What strategies and technologies should we adopt if we’re to turn today’s promising drug molecules into tomorrow’s safe, effective and affordable medicines? That was the focus of the discussion at Aptuit’s one-day workshop, Improving Candidate Selection Strategies: Translating Molecules into Medicines, held in Hertfordshire, UK, on October 23rd 2017. Around 25 experts from UK pharma and biotech, including Novartis, GSK and Johnson & Johnson, met at the 18th Century Farnams Hall for a day of networking and discussion around the future of pharmaceutical development.

Preclinical strategies for increasingly challenging drug molcules

Overcoming tomorrow's formulation challenges to deliver the medicines of the futureModern discovery strategies are increasingly resulting in poorly water-soluble drug candidates. While BCS-II compounds may bind more strongly to target receptors, their lipophilicity poses a significant challenge around bioavailability, and ultimately, clinical effectiveness. The ongoing task for formulation chemists, therefore, is to improve API solubility using enabling technologies.

To ensure formulations yield appropriate dose levels in humans, robust and reliable preclinical models are essential. But the problem, according to keynote speaker Paolo Gatti, Head of Formulation Development and Material Science at Aptuit, is that even with the most physiologically relevant animal models, you’ll never be able to fully predict what happens in the human body.

Factors such as gastrointestinal pH conditions, response to food, and enzymatic digestion can vary significantly between animals. In order to develop drug formulations in a robust and clinically useful manner, understanding the limitations and individual nuances of each animal model is essential.

So how might we collect more useful and relevant preclinical data in future?

“Increasingly we’re seeing preclinical models as models of the mechanism, rather than models of the disease” says Jane Kinghorn, Director at University College London’s Translational Research Office.

She believes that human derived tissues will play an increasingly important role in the future. “More and more the emphasis is on utilizing patient cells and developing more in vitro models, based on three-dimensional organoid approaches.“

Will such models ever replace animal models? Kinghorn thinks this unlikely. However, with regulators increasingly open to using patient materials, for those willing to explore their potential, the benefits for drug development could be enormous.

Formulation shouldn't be a crutch for poor drug design

Do strong enabling technologies at the early lead optimization stage encourage poor drug design? That was one of the questions put to delegates in a workshop focused on finding strategies to address formulation challenges for non-druglike candidates.

Jamie Billsland, Alzheimer’s Research UK Drug Discovery Institute and session chair, believes formulation shouldn’t be seen as a magic bullet. He recounted the development story of a highly potent and selective drug molecule for a kinase target, with complex metabolism and poor solubility. While the developers overcame the challenges around rapid metabolism and poor peak plasma levels using a multi-dose spray dried dispersion formulation, ultimately, the project was shelved. Why? The formulation technology used to address the underlying metabolism challenges proved too costly.

So how can developers manage this type of development risk? While for larger companies, the right balance between risk and reward can be achieved through ensuring a diversified project portfolio, for smaller developers who may only have a single candidate, this approach may not be possible.

For Gatti, the best way to anticipate formulation challenges during development is by building a thorough understanding of the API. He encourages adopting pre-formulation screening in the early stages of development in order to guide formulation decisions. And there’s no excuse – advances in technology mean that this critical planning stage can be conducted using limited amounts of API.

“Even at the interface between discovery and preclinical, small scale formulation studies can help guide your development decisions. These days useful information can be obtained with only a few milligrams of material.”

Moving beyond established drug delivery strategies

Could complementary technologies support formulation efforts in the development of safe and effective products? Here, medical implants and digital technologies look set to play an increased role in drug delivery.

Advances in drug delivery technology are enabling more localized administration – a strategy that has the potential to improve therapeutic indices. Ocular delivery devices implanted into the eye have already been approved for the delivery of steroids to patients with macular edema.

Furthermore, continuous subcutaneous infusion, for example, shows particular promise for drugs where metabolism is an obstacle to bioavailability. With the potential to be monitored and controlled wirelessly, the technology may be used to tailor the rate of infusion to achieve the desired half-life in the body and improve exposure.

Moreover, the potential for data collection through wireless so-called ‘smart pills’ and related devices may enable a deeper understanding of how drugs are acting, helping to realize the benefits of personalized medicine.

With the number of poorly soluble drug candidates entering the development pipeline steadily increasing, the industry should be exploring new strategies and fresh thinking today, in order to meet the drug development needs of tomorrow. Judging by the discussion at Farnams Hall, pharma is well and truly up for the challenge.

Improving Candidate Selection Strategies: Translating Molecules into Medicines will be coming to Boston, US, on December 3rd and 4th. We hope you can be part of the conversation!