Science Pool

In the complex world of biopharmaceutical development, Chemistry, Manufacturing, and Controls (CMC) activities are critical yet often fraught with challenges. Just-Evotec Biologics offers a suite of innovative solutions designed to mitigate these risks, with their J.MD™ Molecular Design service standing out as a key player in this arena.

The Role of J.MD™ Molecular Design

The J.MD™ Molecular Design service is part of Just-Evotec Biologics’ comprehensive J.DESIGN™ platform, which integrates advanced computational tools and high-throughput methodologies to streamline the development process. This service focuses on selecting an optimal lead and optimizing the molecular design of biologics to ensure manufacturability, stability, and efficacy from the earliest stages of development.

Evaluating Early Team Supply Material

One of the primary ways J.MD™ helps derisk CMC efforts is by evaluating early team supply material produced in stable pools. This early biophysical characterization is crucial for identifying potential issues that could arise later in the development process. By addressing these issues upfront, Just-Evotec Biologics helps partners avoid costly and time-consuming setbacks.

Derisking the CMC Journey

The CMC journey involves numerous stages, from initial development to production-scale manufacturing. Each stage presents unique challenges that can impact the overall success of a biopharmaceutical product. Just-Evotec Biologics’ J.MD™ service helps derisk this journey in several ways:

• Predictive Computational Tools: The Abacus™ tool within the J.MD™ toolbox uses predictive algorithms to assess the manufacturability and stability of different molecular variants. This allows for the selection of lead candidates with optimal properties, reducing the risk of failure in later stages¹.

• High-Throughput Screening: By leveraging high-throughput screening methods, J.MD™ can rapidly evaluate multiple variants, accelerating the development timeline and ensuring that only the most promising candidates move forward².

• Integrated Development Approach: The J.MD™ service is part of a larger, integrated approach that includes cell line development, process optimization, and continuous manufacturing. This holistic approach ensures that all aspects of the CMC process are aligned and optimized for success³.

• Regulatory Support: Just-Evotec Biologics also provides comprehensive regulatory support, helping partners navigate the complex landscape of biopharmaceutical regulations. This support is crucial for ensuring that products meet all necessary standards and can be brought to market efficiently⁴.

Conclusion

In summary, Just-Evotec Biologics’ J.MD™ Molecular Design service plays a pivotal role in derisking CMC efforts for biopharmaceutical partners⁵. By evaluating early team supply material, leveraging predictive computational tools, and integrating a comprehensive development approach, J.MD™ helps ensure that the CMC journey is as smooth and successful as possible. This not only saves time and resources but also increases the likelihood of bringing effective and safe biopharmaceutical products to market.

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References

1. Just-Evotec Biologics’ Abacus™ tool 
2. High-throughput screening methods
3. Integrated development approach
4. Regulatory support
5. Derisking CMC efforts for biopharmaceutical partners

Understand if your investigational drug has the potential to be a perpetrator (precipitant) of transporter-mediated drug-drug interactions by evaluating if it is an inhibitor of drug transporters.

Read our fact sheet to learn more about our transporter inhibition service.

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Understand if your investigational drug is a potential victim (object) of transporter-mediated drug-drug interactions by evaluating if it is a substrate of drug transporters.

Read our fact sheet to learn more about our transporter substrate identification service.

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Learn more about how Cyprotex can support you in the design, implementation and interpretation of drug-drug interaction (DDI) studies according to regulatory guidance including the ICH M12 harmonized guideline.

Read our DDI fact sheet to find out more.

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Learn more about how Cyprotex can support you in understanding the metabolism of your compounds by identifying which metabolites are formed during in vitro and in vivo studies.

Read our fact sheet to learn more about our metabolite profiling and identification service.

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Targeting RNA represents a paradigm shift for drug discovery. The ability to seek out and destroy, or modify, a faulty RNA template, before the toxic protein has even been made, has only recently begun to be harnessed for the benefit of patients. 
At the time of writing, 21 Oligonucleotide drugs have been approved for human use, with an exponential increase in clinical trials and development projects involving this new modality. 
There exist several different mechanisms of action for Oligonucleotide drugs, all of which are transient and reversible and do not lead to alteration of patient DNA, unlike Gene therapy. 

Antisense Oligonucleotides harness endogenous systems already existing within a cell to achieve their purpose, with the only limitation being accessibility of the target tissue.
Once bound with great specificity to its RNA target, a short synthetic Oligonucleotide can trigger degradation, upregulation of the translated protein, or alteration of a splicing event leading to a correctly folded protein. Longer Oligonucleotides can fold into 3 dimensional shapes called Aptamers with similar target affinities and applications as antibodies, and shorter Oligonucleotides can act as MicroRNA   mimetics or antagonists to alter multiple targets or pathways concurrently with subtle but broader effect. 

The precision of an Oligonucleotide and its ability to correct a faulty RNA produced by an error in the genetic code, lends itself to applications in the fields of rare disease therapeutics and toxic gain of function mutations. The field of Oligonucleotide therapeutics is developing to address this as a whole and to pioneer a new preclinical and regulatory path that could be adapted for these unique disease biologies to make this type of therapeutic innovation more accessible. 

Evotec is a leader in integrated end-to-end Research and Development and has built substantial drug discovery expertise and technical capabilities that can drive new innovative and diverse modalities into the clinic. In addition, Evotec has developed a deep internal knowledge base in key therapeutic areas including neuroscience, pain, immunology, respiratory, women’s health, aging, fibrosis, inflammation, oncology, metabolic and infectious diseases. Leveraging these skills and expertise, Evotec successfully delivers on superior science-driven discovery and development alliances with pharmaceutical and biotechnology companies.

The global interest in this new modality area has led to high demand in Oligonucleotide synthesis and related chemistry applications, from modified Oligonucleotides to conjugates and complex formulations. 
Evotec offers Oligonucleotide research and development capabilities as well as ligand and linker chemistry expertise to support projects from discovery through to development.

In particular, since 2015 the discovery chemistry group is equipped with MerMade 48X synthesizers (Biosearch Technologies, see Fig. 1) with associated purification, post processing and QC platforms (at the Evotec sites of Toulouse and Verona, see Fig 2), while the development team, since 2022, is equipped with a Cytiva ÄKTA oligosyntTM synthesizer associated to the ÄKTA pureTM 150 and ÄKTA flux 6 purification platforms and with a Virtis Lyophilizer at Evotec’s state-of-the-art Verona site (see Fig. 3 to Fig. 6).
	Figure 1: Biosearch MerMade 48X	Figure 2: Agilent Preparative HPLC for purification
	Figure 3: Cytiva ÄKTA oligosyntTM	Figure 4: Cytiva ÄKTA pureTM 150
	Figure 5: Cytiva ÄKTA flux 6TM	Figure 6: SP Virtis Advantage Pro Lyophilizer
	Figure 7: UPLC with a Thermo ScientificTM Orbitrap ExplorisTM 120 mass spectrometer for oligonucleotides characterization

This fully integrated suite of capabilities allows for the synthesis, purification, isolation, and quality control of complex modified Oligonucleotides (ASOs, siRNAs, etc) on a scale from milligrams up to 25 g (up to 12 millimoles). The objective is to support Oligonucleotide drug discovery and development projects from the earliest phases of discovery, such as the generation of screening libraries, up to the selection of a preclinical development candidate followed by manufacture and release of material to support initial preclinical development studies. 

All these activities are supported by an experienced Oligonucleotide chemistry team operating across two sites and at different scales, to ensure flexible support for projects with highly efficient information and process transfer.
Evotec capabilities also include expert analysts for Analytical Development and QC, capable of developing and validating the analytical procedures needed for a full characterization and routine testing of Oligonucleotide drug substances up to and including IND enabling studies. In addition, Evotec’s support can encompass the release of preclinical batches according to regulatory requirements, including stability and formulation studies.

The journey to commercialization can be challenging. Scaling up production while maintaining process consistency, product quality, and regulatory compliance, requires expert process development capabilities, and the adoption of innovative science and risk management methodologies. A common pitfall for the Sponsor of an innovative therapy is to under-estimate the complexity and intricacy of this enterprise, which involves the coordinated optimization of strategies for process control, risk management, data management, and supply chain management.

With ever-evolving regulatory requirements and the increasing urge to shorten drug development timelines, getting your drug to market can seem like a daunting undertaking. That’s why taking some of the pressure off your organization by outsourcing your drug development and manufacturing activities to an expert partner can be the smartest decision. This will ensure your drug is commercialized in the fastest and most cost-efficient way possible, utilizing expertise, facilities, equipment, and processes to anticipate and overcome any challenges thrown at your program with ease.

Evotec offers an integrated end-to-end solution for innovative drug R&D, with the capabilities to support all phases of your drug development program. Your projects are in safe hands with our team of expert scientists who are pioneers in QbD, process design, scale-up, and validation, operating to full cGMP within FDA, MHRA, AIFA and BfArM approved facilities.

Our experts are just a click away! 

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Don’t miss our educational webinar series on “Oligonucleotides Therapeutics: Discovery to Development”

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The long-awaited ICH M12 harmonised guideline on drug interaction studies was adopted on 21^st May 2024. It is just a matter of time before it is implemented by the main regulatory agencies – in fact, the European Medicines Agency has already reached Step 5 of the process and announced that the guideline will come into effect on 30^th November 2024. Therefore, it is essential companies are prepared for the change and know how the ICH M12 guideline differs from earlier guidance/guidelines so data can be collected and analysed correctly according to the new recommendations.

Cyprotex has produced some easy-to-follow flyers which highlight the key differences between existing guidance/guidelines from the US FDA, European Medicines Agency (EMA) and Japanese PMDA and the new harmonised ICH M12 guideline. These will help you get started on the transition process.

US FDA vs ICH M12 Flyer

European Medicines Agency (EMA) vs ICH M12 Flyer

Japanese PMDA vs ICH M12 Flyer

Cyprotex is a centre of excellence for drug-drug interaction (DDI) studies. Our highly experienced team provide consultancy and guidance, and support you with the design, implementation and interpretation of in vitro DDI studies according to the regulatory guidance/guidelines, including the new ICH M12 guideline.

Discuss your project with us:

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The new ICH M12 guideline harmonises drug interaction guidance from the major regulatory authorities. It is expected that the ICH M12 guideline will be implemented by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and presumably replace their existing guidelines/guidance. In this blog, we explore the differences in the in vitro studies between the new ICH M12 guideline adopted in May 2024 and the Japanese PMDA guideline from 2018. You may also be interested in our blogs comparing with the US FDA 2020 guidance (LEARN MORE), and the EMA 2013 guideline (LEARN MORE) to the ICH M12 guideline.

Reaction Phenotyping

The new ICH M12 and the PMDA guidelines are similar in terms of their recommendations. Both have the same cut-off of ≥25% of total elimination for determining if the enzyme needs further investigation in a clinical study. The ICH M12 suggest investigating a larger range of phase II enzymes if the investigational drug is not metabolised by the main CYP enzymes whereas the Japanese PMDA only specifically name UGT enzymes for phase II.

Enzyme Inhibition

For enzyme inhibition, both the ICH M12 and PMDA guidelines recommend evaluating the main seven CYP isoforms for enzyme inhibition as well as UGT inhibition if one of the major elimination pathways of the investigational drug is direct glucuronidation. However, the ICH M12 suggests evaluating a larger panel of UGT isoforms (UGT1A1, UGT1A4, UGT1A9, UGT2B7 and UGT2B15) compared to the PMDA guideline which suggests only UGT1A1 and UGT2B7 inhibition.

For reversible inhibition, the cut-off for determining if a clinical study is required is the same in both guidelines using the basic model. However, for time dependent inhibition, 5x C_max,u is used in the calculation in the ICH M12 whereas 50x C_max,u was used in the 2018 PMDA guideline, suggesting a less conservative approach is now being used in the new ICH M12 guideline. Interestingly, the PMDA guideline also recommended a different cut-off for CYP3A in the GI tract for time dependent inhibition – this is not covered in the new ICH M12 guideline.

Enzyme Induction

The ICH M12 and the PMDA guidelines are similar in terms of CYP induction. The equation for the relative induction score is the same in both guidelines. Similarly, the basic kinetic model cut-offs are the same for both the ICH M12 and PMDA guidelines.

Transporter Substrate Identification

Both guidelines recommend that the same transporters are assessed. The method for testing and cut-offs for clinical assessment are very similar between the PMDA and ICH M12 guidelines.

Transporter Inhibition

For transporter inhibition, the ICH M12 and PMDA guidelines are the same in terms of the cut-offs. The only omission from the PMDA is that it only considers the oral route for P-gp and BCRP inhibition whereas the ICH M12 also considers the parenteral route for these transporters.

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Read about the newly adopted harmonized drug interaction guideline including:

• An overview of the key highlights of the new ICH M12 harmonized guideline on drug interaction studies (2024)
• A comparison with the Japanese PMDA guideline on drug interaction for drug development (2018)

LEARN MORE

DOWNLOAD OUR HANDY COMPARISON SUMMARY

The new ICH M12 guideline on drug interaction studies provides a harmonised approach which is expected to be implemented by the major regulatory authorities including the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), and presumably replace their respective existing guidelines/guidance. In this blog, we explore the differences between the new ICH M12 guideline adopted in 2024 and the previous EMA guideline which came into effect in 2013. You may also be interested in our blog comparing the US FDA 2020 guidance to the ICH M12 2024 harmonised guideline (LEARN MORE). Our comparison of the Japanese PMDA 2018 guideline with the ICH M12 guideline will follow shortly.

Reaction Phenotyping

The new M12 ICH and the EMA guidelines are similar in terms of their recommendations. Both the ICH M12 and the EMA guideline have the same cut-off of ≥25% of total elimination for determining if the enzyme needs further investigation in a clinical study.

Enzyme Inhibition

For enzyme inhibition, both the ICH M12 and EMA 2013 guidelines recommend evaluating the main seven CYP isoforms for enzyme inhibition. For reversible inhibition, the cut-off for determining if a clinical study is required is the same in both guidelines using the basic model. However, for time dependent inhibition, 5x C_max is used in the calculation in the ICH M12 whereas 1x C_max was used in the EMA 2013 guideline, suggesting a more conservative approach is now being used in the new ICH M12 guidance. Furthermore, in the ICH M12, only a single cut-off is provided for time dependent inhibition whereas the EMA has cut-offs for intestinal enzymes for orally administered drugs as well as systemic enzymes. The EMA currently suggest drug interactions in the GI tract will be addressed with accompanying EMA documentation.

Both guidelines suggest evaluating UGT inhibition if one of the major elimination pathways of the investigational drug is direct glucuronidation, however, the ICH M12 references a larger panel of UGT isoforms including UGT1A1, UGT1A4, UGT1A9, UGT2B7 and UGT2B15 whereas the EMA 2013 references only UGT1A1 and UGT2B7.

Enzyme Induction

The ICH M12 and the EMA 2013 guidelines are similar in terms of CYP induction. The cut-offs for the basic fold-change method and the relative induction score (RIS) are the same. For the correlation method, the ICH M12 guideline gives better clarity on the cut-off value to be used compared to the EMA guideline. The ICH M12 provides clearer guidance on how to interpret the basic kinetic model whereas the EMA 2013 guideline incorporates the model into a mechanistic static equation.

Transporter Substrate Identification

Both guidelines recommend the same transporters are assessed. The method for testing and cut-offs for clinical assessment are very similar between the ICH M12 and EMA guidelines. However, once again the ICH M12 provides more clarity on interpretation of the results especially in the case of the uptake transporters.

Transporter Inhibition

For transporter inhibition, the EMA 2013 guideline recommends screening for OCT1 and BSEP inhibition in addition to the standard transporters recommended by the ICH M12. Although these transporters are not in the standard list for the ICH M12 guideline, it is suggested they may be assessed on a case-by-case basis with other transporters such as OATP2B1 and MRP2. The cut-off values also differ between the two guidelines with the EMA 2013 guideline tending to be more conservative for certain transporters. One final difference is that the ICH M12 recommend a pre-incubation with test article for transporters such as OATP1B1 and OATP1B3 whereas the EMA 2013 guideline does not refer to a pre-incubation as the scientific literature and consensus concerning this topic only started to appear later around 2017.

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