A Locked Nucleic Acid Drug Platform for Hepatitis C

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A Locked Nucleic Acid Drug Platform for Hepatitis C

Art Levin, PhD, Vice President, Chief Development Officer, President, US

Operations, Santaris Pharma A/S, San Diego, Calif.

Drug Discovery & Development - May 14, 2010

Infection with the hepatitis C virus (HCV) leads to inflammation of the liver

and in some cases progressive loss of liver function and liver cancer.

Approximately 3 to 4 million Americans are chronically infected and an

additional 40,000 contract the disease each year.1 The current standard of care

using the antiviral agent ribavarin and PEGylated interferon is only effective

in about 50% of HCV patients and is often associated with severe side

effects.2,3

Developed using the locked nucleic acid (LNA) drug platform from Santaris Pharma

A/S, SPC3649 is the first microRNA-targeted drug to enter human clinical trials.

Unlike other hepatitis C therapies that directly target the virus, SPC3649 works

by inhibiting the liver-expressed miR-122, a microRNA that HCV requires for

replication (Figure 1).

In a recently published study, SPC3649 significantly reduced the amount of HCV

in the bloodstream of chronically infected chimpanzees.4 Four chimpanzees

chronically infected with HCV were treated weekly with 5 or 1 mg/kg of SPC3649

for 12 weeks, followed by a treatment-free period of 17 weeks. The chimpanzees

receiving 5 mg/kg dose experienced a 350-fold decline in viral levels in the

blood and liver.

The Santaris Pharma A/S LNA drug platform is a modification of RNA that contains

an oxy-methylene bridge between the 2’ and 4’ carbons in the ribose ring

creating a bi-cyclic structure that “locks” the conformations of the ribose.

LNA-based therapies have higher stability and increased affinity to its

complementary nucleotide sequence (Figure 2). LNA-based drugs also provide

improved potency in vivo in many different tissues and strong pharmacology upon

systemic delivery in a simple saline solution without any need for complicated

delivery vehicles.

A Phase 1 single-ascending dose safety study of SPC3649 in healthy volunteers

has shown the drug to be well tolerated, with an attractive pharmacokinetic

profile, and a clear dose-dependent pharmacology. SPC3649 is currently in a

Phase 1, multiple-ascending dose study in healthy volunteers. A Phase 2 study in

patients with HCV is expected to begin in the second half of 2010.

References

1. Hepatitis C. American Association for the Study of Liver Diseases. Available

at http://www.aasld.org/patients/Pages/LiverFastFactsHepC.aspx. Retrieved on

April 21, 2010.

2. Chisari FV. Unscrambling hepatitis C virus-host interactions. Nature.

2005;436(7053):930.

3. Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in

treatment of hepatitis C. Nature. 2005;436(7053):967.

4. Lanford R, et al. Therapeutic silencing of miR-122 in HCV-infected primates.

Science. 2010; 327(5962):198.

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