nPT-Cyp

Sanglifehrin-based cyclophilin inhibitors for the treatment of Hepatitis C and Human Immunodeficiency Virus

Cyclophilin as a target for HCV therapy

Cyclophilin (Cyp) is a clinically validated target for treatment of hepatitis C virus (HCV) infection. Blocking Cyp function inhibits viral replication but, critically, Cyp is a host (i.e. human) protein. As a result, Cyp inhibitors have a different resistance profile from HCV therapeutics against viral targets, including a higher barrier to development of resistance. Therefore, Cyp inhibitors combine well with both the current standard of care in HCV and with the Direct Acting Antivirals (DAAs) in clinical development. 

Biotica’s approach is different

Cyp is validated as an HCV target by two cyclosporine-based Cyp inhibitors, which have demonstrated clinical activity alone and/or in combination. Biotica’s sanglifehrin-based nPT-Cyp programme is well differentiated from these pathfinder compounds, alisporivir (DEBIO-025) and SCY-635. It is based on very different chemistry, and Biotica has used the novoPT™ technology to generate improved compounds without the liabilities which may be associated with cyclosporin-based compounds.

On October 31^st, 2011 we announced our drug candidate BC556:

• BC556 is a highly potent inhibitor of HCV replication in all viral genotypes tested.
  • Average EC₅₀ in HCV replicons 0.02 µM (0.013-0.038 µM),
  • Approx. 4-fold more potent than alisporivir
  • Selectivity index >2600 (CC₅₀/EC₅₀)
  • Inhibition of cyclophilin isomerase activity, IC₅₀ 0.0003 µM

• BC556 has an excellent drug-drug Interaction profile suitable for combination with other drugs as part of a combination therapy for HCV  

  • No significant inhibition of major drug transporters (e.g. Pgp, BSEP, OATs, MRP2 etc.)
  • No significant inhibition or induction of major CYP450s
  • Significantly reduced potential for hyperbilirubinaemia, confirmed with in vivo models
• BC556 shows at least an additive antiviral effect with Direct Acting Antivirals (DAAs) and shows no cross-resistance
• BC556 has an excellent barrier to emergence resistance (similar or better than alisporivir)
• BC556 has pharmacokinetic and ADMET properties suitable for once-a-day oral dosing
• BC556 is produced by a scalable process including bacterial fermentation and a 3-step semisynthesis
• BC556 is an engineered polyketide, generated using Biotica’s proprietary novoPT™ technology platform
• BC556 is protected by a multiple layers of IP protection providing commercially-attractive market exclusivity