The last two months have been times of significant activity for those of us involved with drug resistance. In early July, nearly a year after the passage of the Generating Antibiotic Incentives Now (GAIN) Act, the Food and Drug Administration released “Guidance for Industry: Antibacterial Therapies for Patients with Unmet Medical Need for the Treatment of Serious Bacterial Diseases, Draft” for comment. The Guidance is intended to assist sponsors in developing antibacterial drugs to treat serious bacterial diseases. It marks a sea change in which it may be possible to develop drugs for emerging multi-resistant pathogens based on the pathogens they kill - regardless of the site of the infection. The guidance also addresses an overhaul in the clinical trial structure for new antibiotics that qualify for Priority under the GAIN Act. Drugs approved using this expedited pathway would theoretically carry a restrictive label specifying that their used be limited to very sick patients.
You can find the text of the Guidance here. Comments are due by October 1, 2013.In this month’s IDR Newsletter we present an interview with Nicole Mahoney, PhD Senior Officer of the Pew Charitable Trust’s Antibiotics and Innovation Trust. Dr. Mahoney and Pew have been involved with both the GAIN Act and the efforts to create a new pathway for antibiotic innovation.
Whatever is happening in Drug Resistance you’ll find it in the IDR Newsletter!
Interview with Nicole Mahoney: Senior Officer – Antibiotics and Innovation Group, Pew Charitable Trust
Dr. Nicole Mahoney is the Senior Officer of antibiotics and innovation at The Pew Charitable Trusts. The group addresses the growing challenge of multidrug-resistant infections by supporting policies and regulatory efforts that stimulate and encourage the development of antibiotics to treat life-threatening illnesses. The IDR recently had the opportunity to sit down with Nicole to explore the current state of antibiotic development and innovation and to understand why, in the midst of this serious public health challenge, she finds reason for optimism.
How did your interest in antibiotics and innovation develop?
Dr. Mahoney’s work with The Pew Charitable Trusts in Antibiotics and Innovation is a natural outgrowth of her long-term interest in this area. “I am a scientist by training having received by PhD in biochemistry. After completing my postdoctoral training, I served as an American Association for the Advancement of Science policy fellow at both the National Institutes for Health and the National Science Foundation. From there, I moved to the National Institute for Allergy and Infectious Diseases providing patentability and marketability assessments for new technologies. In 2009, I became a Commissioner’s Fellow in the FDA’s Office of Antimicrobial Products. The major project I focused on was analyzing the regulatory pathway for all new antibacterial drugs reviewed by the agency between 1980 and 2011. The purpose was to characterize what types of drugs were being developed and the impact of the regulatory process on development.”
What did you conclude were the major challenges facing antibiotic development, and have those pressures changed in recent years to cause the crisis we now face?
The pressures facing antibiotic development can be characterized as scientific, economic, and regulatory.
In the scientific arena, it’s difficult to discover new antibiotics, especially those that have novel mechanisms of action. Unfortunately, the focus on genomics and high throughput screening has not yielded the results we would have hoped for.In the economic arena the short-term nature of antibiotic use, as opposed to drugs for chronic diseases has meant that antibiotic development is not as financially attractive for pharmaceutical companies as investments in other therapeutic areas. In response to drug resistance, physicians are asked to hold new antibiotics in reserve, further decreasing use and thus, the economic potential of new drugs. Believing that they are not going to be able to make their needed return on investment, many pharmaceutical companies have simply exited the antibiotic development field. The industry in general is suffering from a crisis of innovation currently, but antibiotic development is particularly challenging.
In the regulatory arena, clinical trials for antibacterial drugs can be challenging for a variety of reasons and many stakeholders including drug makers, regulators and academics have been working to make testing more feasible.
These pressures have come to a head with drug-resistance increasing and a decreasing number of effective drugs becoming available for patients. “Today, there are few drugs with which to treat resistant Gram-negative bacteria, for example.”
Given this current state of antibiotic development, what gives you hope that we can address this crisis?
“I don’t think there is ONE silver bullet that will fix this issue. We must address the scientific, economic, and regulatory issues simultaneously, and I think we are beginning to do that.” Several years ago the main focus of conversations regarding antibiotic development was to characterize the nature of the challenges. In both the United States and Europe it seems the conversation has shifted to identifying solutions. For example, the European Innovative Medicines is a public and privately funded effort to develop antibiotics and accelerate early drug discovery. There are several programs funded as part of the initiative, including the development of a clinical research effort to test new antibiotics , and effort project targeted as investigating new pathways for getting antibiotics into Gram-negative bacteria.In the United States we have started to address the incentives issue with the passage last year of the GAIN Act (Generating Antibiotics Incentives Now) as part of the FDA user fee legislation. The GAIN Act, passed in 2012, addresses some economic challenges. New antibiotics for serious infections can be designated to receive benefits under GAIN, including Fast Track status and Priority Review. If a designated drug is approved for marketing, it may receive five additional years of protection from generic competition.. This additional five years of protection can significantly improve the economic return on investment for drug makers.
The GAIN Act also mandated the creation of a pathogen-focused antibacterial drug development pathway. To meet this requirement, at the end of June 2013, the FDA released draft guidance for industry on development antibacterial therapies for patients with unmet needs that included information on pathogen-focused products. This guidance lays the groundwork for a proposed new regulatory pathway that Pew and other stakeholders are advocating for. This pathway—the Limited Population Antibacterial Drug pathway, would streamline the approval process for antibiotics that patients need most. The pharmaceutical industry has responded favorably to GAIN. A year after the passage of the GAIN Act, 12 new antibiotics have received designation under the law. Some companies have reported that the GAIN Act has allowed them to draw new investment for their antibiotic programs. While we still have a long way to go, the focus on solutions is a huge step in the right direction.
The scientific challenges remain difficult to solve, but with the improvement in the incentives for development, new and novel mechanisms may emerge that might not otherwise have seen the light of day. This is all very encouraging.
Recent Drug Resistance Multi-Media
- Download the summary from a one-day conference “A New Pathway for Antibiotic Innovation” recently published by the Pew Trust.
- Watch a podcast interview with Douglas Lauffenburger, PhD, on research identifying the protein behind drug resistant tumors. He and fellow researchers found that increased signaling by the receptor tyrosine kinase AXL predicts the development of resistance to inhibitors of the RTK ErbB.
- Review a market report for antibiotics targeting multidrug-resistant bacteria and gram negative organisms.
- Read: An overview of Antibiotic Resistance 2013: The Antibiotic Development Pipeline and Strategies to Combat Antibiotic Resistance
Latest Drug Resistance Research
- A new study by researchers from Johns Hopkins University finds drug resistance bacteria (Staphylococcus aureus) associated with livestock on industrial livestock workers in North Carolina but not on antibiotic-free livestock.
- Researchers have published the draft genome sequence of P. aeruginosa strain VRFA02, a human bloodstream isolate that has proven to be resistant to broad-spectrum antibiotics. Pseudomonas aeruginosa is responsible for 10% of all hospital-acquired infections.
- Researchers from Baylor College of medicine have conducted a study resulting in the potential repurposing of Ciclopirox as an antibiotic against Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumonia. The discovery resulted from merging a collection of drug-resistant bacterial specimens with a promising new antibacterial compound. Based on the compound’s success, researchers scanned to find an existing antibiotic with similar properties and identified Ciclopirox. Ciclopirox affects the synthesis of lipopolysaccharides, large molecules found in the outer membrane of the gram-negative bacteria. It may explain why there has been no resistance to Ciclopirox in over 20 years of use as an anti-fungal.
- Biological Variability and the emergence of multidrug-resistant tuberculosis. A new study demonstrates that bacterial mutation rates associated with the Mycobacterium tuberculosis lineage most commonly linked to multidrug-resistant tuberculosis are multifold higher than shown in previous studies. This discovery, when considered together with recent findings on pharmacokinetic variability in patients, leads to new models of how multidrug-resistant tuberculosis arises, with direct therapeutic implications.
- Researchers at the Institute Pasteur Korea has isolated a new experimental compound to battle drug resistant tuberculosis through a novel mechanism. The compound, an imidazopppyridine amide (IPA) is successful in wiping out drug-resistance strains of TB isolated from human clinical specimens. In mouse trials, the animals given Q203 showed fewer lesions than those treated with isoniazid, a commonly used first line anti tuberculosis agent.
- The World Health Organization and the Global Fund have identified a funding need of $1.6 billion annually for the treatment and prevention of TB and multidrug-resistant TB in 118 low and middle-income countries.
- Breakthrough in Malarial vaccine development was announced by a team of government, academic, and private researchers. In an early stage clinical trial, the PfSPZ vaccine protected all six volunteers from infection. The Phase I trial represents an important proof of concept but is early stage. The vaccine product includes Plasmodioum falciparum sporozoites that have been weakened by radiation.
- Two letters published in the journals of Nature and Science argue for the commencement of research on the H7Np influenza that may yield more potent strains of the new virus that emerged in China last year. Drug resistance is one area the authors want to examine, along with investigations into vaccine development, adaptation, transmission, and disease severity. H7N9 avian influenza jumped from poultry to humans in spring, 2013. There was one suspected case of person-to-person transmission resulting the death of both individuals. In response to the letter, the U.S. Department of health and Human Services announced a new review process for certain gin-of-function experiments with the H7N9 virus.
- Researchers are investigating whether latent HIV-1 can be reactivated when their host cells are superinfected, and if so, whether they can contribute to the generation of recombinant viruses. This question addresses conditions of poor drug adherence, treatment interruption or treatment failure.
A compound from soybeans may become an effective HIV treatment without the drug resistance issues faced by current therapies according to new research from George Mason University. Genisterin, found in soy and several other plants is a tyrosine kinase inhibitor that works by blocking the communication from a cells surface to its interior. By interfering with cellular processes, Genisterin makes it more difficult for the virus to infect cells.
- Researchers from Harvard have developed a mathematical model describing the evolutionary dynamics of cancer lesions in response to treatment. Based on the experience of 20 melanoma patients receiving vemurafib, the model finds that dual therapy results in long-term disease control for patients.
- Researchers at MIT’s Kock Institute for Integration Cancer Research have identified the protein behind drug resistant tumors. A protein called AXL helps cancer cells to circumvent the effects of ErbB inhibitors, allowing them to grow unchecked. Using a new computer model on the dataset called the Cancer Cell Line Encyclopedia, researchers searched for overexpressed proteins that make tumor cells resistant to EGFR inhibitors. The AXL protein appeared to be the strongest market for EGFR inhibitor resistance. This pattern held across lung, breast, and pancreatic cancer.
- Researchers from Laboratoire Modélisation et Surveillance des Risques pour la Sécurité Sanitaire, Conservatoire national des Arts et Métiers in Paris have developed a model transmission of methicillin-sensitive Staphylococcus aureus ((MSSA) and methicillin-resistant S. aureus (MRSA) to assess the impact of a 10% reduction in antibiotic use over 1 year. The researchers found that class-specific changes in antibiotic use, rather than overall reductions need to be considered to anticipate the impact of an antibiotic reduction campaign.
Drug Resistance Policy and Drug Development Policy
- Researchers from Los Angeles Biomedical Research Institute recently found that the increase in antibiotic resistance among hospital-acquired infections is higher than previously estimated. The study’s authors also believe that the FDA’s promise to reboot the regulations for antibiotic development, while laudable, will fall short.
- FDA have given Tetraphase Pharmaceutical’s drug Eravacycline special designation as a “Qualified Infectious Disease Product” for expedited review and, if approved, 5 additional years of protection from generic competition. The drug will be used for treating multidrug resistant infections such as E. coli, MRSA and C. difficile.
- The U.S. Food and Drug Administration has allowed marketing of the Xpert MTB/RIF Assay, the first FDA-reviewed test that can simultaneously detect bacteria that cause tuberculosis and determine if the bacteria contain markets making they resistant to rifampin.
- Phylogica has formed collaboration with Cubist Pharmaceuticals to evaluate its antimicrobial phylomers in models of drug resistant bacterial infections. In its own assays, Phlogica says these antimicrobials have shown activity against multi-resistant isolated of Gram-negative, a major cause of death from hospital-acquired infections of burn wounds.
- Anthracimycin, a chemical compound derived from Streptomyces bacteria, is a new antibiotic effective against anthrax, and MRSA was discovered off the coast of Santa Barbara California. The compound is a naturally occurring compound, a rare find. Researchers from the Scripps Institution of Oceanography at UC San Diego isolated the compound.