Choppy waters

20150615ep29

A new report reveals that 741 antibiotic candidates are in development, however, new antibiotic development is beset with problems. Shalini Gupta reviews recent reports and milestones on this front

Antibiotic resistance is a much talked about topic, however, the road to developing newer antibiotics is tough. As pathogens continue to evolve, new antibiotics need to be discovered, researched and a robust pipeline developed. The development of antibiotics, particularly progression of drug candidates from discovery to human trials, is notoriously difficult. Data reveals why only 12 new antibiotics have been approved since 2000 and just four of these are first-in-class.

A report released by Globaldata reveals that there are currently 741 products in development, generics dominating the lot. Information on disease targets is not available, however, analysis reveals that the most common diseases are those caused by bacterial species, which are becoming increasingly drug resistant. These include Methicillin-Resistant Staphylococcus Aureus(MRSA), tuberculosis and Pseudomonas aeruginosa in a decreasing order. Although AstraZeneca, Novartis and GSK (three dominant companies in the market) feature in the top ten, the majority of the pipeline is being developed by small, specialist companies. Some of these are Cellceutix Corporation, Cubist Pharmaceuticals, Melinta Therapeutics, Microbiotix, GlycoVaxyn and Beijing Minhai Biotechnology Co.

While it is interesting to note that only three of the top 50 pharmaceutical companies have antibiotics in the pipeline, companies have not yet specified which, if any, specific bacterial infections their pipeline drug is designed to treat. Additional information on whether those being developed are ‘qualified infectious disease products,’ (QIDPs) or being studied for serious or life-threatening infections and receiving benefits provided under the Generating Antibiotic Incentives Now, or GAIN, Act of 2012 is unavailable. “It is difficult to determine the exact number of pipeline products which target QIPDs, as many companies have not yet specified which, if any, specific bacterial infections their pipeline drug is designed to treat. However, initial interrogation reveals that at least 470 of the 741 pipeline products target a QIPD qualifying infection,” says Katie Noon, Senior Analyst, GBI Research. That makes more than half of the candidates in development.

If approved, these drugs will get additional FDA exclusivity, or time free from generic competition—under GAIN. It needs to be noted though that so far, only four QIDPs have been approved. While the GAIN Act helped stimulate development of new antibiotics by increasing their commercial value for serious or life-threatening infection (it extends the period during which the drugs can be sold without generic competition by five years), much needs to be done. “The main issue with antibiotic development isn’t the failure of drugs in the pipeline; it is the significant lack of new antibiotics being developed. These include the exhaustion of natural sources from which the majority of antibiotics over the past few decades were derived, expensive drug development, low return on investment and complex regulatory pathways,” adds Noon.

However, it looks like pharma companies are moving back into antibiotic development. While Merck will start final-stage trials this year for a drug that treats some types of  carbapenem-resistant Enterobacteriaceae (CRE) infections, AstraZeneca’s antibiotic CAZ-AVI is being developed for some of the hardest-to-treat drug-resistant infections. Merck even bought Cubist Pharmaceuticals last year, a company which charges $2,000 and $4,500 for its therapies.

In a recent development, AstraZeneca declared that it will spend $40 million to spin out its R&D business into a separate subsidiary. The standalone company will deal with early stage antibiotics R&D including the novel gyrase inhibitor AZD0914, currently in phase II for the treatment of gonorrhoea.

The US seems to be taking it seriously. In September 2014, the President issued Executive Order (EO) 13676: Combating Antibiotic-Resistant Bacteria, which outlines steps for implementing the National Strategy on Combating Antibiotic-Resistant Bacteria and addressing the policy recommendations of the President’s Council of Advisors on Science and Technology (PCAST)’s report on Combating Antibiotic Resistance. Furthermore, the President’s FY 2016 Budget released earlier this year proposed nearly doubling the amount of Federal funding for combating and preventing antibiotic resistance to more than $1.2 billion. The Centers for Disease Control and Prevention (CDC) estimates that drug-resistant bacteria cause two million illnesses and approximately 23,000 deaths each year in the US alone.

Even as the government and pharma companies are amping up, scientists need to look into new approaches for antibiotic development. In a recent study published in the journal Nature, researchers, at the Northeastern University in Boston, Massachusetts, took soil and created a ‘subterranean hotel’ for the bacteria. One bacterium was placed in each ‘room’ and the whole device was buried in soil. While only one per cent of the microbes present in soil can be grown in the laboratory, scientists involved believe they can grow nearly half of all soil bacteria. Chemicals produced by the microbes, dug up from one researcher’s back yard, were then tested for antimicrobial properties.

According to lead scientist, Prof Kim Lewis, “The study shows uncultured bacteria do harbour novel chemistry that we have not seen before. That is a promising source of new antimicrobials and will hopefully help revive the field of antibiotic discovery,” 25 new antibiotics have been discovered so far using this method and teixobactin is the latest and most promising one. There is hope for the future.”

shalini.g@expressindia.com