Science Pool

Orphan drugs are defined by regulatory authorities as diseases that affect fewer than 200,000 patients in the US, or no more than five in 10,000 people in the EU. These diseases are often genetic and therefore lifelong conditions, typically affecting patients from very early age on.

While financial incentives and flexible regulatory framework present a wealth of opportunities for developers, the complexities around developing drugs for small patient populations can present significant additional challenges for sponsors. But what are the challenges facing developers of drugs for orphan diseases beyond financial and regulatory issues, and how can these be overcome?

A key challenge is understanding the regulatory and financial framework for orphan drugs in different regions. The following table provides an overview of the European, US and Japanese markets:

Another major challenge is the lack of information that is often known about individual conditions and their disease mechanism. This, in turn, makes it very difficult to assess the right endpoints for clinical trials. In addition, the success of clinical trials in orphan diseases is also hampered by the identification of countries with a sufficient number of study participants and suitable study centres with the capabilities to conduct the required type of trial and ensure proper patient retention throughout the trial. Therefore, although orphan drugs might seem a safe and attractive bet at first glance, the implementation of successful drug development programs can be tricky.

The support of an experienced orphan drug development partner can significantly increase the chances of success. Building on a wealth of long-term orphan drug development expertise, Evotec´s tightly integrated approach and culture of close collaboration ensures that development challenges can be solved, and innovative products can be delivered at demanding timelines. By implementing the right strategies and putting careful de-risking plans in place, it is possible to overcome the challenges associated with orphan drug development to put safe and effective medicines in the hands of the patients who need them. 

Evotec is the right partner to support orphan drugs product development because the Company has GMP facilities approved both for clinical and commercial batches manufacturing well suited for the small amounts of active ingredient and drug product required in this field.

Find out more about Evotec´s orphan drug development and manufacturing capabilities:

API Capabilities
Development Manufacturing
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Stem cells are undifferentiated or partially differentiated cells that can proliferate indefinitely and give rise to various types of specialised cells. They are, therefore, very interesting for therapeutic purposes. In 2006, Shinya Yamanaka’s lab in Japan demonstrated that the introduction of four specific transcription factor genes, now known as Yamanaka factors, could convert differentiated, somatic cells into pluripotent stem cells (also known as iPS cells or iPSCs). For this discovery, Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon, honouring their findings that mature cells can be reprogrammed to become pluripotent.

The iPSC technology holds great promise in the field of regenerative medicine. iPSCs represent an invaluable source of cells, e.g. to replace lost, damaged or diseased cells. Specifically, iPSCs have significant potential in disease areas with high unmet medical need, e.g. neurodegenerative diseases such as Alzheimer’s, ALS or Huntington’s or conditions such as diabetes or age-related macular degeneration (AMD). In these indications, the application of iPSC-based models represents a paradigm shift in developing desperately needed new therapies.

Why iPSCs?

Compared to previous models, patient-derived iPSCs are more physiologically relevant and better suited for modelling disease pathophysiology and for understanding a drug’s mechanism of action. Therefore, iPSC-based high-throughput screening approaches provide unique opportunities as a tool for disease modelling and predicting drug efficacy. This is especially important in complex, age-related or genetic indications such as neuronal diseases. Moreover, patient-derived iPSCs may eventually be utilised to stratify patient populations for clinical trials - a key success factor for electing better and safer drugs for clinical development in disease areas with high unmet clinical need.

iPSCs at Evotec

Evotec has built one of the largest and most sophisticated iPSC platforms in the industry. The platform has been developed over recent years with the goal to industrialise iPSC-based drug screening in terms of throughput, reproducibility and robustness to reach the highest industrial standards, and to use iPSC-based cells in cell therapy approaches via the Company’s proprietary EVOcells platform.

While culturing and differentiating iPSC-derived cells in a reproducible manner at industry scale used to be a challenge in the past, Evotec has succeeded in establishing scalable and robust protocols that allow a stable production of specific disease-relevant cell types. This includes generation of a cell bank of fully validated iPSC lines, upscaling of iPSC culture and differentiation protocols to industry standards, as well as automation of iPSC-derived cultures - all meeting the highest quality control standards.

In addition to phenotypic screening, Evotec has developed more complex models, such as co-cultures of multiple cell types or microfluidic organs-on-a-chip approaches, which enable interaction between different cell types. These systems allow the modelling of human diseases under conditions that closely resemble the physiological environment.

Smart Partnerships

Evotec has entered into several long-term partnerships that leverage the Company’s iPSC platform to develop highly relevant disease models, e.g. with Bristol Myers Squibb (formerly Celgene) in neurodegeneration (2016), and with Centogene in rare diseases (2018).

In its TargetRD project in collaboration with Centre for Regenerative Therapies TU Dresden, Evotec is using the advances in iPSC technology to generate iPSC-derived Retinal Pigment Epithelium cells from patients with retinal degenerative diseases to accelerate drug discovery.

Read our DDup on iPSC-Based Drug Discovery

Read our DDup focused on iPSC-Based Drug Discovery and Retinal Disease

 

The idea of targeting messenger RNAs for therapeutic purposes to shut off the translation of proteins dates back to 1978 when researchers discovered the first antisense oligonucleotide, an oligonucleotide complementary to the viral RNA of Rous sarcoma virus. It was capable of binding to the viral mRNA and thereby inhibiting viral replication and protein synthesis.

Meanwhile, a lot of short single-stranded antisense oligonucleotides made from natural or chemically modified DNA and RNA nucleotides have been developed. They all are designed to modify gene expression not only for inhibiting protein synthesis but also for altering RNA and/or reducing, restoring, and modifying protein expression through multiple molecular mechanisms such as splicing. Suppression of target expression is accomplished by binding of the antisense oligonucleotide to the target (pre)mRNA followed by degradation of this (pre)mRNA.

The pharmacology of targeted antisense therapy has provided the basis for translating it to the clinic. Chemical modifications of the oligonucleotides have enhanced the specificity, affinity and efficacy and reduced side effects. Optimisation of delivery and improved resistance to breakdown by nucleases, leading to precisely defined half-life, also have been accomplished. These improvements have brought research from bench to clinic. Additionally, the use of antisense oligonucleotides against long noncoding RNAs (lncRNAs), small interfering RNAs (siRNAs), micro RNAs (miRNAs), and ribozymes have also demonstrated preclinical and clinical responses in the treatment of deadly diseases like cancers.

Antisense oligonucleotides fill a position that is not or only insufficiently addressed by more traditional approaches. As an example, they can address targets undruggable by conventional strategies, e.g. targets that do not have a function or surface that can interact with small molecules or targets that are inaccessible for antibodies. They can also address challenging targets, e.g. targets that need to be addressed selectively as they possess high structural homology to other targets that should not be triggered to avoid unwanted side-effects.

Moreover, they have unique and well-characterized biodistribution and pharmacokinetics and can be manipulated by conjugation to targeting moieties. Also, there are many different administration routes, systemic treatments as well as local (e.g. intrathecal, intravitreal or inhalation) or ex vivo approaches to target cells in the cell therapy setting, e.g. to accomplish a transient target knockdown to improve the manufacturing process, the safety of the cell product or its efficacy.

Several antisense drugs have been approved, most against rare diseases such as Batten disease, cytomegalovirus retinitis, Duchenne muscular dystrophy, or spinal muscular atrophy. As of 2020, more than 50 antisense oligonucleotides were in clinical trials, including over two dozen in advanced clinical trials (phase II or III).

Evotec has considerable expertise in antisense therapy and in 2020 entered into a strategic partnership with antisense specialist Secarna Pharmaceuticals GmbH & Co. KG to build a co-owned antisense drug pipeline based on Secarna’s proprietary LNAplus™ platform. This third generation of LNAs allows to switch off gene expression of single disease-underlying genes in the cell.

The partnership aims to address a number of targets and complex indications, to establish a pipeline of co-owned antisense oligonucleotide therapies and to licence candidates to biopharmaceutical companies.

Learn more:

Antisense Oligonucleotides
Gene Therapy

Reaching IND stage is a major milestone for biopharmaceutical companies. For decades, the biotechnology industry has struggled to align complex functions towards the goal of getting to the clinic. The process is long, expensive, resource straining, and risky due to high attrition rates.

Recent industry benchmark data shows that neither the costs nor timelines of drug discovery have improved significantly in recent years - regardless of digital solutions and AI. Including the cost of attrition, it takes benchmark companies approx. $75 m just to achieve a single regulatory tox study start and still around 5.5 years to go from a target to an FGLP or IND.

Reaching IND Faster - A Significant Competitive Advantage

Evotec’s data shows that its integrated processes have led to high success rates and enabled reaching the IND milestone at around half the cost and in about 30% less time when compared with the above-mentioned benchmark. The approach has been validated by its own R&D activities and is increasingly demanded by its partners, too.

The reason is simple: time saving is very important, as the potential to reach IND 18 months faster than the competition adds real value in a competitive marketplace. This is especially true in a highly connected world, where many players are pursuing the same or similar scientific concepts.

The Solution: INDiGO

In order to provide a standardised, yet versatile solution to advance compounds to IND as a service for its partners and clients, Evotec has established INDiGO as a unique integrated, accelerated IND-enabling platform to reduce tech transfer times and costs. The platform is well-suited for a broad range of indications.

INDiGO offers interdisciplinary integration and expert coordination of all drug development activities under one roof. This enables unmatched timelines from candidate nomination to regulatory submission. The programme is led by experienced, dedicated project managers and drug development professionals, who are responsible for seamless knowledge transfer across disciplines, while maximising the quality of the overall development package and ensuring the highest quality standards.

INDiGO Highlights at a Glance

• More than 40 different functions across multiple disciplines
• Managed on an operational level by more than 100 experienced drug development professionals
• Industry leading timelines and excellent track record of on-time delivery
• > 35 completed programmes in the last 5 years
• High rate of client retention after first successful INDiGO programme

Learn more about:

INDiGO
Fast Tracked Drug Development in Just 37 Weeks

Cell Painting sounds like art for biologists, and indeed it is a tool that leads to colourful and often very aesthetic images. However, it is a serious and, above all, very useful technology. It provides researchers with a multi-parameter, image-based description of the cell response to any condition that perturbs the cell, e.g. the treatment with a compound, a silencing via siRNA, or CRISPR engineering.

Basically, it (https://www.nature.com/articles/nprot.2016.105) is a morphological profiling assay that multiplexes six fluorescent dyes, imaged in five channels, to reveal eight broadly relevant cellular components or organelles. Cells are plated in multi-well plates, exposed to the treatments to be tested, stained, fixed, and imaged on a high-throughput microscope. Next, automated image analysis can be used to identify individual cells and to measure up to 1,700 morphological features (size, shape, texture, intensity, etc) to produce a rich profile that enables the detection of subtle phenotypes.

Profiles of cells treated with different methods or compounds can be compared to suit many goals, such as identifying the phenotypic impact of chemical or genetic changes, grouping compounds and/or genes into functional pathways, and identifying signatures of disease. The assay offers single-cell resolution and is complementary to the Connectivity Map (https://clue.io/cmap), which characterizes cell population responses to perturbation using transcriptomics.

Evotec has implemented a robust Cell Painting workflow to allow for the study of several thousands of compounds, using automated process for cell treatment and labelling, image analysis, data processing and quality control. The Company now uses Cell Painting to support hit triage at the end of a High Throughput Screening in order to select series with optimised phenotypic characteristics, for example to avoid major off-target effect or keep some degree of biological diversity.

To further improve sensitivity of the assay, Evotec is currently testing different approaches:

• Use new combinations of markers, including multiplexing
• Replace well level by cell level analysis
• Use artificial intelligence for image analysis

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Curing paraplegia

In January 2021, researchers from Ruhr-Universität Bochum made headlines after publishing in Nature Communications that they had succeeded for the first time in enabling formerly paralyzed mice to walk. They had accomplished the feat by using gene therapy to transfer the gene for hyper-interleukin-6, a so-called designer cytokine, which does not occur in nature, to the brain of the animals. The gene was packed into Adeno-Associated Viruses (AAV) and the vector injected into the brain, where motoneurons and associated motion-related nerve cells started to produce this growth factor.

“Thus, gene therapy treatment of only a few cells stimulated the axonal regeneration of various nerve cells in the brain and several motor tracts in the spinal cord simultaneously,” said Dietmar Fischer, Professor at the Department for Cell Physiology at Ruhr-Universität Bochum and lead author of the study. “Ultimately, this enabled the previously paralyzed animals to start walking after two to three weeks. This came as a great surprise to us at the beginning, as it had never been shown to be possible before after full paraplegia.”

The development of gene therapy

This breakthrough, which might end paraplegia in injured humans, is just one of many successes accomplished with gene therapy. The approach has come a long way. Its basic concept – modifying human genes by introducing genetic material – was first proposed in 1972. After premature first attempts in the 1980s failed, the science greatly improved and in 2003 China took the lead by approving Gendicine, a recombinant Ad-p53 gene therapy for the treatment of head and neck squamous cell carcinoma (HNSCC)—a cancer that accounts for about 10% of the 2.5 million annual new cancer patients in China.

It took another 9 years until the EU followed with the approval of Glybera, a treatment for patients who cannot produce enough of an enzyme that is crucial for breaking down fat, and in 2017 the first gene therapies were approved in the U.S.: Luxturna to treat RPE65 mutation-induced blindness and Kymriah, a therapy for the treatment of B-cell acute lymphoblastic leukemia (ALL) which uses genetically engineered T cells of the affected patients. Since then, further gene therapies have been approved, e.g. Zolgensma and Patisiran, and hundreds of clinical trials are under way to test gene therapy as a treatment for genetic disorders, cancer, and HIV/AIDS.

The gene therapy market was valued at approx. $ 500 m in 2018 but is expected to reach > $ 5 bn by 2025 with an impressive CAGR of about 34%.

How does gene therapy work?

Gene therapies can work through several mechanisms, the replacement of a disease-causing gene with a healthy copy, inactivation of a disease-causing gene that is not functioning properly and the introduction of a new or modified gene into the body to help treat a disease. The latter approach was used in the study to heal paraplegic mice.

There are various methods for administering gene therapeutics. The most common approaches are the use of viral vectors (mostly AAVs and lentiviruses) to transfer the genes directly to the patient, or the modification of patient-derived cells in the lab with subsequent transfer of the modified cells back into the patient. Most approaches use performing gene insertions in vivo and ex vivo, respectively, but non-viral delivery systems are also being used.

Evotec´s gene therapy strategy

Evotec entered the gene therapy space in 2020 by establishing an alliance with Takeda, adding a team of 20 specialists by creating Evotec GT in Austria, where Takeda’s gene therapy operation GTCA (Gene Therapy Center Austria) is located.

Evotec GT is now an integral part of Evotec’s integrated drug discovery platform. Its services include

• the design of state-of-the-art viral AAV vectors,
• the generation of AAV material for research and non-clinical studies, 
• in vitroand in vivo proof of concept studies for target validation including screening of drug candidates, as well as
• the design, execution and interpretation of non-clinical gene therapy studies.

The services cover both in vivo and ex vivo gene therapy approaches. With this new unit, Evotec is now able to find the best potential drug candidate agnostic of modality for any given biology.

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COVID-19 related delay of clinical research - a shortage in novel drugs?

Among the many fallouts of the COVID-19 pandemic is a disruption of clinical research. Laboratories are closed, conferences have been cancelled, travel is restricted, supply chains for equipment have been interrupted, and resources have been lost. In particular smaller biotechs have or will incur losses as they have to considerably stretch their financial resources and can’t meet milestones.

The biggest effect has been on planned and already ongoing clinical trials of new drug candidates. Thousands of trials have been stopped or called off altogether (an unprecedented event with long-lasting effects on medicine). According to Michael Lauer, Deputy Director for Extramural Research at the US National Institutes of Health, about 80% of non-COVID trials in the U.S. have been interrupted or stopped. A recent world-wide research report by Informa Pharma Intelligence and Oracle Health Sciences revealed that the COVID-19 pandemic has led to longer enrolment timelines (49%), amended protocols (45%), and paused protocols (41%). Also, clinical trials have become more decentralised, i.e. the investigational medical product was shipped directly to the trial participant. 46% of respondents are planning or implementing such decentralised trials, 44% are considering new vendors, and 36% are considering new geographies for trial locations. However, this move is facing challenges such as patient monitoring and engagement, ensuring data reliability, quality, and data collection.

Most people are not aware how many participants and sites are involved in a clinical trial. Apart from the researchers and clinical doctors overseeing the trial and the patients, it’s caregivers and nurses, postgraduate researchers, postdocs, data scientists and people involved in funding and paperwork. Particular problems have been caused by the stress put on hospitals by the admission of so many critically ill patients and the necessity to avoid an infection of trial participants (or vice versa, as well as the staff at the trial sites).

Decentralising clinical trials

Regulators have been quick to react by changing their guidance so that physical distancing has been possible without compromising the safety of patients in testing and treatment. As an example, if possible, trial participants were provided with the test medication for a longer period of time, or the drug was distributed to their homes by a distributor so that they don’t need to visit the trial site – something that is called decentralisation of trials.

Decentralised trials, however, create problems in terms of compliance, medical control and data assessment. Solutions such as telemedicine have been known for a long time, but have not yet been implemented in clinical trials due to administrative and bureaucratic hurdles, cost and reimbursement.

Nevertheless, at least U.S. regulators have accepted patient evaluation and data sampling via remote solutions, either via email, phone calls or videoconferences or by tele-medical monitoring. The same approach has been applied to many COVID-related trials. Even completely decentralised trials have been conducted – from recruiting via social media to medication distribution to data collection. However, researchers have warned that several of these clinical trials lack control groups, have poorly defined endpoints, lack generalisability to those of a lower socioeconomic status or were designed too early in the pathophysiological course of the disease to result in substantive recommendations.

Creating a roadmap for the future of clinical research

The developments described above raise a lot of questions:

• Are design and data of trials conducted during the pandemic solid?
• Can self-reported outcome be equalled to an independent assessment by a specialist?
• Do online recruiting and telemedical assessment increase or decrease patient heterogeneity?
• What impact do concomitant COVID infections and stress caused by social distancing have on side effects and outcome?
• Can telemedicine be implemented in the clinical trial routine in the post-pandemic era to save costs?
• What else can be copied for the future?

At the same time, it is clear to researchers in academia as well as in industry that the way clinical trials are conducted is outdated in many aspects and overly burdened by red tape. Conducting trials can and should be improved and modernised to benefit patients, clinicians, and researchers. Therefore, the pandemic may act as a catalyst for positive changes in terms of recruitment, monitoring and innovation to create a more efficient, integrated research platform for the future.

To discuss your project, contact:

info@evotec.com

In January 2020, the US FDA finalised its 2017 draft regulatory guidance for industry on in vitro DDI studies by publishing the In Vitro Drug Interactions Studies – Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry. This document outlines how experimental in vitro studies should be carried out and provides instruction on how results should be used to determine potential clinical DDI risk.

Functionally, very little has changed between the draft guidance of 2017 and this final version, mainly consisting of clarifications with very few additional requirements. In this blog, we take a closer look at the small differences there are and explain how they impact on data interpretation for in vitro regulatory DDI studies.

In covering the differences from the draft version of the guidance, we will explore metabolism-mediated drug interactions including CYP inhibition, CYP induction and substrate identification (reaction phenotyping) studies, and then discuss transporter inhibition and transporter substrate studies.

Metabolism Mediated Drug Interactions

Initially, the guidance now promotes the investigation of in vitro metabolic studies before conducting first-in-human studies to better inform the necessity and design of clinical PK studies. Further clarifications are focussed on CYP inhibition, induction and enzyme substrate identification.

CYP Inhibition: One of the changes in terms of metabolism mediated drug interactions relates to CYP inhibition where the FDA has indicated that IC₅₀/2 can be used as an estimate of K_i for reversible inhibitors if the probe substrate concentration used is at the K_m for the CYP enzyme. This suggests that assessing Ki may no longer be necessary under these conditions – saving both time and cost in DDI assessment. Of further note is that the K_i and K_I have been corrected to K_i,u and K_I,u to highlight the fact that the unbound values should be used in the calculations.

CYP Induction: The assay design remains the same but the FDA has provided more detail on the data interpretation for CYP induction studies, in particular, for the fold change method. For example, CYP induction is presumed if a concentration-dependent increase in CYP mRNA is observed which is ≥ 2-fold the vehicle control at the expected hepatic concentrations of the drug. The guidance proposes 30-fold of mean unbound maximal steady state plasma concentration at the therapeutic dose as an estimation of the expected hepatic drug concentration. It also recommends, that even if the induction is less than 2-fold, induction potential cannot be ruled out if the increase in CYP mRNA is greater than 20% of the positive control. The alternative methods for calculating CYP induction risk (basic kinetic R3 model and correlation methods) have remained similar to the previous draft guidance.

Enzyme Substrate Identification: In terms of substrate studies, very little has changed, the guidance has extended the panel of possible non-CYP enzymes to consider if CYPs are not found to contribute towards metabolism. These additional enzymes include aldehyde oxidases (AO), carboxylesterases (CES) and sulfotransferases (SULTs) in addition to other non-CYP Phase I and Phase II enzymes.

Transporter Mediated Drug Interactions

Transporter Inhibition: The main change to highlight relates to the basic static equation cut-off for the MATE transporters which has now increased to 0.1 and falls in line with the existing cut-off for the other renal transporters (OATs and OCT2). This amended cut-off is more relaxed than the previous guidance and will reduce the likelihood of investigational drugs being flagged as potential in vivo MATE inhibitors. Another welcome change is the removal of the suggested 30 min pre-incubation time for the duration of the inhibitor pre-incubation step for OATP transporters. This omission recognises research performed by Cyprotex demonstrating that a shorter inhibitor pre incubation time of 15 min is adequate for assessing correct OATP inhibition as no statistically significant difference in IC₅₀ existed following a 15 min or 30 min inhibitor pre-incubation step. Finally, one notable addition to the P-gp and BCRP inhibition guidance is the specific consideration of investigational drugs administered through the parenteral route or of systemically circulating metabolites acting as inhibitors. In these circumstances, a different basic static equation is used to determine DDI risk, namely I₁/IC₅₀ (or K_i) ≥ 0.1, where I₁ is the total C_max of the inhibitor drug or metabolite.

Transporter Substrate Identification: Last but not least, both assay design and data interpretation remain relatively unchanged from the draft guidance for transporter substrate studies.

In summary, the majority of the amendments to the draft 2017 guidance focus on the data analysis stage rather than assay design stage. The main changes affect transporter inhibition studies where new cut-offs have been specified for the MATE transporters. One unexpected amendment relates to the use of IC₅₀/2 as an estimate of K_i for reversible CYP inhibitors, potentially reducing the reliance on K_i studies.

With over 20 years’ experience conducting DDI studies, Cyprotex have a team of experts who can guide you through the process and assist in the planning, execution and interpretation of these regulatory studies. Our popular ADME and DDI guides have also been updated to reflect the 2020 guidance and help you further understand why, when, and how to perform these studies.

Contact enquiries@cyprotex.com to discuss your DDI study

updated ADME and DDI guides

Given the arrival of SARS-CoV-2 vaccines, why do we still need therapeutics?

After more than a year into the COVID-19 pandemic, vaccines against the new coronavirus are all over the news. However, there is still a long way to go until people have been vaccinated worldwide, and as yet it is not clear how long the protection will last and whether the different vaccines will protect against re-infection and/or infection against mutated viruses.

Therefore, it is clear that even in 2021 and beyond millions of people will get infected by the virus and many thousands will become critically ill and require medical treatment.

Strategies for making SARS-CoV-2 therapeutics broadly available

Similar to vaccines, biopharmaceutical companies all over the world are trying to develop medications to combat Sars-CoV-2 infections: some are trying to repurpose existing drugs, others are developing small molecules or biologicals such as antibodies against a variety of targets – viral as well as cellular.

Evotec is also participating in this worldwide effort – but with a twist. The goal is to develop a monoclonal antibody that is not only effective, but can also be produced at low cost so that it is ideally suited to be administered even in the world’s poorest countries. And if all goes well, Evotec will also provide small, efficient manufacturing sites that can be operated all over the world.

Already in April last year, Evotec´s U.S. subsidiary Just - Evotec Biologics, Inc. entered into a partnership with Ology Bioservices, Inc. to evaluate and characterize antibodies against SARS-CoV-2. A few months later, in July, Just – Evotec Biologics was awarded up to $ 18.2 m by the U.S. Department of Defense for the development and manufacturing of monoclonal antibodies that might be able to prevent or treat COVID-19. And in September last year, the Bill & Melinda Gates Foundation joined in by granting another $1.9 million to develop and manufacture monoclonal antibodies at lowest possible cost of goods for the prevention of severe COVID-19 in vulnerable populations in low- and middle-income countries.

The concept of decentralised, affordable drug manufacturing

Just – acquired by Evotec in 2019 – was founded in 2015 in Seattle by former Amgen employees with the goal to make the entire manufacturing process of biotherapeutic drugs more efficient and affordable – not only by lowering development costs, but also by establishing smaller, more efficient manufacturing sites. The initial therapeutic focus was on anti-infectives, as infections constitute the biggest problems in poor countries that often don’t have enough money to purchase lifesaving drugs or to support their manufacturing, so lowering the costs of developing and producing anti-infectives are of great importance.

To accomplish this goal, Just is using artificial intelligence and an entirely data-driven drug discovery and development process. Its J.DESIGN technology platform integrates the discovery and optimization of drug candidates, process and product development, and manufacturing with the goal of providing a product that can be manufactured at low cost of goods. Using large, diverse data libraries and machine learning, the platform from the outset screens and designs biologics that can be developed and manufactured under the most favourable development conditions.

The know-how of the company comprises cell line development, upstream bioreactor design (fed-batch or continuous), and the development of downstream purification, analytical methods, final drug product, formulation, and long-term storage.

Just – Evotec Biologics also has developed a small, flexible, low-cost facility solution to biotherapeutics manufacturing called J.POD. This facility can be installed easily wherever production is needed.

As infectious diseases are on the rise across the globe and SARS-CoV-2 will unlikely be the last pandemic affecting the human population, the approach developed by Just - Evotec Biologics will become even more important in the future.

Interested in learning more?

Just- Evotec Biologics´ technologies and services are being offered to clients and partners interested in the fast and cost-effective development of biologics.

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Cytochrome P450 (CYP) induction plays an important role in the pharmacokinetics of a drug and can have consequences for drug efficacy through the reduction of plasma half-life, or drug toxicity if elevated levels of toxic metabolites are formed. These effects are commonly observed when one drug has an effect on a co-administered medication – a term known as drug-drug interactions or DDI.

Transcriptional gene activation, mediated by nuclear receptors such as the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), is the most common mechanism of CYP induction. These receptors correlate directly to the expression of CYP1A2 (AhR), CYP2B6 (CAR), and CYP3A4 plus the CYP2C enzymes (PXR). Therefore, receptor activation can be used as an early indicator of potential changes in CYP enzyme expression.

A less common mechanism for CYP induction is through mRNA or enzyme stabilisation. In this case, certain drugs don’t necessarily stimulate CYP enzyme expression, but rather, slow down CYP protein degradation.

In drug discovery, cell-based transactivation assays can be used for identifying CYP induction potential. In this assay, stably or transiently transfected cell lines containing the nuclear receptor to be evaluated and reporter gene vectors are used. Activation of the response elements following receptor heterodimerisation serves as a suitable proxy for CYP induction. Results are typically reported as E_max and EC₅₀, or a concentration-dependent fold activation relative to vehicle control.

For more advanced drug development, such as IND-enabling studies and NDA submission, CYP induction is typically evaluated as part of a more extensive DDI package. At this stage, cryopreserved human hepatocytes are the preferred model with at least three donors assessed to account for inter-individual variability in response. The hepatocytes are typically incubated with the test compound over 48 to 72 hours, and CYP enzyme induction is evaluated by measuring mRNA levels and/or measuring the catalytic activity of an isoform-specific probe substrate. Because mRNA detection isn’t subjected to the masking effects of time dependent inhibition, regulatory authorities such as the US FDA and EMA recommend this method. However, if protein stabilisation is expected, catalytic activity analysis should also be conducted. Once again, results are typically reported as an E_max and EC₅₀, or concentration-dependent fold increase in response relative to the control. In addition, measurement of test compound over several time points on the last day of incubation is encouraged.

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