Attrition in drug development has long been an issue for pharma. Despite passing industry trends and pipeline developments, it’s one that isn’t going away. To discuss solutions to this key challenge, experts from pharma and biotech met in Boston on December 4th 2017 for the concluding workshop in Aptuit’s conference series entitled Improving Candidate Selection Strategies: Translating Molecules into Medicines.
Adopting effective candidate selection strategies
A recent report from the Journal of Health Economics found that developers need 12 projects at the Investigational New Drug (IND) phase, and eight in Phase 1 clinical trials, to stand a chance of one successfully making it to market. While large pharma might be able to play the numbers game, for small biotechs and startup companies with limited resources and one or two lead compounds, spreading risk across a portfolio of assets simply isn’t possible.
Attrition, according to the morning session’s keynote speaker Simone Braggio, Vice President and Head of Drug Design and Discovery at Aptuit, can be considered to be a measure of the success of our candidate selection strategies. After all, pick a poor candidate at the drug discovery stage, and there’s little that can be done to improve its odds further down the pipeline.
So how can developers, whatever their size, ensure they’re progressing lead compounds with the greatest chance of success in the clinic? Part of the solution, according to Braggio, is a less rigid interpretation of drug design strategies such as Lipinski’s Rule of Five that have largely dictated candidate selection over the past two decades – or the ‘tyranny of Lipinski’, as he calls it. Here, rather than choosing compounds based on calculated properties, more success could be achieved by building an early understanding of a candidate molecule’s potential through preliminary characterization studies.
That’s a view that’s shared by many within the industry, if the views raised in the subsequent discussion session led by Ganesh Rajaramen, Associate Director of DMPK at Celgene, are anything to go by. While many acknowledged the contribution these tools had made in linking physical properties to general trends in bioavailability, the prevailing opinion was that Lipinski’s rules should be seen as guidelines, and shouldn’t be followed at the expense of other promising areas of chemical space. Indeed, a focus on non-Lipinski like structures such as natural products and macromolecules could hold great potential for moderating so-called ‘undruggable’ targets.
Developing translationally relevant preclinical strategies
With today’s drug discovery strategies resulting in ever more poorly water-soluble APIs, the issue of attrition looks set to become even more of a challenge for pharma. To help overcome this problem and translate these ‘non-druglike’ molecules into safe and effective medicines, formulation strategies are playing an increasingly important role.
Indeed, formulation strategies have advanced significantly over the last decade. Enabling technologies such as microemulsions and self-emulsifying drug delivery strategies (SEDDS) are delivering remarkable results when used to improve the bioavailability of poorly soluble BSC Class II-type molecules. However, these technologies have their limitations, and to ensure effective and predictable results in the clinic, reliable and translationally relevant preclinical studies are essential.
In his keynote talk, speaker Mark Saunders, CEO at Aptuit Potters Bar Ltd highlighted how factors such as gastrointestinal pH conditions, digestive enzymes and food response can have a significant influence on the performance of formulation technologies in preclinical models. With these factors varying considerably between animal species – and even genders – building a strong understanding the nuances of individual models is therefore crucial if we are to improve the translational relevance of preclinical studies.
This was also a key discussion point in the subsequent workshop led by Susan Ashwell, Medicinal Chemistry Senior Director at Forma Therapeutics. Here, several of the delegates voiced their opinion on the importance of committing resources to understanding diseases in sufficient detail. This would enable the development of models that are representative of the underlying disease biology, rather than physiological factors that may simply be a consequence, rather than a cause of the condition.
Take idiopathic pulmonary fibrosis (IPF), for example, a respiratory disease that has had limited success when it comes to translating promising in vitro findings into safe and effective medicines. IPF models have traditionally relied on recreating the symptoms of fibrosis in animals using chemical reagents. However, new technologies such as lab on a chip applications could be used to more closely model the mechanisms underpinning the disease biology.
The current rate of attrition in drug development is one of pharma’s most pressing challenges, and it’s one that industry leaders will continue strive to improve. However, as the molecules we develop become increasingly non-druglike and more challenging to formulate, utilizing the best candidate selection strategies and most translationally relevant preclinical models will become increasingly important if we’re to make inroads in this ‘war on attrition’.
For more information on how attrition is being reduced in drug discovery and development, follow the link to discover more exciting articles and blogs from our experts: http://www.aptuit.com/resources. To find out more on the results we’ve been able to achieve, contact us.