Cubist exec: Challenges mount in antibiotics discovery

Big Pharma has largely exited the antibiotics arena in the past several years, contributing to the dearth of products in the global pipeline as rising antimicrobial resistance becomes a very real public health threat.

Now, just a few companies--among them, Cubist Pharmaceuticals ($CBST)--remain in the antibiotics space. The Lexington, MA-based company in June won FDA approval for Sivextro, an antibacterial drug to treat a range of skin infections, including methicillin-resistant Staphylococcus aureus (MRSA). Now it's on the way to its second drug approval of the year with the combination antibiotic ceftolozane/tazobactam, designed to fight complicated urinary tract and intra-abdominal infections.

With several other candidates in the pipeline, Cubist is succeeding in a field that others have fled. FierceBiotechResearch talked to Ronald Farquhar, senior vice president of discovery and pharmaceutical sciences at Cubist, about the unique preclinical challenges that developing antibiotics presents.

Ronald Farquhar, senior vice president of discovery and pharmaceutical sciences at Cubist

What are some of the scientific difficulties involved in preclinical antibiotics research for the industry at large?

Generally, the dual challenges of preclinical antibiotics research are being able to help infected patients eradicate multidrug-resistant bacteria while doing so in a safe manner. Typically, the required effective dose of an antibiotic may be up to 1 g to 2 g per day, which is at least 10 to 100 times the dose at which other human (nonantibacterial) therapeutics are administered, and this represents a major hurdle in avoiding off-target effects. This explains the reason why, generally speaking, attrition rates for preclinical antibiotic molecules are high. Conversely, once antibiotics have been shown to be effective in preclinical infection models and once rigorous safety studies have been completed, survival through the development process can be greater than for other drug types in other areas of biopharmaceutical development.

What are the financial difficulties associated with antibiotics research?

While there continues to be a need for greater financial incentives in antibiotic research, against the backdrop of increasing attention around the problem of antibiotic resistance, we see a positive trend toward more financial backing of academic efforts, increased government funding, and a return of venture capital investment to antibiotic research.

What is Cubist's discovery/research approach to combating growing antibiotic resistance?

At Cubist, our discovery efforts are driven by a focus on unmet medical needs and addressing serious and life-threatening infections caused by resistant bacteria. We take a holistic view of the infection problem--from prevention and diagnostic testing to new treatment options--as antibiotic resistance inevitably continues to evolve. In this regard, discovery of new antibiotics is critical to combat antibiotic resistance. Cubist has been successful in the discovery of new antibiotics, and our portfolio and pipeline are focused on the most serious and urgent public health threats, including Gram-negative and Gram-positive infections, including those caused by certain pathogens such as MRSA and Clostridium difficile.

Have we picked all the low-hanging fruit when it comes to drug targets in the antibiotics space?

The challenges of discovering new antibiotics are certainly increasing as time goes by, in large part because the extensive resistance mechanisms carried by contemporary, bacterial pathogens means that they are more difficult to eradicate than the bacteria causing infections 10 to 20 years ago. Reductionist approaches to antibacterial discovery--in other words, starting with a previously unexploited, isolated bacterial enzyme, designing inhibitors, and then attempting to achieve the desired spectrum of in vitro and in vivo activity--in general have not been successful.

At Cubist, we believe that using medicinal chemistry to modify existing, successful compound classes can bring clinically meaningful innovations. Our parallel efforts directed toward discovery of entirely new antibiotic classes takes advantage of our extensive experience in natural products, where we have made investments in how we screen and detect actives, as well as how we decide which samples are worth screening. The latter efforts are being transformed by the explosion in genomics data and the ability to predict environmental organisms' abilities to make antibiotics, as well as our access to biodiversity from sampling from a range of different environments around the globe.

-- Emily Mullin (email | Twitter)

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