MDC Connects: How to Get your Molecule into Humans
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This document discusses strategies for efficiently developing the non-clinical package needed to get a molecule into human trials. It outlines top reasons for delays like insufficient API, formulation issues, and unexpected toxicity. It recommends enhancing efficiency by selecting a CRO early, combining study endpoints, using biomarkers to inform clinical decisions, and microsampling to reduce animal numbers. Looking ahead, the future may see increased use of minipigs and humanized models with reduced primate use. Developing a defined strategy, partnership with an experienced CRO, and planning for unexpected events are crucial to improving efficiency.
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MDC Connects: How to Get your Molecule into Humans
- 1. June 2020 CATAPULT Medicines Discovery Webinar Series How to get your molecule into humans. A practical guide for the present and a look to the future Pauline Garner Programme Manager, Sequani
- 2. Non-clinical studies: better, faster, cheaper With as little API as possible Risk benefit assessment De-risking takes longer and costs more (generally) AIMS
- 3. DEVELOPING THE NON-CLINICAL STRATEGY No such thing as a standard “first in man” package Strategy needs to be based on good science and regulatory understanding If in doubt, take regulatory authority advice Helps is available Extent of testing will depend on the nature of the pharmaceutical in development Extent of testing will depend on the design of the proposed clinical trial
- 4. Availability of API • Single most common reason for delay • Quantity and quality of API • Clinical formulation • Contingency Formulation Issues • Also very common • Uses higher doses • Appropriate vehicles • Check solubility at appropriate concentrations • Suspensions more appropriate? Insufficient Capacity • Repeat dose tox are rate limiting • CROs have finite capacity • Select CRO early • Know strategy • Avoid last minute changes ENHANCING NON-CLINICAL EFFICIENCY - TOP REASONS FOR DELAY
- 5. Unexpected TK • May invalidate studies • Include additional dose groups • Animals, API, money and time wasted • Conduct lead optimisation with TK Unanticipated Toxicity • Can result in significant delay • Can result in unnecessary use of TI • Conduct appropriately designed lead optimisation Analytical Method Development • Bioanalysis and formulation analysis methods required • Formulation analysis a GLP requirement • Fully validated (in each matrix) • Start as early as possible ENHANCING NON-CLINICAL EFFICIENCY - TOP REASONS FOR DELAY
- 6. Species Selection • Fundamental basis of all non- clinical programmes • Traditional ‘rat and dog’ approach no longer acceptable • Species selection impacts on price • Species selection impacts on API • Biologicals – relevant species Late Reports • Can delay regulatory submission • Avoid by careful CRO selection • Track record of quality report delivered on time • Experience in FIM programmes • Flexibility • Communication is key! ENHANCING NON-CLINICAL EFFICIENCY - TOP REASONS FOR DELAY
- 7. ENHANCING NON-CLINICAL EFFICIENCY - OPPORTUNITIES – CRO RELATIONSHIP Develop and maintain good lines of communication CRO should be able to advise on the programme design – with the benefit of relevant experience Treat CRO as an extension of your project team Develop a partnership with CRO early Sign a mutual CDA
- 8. ENHANCING NON-CLINICAL EFFICIENCY - OPPORTUNITIES – COMBINED ENDPOINTS Combined male fertility in sub-chronic or chronic rodent toxicity study Safety pharmacology included in repeat dose toxicity studies: non-invasive telemetry and Irwin-style observations Micronucleus and comet assessment combined with repeat dose rodent toxicity study
- 9. ENHANCING NON-CLINICAL EFFICIENCY - OPPORTUNITIES – PATHOLOGY Cost could be reduced by restricting processing to anticipated target organs Opportunity to process all tissues from all animals to slide in first instance; slides available for evaluation immediately when required Histopathology can be rate-limiting
- 10. ENHANCING NON-CLINICAL EFFICIENCY - OPPORTUNITIES – BIOMARKERS Informs clinical decisions Enables dose selection in clinical trials Direct comparison of non-clinical to clinical results Development of clinically relevant biomarkers alongside non-clinical studies
- 11. ENHANCING NON-CLINICAL EFFICIENCY - OPPORTUNITIES – MICROSAMPLING Significant reductions in animal numbers especially for small species: mice, juvenile rats Relate tox findings to exposure directly Serial sampling gives full profile from each animal, potentially from main study (toxicity) animals Aim to have better science with fewer animals Blood volume ≤50µL - reduce or remove satellites for TK
- 12. Increased uptake of minipigs Disease models Humanised transgenics Concomitant reduction in use of primates THE FUTURE
- 13. Significant opportunities to save time and money in implementation of non- clinical package Retaining quality is paramount – strike a balance Need a defined non-clinical strategy Develop a partnership with an experienced and creative CRO, to improve efficiency Forward planning and conducting the right studies at the right time are crucial factors Also crucial to react positively and rapidly to unexpected events SUMMARY
- 14. Thank you for your attention I am happy to take a couple of questions www.sequani.com business.development@sequani.com
Editor's Notes
- Good afternoon Ladies and Gentlemen, my name is Pauline and I would like to present to you to-day on how to get your molecule into humans. I will be specifically covering the aspects you should consider for your First in Man / IND enabling programmes, concentrating on What the aims of a FIM/IND programme are Considerations for developing your non-clinical strategy and How to enhance your non-clinical efficiency, specifically looking at: - Top reasons for delay - Opportunities to improve efficiency And will briefly touch upon some thoughts of what the future may hold.
- The aim for any client conducting a non-clinical programme, is to conduct them better, cheaper and faster. Utilising as little API as possible: But don’t just select mouse because it uses less compound, see my later discussion points on appropriate non-clinical species! Conduct a risk benefit assessment of what is needed and when, to get your compound into clinical trials, but bear in mind De-risking will, typically, take longer and cost more: - But appropriately designed lead optimisation studies could save you further down the line - There is a temptation to add lots of assessments onto toxicity studies to de-risk them as well, but you run the risk of losing the primary objective of the study and could even jeopardise the study!
- When developing the non-clinical strategy, there’s no such thing as a standard FIM: E.g. the duration of dosing, daily or cyclical dosing, inclusion of a recovery period, choice of relevant rodent and non-rodent species, do you even need 2 species, are all things to take into consideration And it goes without saying the strategy needs to be based on good science and regulatory understanding: - There’s a difference between developing an anti-cancer that we will be tested in healthy volunteers vs patients of advanced cancer. So, if you’re developing an oncology compound for advanced cancer under ICH S9, genetic toxicology and safety pharmacology are not required (however, if you do have a particular concern, genotoxicity and safety pharmacology end-points can be included in the pivotal toxicity studies – which I will cover later in opportunities) If in doubt, we would always recommend to take regulatory authority advice – but be careful: - On what and how you ask the questions of a regulator, as you may end up doing something you didn’t anticipate! It’s important to remember help is available: - Whether from the CROs who run these studies day in and day out and are experienced across multiple therapeutic indications - Of from Consultants, so firms such as Apconix, who have a wealth of experience in drug discovery And the extent of testing will depend on the nature of the pharmaceutical in development and design of the proposed clinical trail: - For example, a compound that is only going to be given once clinically doesn’t necessarily need 28 days daily dosing, would cyclical dosing with fewer dosing occasions still give you an appropriate margin
- In terms of enhancing efficiency, I have listed 8 reasons for delay – this list is by no means exhaustive! AVAILABILITY The single most common reason for delay/disruption of non-clinical programmes. Consider early on the quantity and quality of material you are going to need at each stage of the non-clinical programme – if in doubt, ask the CRO as I can guarantee more will be needed than anticipated! - It is also worth bearing in mind that GMP grade material is not absolutely required for GLP pre-clinical studies Don’t try to mould your preclinical programme around the quantity available or the clinical formulation - The formulation for preclinical work does not need to be identical to the clinical formulation And most importantly, try to build in contingency time between the proposed delivery date and starting a programme, especially at this current time due to the pandemic! FORMULATION ISSUES Another common problem Toxicity studies are likely to use higher doses than previous (e.g. pharmacology, PK) studies So it is important to check solubility at appropriate concentrations – take advice from the CRO regarding maximum dose volumes for each test species Limited number of vehicles widely used in non-clinical species - again take advice from the CRO regarding appropriate vehicles and reagents and their proportions in the vehicle, as it’s important to develop a reliable formulation and method as early as possible The nature of the formulation may affect absorption and exposure, so have you looked at suspensions as they can often be appropriate, particularly for oral studies Formulation does not need to be identical to the clinical formulation INSUFFICIENT CAPACITY In terms of timings, repeated dose toxicity studies are always rate-limiting in non-clinical programmes to support FIM CROs have finite capacity - we may be discussing provisional dates with a client one week, the next they have been secured for another client following contracting So it is important to Select your CRO early Have a defined process for CRO selection: - Including a comprehensive RFI - Understand their expertise in your particular therapeutic area - Build a partnership with them or select them as a preferred supplier - Do they have a proven track-record for quality Know your strategy, i.e. what you need and when, and get your studies booked in, having considered the first 2 points just discussed regarding availability of API and formulation And try to avoid last minute schedule or design changes, CROs can’t guarantee they have the capacity in and around your studies; and to maintain GLP compliance paperwork needs to be in place and this takes time!
- UNEXPECTED TK RESULTS Can have serious consequences: Studies may be invalid e.g. - Insufficient exposure - Inappropriate species Additional dose groups may be required, which uses more animals and compound, taking more time and money Therefore, it is important to conduct early lead-optimisation or dose range-finding studies including an assessment of toxicokinetics And conduct early in-vitro metabolism investigations to ensure you have selected the most appropriate rodent and non-rodent species UNANTICIPATED TOXICITY Can also result in significant delay and unnecessary use of test material Conduct preliminary studies at an early stage As I’ve just mentioned, appropriately designed lead optimisation studies can save time, money and animals later down the line So when discussing Lead Optimisation, we’re thinking of: - In-vitro metabolism and protein binding Comparative in-vivo toxicity studies, to include an assessment of toxicokinetics – not only to select your lead candidate but also to assist in dose setting for regulatory studies Screening genotoxicity studies - In-vitro absorption studies - Structure activity relationships (SAR) ANALYTICAL METHOD DEVELOPMENT Analytical methods for bioanalysis of toxicokinetic samples and formulations are required In fact, analysis of formulations is a GLP requirement Therefore, to support GLP studies, methods must be fully validated - Even transferred methods will need some local validation With validation being needed in each matrix Although it may be possible to have a partial bioanalytical method validation in your 2nd species Start method development work as early as possible – non-GLP lead optimisation studies can be supported with “generic” analysis methods Provide as much information from your chemists or previous labs who have worked with this compound as early as possible to help with method development/feasibility/transfer
- SPECIES SELECTION Fundamental basis of any non-clinical programme The traditional ‘rat and dog’ approach is no longer acceptable CRO’s must have justification for the species used e.g. - Have the species previously been used for other drugs of same class/mechanism - Are they supported by in-vitro metabolism data - Do they have particular physiological relevance Species selection can have a huge impact on price Species selection will affect the amount of compound that needs to be produced For example, with biologicals you should use the pharmacodynamically relevant species, for which there may be only one LATE REPORTS Delays at report stage can be irretrievable – resulting in delays to submission You can avoid this by careful CRO selection criteria, such as: Do they have a track record for quality reports delivered on-time - And ask for details of how this is achieved Their experience in FIM programmes Their flexibility - As unplanned events do happen And by having good lines of communication, as two-way communication is key
- Put a mutual confidentiality agreement in place during the early stages of the enquiry process And develop a mutual partnership with the CRO early, treating them as an extension to your project team, as the study directors will definitely feel more invested in the project Allow the CRO to advise of the strategy and programme design, as they have the benefit of years of relevant experience And develop and maintain those 2-way good lines of communication – it will pay dividends
- Getting more out of the toxicology studies Integrated Genotoxicology The flow cytometric analysis of micronuclei and a comet assessment can be conducted in the pivotal repeat dose toxicity studies - Thus, there is no need for stand-alone in vivo studies, assuming various guidelines criteria have been met, thereby reducing animal usage Integrated Safety Pharmacology - You can include jacketed telemetry with mathematical modelling or even just additional ECG measurements in the non-rodent, in lieu of the stand-alone cardiovascular study - And include automated behavioural/activity measurements, i.e. Irwin-style observations, in lieu of the stand-alone rodent Irwin study Reproductive Assessment - And thkning slightly further down the line, with compounds where there is no effect on the reproductive organs from your initial pivotal toxicity studies, a male fertility element could be added onto your sub-chronic or chronic rodent toxicity studies, thus reducing animal usage compared to a stand-alone male fertility study
- Histopathology, the pivotal end-point of the toxicity studies can itself be rate-limiting The normal procedure in rodents is to conduct histopathology in control and high dose groups only, with track-down to affected organs in other dose groups/treatment-free groups, which takes time and will not have been accounted for in the assigned audited draft report issue date So there is an Opportunity to process all tissues from all animals to slide in the first instance, so that slides are available for evaluation immediately when required This saves time by removing: - an additional later histology step - And the need for the pathologist to re-read high dose slides for comparison The cost could be reduced by restricting to this to anticipated target organs only: - This entails a risk, but it can be informed by early lead optimisation studies as previously discussed
- The development of clinically relevant biomarkers alongside non-clinical studies is becoming more common, as it enables a direct comparison of non-clinical data to clinical data, helping to inform on clinical designs and dose levels selection in the clinical trials.
- The development of a micro-sampling bioanalytical method is becoming increasingly important in regard to the 3 Rs. A micro-sample is a blood volume of less than or equal to 50 µl, the aim of it being to have better science with fewer animals, by reducing or removing satellites animals for toxicokinetic sampling – by this we’re specifically talking about it’s applicability to rodents, although it would also be applied to other species where circulating blood volume isn’t such a constraint. Using a micro-sapling approach allows us to serially sample giving us a full TK profile from each animal, potentially from the main study (toxicity) animals themselves, which would allow us to relate the toxicity findings directly to exposure This allows for significant reductions in animals numbers, especially for the small species, such as mice and juvenile rats
- Animal Models Increased uptake of minipigs Minipigs have great value as a model for testing compounds for metabolic disease due to their GI tract and being omnivores, making them a better model than the dog. Reproductively they are also better than dogs as their oestrus cycle is similar to humans and they are sexually mature by 6 mths as compared to the dog at 11-12 mths. And naturally they make a better model than rodents for dermatological products, due to their skin being more similar to humans. Can genetically modify pigs, but it is very much a numbers game and thus can be expensive. Minipig offers a viable non-rodent species or alternative to commonly used rodent (mouse) models for anti-cancer therapies, as you can monitor parameters throughout the study. Although the initial cost is higher, it is outweighed by improved prediction of clinical efficacy. Disease models Seen as being representative of the response in patients as compared to healthy non-clinical species. There is more scope to get into disease models, e.g. diabetes, as you can’t give a reasonable dose of an anti-diabetic to a healthy animal without causing physiological issues. Humanised transgenics There is also more research into using humanised transgenic animal models, for example conducting toxicology studies in mice, where for example the normal strains of mice is resistant to hepatitis c, but by using a transgenic mouse with a humanised liver (70% human), you get a much better read-out. But these humanized transgenic models are VERY EXPENSIVE. Concomitant reduction in use of primates It is preferable both ethically and economically to use fewer NHPs; however, there is little option for biologicals and large molecules whereby the typically more specialized target is not found in other non-clinical species.
- In summary there are significant opportunities to save time and money during the implementation of your non-clinical package, but retaining quality is paramount, therefore, it is important to strike a balance. Have in place your defined non-clinical strategy Develop that partnership with an experienced, flexible and creative CRO to improve efficiency And always forward plan your programme, conducting the right studies at the right time But it is equally crucial for both parties to positively and rapidly respond to any unexpected events – they do happen!
- I would like to thank you for your attention this afternoon and I am happy to take a couple of questions