First, there is BAL-30072, a sulfactam-derivative. It has an interesting dual MoA as it works not only as a traditional B-lactam but also as an Fe-chelator blocking bacteria from accessing this essential nutrient [i]. It has very good anti-pseudomonas activity and often much lower MIC90 against other problem Gram-negatives, like acinetobacter, stenotrophomonas and Burkholderia as well.
It is should be mentioned that MIC testing was performed in the presence of the iron binder bipyridyl; it will be interesting to learn how MIC determinations under these conditions correlate with animal model data and ultimately with clinical efficacy. Basilea just announced the start of a Phase 1 trial of BAL-30072 in combination with meropenem which seems to provide additive/synergistic activity [ii].
Shionogi’s cephem antibiotic S-649266 is expected to enter Phase 2 testing in the US later this year; it also affects the bacterial Fe uptake channel in addition to its classic B-lactam action (interference with cell wall biosynthesis). It has activity against metallo-lactamase (e.g., NDM-1)-producing strains of Gram-negatives and against MDR-P. aeruginosa [iii].
With relatively few antipseudomonal drugs in the pipeline, it makes sense to investigate non-traditional approaches, like phage therapy, antitoxins, blockers of virulence mechanisms and quorum sensing, inhibitors of attachment or biofilm production. However, while animal models often suggest prophylactic and therapeutic benefits with these approaches, efficacy data are sparse or non-existing in the clinical setting.
Antibodies to the recently described Type 3 Secretion System (T3SS) are being developed by various companies. Preclinical studies showed that blocking this key virulence factor holds promise prophylactically and possibly therapeutically. Here just 2 more advanced projects:
- Kalobios is developing its T3SS monoclonal antibody (KB-001 A) which
targets the PcrV protein, a key component of the toxin delivery apparatus of P. aeruginosa in collaboration with Sanofi. In Phase 1/2 studies KB-001 was safe, however, the number of CF patients was too small to make any efficacy claims. Results of a new and more definitive trial in cystic fibrosis patients should become available soon [iv]. In a small study of ventilated patients colonized with P. aeruginosa, KB-001 showed a favorable trends towards clinical improvement [v]. - Shionogi [vi] has filed a patent for h1F3, a humanized monoclonal T3SS antibody directed against PcrV. h1F3 neutralizes the cytotoxic effect exerted by P. aeruginosa in cell culture systems due to high-affinity binding. It is still in preclinical testing.
IC43 is a hybrid P. aeruginosa outer membrane protein OprF/I vaccine currently in Phase 2/3 confirmatory efficacy testing at Novartis. Earlier Phase 2 results from a 400 patient trial in ventilated patients showed good immune responses after the 2nd dose (on Day 7) and significantly lower mortality in the treatment group (22% vs 40%) [vii]. Novartis now aims to replicate these results obtained by Intercell in a larger well-controlled registration trial enrolling 800 patients. Primary endpoint is Day 28 mortality.
NOTE added 7/15/2015:
Kalobios discontinued the KB001 program on Jan. 6, 20/15 due to lack of efficacy in a well-controlled CF study which did not show a benefit on any predefined endpoint of efficacy. [1] For details, please check our blog at The Demise of KB001
References
[i] Page. Antimicrob. Agents Chemother. 54: 2291; 2010
[ii] http://www.cnbc.com/id/101752624#
[iii] http://www.shionogi.co.jp/en/ir/pdf/e_p140319.pdf
[iv] http://kalobios.com/pr_01102013
[v] http://www.kalobios.com/pdf/Updated%20Anti-PcrV%20_KB001A__Fact%20Sheet_111213.pdf
[vi] http://www.google.com/patents/US20120093808
[vii] http://www.news-medical.net/news/20101025/Intercells-IC43-Phase-II-trial-against-Pseudomonas-aeruginosa-infections-meets-primary-endpoint.aspx
[1] http://ir.kalobios.com/releasedetail.cfm?ReleaseID=889910
