The quest for new drugs for forgotten populations is a priority, says Jadel Kratz
In Brazil, only 4% of the clinical studies conducted to date have been focused on neglected diseases. We need an arsenal of new therapies to bring radical change.14/02/2018
Despite the efforts of the past years, and investments in research and development (R&D) for new drugs for neglected diseases, pharmacological treatment for these diseases is still limited to a few options. The available drugs have significant limitations (associated with the properties of their active ingredients), such as toxicity, low tolerability and effectiveness, parenteral administration, long duration treatment, and high cost. Thus the quest for new effective and safe treatments is crucial.
The coordinator of Lead Optimization Latin America (LOLA) at the Drugs for Neglected Diseases initiative (DNDi), Jadel Müller Kratz, explains that multiple strategies can be used when developing new medications. However, the basic steps of the R&D chain, such as pre-clinical and clinical studies, are common to most approaches. New drug formulations and associations of existing drugs are medium-term strategies that could make advances in treating patients. Nevertheless, it is necessary to create a new arsenal of therapies to provide radical change in the course of these diseases. New chemical entities, with a more “drug-like” profile and with different mechanisms of action, are a feasible long-term strategy. They could be used in monotherapy, but also combined with each other or with existing medications, in order to avoid cross-resistance.
“The screening and optimization process for new compounds is highly multidisciplinary and especially difficult for infectious diseases where the parasite is primarily intracellular. In order to provide researchers with the necessary support and tools, it is equally important to have the best possible understanding of the parasites and the pathology of the disease. This knowledge allows the construction and continuous update of in vitro and in vivo models. These models allow us to design, evaluate, and optimize compounds that are selective and effective enough for use against parasites.” he says.
Accordingly, DNDi handles this initial phase of research and development by stimulating innovation and exploring unconventional paths to developing drugs. According to Kratz, this is basically done in two ways: Firstly, by using a global collaboration network, DNDi integrates the capacities and experiences of several partners when implementing all phases of R&D: from the search for new chemical entities to pre-clinical trials, from clinical trials and implementation studies to access to treatment on a large-scale. Secondly, unlike the pharmaceutical industry model, by uncoupling development costs from the final prices of the treatment and negotiating license agreements that promote access, it meets the demand from patients.
Kratz says that in the discovery phase, DNDi is organized into multi-centered research consortia (three in total), gathering partners with different specialties around a common purpose. The first step consists in identifying and validating active compounds (hits), originated from commercial compound libraries or from partner pharmaceutical companies. “Once the new chemical series of interest has been identified, it is submitted to a iterative multiparametric optimization process (pharmacodynamics, pharmacokinetics, and safety). The criteria defined in the target-candidate profile (TCP) guide the optimization cycles until a pre-clinical candidate with acceptable characteristics is found, or the chemical series is abandoned.” he adds.
In Latin America, since 2013, discovery activities have been conducted by Lead Optimization Latin America. Launched in partnership with the Synthetic Organic Chemistry Laboratory at Campinas State University (Unicamp), in São Paulo, this consortium now crosses borders and gathers partners in the region, in Belgium, Switzerland, USA, Australia, Scotland, and China. “In this network, which follows the precepts of open innovation, compounds are tested in vitro and in vivo against Trypanosoma cruzi and Leishmania spp, causative agents for Chagas disease and leishmaniasis, respectively, and are optimized by iterative design-synthesis-trial-analysis cycles.” he points out.
Challenges that hinder the quest for new medications in Brazil and the region
Besides the difficulties intrinsic to the diseases and the limitations of experimental models, there are special obstacles in Latin America that hinder the quest for new treatments for neglected diseases. The LOLA coordinator claims that the investment in research is discontinuous and low, when compared to other fields, such as non-communicable chronic diseases. “Moreover, the difficulty of obtaining consumables, the lack of multicentered and structured efforts, and the lack of harmonization of assays between different groups create a gap in the development chain,” he laments.
According to Kratz, during the search for new chemical entities, many promising results are generated in the compound screening phase. However, the initial hits usually do not follow a rational optimization stage, whereby they would give rise to pre-clinical candidates with appropriate profiles. “From a clinical point of view, in Brazil, only 4% of the clinical studies conducted to date have focused on neglected diseases, probably a reflection of regulatory obstacles, a lack of long-term investment, and priorities in pharmaceutical R&D policy, he said.
In his view, an improvement in this situation requires the formation of local competences and teamwork, in all spheres, through integrated strategies. “And in parallel, involves the support of advances already achieved by establishing an industrial policy for the regional pharmaceutical sector, by creating public-private partnerships and ensuring continuous funding. In this sense, DNDi continuously interacts with the scientific community, publishes its results and TCPs to help in the selection of new compounds with a greater probability of success, and has structured collaborative centers for non-clinical and clinical research in endemic areas.” he adds.
Kratz assures that there have been important advances and collaborations in the field that have helped to populate the current development pipeline. “However, the path to be travelled by a new chemical entity, from discovery to registration, is long and costly, and the attrition rates are relentless. To optimize the chances of access to new treatments by neglected patients, it is crucial that all R&D stakeholders remain focused on understanding the diseases and improving research strategies, without forgetting the importance of enhancing science and promoting a favorable environment for research in the region”, he concludes.…