Corporate Efforts to Research and Develop Therapeutic Agents for Infectious Diseases That Threaten Human

Development of E1224 by leveraging a strategic partnership for the medicines creation against neglected tropical diseases

Neglected tropical diseases (NTDs) are the common denominator for infectious diseases that occur almost exclusively in poor populations in developing countries. The main NTDs include schistosomiasis, filariasis, intestinal helminth infections, leprosy, Buruli ulcer and protozoan infections such as trypanosomiasis (causing sleeping sickness in Africa or Chagas disease in South America) and leishmaniasis.1 While biologically diverse, they share a number of characteristics: all are strongly associated with poverty and flourish best in tropical areas, where they often coexist. Taken together, they are a leading cause of disability, comparable to tuberculosis and malaria, with over a billion people affected.1 Many predominantly target children, compromising physical growth and cognitive development. These ancient ‘companions of poverty’ undermine the wellbeing and productivity of already destitute populations, and severely impede meeting the United Nations 2015 Millennium Development Goals. By definition, NTDs have not ranked high on the national and international political agendas. For most, there are no or few adequate diagnostics, tools or vaccines, the local health systems are deficient and overburdened and financial resources scarce. In terms of research and development, these diseases are also truly neglected; less than 1% of new therapeutic developments over the past decades have concerned tropical diseases.2 The treatment of Chagas disease and African trypanosomiasis still relies on drugs that were developed more than 40–60 years ago. NTDs have fortunately received increased attention more recently from funders, global philanthropists, policy makers and researchers. A number of new global international networks have been established, and several ambitious initiatives have been launched, including some directed at the elimination of a range of NTDs.3 A major new initiative aims for the integrated control and elimination of lymphatic filiariasis, onchocerciasis, schistosomiasis, intestinal helminthiases and trachoma through the use of mass drug treatment (preventive chemotherapy) with a combination of drugs.4 However, huge knowledge gaps currently exist on how to widely implement this strategy in the most acceptable, (cost-) effective and sustainable way. Its global health impact and its interaction with and effect on already overburdened health systems remain to be better defined.5 Issues such as safety and the emergence of drug resistance also need to be carefully assessed. For other diseases, early diagnosis and treatment constitute key control measures. Although improved diagnostic tools and drugs have been developed, for example for visceral leishmaniasis, their large-scale implementation has proved challenging. While India, Nepal and Bangladesh have committed to eliminating visceral leishmaniasis by 2015, they struggle to make timely diagnosis and treatment widely accessible.6 Monitoring and surveillance systems are suboptimal. Additional operational research will need to be conducted to enhance the effectiveness of current strategies and to evaluate novel approaches. The same applies to East Africa, where treatment for visceral leishmaniasis is still predominantly provided by non-governmental organisations.6 For diseases such as African trypanosomiasis and Chagas disease, there are no easy to use, reliable tests for diagnosis and/or test of cure. Therapy is lengthy, complicated and/or often poorly tolerated. Efforts of not-for-profit research and development organisations such as the Drugs for Neglected Diseases initiative (DNDi) and the Foundation for Innovative New Diagnostics (FIND) will hopefully help fill this gap. As most NTDS are vector-borne or zoonotic in nature, efforts directed towards the control of the vector, intermediate host or animal reservoir will also be key.1 Successful control of NTDs will ultimately hinge on the concerted efforts of all stakeholders, within a multi-disciplinary approach. How to maximise the impact of these efforts will have to be carefully assessed, and innovative strategies will have to be explored. Operational research will have its role to play.7 Research findings will need to be easibly accessible, widely disseminated and able to reach decision makers and programme managers. Public Health Action is a new, open-access journal ‘disseminating new knowledge on health systems and health services for vulnerable groups’, and aiming to provide a ‘voice for operational research’. Hopefully, we can expect many operational research studies on NTDs from the field in the years to come, including in this journal.

Parasites and infectious agents are responsible for neglected tropical diseases (NTDs) that affect many countries worldwide. At least one NTD is found 149 countries, mostly in low-income countries with poor sanitation, and it impacts over a billion people. According to the World Health Organization, trypanosomiasis is a group of protozoan infections that cause Chagas disease (Trypanosoma cruzi), Human African Trypanosomiasis (sleeping sickness - <i>Trypanosoma brucei</i> rhodesiense or <i>Trypanosoma brucei</i> gambiense), and <i>Leishmaniasis</i> (<i>Leishmania</i> spp. - Trypanosomatidae family), which are all considered NTDs. It is estimated that approximately 500,000 deaths from NTD infections occur annually worldwide. Despite the many cases associated with NTDs, treatments for most of these diseases are available. However, they are associated with significant adverse effects and a growing number of drug-resistant microorganisms and require parenteral administration. Besides that, many trypanosomatid diseases are zoonotic, making eradication extremely difficult. In this way, despite scientific progress over the years, some drug discovery goals remain unmet, such as the development of new therapeutic classes, reduced toxicity, improved administration regimens, or the development of combination therapies. Therefore, this chapter intends to present the six categories of drugs,<i> i.e</i>., the currently used therapeutic agents, nitroaromatic compounds, azole antifungal, benzoxaboroles, nitrogen heterocycles, and miscellaneous agents in clinical trials for NTDs, focusing on infections caused by trypanosomatids. In addition, the review approach presents the development process of the new drugs or treatment regimens in Phase I, II, III, and IV studies of the clinical trials based on the Drugs for Neglected Diseases initiative (DNDi) portfolio published in December 2020.

Neglected tropical diseases (NTDs) are a diverse group of tropical infections caused by various pathogens including viruses (eg, dengue or rabies), bacteria (eg, Buruli ulcer or yaws), protozoa (eg, human African trypanosomiasis), and parasitic worms or helminths (eg, dracunculiasis or soil-transmitted helminthiasis). Among the consequences of infections are pain, blindness, disability, disfiguration, and sometimes death. For example, Buruli ulcer is a debilitating skin and soft-tissue infection leading to permanent disfigurement and disability.

Obama vs McCain on global health

Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chemical starting points for such projects is a key factor in improving the likelihood of clinical success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compounds. With this in mind, the Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.

Neglected tropical diseases (NTDs), such as Chagas disease, human African trypanosomiasis (sleeping sickness), and leishmaniasis, disproportionately affect low-income populations in tropical and subtropical regions, leading to high morbidity and mortality rates. Consequently, these diseases, historically overlooked in global health agendas, perpetuate cycles of poverty and impede economic development. Drug repositioning, the repurposing of existing drugs for new therapeutic uses presents a promising strategy by reducing drug development time and cost while leveraging known safety profiles. However, despite its success in other therapeutic areas, this approach remains underutilized for NTDs due to challenges such as a limited drug pool, intellectual property barriers, regulatory complexities, and ethical concerns. Essential strategies to overcome these obstacles include expanding approved drug libraries, fostering multi-sector collaborations, streamlining regulatory processes, and adopting innovative funding models. Collaborative efforts among governments, pharmaceutical companies, research institutions, and non-profit health organizations are crucial to fully unlock the potential of drug repositioning. By working together as a united front, these stakeholders can ultimately transform NTD treatment and improve global health outcomes.

Neglected tropical diseases (NTDs) have seen a welcome bolstering of activities focused on discovery of new therapies for these diseases. By and large, NTD drug discovery happens in the nonprofit sector—in academic laboratories and in public–private partnerships—though there has also been a significant and tangible influx of data and research contributions from the for-profit biopharmaceutical industry. Sets of screening data against the parasites that cause Chagas disease and African sleeping sickness have been released to the public via ChemBL (https://www.ebi.ac.uk/chemblntd), Collaborative Drug Discovery (http://www. collaborativedrug.com), and PubChem (https://pubchem.ncbi.nlm.nih.gov), and a fair quantity of these data have been produced by the pharmaceutical industry, many times in collaboration with groups in the nonprofit or academic environment. These initial public releases have begun to enable credible drug discovery for tropical diseases, particularly when taken together with new collaborative opportunities with industry that provide access to state-of-theart drug discovery and development capabilities. These facilities include the Tres Cantos Open Lab initiative [1], therapeutics development resources at the National Institute of Allergy and Infectious Diseases [2], and compound screening sets now made available for testing against other pathogens, such as the Malaria Box [3]. Thus, perhaps there has never been a better time to be performing hit-to-lead and lead optimization drug discovery for NTDs.

Introduction Effective medicines exist to address global health challenges including Neglected Tropical Diseases (NTD) and Noncommunicable Diseases (NCD) however these are often unavailable and unaffordable. To date, little literature exists comparing medicine unavailability across broad disease areas. Areas covered Using insulin and praziquantel as tracer medicines this review aims to demonstrate that separating global health governance agendas for NCDs and NTDs ultimately impacts the effectiveness of coalitions for access for the poorest populations. Electronic literature searches were performed through Science Direct, PubMed, and Google Scholar (March–May2017 and updated in September–December2019) using keywords from Shiffman’s framework; NCDs; NTDs; and for each medicine. Best practice from each area was analyzed. Expert opinion Many actors responded to the London Declaration which reinforced praziquantel’s central role in control and elimination of schistosomiasis whereas access to affordable insulin emerged secondary to framing around prevention and management of diabetes. For insulin key stakeholders are not aligned around access. The position taken by pharmaceutical companies as donors versus commercial actors was critical to sustainable affordable access to these medicines. Integrated access models for low resource populations need shared pathways given the increasing need for essential medicines in the context of Universal Health Coverage.

Diseases such as trypanosomiasis, leishmaniasis, and lymphatic filariasis impose substantial health burdens in developing countries [1], [2]. These diseases are widely neglected because there is little financial incentive for biopharmaceutical companies to invest in developing new treatments, vaccines, and diagnostics. Most of the 1,000,000,000 people affected by neglected diseases are poor and live in low-income countries [3]. Although there is a significant need for new cost-effective drugs and vaccines, from 1975–1999 less than 1%–2% of new chemical entities marketed were for tropical diseases and tuberculosis [1], [4]. Market incentives play an important role in mobilizing companies toward neglected tropical disease (NTD) research. Pharmaceutical companies have a fiduciary responsibility to shareholders to maximize profits. Absent of other incentives, companies will focus research and development (R&D) on products and programs that possess a profitable market, have a sufficient likelihood of technical success, and are likely to achieve a maximum return on investment. In contrast, the global burden of neglected infectious diseases is concentrated in developing countries with inadequate health budgets and poor patients who can pay only low prices for drugs, if they can afford to pay at all. Drugs and vaccines that target neglected diseases thus typically cannot compete with potentially profitable products for internal company or investor R&D dollars. Governments and foundations have recognized the dearth of private-sector incentives for investment in NTD research and have responded with “push” funding (up-front funding for drug development) and “pull” mechanisms (rewards for output) to promote successful development [5], [6]. The priority review voucher (PRV) program, currently administered by the US Food and Drug Administration (FDA), was passed into United States law in 2007 as a pull mechanism to help promote R&D for new medicines targeting NTDs, malaria, and tuberculosis [7]. Under this law, companies that receive FDA approval for a novel drug or vaccine targeting one of 16 tropical diseases are awarded a transferable voucher. This voucher can be sold to a second organization or can be redeemed to grant the bearer priority six-month review for a future medicine of their choosing [8]. As average standard review periods can range between 10–16 months, the voucher could potentially allow drugs to reach the market up to eight months earlier. Economic models have predicted that this faster time to market could be worth between US$50 million to US$300 million [9], [10]. However, the impact of the PRV incentive in developing new medicines for NTDs has been questioned, in part due to uncertainty around the value of the voucher among pharmaceutical and biotech companies [11], [12]. The PRV program as implemented carries restrictions that make earning or using a voucher difficult or impractical, such as a requirement that developers provide notice to the FDA at least one year prior to the use of a voucher (often before clinical trials have concluded). Further, the voucher has not resulted in demonstrated value for any company to date. At writing, Novartis is the only company to have received a PRV, which they used in 2011 to accelerate the review of a supplemental new drug application (sNDA) for their gouty arthritis drug candidate Ilaris (canakinumab) [13]. The FDA fulfilled their responsibilities under the PRV program to conduct a six-month priority review, but ultimately denied approval of Ilaris citing the need for further data to assess the overall safety profile [14]. It is possible that Novartis gained some benefit from the use of the PRV for the review of Ilaris, but this value is difficult to quantify.

Certain product development partnerships (PDPs) recognize that to promote the reduction of global health disparities they must create access to their products and strengthen research capacity in developing countries. We evaluated the contribution of 3 PDPs--Medicines for Malaria Venture, Drugs for Neglected Diseases Initiative, and Institute for One World Health--according to Frost and Reich's access framework. We also evaluated PDPs' capacity building in low- and middle-income countries at the individual, institutional, and system levels. We found that these PDPs advance public health by ensuring their products' registration, distribution, and adoption into national treatment policies in disease-endemic countries. Nonetheless, ensuring broad, equitable access for these populations--high distribution coverage; affordability, particularly for the poor; and adoption at provider and end-user levels--remains a challenge.

Neglected tropical diseases (NTDs) are communicable diseases caused by a group of bacteria, viruses, protozoa and helminths prevalent in more than 145 countries that affect the world's poverty stricken populations. WHO enlists 18 NTDs amongst people living in endemic areas having inaccessibility to preventive measures. Steps to reduce the global disease burden of the NTDs need attention at multi-factorial levels. Control programmes, mass drug administrations, transmission checks, eradication surveillances and diagnoses are some of them. The foremost in this list is confirmatory diagnosis. A comprehensive summary of the innovative, high-impact, multiplexed, low-cost diagnostic tools developed in the last decade that helped to meet the needs of users can depict a holistic approach to further evaluate potential technologies and reagents currently in research. Major Advancements: A literature survey based on developing nano-biotechnological platforms to meet the diagnostic challenges in NTDs towards development of a useful point-of-care (POC) unit is reported. However, in order to pave the way for complete eradication more sensitive tools are required that are user-friendly and applicable for use in endemic and low-resource settings. There are various novel research progresses/advancements made for qualitative and quantitative measurement of infectious load in some diseases like dengue, Chagas disease and leishmaniasis; though further improvements on the specificity and sensitivity front are still awaited. Strategies to combat the problem of antimicrobial drug resistance in diagnosis of NTDs have also been put forward by various research groups and organizations. Moreover, the state-of-the-art "omics" approaches like metabolomics and metagenomics have also started to contribute constructively towards diagnosis and prevention of the NTDs. A concrete solution towards a single specimen based common biomarker detection platform for NTDs is lacking. Identifying robust biomarkers and implementing them on simple diagnostic tools to ease the process of pathogen detection can help us understand the obstacles in current diagnostic measures of the NTDs.

Context: Antibiotic resistance (ABR) is an important growing global health issue which needs urgent addressal. Judicious use of antibiotics is the only solution to curb this problem. Awareness of this fact among UG students, who are the future physicians is extremely vital. Aims: To assess the knowledge, attitude and practices (KAP) related to antibiotic resistance and usage in UG students. Settings and Design: cross sectional, questionnaire based survey. Methods and Material: The questionnaire was distributed to a batch of 86 medical students in their second year of MBBS, whereby their KAP regarding antibiotic use and resistance was assessed by a five point Likert scale, whose responses ranged from „strongly agree‟ to „strongly disagree,‟ and „always‟ to „never. Some questions were of true and false type. Statistical analysis: The data was analyzed by using simple descriptive statistics to generate frequencies, percentages and proportions. Wherever it was relevant, the Chi-square test was used to determine any significant difference. Results: Indiscriminate antimicrobial use leads to the emergence of the growing problem of resistance was known to all n=86(100%) of the participants. The number of respondents who agreed that ABR was an important and a serious global public health issue was 83(96.51%).Ninety four per cent (n = 81) of the respondents were aware that bacteria were not responsible for causing colds and flu. Conclusions: Our study provides an important insight regarding the knowledge, attitudes and practices regarding antibiotic resistance and usage among the future doctors, which can be considered, in order to plan for an effective undergraduate curriculum.

In the age of globalization, infectious diseases can easily cross national boundaries and regional epidemic can easily develop into an international crisis. Therefore, the international community is paying more attention to global health issues than before. Globalization of infectious diseases compels the international community to consider the reasonable and effective governance of public health, and the outdated International Health Regulations (IHR) in 1969 becomes the target of revision. The revised IHR has in many ways fulfilled the need of the international community to deal with the serious public health threats, but it also raised the sovereignty concern in some member states. This article first addresses the relationship between the multilateral agreement and the state sovereignty, and secondly, introduces the impacts of multilateral agreements on global public health and the concern of the member states when the revised IHR enters into force. Finally the paper presents the coping measures of the Taiwanese government.

Developing safe and effective drugs and other medical products is a complex and costly process. Drug development has been, historically, commonly competitive and uncollaborative, and this tendency toward a lack of interaction between stakeholders—the pharmaceutical industry, academia, regulatory agencies, healthcare providers, and communities, among others—can lead to missed opportunities to improve efficiency and, ultimately, public health. The Forum for Collaborative Research was established in 1997 to address current scientific, policy, and regulatory issues in global health through multistakeholder engagement and dialogue. By providing a neutral and safe space for discussion, the Forum's model has impacted how clinical trials in diverse health areas are conducted, supported broader and more equitable clinical trial participation, and accelerated delivery of new drugs. The Forum's focus and directions have shifted over time, and this responsiveness to the needs of the global health community will be critical to ensure that the Forum continues to support collaboration in global health. In this article, we present lessons learned from this innovative model of collaborative research and regulatory science, pioneered by the Forum for over 25 years, including the importance of collective ownership and governance by all stakeholders, and emphasis on common goals and advantages of collaboration.