Targeting transformative treatments

Published on 20/09/2023

Thomas Holbro was going through one of the most difficult times during his career back in 2017. An important trial in the acute heart failure space he oversaw as part of his work in the Novartis Global Drug Development (GDD) unit had just read out with neutral results and he was tasked to sift through the data to extract some key findings.

It could have all been different. The outcome of the trial had been eagerly awaited and would have given Novartis fresh impetus to extend its leadership position in the cardiology space. But although previous clinical trial data showed the compound to be effective, late-stage tests failed to corroborate the early results.

Late-stage development failures are always hugely disappointing and lead to significant uncertainties for involved teams, possibly with personal and or even larger organizational implications. This time, it was different. Leadership appreciated that failure is part of drug discovery.

“Our leadership made it clear that together with a small team we should wind down the program. But they also told us in advance that they wanted us to stay and take over a new program later,” Holbro told live magazine back in 2018.

This not only took the pressure off Holbro and his colleagues but motivated them to stay alert and gather as much information that would help them for the next trials. This, as leadership had hoped, would also give them the extra motivation to redouble their efforts in future.

It played out exactly in that way – if not better. Holbro moved to lead another program, which now looks to be a potential game changer in several disease indications.

Think big

“As a scientist, I was always guided by facts, and the lesson we learned from the failed cardiovascular trial also helped me during the next clinical tests that I led. Furthermore, gaining the trust from the leadership motivated me to go on.”

The motivational boost came at the right time, as the upcoming program could have hardly been more challenging. Colleagues at the Novartis Institutes for BioMedical Research (NIBR) had developed a new molecule that could be used to interfere in a series of diseases in which the complement system – a part of the human immune system – is misfiring.

Besides the complex biology underlying the complement system as well as the intricate decision about which of the many possible indications to pursue first, the team faced the added challenge of setting up trials in rare disease areas, which are notoriously challenging from both the medical and the commercial point of view. But the team was ready to go full speed and take the risk, as they were fully convinced of the underlying science and the huge patient need.

To gain time and to resolve concerns about potential side effects, colleagues from NIBR and Holbro’s development team connected very early to set up a Phase II study that served as a proof-of-concept test but at the same time answered key questions for further development. The goal was to complete this step immediately and move into late-stage clinical trials – typically referred to as Phase III studies.

This joint team also did another unusual thing. Instead of testing the compound in different disease areas one by one sequentially, they launched several studies in parallel. “The reasons for this move were relatively simple. First, it made scientific and strategic sense, second it was valid from a patient perspective, and third, it was also convincing from a commercial point of view because we were able to create necessary synergies by building what we now call ‘a pipeline in a pill,’” Holbro said.

Also, they were thinking big when it came to late-stage trials. “We designed a head-to-head study against the most efficacious drug in the market and decided to test our drug candidate for superiority,” Holbro explained. “The study would only have a positive outcome if we were able to deliver better results than the current gold standard.”

“We did all of this in the spirit of bringing transformative treatments to as many patients as fast as possible,” Holbro said. While this was a risky endeavor, the strong underlying science of the molecule and the strategic decision to pursue a bespoke development plan was crucial for the team to make progress, as was the fact that the seamless collaboration played a key role.

So, the lessons for Holbro so far are clear. “Do things together early,” Holbro said, referring to the collaboration between NIBR and GDD in setting up the trials. “Also, from my point of view, go in multiple indications early on and in parallel as long as these are commercially compatible. And design for what we really believe is a transformative treatment that can be achieved with the molecule in question.”

This essentially means designing clinically meaningful studies in the context of existing therapies. “This is about taking smart risks. Of course, you can go for a much bigger study, use much softer endpoints or show to be comparable to what exists already. And then the study just gets longer. But if you really want to show that you are better and superior, then you assume a treatment effect that really shows that your therapy offers an added benefit to patients.”

With the benefit of hindsight, this might look easy. But Holbro is convinced the company can repeat such a feat in future too. Especially if Novartis is continuing to aim for breakthrough science and is prepared to accelerate collaboration between early drug discovery and Global Drug Development, while at the same time being led by what are true unmet needs for patients and taking commercial considerations into account.

Team spirit

To achieve this, team spirit is decisive, and for Holbro collaboration is not just a marginal notion. “I believe that, by default, people like to work together, to listen, learn and help each other for a common goal or purpose. At least that is my naive view of human beings,” he explains.

After going through a few cycles of team changes as the program expanded and advanced, Holbro’s view is also pragmatic. A steady influx of new roles means things are constantly moving. While initially it was the core group that has been with the project from the start that was making on-boarding of new team members efficient, it now is really the collective knowledge and culture of a team that has grown beyond a critical mass.

“Whenever someone joins, I tell them to pick one document that is most relevant for what they do. I don’t even know how many documents we have, and because of the program size and speed they also become outdated so quickly. I then advise the newcomers to spend the rest of the week talking to the people. That is how they can get to know and build trust with the team, plus they can find out what is really current and ‘hot’ – and that is not in any document,” Holbro said.

This collaborative mindset and ease of transition probably explain why Holbro had little difficulty finding teammates to join his call when he embarked on the new project.

One of them was Marion Dahlke, who joined Novartis as a medical doctor some 15 years ago, first starting in NIBR before she moved to full drug development, where she worked in the cardiovascular arena. “Thomas approached me and asked if I wanted to work with him again, this time on something different,” Dahlke said. “He told me, it was an exciting new program. The indications were rare. The team was great. And I believed him.”

Dahlke, who had worked with Holbro on the acute heart disease trial before, jumped ship and joined him. “It is always the people that make the difference,” she said. “If the team is committed and exhibits a we-can-do-it attitude, many things are possible. But it comes down to a few individuals that make the change – people who take others with them and say: Let’s try to do it. We can’t be sure if it will work, but we will never know if we don’t try.”

With the patient in mind

Her own motivation has always been to help patients in need, particularly patients suffering from severe diseases with limited treatment options. “At heart, I am still a medical doctor,” she said.

What drew her most to this project, she said, was the fact that the trials targeted rare and severe diseases. Also, the fact that innovative endpoints as well as assessing patient-reported outcomes were considered in the trial attracted her to this project.

“Collaboration is important from the very beginning because many things can happen in early studies that are relevant for later development. It is critical to have communication related to safety and dose finding early on,” Dahlke stressed.

Dahlke’s motivation is also personal since she herself had undergone medical treatments that left her with similar challenges faced by the participants in the trials she conducted. “I know full well the difference that even a seemingly slight shift can make in someone’s life. And with such treatments that can make a change, we also need to think ahead. Post-trial access is very important in rare diseases,” Dahlke pointed out.

Unlike common diseases, where there are usually many treatment options, the choices are notoriously limited for patients suffering from rare diseases. “Finding a solution for patients to have access to the drug after the core trial ended was another important collaborative task,” Dahlke explained.

For this reason, she also helped a so-called Rollover Extension Program, that under certain conditions allows patients to receive treatment after a core trial has ended.

The challenges of aligning expertise that fans out across indications, functions and geographies are many, but this program gives a glimpse into how bold approaches to collaboration can usher new standards and accelerate drug development, Dahlke said.

She, like Thomas Holbro, is convinced that a bold mindset and the goal to develop transformative treatments have helped the team to go the extra mile – a feat, they say, that should become the norm in the future.