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Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5–14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5–18 years randomized to receive daily subcutaneous injections for 52 weeks). Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. The exposure–response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 μg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 μg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 μg/kg to patients with achondroplasia aged 5–18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed. NCT02055157, NCT03197766, and NCT01603095.

This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control.In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing.A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward.This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.

Author(s): Savarirayan, Ravi; Tofts, Louise; Irving, Melita; Wilcox, William R; Bacino, Carlos A; Hoover-Fong, Julie; Font, Rosendo Ullot; Harmatz, Paul; Rutsch, Frank; Bober, Michael B; Polgreen, Lynda E; Ginebreda, Ignacio; Mohnike, Klaus; Charrow, Joel; Hoernschemeyer, Daniel; Ozono, Keiichi; Alanay, Yasemin; Arundel, Paul; Kotani, Yumiko; Yasui, Natsuo; White, Klane K; Saal, Howard M; Leiva-Gea, Antonio; Luna-Gonzalez, Felipe; Mochizuki, Hiroshi; Basel, Donald; Porco, Dania M; Jayaram, Kala; Fisheleva, Elena; Huntsman-Labed, Alice; Day, Jonathan RS | Abstract: PurposeAchondroplasia 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.MethodsAfter 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.ResultsIn 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.ConclusionVosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

Summary Background Otilimab is a human monoclonal antibody that inhibits granulocyte–macrophage colony-stimulating factor (GM-CSF), a driver in many immune-mediated inflammatory conditions. We evaluated the effect of otilimab on the GM-CSF–chemokine (C-C motif) ligand 17 (CCL17) axis and synovitis in patients with rheumatoid arthritis. Methods This phase 2a, randomised, double-blind, multicentre, placebo-controlled, parallel-group study was done at nine sites across the USA, Poland, and Germany. Patients aged 18 years or older with rheumatoid arthritis per American College of Rheumatology–European League Against Rheumatism 2010 criteria and receiving stable methotrexate were randomly assigned (3:1) by an interactive response technology system to either subcutaneous otilimab 180 mg or placebo once weekly for 5 weeks, then every other week until week 10 (within a 12-week treatment period), followed by a 10-week safety follow-up. Randomisation was stratified by early rheumatoid arthritis (≤2 years since diagnosis) and established rheumatoid arthritis (>2 years since diagnosis). Patients and study personnel (except for an unblinded coordinator or nurse who prepared and administered the study drug) were blinded to treatment assignment; the syringe was shielded during administration. Patients were enrolled by study investigators and allocated to a treatment by central randomisation on the basis of a schedule generated by the sponsor. The primary endpoint was change over time (assessed at baseline and weeks 1, 2, 4, 6, 8, 12, and 22 of follow-up) in 112 biomarkers, including target engagement biomarkers and those that may be indicative of rheumatoid arthritis disease activity and response to otilimab. Secondary endpoints were change from baseline in synovitis, osteitis and erosion assessed by rheumatoid arthritis MRI scoring system (RAMRIS) and rheumatoid arthritis MRI quantitative score (RAMRIQ), and safety evaluation. The primary, secondary, and safety endpoints were assessed in the intention-to-treat population. Biomarker and MRI endpoints were analysed for differences between treatment groups using a repeated measures model. This study is registered with ClinicalTrials.gov , NCT02799472 . Findings Between Aug 9, 2016, and Oct 30, 2017, 39 patients were randomly assigned and included in the analysis (otilimab n=28; placebo n=11). In the otilimab group, mean serum concentrations of GM-CSF–otilimab complex peaked at week 4 (138·4 ng/L, 95% CI 90·0–212·9) but decreased from week 6–12. CCL17 concentrations decreased from baseline to week 1, remained stable to week 8, and returned to baseline at week 12; least-squares mean ratio to baseline was 0·65 (95% CI 0·49–0·86; coefficient of variation 13·60) at week 2, 0·68 (0·53–0·88; 12·51) at week 4, 0·78 (0·60–1·00; 12·48) at week 6, and 0·68 (0·54–0·85; 11·21) at week 8. No meaningful change in CCL17 concentrations was observed with placebo. In the otilimab group, the least-squares mean ratio to baseline in MMP-degraded type I collagen was 0·86–0·91 over weeks 1–8, returning to baseline at week 12; concentrations remained above baseline at all timepoints in the placebo group. There were no observable differences between otilimab and placebo for all other biomarkers. At week 12, least-squares mean change in RAMRIS synovitis score from baseline was −1·3 (standard error [SE] 0·6) in the otilimab group and 0·8 (1·2) with placebo; RAMRIQ synovitis score showed a least-squares mean change from baseline of −1417·0 μl (671·5) in the otilimab group and −912·3 μl (1405·8) with placebo. Compared with placebo, otilimab did not show significant reductions from baseline to week 12 in RAMRIS synovitis, osteitis and bone erosion, or in RAMRIQ synovitis and erosion damage. Adverse events were reported in 11 (39%) of 28 otilimab-treated and four (36%) of 11 placebo-treated patients, most commonly cough in the otilimab group (2 [7%] of 28; not reported in placebo group), and pain in extremity (four [36%] of 11) and rheumatoid arthritis (two [18%] of 11) in the placebo group (not reported in otilimab group). There were no serious adverse events or deaths. Interpretation Serum concentrations of GM-CSF–otilimab complex indicated that target engagement was achieved with initial weekly dosing, but not sustained with every other week dosing. CCL17 might be a pharmacodynamic biomarker for otilimab activity in future studies. Otilimab was well tolerated and, despite suboptimal exposure, showed some evidence for improved synovitis over 12 weeks in patients with active rheumatoid arthritis. Funding GlaxoSmithKline.

Background Vosoritide increases annualized growth velocity (AGV) in children with achondroplasia aged 5 to 18 years. This global, phase 2, randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of vosoritide on growth in children with achondroplasia aged 3 months to Methods This study compared once-daily subcutaneous administration of vosoritide, at doses of 15 or 30 μg/kg of body weight, with placebo. Eligible patients had participated, for up to 6 months, in an observational growth study to calculate their baseline AGV. The primary objective was to evaluate the safety and tolerability of vosoritide in children with achondroplasia. The primary efficacy evaluation was the change from baseline in height Z-score versus placebo at week 52 using an ANCOVA model. Secondary efficacy analyses included change from baseline in AGV and upper-to-lower body segment ratio versus placebo at Week 52 using an ANCOVA model. Results A total of 75 patients were enrolled, with 11 sentinel subjects who received vosoritide to establish PK and safety. A further 32 were randomized to receive vosoritide and 32 to receive placebo. A total of 73 patients completed the 52-week trial. All patients reported at least one adverse event. Four serious adverse events occurred with vosoritide and 8 with placebo, none were treatment-related. Two participants discontinued, one on vosoritide with pre-existing respiratory morbidity who had a fatal respiratory arrest and one on placebo who withdrew consent. In the full analysis population, vosoritide (n=43) compared to placebo (n=32), increased height Z-score by 0.30 SD (95% CI 0. 07, 0.54); increased AGV by 0.92cm/year (95% CI 0.24, 1.59); and did not worsen upper-to-lower body segment ratio which changed by -0. 06 (95% CI -0.15, 0. 03). Conclusions Daily, subcutaneous administration of vosoritide to young children with achondroplasia was safe and resulted in increases in height Z-score and AGV. (Funded by BioMarin; ClinicalTrials.gov NCT03583697) Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Vosoritide is a drug developed for the treatment of achondroplasia and has demonstrated increases in the growth velocity of children with this condition. Achondroplasia is a skeletal dysplasia (a condition affecting children’s bones and joints meaning they do not grow in the typical way) and is also referred to as dwarfism. There are currently no approved treatments for achondroplasia, except for growth hormone in Japan. When a new drug is being developed, it is essential to conduct clinical studies after many other steps to assess how well the drug works and whether it has any side effects. These studies of new drugs are carried out before the drug is approved to treat, improve, or reduce physical problems of certain conditions. This summary reports the results from two clinical studies looking at vosoritide as a potential treatment for children with achondroplasia. Study A compared different doses of vosoritide to find out which is the safest and shows the best results with the fewest side effects. Study B looked at how well vosoritide works compared with a nonactive medicine (known as a placebo) and the side effects. In these studies, vosoritide increased bone growth velocity in children with achondroplasia. Children receiving the drug every day generally only had mild side effects. Serious health conplications were generally medical events seen in children with achondroplasia even if they do not take vosoritide. No children stopped taking vosoritide during the studies due to safety reasons. How well vosoritide works and the side effects in children over a longer period of time are still being studied. ClinicalTrials.gov NCT numbers: NCT02055157 and NCT03197766 .

Objectives: Vosoritide is a potent stimulator of endochondral bone growth and is in development for the treatment of achondroplasia, the most common form of disproportionate short stature. We previously reported on a 52-week, phase 3, pivotal study that demonstrated a highly statistically significant improvement in annualized growth velocity (AGV) when vosoritide was compared to placebo in children with achondroplasia aged 5-18 years (Savarirayan et al, Lancet, 2020). This is an analysis of data after an additional 52 weeks of treatment in the ongoing phase 3 extension study. Methods: After completion of the phase 3 placebo-controlled study, 119 children were enrolled into the extension study, where they all receive open label 15 μg/kg/day vosoritide. AGV, height Z-score and body proportion ratio were analyzed to assess efficacy of vosoritide in children who were treated with vosoritide for up to 2 years. Fifty-eight continued treatment with vosoritide and 61 switched from placebo to vosoritide. Two participants on continuous vosoritide treatment discontinued before the Week 52 timepoint. Four participants on continuous vosoritide treatment and 7 participants who switched from placebo to vosoritide missed the Week 52 assessment due to Covid-19. Results: In children randomized to receive daily vosoritide, baseline mean (SD) AGV was 4.26 (1.53) cm/year. After the first 52 weeks of treatment, mean (SD) AGV was 5.67 (0.98) cm/year. Mean (SD) AGV over the second year was 5.57 (1.10) cm/year. Mean (SD) change from baseline in height Z-score improved by +0.24 (0.31) at Week 52 in the pivotal study and +0.45 (0.56) at Week 52 in the extension study. Mean (SD) upper-to-lower body segment ratio improved with a change from baseline of -0.03 (0.11) at Week 52 in the pivotal study and -0.09 (0.11) at Week 52 in the extension study. In children who switched from placebo to vosoritide after 52 weeks, baseline AGV was 4.06 (1.20) cm/year and 3.94 (1.07) cm/year after 52 weeks on placebo. In the second year, after receiving 52 weeks of vosoritide, mean AGV was 5.65 (1.47) cm/year, the mean (SD) change in height Z-score was +0.24 (0.34), and the change in upper-to-lower body segment ratio was -0.03 (0.08). No new adverse events associated with vosoritide treatment were detected with up to 2 years of continuous daily, subcutaneous treatment. Most adverse events were mild and no serious adverse events were attributed to vosoritide. The most common adverse event remains mild and transient injection site reactions. Conclusions: The effect of vosoritide administration on growth as measured through AGV and height Z-score was maintained for up to 2-years in children with achondroplasia aged 5 to 18 years, with an improvement of body proportions.

Background The human monoclonal antibody otilimab inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF), a key driver in immune-mediated inflammatory conditions. We aimed to evaluate the efficacy, safety, and key patient-reported outcomes related to pain in patients with active rheumatoid arthritis receiving otilimab. Methods This phase 2b, dose-ranging, multicentre, placebo-controlled study was done at 64 sites across 14 countries. Patients aged 18 years or older with rheumatoid arthritis who were receiving stable methotrexate were randomly assigned (1:1:1:1:1:1) to subcutaneous placebo or otilimab 22·5 mg, 45 mg, 90 mg, 135 mg, or 180 mg, plus methotrexate, once weekly for 5 weeks, then every other week until week 50. The randomisation schedule was generated by the sponsor, and patients were assigned to treatment by interactive response technology. Randomisation was blocked (block size of six) but was not stratified. Investigators, patients, and the sponsor were blinded to treatment. An unblinded administrator prepared and administered the study drug. The primary endpoint was the proportion of patients who achieved disease activity score for 28 joints with C-reactive protein (DAS28-CRP) 3·2 (week 24) escaped to otilimab 180 mg. Patients who escaped were treated as non-responders in their original assigned group. Safety endpoints were incidence of adverse events and serious adverse events, infections, and pulmonary events. Efficacy and safety outcomes were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02504671. Findings Between July 23, 2015, and Dec 29, 2017, 222 patients were randomly assigned (37 to each group). 86 (49%) of 175 escaped to otilimab 180 mg at week 12 and 57 (69%) of 83 at week 24. At week 24, the proportion of patients with DAS28-CRP Interpretation Otilimab plus methotrexate was well tolerated and, despite not achieving the primary endpoint of DAS28-CRP remission, there were improvements compared with placebo in disease activity scores. Of note, patients reported significant improvement in pain and physical function, supporting further clinical development of otilimab in rheumatoid arthritis.

Background: Achondroplasia is a disorder caused by specific mutations in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) protein. Open-label, phase 2 trials in children with achondroplasia showed that administration of vosoritide, an analogue of C-natriuretic peptide, resulted in sustained increases in annualized growth velocity. Methods: This international, randomized, double-blind, phase 3 trial compared once-daily subcutaneous administration of vosoritide, at a dose of 15 μg per kg of body weight, with placebo in children with achondroplasia aged 5 to

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

Achondroplasia causes narrowing of the foramen magnum and the spinal canal leading to increased mortality due to cervicomedullary compression in infants and significant morbidity due to spinal stenosis later in adulthood. Vosoritide is a C-natriuretic peptide analogue that has been shown to improve endochondral ossification in children with achondroplasia. The objective of this trial is to evaluate the safety of vosoritide and whether vosoritide can improve the growth of the foramen magnum and spinal canal in children that may require decompression surgery. An Achondroplasia Foramen Magnum Score will be used to identify infants at risk of requiring decompression surgery. This is a 2-year open label randomized controlled trial of vosoritide in infants with achondroplasia ages 0 to ≤12 months. Approximately 20 infants will be randomized 1:1 to either open label once daily subcutaneous vosoritide combined with standard of care or standard of care alone. The primary and secondary aims of the study are to evaluate the safety and efficacy of vosoritide in children with cervicomedullary compression at risk of requiring decompression surgery. The trial will be carried out in specialized skeletal dysplasia treatment centers with well established multidisciplinary care pathways and standardized approaches to the neurosurgical management of cervicomedually compression. After 2 years, infants randomized to standard of care alone will be eligible to switch to vosoritide plus standard of care for an additional 3 years. This pioneering trial hopes to address the important question as to whether treatment with vosoritide at an early age in infants at risk of requiring cervicomedullary decompression surgery is safe, and can improve growth at the foramen magnum and spinal canal alleviating stenosis. This in turn may reduce compression of surrounding structures including the neuraxis and spinal cord, which could alleviate future morbidity and mortality. Trial registrations: ClinicalTrials.gov, NCT04554940; EudraCT number, 2020-001055-40

Overview. The GiACTA trial is a multicenter, randomized, double-blind, and placebo-controlled study designed to test the ability of tocilizumab (TCZ), an interleukin (IL)-6 receptor antagonist, to maintain disease remission in patients with giant cell arteritis (GCA).Design. Approximately 100 centers will enroll 250 patients with active disease. The trial consists of a 52-week blinded treatment phase followed by 104 weeks of open-label extension. Patients will be randomized into one of four groups. Group A (TCZ 162 mg weekly plus a 6-month prednisone-taper); group B (TCZ 162 mg every other week plus a 6-month prednisone-taper); group C (placebo plus a 6-month prednisone-taper); and group D (placebo plus a 12-month prednisone taper). We hypothesize that patients assigned to TCZ in addition to a 6-month prednisone course are more likely to achieve the primary efficacy endpoint of sustained remission (SR) at 52 weeks compared with those assigned to a 6-month prednisone course alone, thus potentially minimizing the long-term adverse effects of corticosteroids.Conclusion. GiACTA will test the hypothesis that interference with IL-6 signaling exerts a beneficial effect on patients with GCA. The objective of this paper is to describe the design of the trial and address major issues related to its development.