Investigación y desarrollo
Doctors first noted the presence of fibres in blood more than 2400 years ago. Today, scientific progress allows us to produce high-purity human fibrinogen concentrate to treat acquired fibrinogen deficiency.
The 2011 launch of the clinical trial to investigate the use of our high-purity human fibrinogen concentrate in congenital fibrinogen deficiency was the start of a clinical development programme in a very rare disease. But it also became an early step in one of the most audacious clinical programmes which Octapharma has conducted, targeting acquired fibrinogen deficiency (AFD).
AFD is caused by high blood loss due to, for example, major surgery or trauma. With no other alternatives, AFD is treated with cryoprecipitate in many countries around the world and thus there is a high medical need for a fibrinogen concentrate approved in this indication. The ambitious goal of this programme was to show that our high-purity human fibrinogen concentrate is at least as effective as cryoprecipitate for AFD – and is a more practical and reliable alternative to it. Eight years on, and after the detailed design, planning and conduct of clinical trials by a dedicated Octapharma team, our high-purity human fibrinogen concentrate has now been approved for use in AFD in 15 countries of the EU.
This approval extends the original 2017 marketing authorisation for Octapharma’s high-purity human fibrinogen concentrate for use in congenital fibrinogen deficiency. Other major markets are planned to follow.
“If you ever needed proof that Octapharma is a company with the courage to take a calculated risk and invest in science to develop new medicines that could save the lives of patients with bleeding abnormalities, then this AFD project is it,” says Sigurd Knaub, Senior Vice-President of Clinical Research & Development Haematology.
Fibrinogen, also known as factor I, is a naturally occurring blood plasma glycoprotein. It is essential for blood clot formation and stops excessive bleeding resulting from various injuries and traumas, or during surgery. Reduced or dysfunctional fibrinogen occurs in various congenital fibrinogen-related disorders. However, unlike in congenital fibrinogen deficiencies, AFD arises due to consumption of fibrinogen after excessive blood loss.
After Octapharma’s high-purity human fibrinogen concentrate obtained regulatory approval in the USA, Canada and the EU in 2017 for the treatment of very rare congenital fibrinogen deficiencies (with further approval obtained in Switzerland in 2018 for both acquired and congenital fibrinogen deficiencies), clinical initiatives continued with FORMA-05, the first new clinical study in AFD.
The rationale for the FORMA-05 study was to investigate whether a fibrinogen concentrate is an effective alternative to cryoprecipitate in a model indication of AFD. “We wanted to develop a practical and safe alternative to cryoprecipitate,” explains Sigurd. “In many parts of the world, patients are still treated with cryoprecipitate, as a fibrinogen concentrate is not licensed for AFD. Cryoprecipitate is less pure, contains several coagulation factors, and a higher volume is required than for fibrinogen concentrate. Furthermore, cryoprecipitate is not virus inactivated with a higher risk of virus transmission.”
The FORMA-05 clinical study was a prospective, randomised, single-blind, controlled, non-inferiority study which compared the efficacy of Octapharma’s high-purity human fibrinogen concentrate to that of cryoprecipitate during cytoreductive surgery to treat pseudomyxoma peritonei, a rare cancer that usually starts in the appendix. This major and complex surgical procedure is associated with extensive blood loss and patients are at high risk of developing AFD.
The trial process was arduous but “where others experienced setbacks and gave up, we had the courage to continue with an excellent and experienced team at the study centre,” remembers Sigurd. The results of FORMA-05 were encouraging, indicating non-inferiority against existing therapies, with several advantages.
Meanwhile, for Sigurd and the team involved, work continued at a fast pace. In 2017, Octapharma started discussing another study using Octapharma’s high-purity human fibrinogen concentrate in cardiac surgery with a group of Canadian physicians led by Dr Keyvan Karkouti in Toronto. Further discussions of the final study design with Health Canada led to the launch of the investigator-initiated FIBRES trial, a multi-centre, single-blind, randomised, comparator-controlled confirmative trial conducted to assess the non-inferiority of the product compared to cryoprecipitate in patients undergoing cardiac surgery. In fact, this study was stopped early at a pre-planned interim analysis as the primary endpoint was already met.
“It was the largest study ever made with a fibrinogen concentrate comparing cryoprecipitate against our product. And again, the endpoint was non-inferiority,” explains Sigurd, adding: “This confirmative phase 3 study has basically achieve what no other trials in patients with an acquired coagulation disorders have achieved with a single product, showing efficacy in a complex indication.”
Clearly, the entire development and approval process was an eventful journey. “I think with every development journey there are challenges, but probably even more so with a unique project like this one,” remembers Petra Schulz, a senior scientist. “But,” adds Petra, “looking back, the rewards and satisfaction are great if you have been willing to pioneer something you really believe in and it pays off.”
“Finally we succeeded in providing a product of very high purity, safety and efficacy with important and attractive properties,” says Werner Gehringer, senior scientist, who was A member of the team from the outset.
The entire team – including research teams in Vienna, Frankfurt and Berlin, and production, quality, pre-clinical, clinical, marketing and regulatory affairs teams – has always had a very good identity and a feeling that they are doing something really worthwhile. “Many people have commented what a great team this is. We trust each other, we stick together. I believe that has been fundamental to keeping the programme on track and it is something everyone can feel very proud of,” says Sigurd.
Although they experienced a few sleepless nights, with endless discussions internally and externally, and with inevitable resourcing and project management pressures, no one gave up. “After so many years, it is gratifying to see that we have reached the point where we are today,” says Werner. “I’m very excited. We all are! Our ultimate goal is to improve the lives of patients.”
Investigación y desarrollo