Persistence - and ingenuity - pays off

Long-term medical conditions often impact patients beyond their physiological effects. Time off work may be needed for treatment, for example, or the treatment itself may affect a patient’s quality of life. Such is the case with haemophilia A, the treatment of which requires regular intravenous injections. But thanks to the determination of researchers at our Octapharma Biopharmaceuticals centres in Berlin and Heidelberg, Germany, a breakthrough is on the horizon that could lead to this debilitating condition being treated with a true FVIII product via a much more convenient subcutaneous route.

Things started back in 2014 when Christoph Kannicht and Barbara Solecka-Witulska, together with their teams, set out to develop an innovative and “easier” treatment. As Barbara Solecka-Witulska, Senior Scientist, Molecular Biochemistry, in Berlin explains, “The treatment has been that recombinant factor FVIII is injected into a patient’s veins. This can be extremely challenging with newborns, for example, where it is difficult to find a vein. So, having the treatment given subcutaneously would be an enormous advantage.”

Developing a subcutaneous treatment is more difficult than it may sound. Despite haemophilia A being a well-studied genetic disorder, characterised by abnormalities in a single gene, it is challenging to treat. Recombinant factor FVIII administered intravenously remains the therapeutic cornerstone.

The search begins

When Octapharma launched its SubQ-8 study, there was no product on the market which could achieve subcutaneous administration of FVIII. But Christoph Kannicht and his team relish a challenge. “We’ve learned that if you administer FVIII without any protection subcutaneously, it will not reach the bloodstream. So, the goal was to identify a fragment of the von Willebrand factor (VWF) with the best affinity to FVIII and use that as a “protective wrapping”,” explains Christoph.

FVIII and VWF are two distinct but related glycoproteins that circulate in plasma as a tightly bound complex. Their deficiencies or structural defects are responsible for the most common inherited bleeding disorders, namely haemophilia A and von Willebrand disease. By adding a certain fragment of the VWF to FVIII, the compound safely carries FVIII into the bloodstream and protects it from degradation. The team had to analyse numerous fragments of VWF. “We knew that we could not take the entire VWF,” says Tobias Stuwe, Head of Recombinant R&D in Heidelberg. A FVIII complexed with full-length VWF multimers would likely be trapped in connective tissues and not enter the veins. “The challenge was to find the right size and type of VWF fragment. Was a monomeric or dimeric molecule the best choice?” Tobias asks.

Eventually one molecule, later named OCTA12, turned out to be a promising candidate. The team had to test the bioavailability, efficacy and many other key aspects of the fragment relating to its function to bind FVIII with high affinity. The hypothesis was confirmed in subsequent experiments in animal models, and at the World Federation of Hemophilia (WFH) 

2018 World Congress in Glasgow, a team of scientists led by Christoph Kannicht presented for the first time this promising data from the pre-clinical study for SubQ-8. A successful Investigational New Drug (IND) approval followed, and now researchers can plan the clinical phase of SubQ-8’s development.

Team spirit

Looking back, Christoph, Barbara and Tobias believed in the idea. After three years, their resilience paid off. “It was certainly a difficult and challenging time,” recalls Barbara.

We hope that the data from our pre-clinical studies of the new subcutaneous FVIII product, SubQ-8, will ensure an easier route of administration for haemophilia A patients.

“Ever since this project started, I have always reminded my team members how important it is to understand the patients before they start working on a study or product,” Christoph adds. “We have to understand what patients’ daily lives look like, what their environments are like, what are they missing, and what they need. With this information in hand, and the incredible efforts of the team, we can then start looking for solutions hopefully with as much success as our SubQ-8 work!”

Octapharma invested into the project, trying to approach the challenge from various angles and leveraging its scientific talent base. “It is gratifying to see what we have achieved. Much of this is owed to our belief that we have to innovate to help patients. But it was the courage and incredible teamwork of many different people from very different backgrounds that brought us here in the first place,” says Tobias.