effect on plasma levels of aldosterone/corticosterone and BP in anaesthetized rats.
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CKD-519 does not induce blood pressure elevation in rats
 

  • Does not induce aldosterone or cortisol synthase mRNA production in vitro
  • No genetic toxicity (AMES, Chromosomal Aberration)
  • GLP_Tox NOAEL (4weeks-repeated toxicity): 300 mg/kg (hamster, monkey, rat)

Intellectual Property

  • A Korea patent & PCT have been published(4Q, 2012)
  • Pending : USA, Japan, India, Vietnam, Brazil, Mexico, China, Canada, Philippins, New Zealand, Australia, Russia, EU
  • Additional Patent Application has been filed (PCT, 2014,1Q)

Competitive Advantages

       No CV issues observed with Torcetrapib (Blood pressure, aldo/cortico)
Based upon efficacy, PK and safety profiles, CKD-519 is expected to become one of the leading HDL therapies for the treatment of atherosclerotic cardiovascular diseases.


(1) J. Lipid Res. 2011, 52, 2169-2176.
(2) Atherosclerosis 2011, 219, 761–767.
(3) J. Lipid Res. 2011, 52, 1965-73.
(4) J. Lipid Res. 2010, 51, 3443-54.
(5) Clin Transl Sci. 2011, 4, 414-20.
(6) Nature 2000, 406, 203-207.
(7) J. Lipid Res. 2007. 48, 1263–1272.
(8) Drugs 2012, 72, 491-507.
(9) Eur J. Pharmacol 2003, 466, 147–154.
 

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