Translating Hidden Gems Into Medicines
By Louise Modis, Ph.D.
Imagine a gem hunter facing a vast and uncharted landscape to uncover a single beautiful diamond. It is a bit like drug discovery. Scientists create and evaluate hundreds and thousands of molecules in their relentless pursuit of a transformative discovery that could revolutionize health.
It is this pursuit that drives me. If we want to discover a medicine that could change many lives, we need to constantly push the boundaries of what is known and unknown. Having spent more than 20 years in biotech and pharma, initially as a research scientist and now as CSO of Amphista Therapeutics, I know that drug discovery requires a fighting spirit with the curiosity and an open mindset of a bold explorer who looks beyond the obvious. It involves marrying expertise from academia and industry, and of course a little bit of serendipity, to develop transformative medicines.
I have been fortunate to oversee the journey of identifying a hidden molecular gem through its progression into clinical development. And from my experience, success largely hinges on three key elements that exquisitely blend scientific expertise with human behavior:
Define And Refine The Problem
It is essential to focus on the medical problem to be solved, gathering insights from the medicine and patients to define it as clearly as possible. In an ever-evolving landscape, it is important to continually refine the problem with deepened scientific understanding, and to figure out what technical solution would work best.
It’s like charting a course in a new land. A topographical map is improved when approached from different vantage points. By trying things that work and don’t work, the focus will change, especially when working with other experts who bring different views and complementary skills. New vistas may open up.
I like to reference the story of the scientists behind rituximab, a monoclonal antibody that targets cells expressing CD20 protein, to exemplify this approach. It was used originally to deplete B cell lymphoma cells (such as in non-Hodgkin’s lymphoma patients). Researchers discovered that not only could rituximab be used for targeted cancer treatment but could also achieve therapeutic effects for patients suffering from multiple sclerosis — a wholly different disease from cancer. Observing the depletion of healthy B cell progenitors in the cancer patient studies, combined with observation of B cell dysfunction including autoantibody production in multiple sclerosis, led to the insight and courage to test rituximab to deplete B cell progenitors in this autoimmune disease. The approach taken demonstrates the interdependence of disease understanding, scientific understanding, appropriate technology and importantly, the human insight and tenacity to bring it all together. Here, the researchers had the tenacity to explore a new frontier to maximize the use of the drug in a completely different disease. They were able to go beyond what was originally thought possible, and that insight has since spawned the development of multiple new B cell targeting therapies for autoimmunity. Therein lies the beauty of the biotech industry, where scientific teams cultivate a culture of tenacity and robustness to discover the hidden opportunities in these gems.
Create An ‘Idea-Nurturing’ Network
Breakthroughs are driven by people; scientists and medics with diverse experiences and views pushing each other to come up with new solutions for medical problems. This human component and the serendipitous realizations that it leads to is critical and needs to be valued and nurtured.
I saw this in action in one of my previous roles when I led the GSK Immunology Network, conceived and sponsored by Paul-Peter Tak. Established in 2014 as a novel way of fostering industry-academia collaborations, it exemplified the importance of relationships, robust challenge, and curiosity to facilitate idea sharing. It was designed to marry two parallel research streams in academia and industry. It brought together the best immunologists around the world — academics on sabbatical, members of the immunology network, and clinical and scientific experts at GSK — to expedite advances in immunology research and ultimately bring effective therapies to patients sooner.
An example of its success was the anti-CCL17 asset, now in Phase II development at GSK for both osteoarthritis pain and diabetic peripheral neuropathic pain. The unmet need to treat pain in inflammatory and other indications is enormous; pain is the hallmark of osteoarthritis, and there are approximately 600 million patients worldwide. Novel approaches are needed, and through the Immunology Network we explored the ideas of blocking this chemokine to treat pain, and developed it with a robust collaboration between multiple academic and industry scientists and clinicians. This is a completely different indication than blocking this chemokine ligand for the treatment of respiratory disease, where it was originally explored. It would not have advanced without the relationships that underpinned the passion for the project and the robust challenge by diverse teams within GSK.
By seeking out the best people in the field and having generous discussions with them, idea sharing and challenging in equal measure, you achieve shared learning and an understanding that is greater than sum of its parts. You can identify what people are most passionate about and tap into their enthusiasm to support your ideas and then challenge them to do the same with others (aptly explored in Give and Take by Adam Grant). It is vital to nurture these productive relationships. With every conversation you never know where you will find a spark that may uncover the next hidden gem and transform patient lives. As a senior leader in a biotech company, it is important to recognize that those sparks may not always come from the most senior person on your team or even the person giving the keynote speech. The leading-edge ideas are often from young fresh perspectives.
We must do our best as leaders and mentors to cultivate a culture of curiosity and awareness to translate that initial idea into a fully-fledged drug discovery pathway.
Design Killer Experiments
In the quest to clearly understand and define the medical problem, it is critical to conduct the experiment that you are afraid will prove the idea wrong. This bold and brave path will reveal whether the hidden gem has the potential to become a novel medicine. In the industry we refer to these as the ‘killer experiments’ because they have the power to nullify the hypothesis. Have that conversation with an expert who will disagree and see if you can prove them wrong! Be open to recognizing when it is time to move on to the next problem.
This is what we are trying to achieve with our targeted protein degraders at Amphista Therapeutics, where we are investigating whether our targeted glues can achieve CNS penetration. Setting these challenging end goals and achieving them will consolidate the passion within your team. Amphista recently demonstrated that our degraders could achieve CNS penetrance across multiple targets and showed significant degradation of target protein in the brain.
In summary, defining and refining the problem, creating an idea-nurturing network and designing killer experiments will enable the translation of hidden molecular gems into medicines that could transform patient lives: the ultimate goal for all biotech companies.
About The Author:
Louise Modis is an accomplished scientific leader with over 20 years’ experience across biotech and pharma, in target selection and preclinical and clinical advancement of small and large molecules across multiple therapy areas. Prior to joining Amphista, Louise was most recently Chief Scientific Officer at Mogrify and Vice President of Immunology Research at GSK. She has a BSc in Biotechnology and a Ph.D. in molecular and cell biology, and over 30 peer-reviewed publications.