NS4B - the primary target
The bipartite nature of the NS4B-RNA target causes mutational constraints that should decrease HCV resistance to the inhibitors in development at Eiger. These virus specific agents in development at Eiger possess the promise of more effective, all oral cocktails for future HCV therapy.
Inhibitors of NS4B-RNA
Binding of the non-structural protein NS4B to the 3' terminus of the HCV negative RNA strand is a recently identified target for drug intervention. The requirement of this target for viral replication has been genetically validated. A screen of a small molecule library identified clemizole hydrochloride as a specific inhibitor of NS4B-RNA binding.
Clemizole was widely used in Europe and in the U.S. beginning in the 1950's, marketed under various brand names. Indications included management of allergic disorders, such as seasonal and perennial hay fever, and various dermatological conditions, especially pruritus (e.g., urticaria, neurodermatitis, eczema, and food and drug allergies). In the United States, clemizole was marketed as Allercur®, a product of Roerig Pfizer, and available in oral suspension, parenteral, and tablet formulations. Typically, 20 or 40 mg tablets in total daily doses of up to 160 mg/day were used for up to 60-90 days continuously. Clemizole is no longer marketed for single agent use.
In vitro, clemizole exhibits remarkable synergy with HCV NS3 protease inhibitors, increasing the efficacy of the latter by up to several logs. A Phase 1 proof of concept study evaluating the safety and efficacy of clemizole as a single agent therapy is underway in Australia and New Zealand in HCV patients.
Preliminary SAR indicates that the anti-HCV activity of clemizole is unrelated to its antihistamine activity. Moreover, several NCE analogs have been identified that are devoid of the moiety responsible for H1 receptor antagonism, yet are more potent than clemizole in inhibiting NS4B-RNA binding and HCV RNA replication in vitro.
The company has secured the patent space around the use of clemizole and clemizole analogs, including NCEs, for the treatment of HCV, providing Eiger with a remarkable intellectual property position. Taken together, these attributes provide the company with a compelling opportunity for developing clemizole and second generation compounds that target NS4B-RNA binding with a variety of improved features and NCE patent protection. See PCT patent publication numbers 2009/039246 and 2009/039248.