A new vision for AMR innovation to support medical care

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1 APRIL 2019 A new vision for AMR innovation to support medical care About the BEAM Alliance The BEAM Alliance (Biotech companies from Europe innovating in Anti-Microbial resistance research) represents over 60 European SMEs that develop solutions to fight antimicrobial resistance on a European and national level. The BEAM members are collectively developing over 140 new, diversified R&D projects focused upon prevention, diagnosis and cure of microbial infections. The goal of the BEAM Alliance is to maintain and promote awareness of SME-driven innovation in the field and to support policymakers in understanding economic business models around AMR. The BEAM Alliance closely cooperates with all stakeholders dedicated to the fight against AMR. Although being a member of and closely collaborating with the AMR Industry Alliance to curb antimicrobial resistance, the BEAM Alliance is advocating for the specific SME needs with regards to investment in R&D to meet public health needs with new innovative diagnostics and treatments. BEAM Alliance A new vision for AMR innovation to support medical care 1

2 Key messages Antimicrobial resistance (AMR) is a global, multi-sectoral issue that affects all countries and, if unaddressed, would widely stress health systems To curb the AMR threat, the range of infection challenges and medical needs must be matched with a diversity of informed treatment approaches A diverse pipeline of innovative solutions is being developed by SMEs to meet this challenge New outcomes, and tools to quantify them, are now awaited to help differentiating existing and upcoming products and measure their performance To do so, a categorization of the antimicrobial approaches based on the pathogenesis of infectious disease is proposed. BEAM Alliance A new vision for AMR innovation to support medical care 2

3 Changing paradigm to overcome the growing AMR threat Evolutionary pressure inevitably leads to microbes acquiring resistance against every generation of antimicrobials. In this never-ending race, bacteria have been particularly efficient in outpacing the development of new classes of antibiotics thus leading to increased antibiotic resistance. However, while new microbicidal approaches are awaited, the complex interplay between pathogens and their hosts remains relatively unexploited from the standpoint of antimicrobial drug development. Hence, a better understanding of the different steps underlying the infection process could enable alternative or adjunctive approaches that differently target morbidity, mortality, resistance or transmission; with either prophylactic or therapeutic modality. Although substantial basic research has been devoted to the field of host-pathogen interactions, product development in this area is only just emerging, with only a few programs currently progressing through clinical trials. From a global patient management perspective, it is also crucial to develop diagnostic tests that can quickly and reliably identify pathogens and inform decision-making. While some tests are already available, market uptake is still very low, even though their use could potentially deliver a more personalised medicine, avoid misuse of antimicrobials (ATM) while improving patient outcome and enabling better stewardship. The value of diagnostics is currently underestimated and reimbursement is not aligned with the medical benefit, leading to the cost-driven selection of empiric broad spectrum antibiotic therapy. As a consequence, it is crucial we develop new tools to inform on the performance and utility of the all (new and existing) products in this therapeutic setting. These are critical issues to convince prescribers and healthcare payers of the proposed added value and ensure uptake of these products to deliver better medical care and patient outcomes. SMEs are at the forefront of this paradigm shift by collectively developing a breadth of innovative strategies. Meeting patient needs with a range of innovative antimicrobial solutions We propose an approach based on the pathogenesis of infectious diseases that allows classifying ATMs on the basis of the specific phase that they target within the process of infection. By linking a specific ATM to a specific step of the infectious process, novel clinical outcomes could be identified that could enable a better and more physiologically-relevant measurement of ATM efficacy. The proposed categorization of approaches (depicted under Figure 1) captures patient needs, in clear alignment with the perspective taken by regulatory and Health Technology Assessment (HTA) bodies. Indeed, patients need: 1. To avoid infection and thus to prevent disease and/or to enable surgical/medical interventions; 2. To get diagnosed and thus to enable an informed and timely choice of treatment; 3. To quench infection and thus to resolve the disease symptoms as efficiently as possible; 4. To avoid damage to the body and thus to decrease the level of infection virulence; 5. To avoid treatment failure and thus to prevent long lasting, recurrent and potentially lifethreatening disease states; 6. To avoid transmission and contagion and thus to prevent the spread to relatives or the close community. BEAM Alliance A new vision for AMR innovation to support medical care 3

4 Figure 1: The 6 Ways Innovative Products Address Patient Needs to Combat AMR Prior to evidence of infection, colonisation by the pathogen can be a complex process initiated by the opportunistic access (within a host) by either a foreign microbe or a microbe from the microbiota, followed by multiplication. The different ways ATM can avoid infection (1) can be grouped under two categories: First, by preventing entry and/or early spreading through the boosting of immune modulation (1a); Second, by disabling the presence of the pathogen from the commensals either through its direct exclusion or through the ability to counteract colonisation mechanisms (1b). When the pathogen is able to invade the host and starts to multiply, the level of antigens, microbe s cell or cell fragment and corresponding immune effectors from the host are increasing accordingly, reaching a detectable amount: the patient can now get diagnosed (2). Diagnostic tests can deliver valuable information on a microbe s precise identity and susceptibility profile (2a). A rapid result enables the timely start of the most suitable treatment, avoiding improper strategies. As the microbe becomes established in the body, quenching the infection (3) has been traditionally achieved by killing or preventing growth of the pathogen. Innovation under this category of directly-acting products can be classified as: Direct active ATM with optimized efficacy, potency, sensitivity and kinetics (3a); Indirect action of ATM compounds able to enhance the kinetics of the pharmacological effect in combination with other ATMs, reducing the duration of the disease state in the patient (3b). Another approach consists in circumventing the mechanisms developed by pathogens to bypass the host immune responses. ATMs could promote the immune system efficacy (3c) either through a direct stimulation or through suppression of bacterial pathogenicity. In some but increasing number of cases, the fight against the pathogen is hampered by existing resistance mechanisms (3d). A better understanding of how these mechanisms are operating can promote the discovery of resistance-neutralizing drugs that will help revitalizing existing medicines. Standard treatments are not specifically designed to target slow-growing or non-dividing microbes. This also applies when other tolerance mechanisms are used by the pathogen, such as in the formation of bacterial biofilms in chronic infections. Circumventing such metabolic avoidance (3e) has the potential to enable an improved clearance of infectious agent and reduce likelihood of recurrence. BEAM Alliance A new vision for AMR innovation to support medical care 4

5 A pathogen can also exert its pathogenicity through cytopathogenic effects that can be direct (when caused by virulence effectors such as endo- or exotoxins), or indirect (as a consequence of the host (over)reacting to the cytotoxic effect of toxins). These effects can be targeted in order to avoid damage (4) to the body. The ability of an ATM to inhibit the secretion of toxins, or to neutralize them, is a promising way to preserve cells and avoid tissue damage (4a). Another part of the body at stake during an infection is the microbiota, in particular in the gut. Qualitative, quantitative or functional disruption of the microbiota is now known to impact the patient s health in the shorter and the longer term. Preventing microbiota dysbiosis (4b) by neutralizing the disrupting agents or by controlled rebuilding of a rich and diverse flora is a supportive approach to discourage opportunistic infection (enabled by microbiota dysbiosis) and improved patient outcomes. During treatment, pathogens can acquire resistance to an ATM used to tackle the infection, resulting in treatment failures. Avoiding such treatment failure (5) is of tremendous importance to preserve the sustainability of the medicine portfolio. Preventing the pathogen from developing or acquiring resistance (5a) or counteracting horizontal or vertical resistance gene transfer (5b) are relevant approaches to maintain the pathogens susceptibility to the available drugs. The better control of the outbreaks implies the capacity to avoid transmission and contagion (6). Different approaches intend to lower the probability of transmission during the contagious phase (6a) thus limiting the epidemic spread within the community. The BEAM pipeline: a diversity of approaches Many of these approaches are novel and open up new clusters of innovation that are being carried out within SMEs. Many products may simultaneously exert a diversity of actions, thus belonging to multiple categories at the same time. As a consequence, the coverage of patient needs can be achieved with a smaller number of products. As an example, the 142 products of the BEAM pipeline (as of , see display 341 occurrences broadly distributed among the abovementioned categories (Figure 2). Figure 2: BEAM pipeline distributed across the different categories according to their development stage BEAM Alliance A new vision for AMR innovation to support medical care 5

6 Such a diverse portfolio is paving the way to a powerful, reinvigorated armamentarium. It is also forecasting a new way to address the real diversity of infectious contexts in a patient-centric manner, and offers a prospective vision of how to curb the AMR threat. The BEAM Alliance task force is now actively working with Health authorities in Europe and in the USA to validate non MIC 1 -outcomes supported by clinical-based evidence 2. Conclusion Lessons learned from the history of antimicrobial resistance are calling for new thinking and approaches to curb the steadily growing AMR threat. To better support medical care, new R&D concepts are emerging throughout the pathogenesis steps of infections, together with a more global and dynamic view of what infections are and how to address what they do. Innovative ways to evaluate these approaches are required in order to improve the related clinical development, evidence collection, surveillance and health technology assessment. Our ability to set up a solution-oriented, collective scrutiny of the healthcare ecosystem (including regulatory, HTA, practitioners, industry players ) provides our best chance of crossing the chasm and all interested parties are welcome to join. Connect with us contact@beam-alliance.eu 1 Minimum Inhibitory Concentration 2 This work is partially supported by a JPIAMR grant BEAM Alliance A new vision for AMR innovation to support medical care 6