Updated: 6/7/2017 at 4:08 PM EST.
Experts agree that there is a need for a steady stream of innovation to address the constantly increasing rate of antimicrobial resistance. In a session entitled, “Bridging the ‘Valley of Death,’” the speakers described the gaps in antimicrobial development and discussed how government and private industry are working to address these gaps in antimicrobial drug development.
Joseph Larsen, PhD, Director of Biomedical Advanced Research and Development Authority (BARDA) with the US Department of Health and Human Services, described how BARDA is working to help pharmaceutical companies develop new drugs for emerging infectious diseases. The general focus is on chemical, biological, radiological and nuclear defense, where antibacterial development is one of the key areas of focus. The pace of antimicrobial drug development has not kept up with the rate at which resistance is developing. So, BARDA has been providing incentives for development and marketing.
Dr. Larsen pointed out that the current antibiotic drug â€‹development
model takes many years to bring to market, and profit is only achieved after an average of 23 years. This kind of failure to market the drugs has led to significant innovation gaps for addressing antimicrobial resistance. Moreover, for the last 6 antibiotics approved in the United States, the projected first 2 years’ sales ranged between $30 million to $80 million, which is not much when compared to medications used to treat more chronic diseases, which routinely have first 2 year sales in excess of a billion dollars. So, investors are choosing to focus their efforts on developing drugs for chronic diseases.
Moreover, Dr. Larsen pointed out that there has not been a new class of drugs for treating gram-negative bacilli for over 5 decades. There are between 40 and 50 candidate antibiotic drugs in phase 3/4 studies, as compared to over 500 for oncology. Smaller biotech companies are doing most of this research, while larger companies have generally left this area of research and development (R & D). The first few years in the market, no one really knows how often these drugs will be used. Moreover, the vast majority of infections are treatable with broad-spectrum antibiotics.
To address the uncertainties that drug developers face, push and pull incentives have been offered by BARDA. Push incentives include providing direct support for developers as grants or contracts. Pull incentives include incentives to private investors that create visible market demand or rewards for milestone successes. Examples include milestone payments and regulatory incentives. Currently, there is a lack in substantial pull incentives.
BARDA’s antibacterial pipeline is underway with collaborations with many companies. BARDA also created CARB-X, which is one of the world’s largest public-private partnerships focused on developing new antibacterial products. When they started this program, BARDA expected 50 grant applications, but received 368 applications within the first 2 cycles. The goal is to deliver at least 2 antibacterial products to clinical development within 5 years. BARDA is planning on investing $250 million over the next five years to CARB-X. The program has already committed $85 million. In addition, the Wellcome Trust and NIAID are planning to commit $155 million and $50 million, respectively. For funding from the USG, it would still be subject to annual approval of appropriations by Congress. BARDA's conventional antibacterial program is also investing approximately $135 million annually in the clinical development of new antibiotics.
The current portfolio of drugs under development by CARB-X includes 7 completely novel targets. Non-traditional approaches are also being considered. This includes antibody-drug conjugates, virulence disruptors, potentiators, and bacteriophage. There are a variety of pull incentives under consideration involving reimbursements, patent vouchers, and market entry rewards. Dr. Larsen noted that the program must be sustainable in order for companies to have faith in these programs.
In summary, CARB-X supports pre-clinical development, BARDA supports clinical development, and then CARB to provide marketing post approval. Together, these provide holistic incentives to promote antibacterial product innovation. Finally, Dr. Larsen stressed that market entry rewards can be used to reward innovation while achieving public health objectives.
Next, Nicole Mahoney, PhD, of Merck, discussed incentives to encourage antibiotic development for treating antimicrobial resistance (AMR). She gave an overview of partnerships and policies used to stimulate antibiotic development from a drug developer’s point of view.
Dr. Mahoney pointed out that an estimated 50,000 lives are lost each year to due to antimicrobial resistant infections. The cost burden of AMR infections to patients is expected to increase if novel antimicrobial agents are not developed.
Fortunately, the US government is very active in this area. The goal of these global and national efforts is to recognize the problem that is AMR. Several countries have developed action plans, such as the World Health Organization (WHO) and United Nations. In addition, DRIVE-AB, which stands Driving Reinvestment in R&D and Responsible Antibiotic Use, is a public-private partnership between the academic community, government, and the Innovative Medicines Initiative of the EU.
We are going to have efforts to increase awareness of AMR, strengthen surveillance, and insure that there is a sustainable investment in AMR research at all times.
Dr. Mahoney also noted that the current antibiotic drug development pipeline is inadequate, citing work of the Pew Charitable Trusts. There are only 41 antibiotics currently under development, and, typically, only 1 in 5 drugs (of those getting to phase 1) will make it to market. Finally, only 2 antibiotics potentially represent new classes of drugs against ESKAPE pathogens, which constitute the 6 pathogens with growing multidrug resistant virulence: Enterococcus faecium
, Staphylococcus aureus
, Klebsiella pneumoniae
, Pseudomonas aeruginosa
. These drugs are predominately (80%) coming from small companies, because large pharmaceutical companies are no longer investing in this space.
Dr. Mahoney believes that we need to create sustainable innovation ecosystems that support a diverse pipeline that is sufficient for today’s infections. Incremental advances and novel innovations are needed. We need to work on incentives that promote scientific, clinical development/regulatory, and economic challenges, according to Dr. Mahoney.
One way to prioritize novel product development is to consider the medical needs identified by experts. In late February, WHO published a list of global priority pathogens
. Moving forwards from an industry perspective, this list gives companies the predictability that they need for considering the more than two-decade long investment that is typically needed for new drug development.
Dr. Mahoney explained that she just wanted to make people aware of that there are new approaches to assessing value that consider unmet need and consider the value of antibiotics in population health. They also need to account for the benefit of multiple treatment options.
In summary, industry is committed to being a part of the solution. Merck joined more than 80 companies in a partnership to work together against AMR, signing a declaration at the 2016 World Economic Forum calling for joint action against AMR. Moreover, 12 pharmaceutical companies published a roadmap together with commitments to reduce AMR by 2020. This includes consideration of environmental impact, while balancing innovation and stewardship. Finally, the AMR Alliance was formed by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) and is being used to track progress on the roadmap.
Through their collaboration, private, public, and national partnerships should be able to get back on track for the development of better antimicrobials.
Editor's Note: A previous version of this article incorrectly referred to Dr. Nicole Mahoney as "Dr. Maloney." This has since been corrected.
W. Todd Penberthy, PhD is a medical writer with over 4 years of experience based in Orlando, Florida. Prior to that Todd was a professor directing biomedical research using zebrafish models of human disease with expertise in orthomolecular niacin-related science for 10 years.
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