infectious diseases

According to the World Health Organization, infectious diseases are now the world's biggest killer of children and young adults. They account for more than 13 million deaths a year - one in two deaths in developing countries. For a significant number of infectious diseases, effective treatments are still either lacking or inadequate, creating a significant need for novel treatments that can help patients live longer and better lives.

One of the diseases where new therapies are desperately needed is for the treatment of Hepatitis C, a progressive disease of the liver that is caused by infection by the Hepatitis C virus, which can cause liver cirrhosis and/or liver cancer. The most advanced clinical program at Santaris Pharma A/S is focused on a novel approach to helping patients infected with the Hepatitis C virus.

The World Health Organization estimates about 3% of the world's population has been infected with Hepatitis C and that some 170 million are chronic carriers at risk of developing pathologies. Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per year. In Europe, there are about 4 million carriers. The current standard of care consists of a 48-week treatment with a combination of the antiviral agent ribavirin and pegylated-interferon. The treatment, however, is only effective in about 50% of the patients and is associated with very harsh side effects that cause many patients to stop taking the treatment.

Miravirsen (SPC3649): a novel treatment for Hepatitis C Virus (HCV)
miravirsen is a specific inhibitor of miR-122, a liver specific microRNA that the Hepatitis C virus requires for replication. Thus, unlike many other Hepatitis C therapies that directly target the virus, miravirsen works by removing a "helper" molecule (miR-122) that the virus needs in order to make new copies. As a result, miravirsen is expected to provide a very high barrier to the generation of viral resistance - a significant problem with direct acting drugs due to the very high mutation rate of the virus.

Data from the Phase 2a trial showed that miravirsen given as a four-week monotherapy treatment provided robust dose-dependent anti-viral activity with a mean reduction of 2 to 3 logs from baseline in HCV RNA (log10 IU/mL) that was maintained for more than four weeks beyond the end of therapy. The clinical data was presented in a late-breaking oral presentation at The Liver Meeting® 2011, the 62nd annual meeting of the AASLD. Data from the Phase 2a clinical study also demonstrated that four out of nine patients treated at the highest dose (7 mg/kg) with miravirsen became HCV RNA undetectable with just four weeks of dosing. These data provide clinical evidence that miravirsen’s unique mechanism-of-action offers high barrier to viral resistance and the potential for cure with monotherapy. Miravirsen was also well tolerated in patients with HCV, signaling a possible advantage over standard of care treatment.

Data from a Phase 1 single-ascending dose safety study in healthy volunteers show that miravirsen is well tolerated, has an attractive pharmacokinetic profile and clear dose-dependent pharmacology.

In preclinical studies, miravirsen produced a potent, dose-dependent and long lasting inhibition of miR-122 in mice, cynomologus monkeys and green African monkeys as indicated by decreases in cholesterol levels, a biomarker of miR-122 activity. In chimpanzees chronically infected with Hepatitis C, miravirsen caused a significant (350 fold) and long-lived reduction in viral load. Indeed, as expected from the mode-of-action of miravirsen, there was no evidence of viral resistance during the extended study. The preclinical data also showed changes in the expression of key genes, signaling that the drug may help patients who do not respond to interferon treatment to become responsive. In all animal studies, including IND enabling toxicology studies, the drug has been well tolerated, suggesting that miravirsen could become an important new therapeutic in the fight against Hepatitis C.

How does miravirsen work?
In healthy individuals, miR-122 is an abundant, liver specific microRNA that regulates a host of messenger RNAs in the liver, many of which encode proteins involved in lipid and cholesterol metabolism.

When normal liver cells are infected by the Hepatitis C virus, the virus co-opts miR-122 to two binding sites located close to the 5'end of its linear RNA genome. This binding enables the virus to replicate and create new copies of itself, which can further spread the infection throughout the liver. Miravirsen is designed to specifically recognize and sequester miR-122 thus making it unavailable to the Hepatitis C virus. As a result, the replication of the virus is effectively inhibited.

Schematic representation of the function of miR-122 in HCV replication (upper panel) and the mode-of-action of miravirsen (lower panel)