Systemic Pleuromutilin BC-3781
BC-3781 belongs to the first generation of pleuromutilins to combine excellent systemic bioavailability with substantial activity against gram-positive pathogens, atypicals, and fastidious gram-negative pathogens. In particular it is highly active against multi-drug resistant (MDR) pathogens including methicillin resistant Staphylococcus aureus (MRSA), MDR Streptococcus pneumoniae, and vancomycin resistant Enterococcus faecium. BC-3781 is characterized by excellent in vivo efficacy in stringent infection models of skin disease, pneumonia (MRSA and S. pneumoniae) and bacteremia, favorable PK/PD parameters, and a novel mode of action.
BC-3781, is being developed for both oral and IV administration. Extensive Phase I data has demonstrated that therapeutically relevant drug levels can be achieved by both oral and intravenous administration. In addition BC-3781 has been shown to be safe and well tolerated and to have no clinically significant drug-drug interactions.
Phase II trial
BC-3781 recently successfully completed a Phase II trial for the treatment of serious multi-drug resistant skin & skin structure infections (now called ABSSSI, Acute Bacterial Skin and Skin Structure Infections).
The double blind randomized active controlled study was conducted at 23 centers in the USA and compared two doses of BC-3781 with Vancomycin. In 207 patients with ABSSSI who received 100mg or 150mg of BC-3781 or 1,000mg Vancomycin intravenously twice-daily. All patients had at least two signs of systemic infection (e.g. fever, raised level of white blood cells, C-reactive protein or lymphadenopathy). Approximately 50% of the patients had cellulitis and approximately 30% had abscesses with cellulitis. The average area of cellulitis was more than 160cm2. 60% of the ITT (intention to treat) population were microbiologically evaluable and of those 69% had documented MRSA infection.
The results show that both doses of BC-3781 were comparable to Vancomycin in terms of clinical response at the primary end point, test-of-cure:
- 91% of the patients (55/60) treated with 100mg of BC-3781
- 89% of the patients (48/54) treated with 150mg of BC-3781
- 92% of the patients (47/51) treated with 1000mg of Vancomycin
In addition, following the recent FDA guidance, the early clinical response was assessed using a composite endpoint (cessation of spread of erythema and swelling with a lack of fever) at day 3 with 80%, 77% and 80% of patients achieving this endpoint within the 150mg, 100mg BC-3781 and Vancomycin arms respectively.
Topical Pleuromutilin BC-7013
Nabriva is developing the pleuromutilins for topical application. BC-7013 is the most advanced drug candidate. BC-7013 has outstanding activities against resistant gram-positive pathogens, including MRSA, and excellent PK/PD parameters in skin.
BC-7013 is being developed for the topical treatment of a number of bacterial associated or derived dermatological diseases. The Phase I program has demonstrated excellent tolerability of topical formulations and no systemic exposure.