Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study.

PURPOSE: Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported. METHODS: After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 µg/kg/day. RESULTS: In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected. CONCLUSION: Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial.

BACKGROUND: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings. METHODS: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 µg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11. FINDINGS: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred. INTERPRETATION: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be. FUNDING: BioMarin Pharmaceutical.

Staged upper and lower limb lengthening performing bilateral simultaneous surgery of the femur and tibia in achondroplastic patients.

INTRODUCTION: Surgical lengthening and angular correction of the limbs are an option for treating the orthopedic clinical manifestations in patients with achondroplasia. This study assesses a staged limb lengthening protocol, performing simultaneous bilateral lengthening of the femur and tibia (stage I [S1]), and humeral lengthening (stage II [S2]). MATERIALS AND METHODS: Twenty-one achondroplastic patients were included in this study, and 106 segments (34 femurs, 34 tibias and 38 humeri) were lengthened. Achondroplasia patients with a growth curve below the mean of the standard growth curves for achondroplasia were included in S1. The remaining patients were included directly in S2. Variables analyzed included anthropometric measurements, lengthening outcomes, difficulties, and functionality. RESULTS: Of the all patients included in the protocol, 15 patients completed S1 and S2, 4 only completed S2, and 2 only completed S1. Height and limb-trunk ratio before S1 were 107.65 ± 7.14 cm and 1.89 ± 0.10 and after S1 were 126.50 ± 9.19 cm and 1.64 ± 0.09, respectively. Limbs were lengthened 14.43 ± 1.41 cm (femurs and tibias) for S1 and 9.95 ± 0.60 cm for S2 (humeri), with a stage healing index of 18.23 ± 3.54 in S1 and 28.92 ± 4.42 in S2. Correction of lower angular deviations, functional improvement, and a controlled complications rate were achieved in all patients. CONCLUSIONS: The limb lengthening protocol proposed in this study is a suitable treatment for achondroplasia patients to achieve the agreed-upon objectives (limb-trunk ratio, improved functionality, and lower limb alignment). The reproducibility of the procedure and patient safety were upheld.

Simultaneous anterior and posterior compression of the pelvic ring with external fixation using a pre-tensed curved bar: A biomechanical study.

INTRODUCTION: External fixators continue to be essential tools in the urgent treatment of pelvic fractures for compression and stabilization of the pelvic ring. Current systems fail to produce simultaneous anterior and posterior compression. A modified application of an existing curved bar fixator is proposed using a specifically designed tensioner to pre-tense the bar prior to its connection to Schanz screws. Subsequent pre-tension release and elastic recovery of the bar could potentially compress the pelvis. The aim of this work was to determine if the modified application could produce greater simultaneous compression across the sacroiliac joint and the symphysis of an unstable fractured pelvis than the standard application without pretension. MATERIALS AND METHODS: Six synthetic pelvis models with symphyseal and unilateral sacroiliac joints disruptions, simulating a Tile type C pelvic ring fracture, were used. Each specimen was stabilized using two 5mm×250mm supra-acetabular Schanz pins, a couple of open adjustable clamps and a semicircular carbon fibre rod applied without and with pre-tension. Two distances from bar to bone and three levels of pretension were compared. Each pelvis was tested with the six possible parameter combinations. Compressive forces at the disrupted joints were measured using pressure sensitive film sensors. RESULTS: The modified application produced forces significantly higher than the minimal compression achieved with standard application. At the sacroiliac joint, after pre-tension release, mean compressive forces measured ranged from 28.7 to 85.6N. The closest bar-to-bone distance always produced a significantly higher force; similarly, a significant increase in compression was found as the pre-tension level rose. At the symphysis, mean compressive forces between 35.3N and 49.0N were determined. No significant variations were seen with changes of any of the two factors analyzed CONCLUSIONS: To pre-tense a semi-circular bar before its use for external fixation of the fractured pelvis, is an effective means of applying compression simultaneously through the sacroiliac joint and the symphysis. The proposed method generates the highest compressive forces at the sacroiliac joint when the rod is subject to the highest pre-tension level not producing subluxation and is subsequently positioned as close as possible to the bone depending on patient's condition.

Pulsed electromagnetic stimulation of regenerate bone in lengthening procedures.

Distraction osteogenesis for limb lengthening represents the treatment of choice in patients with small stature or limb length discrepancies. Bone lengthening and callus formation requires a long therapy. Pulsed electromagnetic fields (PEMF) are normally used to enhance osteogenesis in patients with non-unions. In this study we investigated whether pulsed electromagnetic fields could be used effectively to encourage callus formation and maturation during limb lengthening procedures. Thirty patients underwent bilateral bone lengthening of the humerus, femur or tibia. At day 10 after surgery, PEMF stimulation was started on one side, for 8 hours/day. Stimulated distraction sites exhibited earlier callus formation and progression, and a higher callus density compared to non-stimulated sites. External fixation could be removed on average one month earlier in PEMF stimulated bones. Our results show that the use of pulsed electromagnetic fields stimulation during limb lengthening allows shortening the time of use of the external fixation.