Over half a century ago, antibiotics revolutionized the therapy of infectious diseases and enabled advanced medical care in surgery, cancer therapy, transplantation, and intensive care. Although the widespread use of antibiotics causes the emergence of antibacterial drug resistance, the constant supply of new antibiotics designed to counteract specific resistance mechanisms has provided a much needed flow of improved, effective drugs (more or less). In recent years however, antibiotic research investment by big pharma companies has fallen as the return on investment cannot compete with other fields such as HCV or cancer. Meanwhile, multidrug resistance rates continue to rise and may affect all major groups of available antibiotics, leaving clinicians with few or even no treatment options.
While most big pharma companies left the field of antibiotic research, small companies—mostly backed by promising academic discoveries—are stepping in to drive research and early clinical development in the antibiotics field. Research at specialized academic centers provides a strong basis for the creation of new SMEs and collaboration strategies in Europe. Hardly any new antibiotics would be available in the future without the basic discoveries of academic research groups.
Future Antibiotic Drug Development
With large pharmaceutical companies continuing to move out of R&D of new antibacterial treatments, we should look to the small innovative companies and start-ups for novel solutions. In Europe alone, over 60 SMEs explore antibacterial approaches in a broad range of bacterial infections. The programs focus on Gram-negative and Gram-positive infections, as well as pathogen-specific conditions caused by Clostridium difficile, Helicobacter pylori, Mycobacterium tuberculosis or Staphylococcus aureus, and Pseudomonas aeruginosa.
Due to the lack of healthy discovery pipelines in this field, attitudes have changed over the last two decades, and antibacterial approaches outside the mainstream are increasingly pursued and publicly funded. It is hoped that targeted approaches will contribute to more personalized treatments and, potentially, to one drug for one bug. If this strategy will be appreciated in clinical practice remains to be seen and depends on strong diagnostic capabilities. More than half of European SMEs with anti-infective programs focus exclusively on antibacterial therapies and are therefore very motivated, focused, and knowledgeable in this field.
Their approaches range from classical small molecule antibiotics and peptides to antibodies, prophylactic and therapeutic vaccines, adjunctive therapies, phages, and drug-potentiating strategies. A few programs with classical small molecule antibiotics against Gram-negative problem bacteria are usually in the earliest research phase and difficult to assess. Potentiating strategies are focused on blocking specific resistance mechanisms such as beta-lactamases or resistance-regulating determinants, preventing transfer of resistance plasmids or on protecting the microbiome, disrupting biofilms, targeting dormant bacteria, blocking virulence factors, or supporting the immune response.
SMEs use a variety of R&D strategies for finding new leads: they search for natural products from unexplored sources, utilize new screening methods, and take advantage of sophisticated computer aided drug design and computational chemistry methods, or genome engineering. Also, known medicines are used to rejuvenate the potential of older antibiotics and drugs originally developed for other indications are repurposed.
Antibodies, peptides, peptidomimetics, and phage cocktails or phage products have seen a resurgence in recent years. At least eight European companies are working with lytic phages or phage products. Given high attrition rates in early phases of R&D, a large assortment of research approaches is seen as a vibrant sign of entrepreneurship and a vital basis for increasing the likelihood of advancing programs to late clinical stages of development.
Though most European SMEs with antibacterial programs are engaged in the discovery and early research stages of new antibacterial drugs, increasingly more companies are transitioning from discovery to clinical-stage companies. Over half of the programs are estimated to be in early research stage and around 40% advanced to the clinical candidate or clinical development phase. Not an option in the past, developing a compound up to filing registration has been successful in the U.S. and is also increasingly seen as a viable opportunity by European SMEs.
The Difficulties with Antibacterial Drug R&D
Most small companies face serious hurdles when focusing on antibacterial drug R&D in addition to financial limitations—such as scientific problems, shortage of experienced personnel, dependence on external support, lack of appropriate diagnostics, the need for R&D short cuts, and IP issues in collaborations may impact directly on these companies. In addition, public funding in Europe is common in the start-up phase of a company but cannot make up for the funding gaps in most SMEs. Generally, switching to survival mode in unfavorable economic environments or stretching out inadequate funding is not a good basis for success.
Insufficient public as well as venture capital funding based on current economic models results in severe bottlenecks in antibacterial drug R&D and a low supply of new antibiotics—universally agreed upon alternative sustainable models are needed to create incentives for R&D of novel antibiotics, while also reconciling these incentives with responsible antibiotic use and access for all patients in need. Overuse and misuse of new antibiotics is not a sustainable way of dealing with antibiotics as essential part of modern medicine. Alternative economic models may be the basis for the global recovery of the antibacterial drug pipelines and the future of antibacterial treatment options.
The multistakeholder, collaborative DRIVE-AB project (Driving Re-InVEstment in R&D and responsible AntiBiotic use) is a large multinational public-private consortium funded by the EU Innovative Medicines Initiative (IMI) with in-kind support from EFPIA partners (European Federation of Pharmaceutical Industries and Associations). DRIVE-AB brings together expert partners from academia and large pharmaceutical companies and is currently developing and testing concrete recommendations for new economic models that could provide a favourable environment for investment in this area. These models will be presented in 2017.
To facilitate the implementation of new models, DRIVE-AB convenes a large international stakeholder platform of experts and advisory groups. As the discovery of new antibiotics mainly relies on research in SMEs powered by academic research, small companies are critical stakeholders in developing and implementing alternative economic models.
Call to Action
ESCMID partnered with DRIVE-AB to bring the science and discoveries of SMEs to the attention of a broader audience at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Copenhagen. The ECCMID Pipeline Corner provided a platform for 12 companies (all BEAM alliance members) with products in early stages of R&D to display electronic posters and hold oral presentations of their approaches and programs.
DRIVE-AB facilitated the founding of this networking group BEAM alliance that represents European “antibacterial” small companies, with the goal of giving members a voice in this field, and promoting collaboration between stakeholders involved in developing innovative antibiotics. In the face of global initiatives battling growing resistance, ESCMID will continue to strengthen the presentation of new scientific results of antibacterial drug R&D activities at next year’s ECCMID in Istanbul. Pipeline Corner in 2016 will expand its geographical scope and invite SMEs globally to present their antibacterial R&D pipelines. After long years of dried up R&D pipelines and alarming resistance trends there is light on the horizon; still, a lot more work needs to be done.