Antibiotics: Start-Ups Ply Novel Targets and Technologies
This article was originally published in Start Up
Microbial drug resistance is a real and growing problem, but drugmakers face disincentives: a plethora of products already on the market, the difficulty of differentiating drugs, and the habit of reserving truly new drugs for emergencies. Big Pharmas are backing out, creating opportunities for small companies who feel they can play successfully. But lack of interest from large partners means biotechs can't access the assets those firms hold, so many start-ups are pairing up with peers. Some firms are building businesses around an abundance of targets derived through genomics. But others are deliberately avoiding working with novel genetic code and instead studying whole cells and physiological changes in organisms. Many firms are addressing the lack of chemical diversity against targets. Some of these are pursuing diversity through natural products like marine microbes, insisting they'll fare better than earlier firms did, in part because of technological advances. Others are trying to create diversity synthetically, by taking structural approaches to understanding targets new and old, as well as compounds. Crystallography, in silico libraries, computational models and mass spectroscopy are key tools in iterative development processes that remain unproven in the anti-infectives field. Some firms are seeking to minimize the risks of novelty, by putting their efforts into developing new versions of antibiotics that worked well before resistance grew. No matter what technological approach start-ups take to developing antibiotics, all face similar challenges external to themselves-primarily in regulatory affairs and funding, but also in hunting Big Pharma partnerships.
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Despite the global increase in resistant bacterial infections, investment in development of new antibiotics and antimicrobials has declined over the past few years. Siena-based Molteni Therapeutics is taking a new look at antibacterials and antifungals, creating small-molecule photosensitizers activated by visible red light that destroy fungal and bacterial cells, in an approach known as antimicrobial photodynamic therapy.
Trius Therapeutics Inc. intends to create drugs that are capable of combating resistant bacteria and are meaningfully differentiated from currently marketed products. It says its lead candidate will be "a true second-generation" version of linezolid (Zyvox), as yet the sole marketed compound in the class of drugs known as oxazolidinones. Linezolid's proven ability to combat Gram-positive bacteria such as MRSA and Streptococcus has made it a blockbuster on track to generate $1 billion in revenues this year. If Trius can develop an antibiotic that is safer and more effective than Zyvox, and that also possesses additional attributes that improve on the original drug, that new compound could commandeer significant market share.
Antibiotic R&D has always been one of the most challenging areas in biopharmaceutical drug development. Designing novel drugs that deter bacterial resistance is a technical hurdle to be sure, but it's also a commercial one: drugs doomed to rapid obsolescence don't promise a strong return on investment. There are regulatory uncertainties, too. Although FDA is now asking drug sponsors to compare the effectiveness of products against a placebo or marketed drug for some indications--for the most part, certain infections in the primary care setting--non-inferiority studies remain the norm for life-threatening infectious diseases. But the agency has yet to issue hard and fast rules on where to apply these studies and how to evaluate the use of non-inferiority margins. A recent meeting of FDA's Anti-Infective Drugs Advisory Committee provided some clarity.