Science Pool

Continuous biomanufacturing is reducing the cost of goods of biopharmaceuticals. Achieving continuous manufacturing requires expertise in equipment design.

Download the highlights of Andrea Isby's presentation at Repligen's DSP Workshop in Estonia from May 23rd, 2024 to learn more. 

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Biomarkers are very useful tools for drug developers as well as for clinicians. In drug research and development, they add value as they improve the success rate of clinical trials. In the clinic, they validate the eligibility of patients as well as the efficacy of an approved treatment. In the recent Evotec webinar on aging, Elizabeth van der Kam, SVP, Translational Biomarkers and Human Sample Management, gave an overview on biomarkers in general and the role of biomarkers in aging.

In fact, the success rate of clinical studies can by doubled by introducing biomarkers early on, that can predict efficacy and potential safety issues. Biomarkers also may be important to reduce costs by running smarter trails in smaller groups of patients and if translated to companion diagnostics, biomarkers enhance the readiness of payers to reimburse a novel drug, but they also enable higher profits as the drug can be sold together with a diagnostic test. Therefore, Evotec´s strategy is to develop a biomarker as early as possible during the R&D process.

Types of biomarkers

There are several types of biomarkers. Useful for early studies are biomarkers that demonstrate target engagement, meaning they show that a drug candidate hits the target in the relevant organ and triggers a response. However, target engagement not necessarily means that this is relevant for the disease.

Another classification consists of surrogate biomarkers, which exhibit correlations with the disease or its progression and could hold relevance in the context of the disease More useful are efficacy markers which are not just correlated but causative for the disease. Another important class of biomarkers are safety biomarkers which, as an example, alert a clinical trial leader or a physician that the drug also hits another target and could potentially cause an issue. Then there are stratification markers indicating the likelihood of a patient to respond to treatment. This is important as non-responders should not be included in trials or prescribed an ineffective treatment. Last but not least, there are diagnostic and prognostic biomarkers that help to better understand the disease and its progression, to establish the right dosage, assess efficacy and predict disease progression and monitor the patients.

In any case, a biomarker needs to be translatable and relevant, and its measurement should be feasible, robust, reliable, and durable.

Biomarkers in aging

The situation is complex in aging. Chronological age is not the best inclusion criterium for clinical trials of medicines trying to improve the health span of elderly patients as chronological age can be very different from biological age.

But how to define biological age? What markers are out there? Of course, there are a lot of markers of biological age, e.g., body composition, body fat, physical appearance and function, muscle mass, grip strength, walking speed, balance, wrinkles, grey hair, but also blood-based changes in terms of hormone and vitamin levels and progressing diseases such as poor eyesight, osteoporosis, declining kidney function, and many more.

However, none of these markers is sufficient as a stand-alone data point. Some of the changes observed in elderly people can also be found in younger people or in patients with non-age-related diseases. The best biomarkers are the ones that can be established without subjective assessments.

The situation is further complicated by the fact that aging is not a disease, and that any intervention should be made early before the onset of typical signs of aging. Ideally, one would have biomarkers that can tell which category of older people will develop certain diseases. At present however, there are biomarkers indicating changes in many pathways and targets, but these often only indicate a certain chance of getting a disease.

The challenge

At present, biomedicine does not have access to markers that can predict certain biological deteriorations, let alone predict potential success of a treatment. And how to define a subpopulation and forecast treatment success without waiting for years to see an effect?

Currently one of the best overall indicators of biological aging is inflammaging. It demonstrates changes in the immune system, inflammation, and an imbalance in the innate or the adaptive immune system, thereby predicting a high risk of unhealthy aging. However, inflammaging can also be caused by lifestyle and gender, so it is not an ideal biomarker. Recently, under review of the U.S. National Institute for Aging, the TAME BIO (Targeted Ageing with MEtformin) project tried to establish a basis for future biomarker discovery and validation and accelerate the pace of ageing-research. 

The project started out with more than 200 potential biomarker candidates that were screened for feasibility, dependency on gender, and environmental factors, etc., bringing down the list of candidates to less than 90. Then they were assessed for disease-relation, robustness, their association to multi-morbidity and the usefulness to clinical trials, leaving a final set of eight candidates. This was, however, a purely theoretical exercise and whether these candidates are useful in real life needs to be proven. At present, the jury is still out on useful biomarkers for trials and therapies to prolong health span and quality and duration of life.

Learn more in the webinar "A Spotlight on Ageing" by Elizabeth van der Kam, SVP, Translational Biomarkers and Human Sample Management at Evotec

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Enhancing Single-Pass TFF for Antibody Therapeutics Manufacturing

Single-Pass Tangential Flow Filtration (TFF) plays a pivotal role in enabling fully end-to-end continuous manufacturing of antibody therapeutics. In this poster, we delve into the study of two distinct SP-TFF membrane configurations to determine which one is most effective for clinical and commercial production.

Key Findings:

1.    Concentration Factor Achievement: Both tested configurations successfully achieved the required concentration factor without encountering fouling issues.
2.    Shear Forces Mitigation: Neither setup generated significant shear forces that could harm the antibody product.
3.    Operational Success at Low Feed Flux: Both configurations demonstrated successful operations even under low feed flux conditions, reinforcing their suitability for large-scale manufacturing.

Future Directions: Our team of scientists and engineers will continue their investigation, exploring various load challenges, system perturbations, and methods for in-line concentration measurements. These efforts aim to enhance the robustness and efficiency of our manufacturing processes.

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In many diseases, genes are not altered, but their regulation is disturbed, and only recently have approaches emerged to target gene regulation as a therapeutic tool.

How are genes and their expression regulated? While the central dogma of the 1960s DNA->RNA->protein still holds true, recent advances in molecular biology have provided much insight into how cells regulate which genes are transcribed into mRNA and how translation of RNA into proteins is regulated. It is now known that mRNA can undergo many chemical modifications, induced by a variety of enzymes. These modifications affect mRNA maturation, stability, and lifespan, as well as the rate and duration of translation and mRNA degradation. Likewise, some small modifications can either prematurely terminate protein synthesis, reduce peptide yield, or alter the amino acid sequence of the translated protein.

While the existence of post-transcriptional RNA modifications has been known for more than 30 years, their mechanisms, functional consequences and connection with human diseases including cancers have only recently been elucidated, making RNA epitranscriptomics an unexplored and exciting field for drug discovery. Meanwhile, more than 150 RNA modifications have been reported and approximately 300 RNA-modifying enzymes have a potential as novel therapeutic targets.

Evotec's partner Storm Therapeutics is amongst the first companies to pursue RNA-modifying enzymes as drug targets. The company identified RNA methyltransferases, a class of approximately 75 enzymes, as the most promising target class. Some have been identified as important regulators of cancer development and progression and thus represent promising novel antitumoral targets. Storm focused on METTL3, an enzyme involved in the co-transcriptional methylation of internal adenosine residues in eukaryotic mRNAs. This enzyme regulates fundamental aspects of mRNA life cycle, such as splicing, transport to the cytoplasm, stability, and translation into protein. It was known that in AML cell lines, knocking out METTL3 leads to a pronounced antiproliferative effect associated with a reduction of the BCL2 (anti-apoptotic factor). In other models, a marked upregulation of genes associated with innate immunity, such as those in the interferon (IFN) signaling pathway was demonstrated following METTL3 depletion.

However, tackling new classes of enzymes such as RNA methyltransferases requires breaking new ground in assay development, screening, and downstream hits to guide progression. To address these challenges, Storm and Evotec began collaborating in 2016, which later evolved into an integrated drug discovery and development alliance focused on novel small molecule RNA epigenetic drugs for oncology and other diseases. Using Evotec's fully integrated small molecule drug discovery and development platform, including biomarker support (development of a m6A-mRNA level evaluation technic), STC-15 was identified. STC-15 is a potent, selective small molecule inhibitor of the mRNA modifying enzyme, METTL3. STC-15 was developed from high throughput screening to candidate nomination in less than three years.

In preclinical cancer models, treatment with STC-15 significantly inhibits tumor growth. In addition, a profound cell-intrinsic interferon response was observed, following an accumulation of double-stranded RNA. In mouse models, the induction of innate immunity mechanisms, such as the interferon pathway, enhanced T-cell mediated cancer cells killing. This work has been recently published in Cancer Discovery, a leading cancer journal (Guirguis, Ofir-Rosenfeld et al., 2023). Notably, it activated innate immune pathways and inhibited tumor growth as effectively as anti-PD1 therapy in some models. In addition, the data showed that the combination of the two agents resulted in significantly greater activity, leading to tumor regression and durable anti-cancer immunity. Detailed investigation of the mechanism of action of the two treatments revealed that they act independently, providing a strong rationale for their combination. This added significantly to previous studies where STC-15 demonstrated efficacy in leukemia models through mechanisms such as inhibition of leukemia stem cell function (Yankova et al., Nature, 2021). Furthermore, additional combination studies revealed a high degree of synergy between STC-15 and Venetoclax, a BLC2 inhibitor and standard of care therapy for acute myeloid leukemia (AML) patients.

This data provided the rationale for the development of STC-15 both as a monotherapy and as a combination partner for immune checkpoint inhibitors or with BCL2 inhibitors for the treatment of solid tumors and leukemias, respectively. Following the selection of STC-15 as a first-in-class development candidate in 2020, the seamless integration from project initiation to IND using Evotec's INDiGO platform led to the entry of STC-15 into Phase I clinical trials in 2022. The orally bioavailable, highly selective METTL3 inhibitor is being developed for the treatment of solid tumors and may also have potential in AML.

A phase 1, multi-center, open-label, first-in-human study is evaluating multiple ascending daily oral doses of STC-15 in a 3+3 cohort design. The study is designed to systematically evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of STC-15 in adult patients with advanced malignancies. Dose levels for further evaluation in expansion cohorts will be selected based on all available PK, PD, target engagement (including m6A-mRNA level evaluation), efficacy, safety, and tolerability data, including long-term safety data beyond dose-limiting toxicities (DLTs).

Patient enrolment started in November 2022, and the company anticipates top-line results in 2024.

The development demonstrates the benefits of Evotec's integrated, accelerated IND-enabling platform to support the exploration of novel and exciting biology to maximize innovation, to execute efficiently with rapid and seamless integration from target to IND.

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Our 3 part "Spotlight on Aging" webinar series is now available to stream on demand.

In the last fifty years, life expectancy has increased dramatically thanks to advances in science, medicine, and public awareness. The population is living longer, but with it comes the challenge of improving Healthy Life Expectancy.

Join our speakers in our innovative 3-part webinar series where they will openly discuss 3 key topics:

• Therapeutic approaches for aging and age-related disease
• Aging and precision medicine
• Why older adults should not be underrepresented in clinical trials. 

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Can we age healthier?

Due to better hygiene and medicines, the aging population has been growing steadily over the last 30 years. By the year 2031 1.4 billion people will be aged 60 or over, comprising one in six of the worlds population.. This figure will reach 2.1 billion by 2050, with 426 million being aged 80 or more. Unsurprisingly, the UN declared 2021 -2030 the Decade of Healthy Aging. The aging global population brings considerable societal challenges. In developed nations, old age increases the financial pressure on healthcare systems because healthcare spending rises sharply with age. This is in part due to the increased use of medications with advanced years, but also the associated support and care costs.

Increasing healthspan

However, the underlying problem is not life span but healthspan. Being of advanced age does not necessarily mean being frail, sick and in need of care. Already today, there are many healthy seniors living an active life. To promote this notion, the WHO set the goal to provide every person in every country in the world the opportunity to live a long and healthy life. This is encapsulated perfectly with the definition of healthy aging being ‘the process of developing and maintaining the functional ability that enables well-being in older age’. Functional ability means having the capabilities to be and to do what people have reason to value, i.e. meeting not only basic needs but also allowing them to learn, grow, and make decisions, to be mobile, to build and maintain relationships, and to contribute to society. This is very different from life extension calculated as accumulation of human years.

What is biological aging?

Aging can be defined as a time-dependent decline in body function and is observed in virtually all living organisms. The accumulation of cellular damage due to dysfunction in multiple biochemical systems increases the susceptibility to disease and ultimately results in death. This is most likely a result of evolution, once an organism has reached sexual maturity to enable reproduction and raising offspring, it makes no biological sense to invest more energy in maintaining the organism. However, the case is more complex for long-lived mammals, with offspring that need to be protected for a protracted time to enable them to reach sexual maturity. Hence mammals have evolved sophisticated and very efficient repair and maintenance mechanisms in order to correct any cellular dysfunction. With this perspective in mind, aging can be defined as the gradual deterioration of this biological maintenance. We can then view improving healthspan through the lens of slowing this decline or improving restorative or regenerative capacity within tissues and organs.

Already, science has identified a number of factors that can contribute or accelerate the aging process and these include genetic predisposition, obesity, smoking and the status of the gut microbiome. Downstream of these drivers is frequently low-level chronic inflammation – ‘inflammaging’ that contributes to the gradual deterioration in cellular and tissue function. The immune system itself is also subject to decline over time, meaning that many of the protective and repair mechanisms of the adaptive and innate immune system become less effective over time. A combination of these factors are thought to contribute to the common diseases associated with advanced age, such as cancer, cardiovascular disease, chronic liver and kidney diseases, type-2 diabetes and dementia. We are all familiar with how these diseases lead to a reduced life expectancy, but also significant impairment in the individual’s quality of life.

At the cellular and molecular level, there are key biochemical mechanisms that promote gradual deterioration of function across all cell types, that we believe underpins loss of physiological performance - consistent with the process of aging. These are well recognized as the classical ‘hallmarks of aging’. These include the emergence of cellular senescence and the senescence-associated secretory phenotype- which drives much of the chronic inflammation in tissues. Telomere shortening, genomic instability and the accumulation of genetic damage which can lead to tumour formation, epigenetic changes, exhaustion of stem cells, altered cell-cell communication, loss of control of proteostasis, aberrant nutrient sensing and mitochondrial dysfunction. In addition there are more generalised drivers of the aging process such as those linked to dysbiosis.

There is therefore no single driver of biochemical and physiological aging, but the concerted influence of an array of many contribuing factors at play. These complex systems can seem daunting to address, but within each of these pathways there are potential points for pharmacological intervention that constitute targets for drug discovery programs. The goal of pharmacotherapy can therefore be viewed as intervening in key node points to slow the accumulation of dysfunctional processes and maintain cellular integrity for longer. Targeting these fundamental pathological mechanisms will be key to providing a systems-wide (i.e. holistic) benefit to the individual.

How to prolong health span?

It is known that medical interventions, good health practice, refraining from smoking, eating appropriately, and exercising, can all help protect our health. But as mentioned above, there are opportunities to improve healthspan, through targeting key points within the pathways that are recognized as the classical hallmarks of aging.

Developing novel senolytics - challenges and opportunities

One of the hallmarks of aging that has been very well characterized is cellular senescence. This occurs when cells reach the end of their ability to divide resulting in stasis, a state associated with the ‘senescence associated secretory phenotype’ (SASP). Under these conditions, the senescent cells release a cocktail of proinflammatory mediators which in the young targets them for removal by the immune system. However, in the aged, where the immune system itself is subject to gradual decline, senescent cells continue to release the cytokines, chemokines, growth factors and other bioactive components which contribute to inflammaging. As such, the use of senolytic agents which are aimed at killing off senescent cells by suppressing the pathways that keep them alive, is receiving significant attention in the aging field. According to a recent report in Nature Medicine, around 20 clinical trials of senolytic compounds are ongoing. Clearly, blocking the ‘keep me alive’ signals in the cell and triggering cell death offers a compelling approach in the treatment of cancer, but such a powerful pharmacological mechanism carries risk. In keeping with this, at present the majority of the ongoing clinical studies are for very severe indications and not aging. However, it seems likely that if the risk-benefit of such a pharmacological approach in man is understood and favourable, senolytics could find utility in aging.

An additional or maybe complimentary approach would also involve the immune system. A healthy lifestyle suppresses pro-inflammatory mediators and at a very simplistic level, agents which inhibit inflammation may prove beneficial. However, inflammation also plays a very important protective function in the body and so such an approach may not prove advantageous for chronic treatment. Conversely, boosting the performance of the immune cells seems like a more viable approach since it would enable the body to fight off infectious agents and correct and repair cellular and tissue dysfunction in a more effective way. The stem cells giving rise to immune cells reside in the bone marrow and their accessibility means their biology is very well understood, especially with respect to stem cell maturation and differentiation. Manipulation of these precursor cells in a positive way could offer the potential to regenerate the immune system and hence slow many of the downstream effects of inflammaging and the damaging consequences of infectious disease, which we know is more prevalent in the aged population.

Before we go in search of completely novel agents to address aging, there may already be therapeutic agents available which may be beneficial. Metformin and rapamycin are generic and widely used in the treatment of Type 2 diabetes and as an immunosuppressant for organ rejection, respectively. However, several clinical studies have suggested that there are health benefits to these agents which seem to be driven by pharmacology that lies outside of that recognized in their primary indications. In the preclinical setting, both compounds have been reported as extending lifespan in mice, but these findings have proven controversial. Metformin improves insulin sensitivity, so it seems reasonable to assume that metformin reduces the risk of cellular damage and oxidative stress by improving cellular homeostasis. On a more global level, improved glycaemic control will reduce the emergence of some cardiovascular disease and peripheral nerve damage. The immunosuppressive effects of rapamycin can be theoretically linked to a dampening of inflammaging, however it seems that the agent may have a more cryptic pharmacological effect associated with improving energy homeostasis in cells.

The bisphosphonates are a group of compounds used clinically in the treatment of osteoporosis, but there are observational studies emerging from the clinic suggesting that they could have beneficial effects on human health beyond that associated with bone homeostasis.

Collectively, these widely used agents may have uncovered key pathways in which to focus efforts to identify more potent or selective agents to address cellular aging. What is required is a deeper mechanistic understanding of the cellular pharmacology of these drugs to determine where best to intervene. A key approach to address this is the possibility of using phenotypic screens in cellular models which capture one or more of the hallmarks of aging, to determine modes of action of known agents. In addition, such models can also be used in a blind fashion to screen libraries of compounds to uncover completely novel pathways and identify agents that may be beneficial.

One of the big challenges in the search for treatments to improve healthspan is having robust endpoints by which to measure efficacy. Clearly extension in chronological time to death provides a very clear endpoint, but it seems likely that clinical trials aimed purely at increasing longevity are a long way off. As such, there is a growing need to accurately measure biological age, as chronological age fails to capture the heterogeneity of signs and symptoms with which people age. For example, we probably all have family members who we think look and behave much younger than we know their chronological age to be. How do we measure healthspan in the context of a clinical setting? How do we define quality of life? These are big challenges but we do have the ability to measure directly improvements in, for example, heart or liver function, muscle strength, mobility, cognition and the performance of the immune system. It seems probable that the identification of pharmacological agents that improve healthspan will be found via exploration in multiple surrogate indications where hard endpoints can be measured and beneficial or detrimental effects become clear.

We need to continue to develop biomarkers and translational strategies which are able to inform us of whole-body cellular ‘health’ and with the gathering interest in this area, we will likely have an increasing array of tools to more accurately assess biological age over time.

However, we should always remember that patients don’t care about biomarkers. They are interested in whether they ‘feel’ better, i.e. can meet their basic needs, whether they can learn and grow and make decisions, can be mobile, build and maintain relationships and contribute to society. That is the patient’s perspective which is encapsulated perfectly in the goals as stated by the WHO.

So, while there is a growing understanding of potential ways we can measure and improve healthspan, there are some challenges in clinical development of novel anti-aging compounds. Study subjects may be aged but otherwise healthy, leading to ethical considerations associated with treating healthy patients in a preventative manner. There is no regulatory path at present, and there is the fundamental question of who is going to pay for agents that improve healthspan. Currently there is an argument over whether old age can be regarded as a disease or not. This is irrelevant as approval of any novel agents or use of an existing therapeutic in an age-related condition will require properly controlled, randomized clinical trials. Given the likely heterogeneity in such a trial population and the differing rates at which individuals age (i.e. manifest the hallmarks of aging), the trials will need to be large and long in duration. There would be parallels to the many trials in Alzheimer's disease, where the cost is enormous and efficacy hard to find. Moreover, it seems probable that like the thinking around AD, treatments should start early before symptoms appear. An additional confounder is the likely variations in ADME in individuals. We know elderly subjects often have reduced hepatic and renal function which could introduce significant variability in the exposure to novel agents.

We can meet these challenges as we believe there is significant will within society to succeed. We all share the common goal of living long and healthy lives.

If you’d like to hear how Evotec has developed capabilities to measure the hallmarks of aging which can support efforts to identify novel agents to treat age-related disease then reach out to us. You can also learn more from our webinar "Therapeutic approaches for aging and age-related diseases" by Steve England, SVP, Head of in vitro Biology and Disease Area Lead for Aging and Senescence at Evotec.

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Learn more about fully integrated development at Evotec.

Evotec is a fully-integrated drug discovery and development partner, providing a comprehensive source of high quality scientific solutions with consultant-level expertise to our partners, which includes fully integrated research and development as well as clinical development through to Proof of Concept.

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Autotaxin (ATX) is a secreted glycoprotein that hydrolyzes lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA). LPA signalling directly modulates tumour cell function and contributes to the development of the fibrotic tumour microenvironment, resulting in reduced host immunity and impaired response to therapy.

iOnctura, a clinical-stage oncology company, based in Switzerland (Genève), targeting core resistance and relapse mechanisms at the tumor-stroma-immune interface, has developed a potent and orally available autotaxin inhibitor, IOA-289, as a novel treatment for pancreatic cancer and other highly fibrotic tumours.

The first Phase I clinical study in healthy volunteers has been successfully completed. Evotec is very proud to have actively contributed in conducting the trial and analyzing the results that led to the achievement of this exciting goal.

Read the poster presented by iOnctura at the ESMO Immuno-Oncology Congress held in December 2021 to learn more about IOA-289 and its activity as autotaxin inhibitor. IOA-289 was also presented by iOnctura at the recently held AACR Annual Meeting in New Orleans.

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Chemoprophylaxis is a well-known strategy to prevent infectious diseases in populations at risk, e.g., in malaria, tuberculosis, or Neisseria meningitidis. Therefore, it is also being discussed for other diseases, such as Chikungunya virus (CHIKV) infection. This disease is spread by Aedes mosquitoes and leads to acute febrile illness, as well as to inflammation and disabling pain in the joints. While the acute fever often resolves within days, musculoskeletal, arthritis-like symptoms can persist for months and years, leading to a substantial burden of disease in tropical and subtropical areas.

There is a need not only for therapeutic, but also prophylactic treatments against Chikungunya disease – like those available for malaria. However, the design of clinical trials is complex as Chikungunya outbreaks are challenging for studying interventions: They are unpredictable in time and place, spreading rapidly, but with usually short life-spans and differential diagnosis is complex, so that there is a high risk that the outbreak is over before a trial can be conducted.

However, there is a potential solution, following evidence on the risk of secondary household infections in chikungunya outbreaks. Household transmission is well-known from respiratory viruses transmitted via aerosols. At first glance the transmission via a mosquito seems not comparable to the transmission mode of airborne viruses, but it is known that the main vector, Aedes mosquitos, has a very limited flying range, resulting in spatial microclustering of CHIKV outbreaks: household members and near neighbors have the highest risk of secondary infections. Therefore, enrolling such a high-risk population could allow for a more feasible, smaller, shorter and conclusive trial.

Evotec teamed up with scientists from Aarhus University (Denmark), the Institut Pasteur du Cambodge (Phnom Penh, Cambodia), the Fundação Oswaldo Cruz, (Salvador, Bahia, Brazil), and the Instituto Nacional de Infectologia Evandro Chagas-Fiocruz (Rio de Janeiro, Brazil) to develop an innovative chemoprophylaxis trial design for CHIKV.

As a first step, such a trial requires a surveillance study design to determine household secondary attack rate. For this study, index cases need to be identified by RT-PCR to confirm a CHIKV infection, followed by serosurveillance of household members. There is a caveat as household secondary attack rates may not be accurately predicted from one chikungunya outbreak to another. Therefore, estimates of household secondary attack rates from different countries and cultural environments are needed.

The objective of such a study will be first to establish a range of estimates around which the feasibility of prophylaxis trials can be evaluated and a sample size calculated. Subsequently, evidence-based prophylaxis trials can be conducted based on the estimated rate of secondary household infections.

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Learn more about how our INDiGO-Select services help in profiling and selecting your optimal clinical development candidate with:

• Enhanced quality profile, speed of delivery, and probability of success of clinical candidates
• Early identification of developability gaps and liabilities in selection process, enabling thorough
  de-risking of your candidate with flexible advanced lead optimization approaches
• Managed by skilled discovery scientists and complemented by experienced drug development
  experts in CMC and preclinical development all under one roof

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