Innovation for the Elimination of Neglected Tropical Diseases

The more genetic and non-genetic variants contribute to an adverse event, the less it is likely the genetic variant of interest will cause an adverse event: therefore, its positive predictive value will be low.

Examples of genetic testing utility

Not all adverse reactions are characterised by a complex interplay of multiple genetic and non-genetic factors as is the case of warfarin.

Abacavir, is a reverse transcriptase inhibitor indicated for human immunodeficiency virus infection (HIV). It can cause a hypersensitivity syndrome characterised by respiratory, gastrointestinal disorders and rash. In patients who are rechallenged with abacavir after having experienced a hypersensitivity syndrome, this adverse reaction can be fatal. A study in about 1900 patients showed that avoiding abacavir in patients with human leukocyte antigen (HLA)-B*57:01 variant eliminated immunologically confirmed hypersensitivity reactions. In this study, the test negative predictive value was100 per cent: this meant all the patients that had a negative genetic test did not experience the adverse reaction. Considering an overall prevalence of HLA-B*57:01 variant of 6 per cent and being the positive predictive value of the test of 47.9 per cent,it has been calculated that 25 patients need to be screened to avoid one case of abacavir induced hypersensitivity syndrome.Therefore, the medicine’s Summary of Product Characteristics requires that before taking abacavir all patients are screened for HLA-B*57:01 variant; patients who are found to carry this allele should not be treated with abacavir.

A very different example is that of flucloxacillin, a medicine used to treat bacterial infections. The strongest known genetic association for drug-induced liver injury is that between flucloxacillin and HLA-B*57:01 (the odds ratio of the association is 80). The genetic test accurately identifies the patients who have the variant, but flucloxacillin drug induced liver injury occurs (luckily) in only 8.5 out if 100,000 patients who take the drug and the positive predictive value of the test for the HLA-*B57:01 allele is of 0.12 per cent. It has been calculated that around 13,500 patients need to be screened to avoid one case of drug induced liver injury and due to the low positive predictive value of the test, only 1 out of about 830 patients who take flucloxacillin and have the HLA-B*57:01 variant will suffer from drug-induced liver injury.Considering that the prevalence of the HLA-B*57:01 variant is relatively high (in Caucasians, for example, it is of around 7 per cent) and that only a small fraction of patients with the variant will experience drug-induced liver injury due to flucloxacillin, it has to be decided if these patients should take the medicine or if they should be denied flucloxacillin. Another non-trivial point to examine is the cost-effectiveness of screening around 13,500 patients to avoid one case of liver injury.

Genetic testing clinical utility is therefore being pondered: what is the balance of benefits and risk associated with using a test in everyday practice, including its ability to inform clinical decision making and prevent adverse reactions.

As for abacavir, also for flucloxacillin, the answer can be found in the medicine’s Summary of Product Characteristics: HLA-B*57:01 variant is only mentioned in section 4.8 ‘Undesirable Effects’ where

it is stated there is evidence that the risk of flucloxacillin induced liver injury is increased in patients who carry the abovementioned allele. However, since very few carriers of the allele will develop liver injury, routine screening for the variant is not recommended.

A look in the future of personalised medicines: pros and cons

The effect of a genetic variant on an adverse reaction varies from being the most important risk factor to being only a minor contributor. In the future, it is possible that all the gene variants affecting the efficacy and safety of a drug and how they interact with the environment will be known. The human population could all be genotyped, and the genotype could be included in electronic medical records so that artificial intelligence can consider all the individual variables and tell which is the best medicinal product and the most appropriate dose for each patient suffering from a pathology. Therefore, the benefit-risk balance of a drug could be assessed based on individual needs.

However, like everything pertaining to this world, there will also be some cons. For example, the data on the genetic characteristics of a person could be hacked and used to discriminate some individuals. Health insurance companies might require access to individuals’ genotype, and the cost of health insurance could be higher for subjects with genes predisposing to certain pathologies. Will everyone really want to know, through the analysis of our genotype, what is our risk of suffering from a pathology, or will this only increase people’s anxiety? Finally, it is uncertain if everyone will understand the meaning of their genetic characteristics, especially since in an era where infodemic and fake news are rife. Unluckily, it is easy to imagine that those who will not understand the meaning of their genetic characteristics will look for information in the web and will easily fall prey to those who want to sell improbable remedies for their risk factors or, even worse, who have political agendas.

References are available at www.pharmafocusasia.com

AUTHOR BIO

Giovanni Furlan has more than 20 years’ pharmacovigilance experience. He has overseen pharmacovigilance medical, operational and compliance activities and has managed, merged, and developed pharmacovigilance departments. A fellow of the International Society of Pharmacovigilance, he has given many presentations at international congresses.

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The World Health Organization (WHO) roadmap on neglected tropical diseases (NTDs) for 2021-2030 highlights the pivotal role of pharmaceutical innovation in the control and elimination of these conditions. However, sustained funding for well-structured and innovation-oriented drug discovery programmes, especially in the postCovid-19 era, is a necessary condition for the translation of the roadmap goals into concrete achievements.

Leonardo L G Ferreira, Researcher, São Carlos Institute of Physics (IFSC) - University of São Paulo (USP) Josué de Moraes, Professor, Guarulhos University Adriano D Andricopulo, Full Professor, São Carlos Institute of Physics (IFSC) - University of São Paulo (USP)

Neglected tropical diseases (NTDs) affect more than one billion people worldwide. Although this group of 20 infectious conditions corresponds to 11 per cent of the global disease burden, no innovative drugs have been developed in this field. The World Health Organization (WHO) has played a central role in raising global awareness on the subject. Recently, WHO launched its roadmap on NTDs for 2021-2030, which highlights the advances made over the past years and sets the strategies to eliminate these diseases by 2030. According to this agenda, pharmaceutical innovation will be central for the achievement of the agreed goals, especially for protozoan and helminthic NTDs. Unfortunately, drug research and development (R&D) for highly prevalent NTDs such as schistosomiasis, human African trypanosomiasis, Chagas disease and leishmaniasis, has, for decades, been characterised for insufficient funding and low-technology approaches. This paradigm has recently changed given the rising of initiatives that involve notfor-profit organisations, universities, and pharma companies. Among these partnerships we can cite the NTD Drug Discovery Booster, the Lead Optimization Latin America (LOLA),the WIPO Re: Search project, and the Welcome Trust for NTD drug discovery programme, the first two being administered by the Drugs for Neglected Diseases initiative (DNDi). These programmes have proven invaluable to catalyse drug R&D for NTDs by integrating medicinal chemistry and parasite biology and allowing multi-parameter optimisation (MPO) of high-quality hits and lead compounds. Despite these efforts, innovative products have not been regularly developed and approved for NTDs. The few products that have recently been approved for these conditions are known or repurposed drugs, new formulations, or combination chemotherapies.

The case of leishmaniasis is emblematic. Leishmaniasis is caused by more than 20 species of Leishmania parasites and affects 700,000 to 1 million people each year. Chemotherapy for this NTD is complex, costly, lengthy, and can cause severe adverse effects. Most drugs require intravenous or intramuscular administration by highly skilled health professionals