A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures
Authors: Dina Miklic
Tomislav Vlahovic
Snjezana Martinovic
Ismet Gavrankapetanovic
Tatjana Bordukalo-Niksic
Mehmed Jamakosmanovic
Hermann Oppermann
Slobodan Vukicevic
T Kuber Sampath
Sanja Pehar
Mihaela Peric
Lovorka Grgurevic
Dragan Durdevic
Milan Milosevic
Journal: Bone (2020)
Discipline: CLINICAL MEDICINE
Keywords: BMPs; Clinical trials; Implants; Injury/fracture healing.
Affiliations: Clinical Hospital Center "Sisters of Mercy", Clinic of Traumatology, Draskoviceva 19, 10000 Zagreb, Croatia., Laboratory for Mineralized Tissues, Centre for Translational and Clinical Research, University of Zagreb School of Medicine, Salata 11, 10000 Zagreb, Croatia., Genera Research, Svetonedeljska 2, Kalinovica, 10436, Rakov Potok, Croatia., University Clinical Center Sarajevo, Clinic of Orthopedics and Traumatology, Bolnicka 25, 71000 Sarajevo, Bosnia and Herzegovina., School of Public Health "Andrija Stampar", University of Zagreb School of Medicine, Rockefellerova 4, 10000 Zagreb, Croatia., SmartMedico, Zupanova 5, 10000 Zagreb, Croatia., perFormBiologics Inc., Holliston, MA 01746, USA., Department for Intracellular Communication, Centre for Translational and Clinical Research, University of Zagreb School of Medicine, Salata 2, 10000 Zagreb, Croatia., Laboratory for Mineralized Tissues, Centre for Translational and Clinical Research, University of Zagreb School of Medicine, Salata 11, 10000 Zagreb, Croatia. Electronic address: .

Abstract:  Bone morphogenetic proteins (BMPs) are known to induce new bone formation in vivo but treating trabecular bone defects with a BMP based therapeutic remains controversial. Here, we evaluated the safety and efficacy of a novel Autologous Bone Graft Substitute (ABGS) comprised of recombinant human BMP6 (rhBMP6) dispersed within an autologous blood coagulum (ABC) as a physiological natural carrier in patients with a closed distal radial fracture (DRF). We enrolled 32 patients in a randomized, standard of care (SoC) and placebo (PBO) controlled, double-blinded Phase I First in Human (FiH) clinical trial. ABGS was prepared from peripheral blood as 250 Œºg rhBMP6/mL ABC or PBO (1 mL ABC containing excipients only) and was administered dorsally via a syringe injection into the fracture site following closed fracture fixation with 3 Kirschner wires. Patients carried an immobilization for 5 weeks and were followed-up for 0 to 26 weeks by clinical examination, safety, serial radiographic analyses and CT. During the 13 weeks follow-up and at 26 weeks post study there were no serious adverse reactions recorded. The results showed that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 32 patients at 13- and 26-weeks following treatment. Pharmacokinetic analyses of plasma from patients treated with ABGS showed no detectable rhBMP6 at any time point within the first 24 h following administration. The CT image and radiographic analyses score from patients treated with AGBS showed significantly accelerated bone healing as compared to PBO and SoC at 5 and 9 weeks (with high effect sizes and P = 0.027), while at week 13 all patients had similar healing outcomes. In conclusion, we show that intraosseous administration of ABGS (250 Œºg rhBMP6/mL ABC) into the distal radial fracture site demonstrated a good tolerability with no serious adverse reactions as well as early accelerated trabecular bone healing as compared to control PBO and SoC patients. 

Retracted: No

PubPeer comments:
 An overall interesting report - but it seems to me that the authors were overtly  enthusiastic with their  efficacy claims . I think that inappropriate method for data analysis was used resulting in an artifact suggesting a particular treatment effect. I wrote a letter to the Editor documenting my views. The reply by the authors was sensless, i.e., full of  statements and not providing a single argument against my comments (comments and authors reply are available - 10.13140 RG.2.2.12938.90563 1) - still, the Editors of the Bone journal decided not to publish my comment. Would be grateful to anyone pointing-out to me whether indeed I  missed the point about this trial. , 
 The document link seems to be broken. Can the authors or Vladimir Trkulja provide the correspondence? , 
 #2 for some reason, which I am not aware of, ResearchGate decided to remove my comment. v. trkulja ,