The discovery and characterization of the anticoagulant protein factor pathway inhibitor (TFPI) has led to the realization that inhibiting TFPI activity could restore functional hemostasis through the extrinsic pathway of blood clotting in a way that does not require the activity of factors VIII or IX. Neutralization of TFPI can restore disordered thrombin generation and, therefore, inhibition of TFPI is an attractive concept for hemostatic control in hemophilia.
The first TFPI inhibitor designed for this purpose was a nucleic acid aptamer, BAX 499, which specifically binds TFPI. Phase 1 studies revealed, however, that the number of bleeding episodes increased in the higher dose cohort. This appears to be due to a 25-fold increase in full-length TFPI plasma concentration and resulted in the discontinuation of the clinical trial.
The second class of therapeutics based on TFPI inhibition involves anti-TFPI monoclonal antibodies, which are currently under clinical investigation.
Although many big names like Novo Nordisk, Bayer, Baxter have embarked on the development of drugs for haemophilia with the TFPI mechanism but discontinued their program due to drug-related adverse events.
On 15th Oct 2019, Bayer ended Phase II trial of BAY 1093884 (anti-TFPi antibody) in Hemophilia (NCT03597022). In addition, they also withdrew a phase I trial in Haemophilia prior to enrolment in USA and Ukraine (SC) (NCT03996486) in 22nd Oct 2019
On March 17, 2020, NovoNordisk suspended concizumab (anti-TFPI mAb) in hemophilia A and B due to non-fatal thrombotic events in 3 patients in ongoing ph3 studies started 4Q2019. They suspended two clinical studies in the concizumab phase 3 program (explorer7 and 8) and one clinical study in the phase 2 program (explorer5) for the prophylactic treatment of patients with hemophilia A and B regardless of their inhibitor status.
“While it is disappointing to pause the trials, patient safety is of utmost importance to Novo Nordisk – both for those taking part in our clinical trials and those who use our products on a daily basis” said Mads Krogsgaard Thomsen, executive vice president and chief science officer of Novo Nordisk. “Together with relevant authorities, we will now carefully evaluate all available data and decide how to best move forward”.
Novo Nordisk and an independent data monitoring committee are currently assessing the relevance of the events for the continuation of the program and no conclusions have yet been drawn.
Novo Nordisk did not provide any further details on the side effects that the patients had, except to say that they were not fatal. The company said the connection between the side effects that prompted it to stop concizumab trials and the drug was still unclear and that an evaluation of the data would determine whether the program could continue.
A single ray of light
Now all eyes are on the Pfizer trial NCT03938792, which will study the efficacy and safety of PF-06741086 in adult and adolescent patients with severe hemophilia A or B.
Would PF-06741086 Ph3 started this month experience similar safety issue?