Summary
An Extensive Developmental Pipeline, but Limited First in Class Innovation
The antibiotics pipeline is very active, with 741 products in development. Of these, the majority (85%) are at the Discovery or Preclinical stages and have not yet entered human trials. Such a high proportion of drugs at the earliest stages of development would, in other indications, provide hope of a steady stream of drugs due to advance through the stages of development and be approved within the next decade. However, the development of antibiotics, particularly the progression of drug candidates from Discovery to human trials, is notoriously difficult, with only 12 new antibiotics approved since 2000. Of these pipeline drugs, the distribution of molecular targets is very limited, with the majority having targets observed among marketed products.
Reflecting this trend is the fact that despite the large pipeline, first-in-class drug development is minimal, with only 10% of pipeline drugs acting on a first-in-class target. This distribution reflects the pipeline, in which 85% is at either Discovery or Preclinical. Three first-in-class drugs are at Phase I, eight are at Phase II, but none are at Phase III. These 75 drugs act on 38 first-in-class targets.
Diversity is low among these 38 targets, of which 21, acted upon by 39 products, have mechanisms of action that can be classified under the broad modes of action common to established classes of antibiotics. One of the most common is protein synthesis inhibitors, under which eight first-in-class targets can be grouped. Other categories include RNA and DNA synthesis inhibitors, as well as bacterial cell wall and membrane disruptors. Of the drugs targeting first-in-targets, clinical trial data regarding their safety and efficacy are limited, with the majority of drugs being at either the Discovery or Preclinical stages of development. As such, firm conclusions can only be drawn on a select number of targets. Those with the most promising results include inhibitors of UDP2 epimerase, Methionine tRNA synthase, the FtsZ proteins, and NDM-1 beta lactamase.
Many of the targets under these categories were highlighted by research into conserved genomes of bacteria, driven by a desire to generate antibiotics with as broad a spectrum of use as possible. These studies have uncovered a plethora of targets that act upon mechanisms not yet utilized in the treatment of bacterial infection. It was hoped that high-throughput screens against these targets would lead to the development of novel classes of antibiotics; however, since the 1990s, only four new classes of antibiotics have been approved. With the failure of the genomic approach and the fact that the natural sources of many bacteria are thought to be exhausted, many companies have left the field altogether. However, incentives to draw pharma back to the field, and methods of improving success with compound searches, as outlined in this report, provide hope for the future.
A Moderate Number of Deals and Strategic Consolidations, but Little Interest in First-in-Class Products
Deals involving antibiotics are common, with 266 conducted from 20062014. Of these, the majority were licensing deals (64%), with 46% conducted once the product was marketed. This reflects the fact that drug development in antibiotics is relatively simple and has easy-to-assess endpoints, reducing the requirement of co-development deals to develop an antibiotic successfully once a strong lead candidate has been identified.
Deal values varied widely from $4.3m to $480m, but most were below $100m. Only 19% of deals were completed before the drug entered human trials, again supporting the theory that drug development in antibiotics does not require significant investment.
Reflective of the lack of first
