Cardiac Amyloid Detection by PET/CT Imaging of Iodine (124I) Evuzamitide (124I-p5+14): A Phase 1/2 Study.

BACKGROUND: The noninvasive detection of cardiac amyloid, as well as deposits in other vital organs, is critical for early diagnosis and quantitative disease monitoring. Positron emission tomography is an intrinsically quantitative imaging modality suitable for high-resolution amyloid detection. OBJECTIVES: This study sought to evaluate the safety and efficacy of a novel amyloid-reactive peptide, designated p5+14, labeled with iodine-124 (124I), in patients with diverse types of systemic amyloidosis. METHODS: In a single-site, open label phase 1/2 study (NCT03678259), the safety, biodistribution, and sensitivity of a single intravenous infusion of 124I-evuzamitide was assessed in patients with systemic amyloidosis (n = 50), asymptomatic transthyretin sequence variant carriers (n = 2), and healthy volunteers (n = 5). Subjects were administered 1.4 ± 0.2 mg of 124I-evuzamitide (71.5 ± 12.4 MBq) and positron emission tomography/x-ray computed tomography images acquired at 5.2 hours (Q25-Q75: 4.9-5.4 hours) postinfusion. Images were assessed visually and semi-quantitatively for positive uptake of radiotracer in the heart and other major organs. RESULTS: Uptake of 124I-evuzamitide in the heart and other abdominothoracic organs was consistent with the patient's clinical presentation and the type of amyloidosis. The patient- and cardiac-associated sensitivity for imaging and clinical observations was 93.6% (95% CI: 82.8%-97.8%) and 96.2% (95% CI: 81.8%-99.8%), respectively. Semi-quantitative uptake of the radiotracer correlated significantly with serum N-terminal pro-B-type natriuretic peptide measurements in patients with light chain-associated amyloidosis. Cardiac uptake was not observed in any healthy volunteers. The agent was well tolerated, with 1 drug-related adverse event and no deaths. CONCLUSIONS: 124I-evuzamitide is an amyloid-binding radiotracer capable of detecting cardiac amyloid in patients with high sensitivity.

Clinical Confirmation of Pan-Amyloid Reactivity of Radioiodinated Peptide 124I-p5+14 (AT-01) in Patients with Diverse Types of Systemic Amyloidosis Demonstrated by PET/CT Imaging.

There are at least 20 distinct types of systemic amyloidosis, all of which result in the organ-compromising accumulation of extracellular amyloid deposits. Amyloidosis is challenging to diagnose due to the heterogeneity of the clinical presentation, yet early detection is critical for favorable patient outcomes. The ability to non-invasively and quantitatively detect amyloid throughout the body, even in at-risk populations, before clinical manifestation would be invaluable. To this end, a pan-amyloid-reactive peptide, p5+14, has been developed that is capable of binding all types of amyloid. Herein, we demonstrate the ex vivo pan-amyloid reactivity of p5+14 by using peptide histochemistry on animal and human tissue sections containing various types of amyloid. Furthermore, we present clinical evidence of pan-amyloid binding using iodine-124-labeled p5+14 in a cohort of patients with eight (n = 8) different types of systemic amyloidosis. These patients underwent PET/CT imaging as part of the first-in-human Phase 1/2 clinical trial evaluating this radiotracer (NCT03678259). The uptake of 124I-p5+14 was observed in abdominothoracic organs in patients with all types of amyloidosis evaluated and was consistent with the disease distribution described in the medical record and literature reports. On the other hand, the distribution in healthy subjects was consistent with radiotracer catabolism and clearance. The early and accurate diagnosis of amyloidosis remains challenging. These data support the utility of 124I-p5+14 for the diagnosis of varied types of systemic amyloidosis by PET/CT imaging.

First in Human Evaluation and Dosimetry Calculations for Peptide 124I-p5+14-a Novel Radiotracer for the Detection of Systemic Amyloidosis Using PET/CT Imaging.

PURPOSE: Accurate diagnosis of amyloidosis remains a significant clinical challenge and unmet need for patients. The amyloid-reactive peptide p5+14 radiolabeled with iodine-124 has been developed for the detection of amyloid by PET/CT imaging. In a first-in-human evaluation, the dosimetry and tissue distribution of 124I-p5+14 peptide in patients with systemic amyloidosis. Herein, we report the dosimetry and dynamic distribution in the first three enrolled patients with light chain-associated (AL) amyloidosis. PROCEDURES: The radiotracer was assessed in a single-site, open-label phase 1 study (NCT03678259). The first three patients received a single intravenous infusion of 124I-p5+14 peptide (≤37 MBq). Serial PET/CT imaging was performed during the 48 h post-infusion. Dosimetry was determined as a primary endpoint for each patient and gender-averaged mean values were calculated. Pharmacokinetic parameters were estimated from whole blood radioactivity measurements and organ-based time activity data. Lastly, the biodistribution of radiotracer in major organs was assessed visually and compared to clinically appreciated organ involvement. RESULTS: Infusion of the 124I-p5+14 was well tolerated with rapid uptake in the heart, kidneys, liver, spleen, pancreas, and lung. The gender-averaged whole-body effective radiation dose was estimated to be 0.23 (± 0.02) mSv/MBq with elimination of the radioactivity via renal and gastrointestinal routes. The whole blood elimination t1/2 of 21.9 ± 7.6 h. Organ-based activity concentration measurements indicated that AUClast tissue:blood ratios generally correlated with the anticipated presence of amyloid. Peptide uptake was observed in 4/5 clinically suspected organs, as noted in the medical record, as well as six anatomic sites generally associated with amyloidosis in this population. CONCLUSION: Peptide 124I-p5+14 rapidly distributes to anatomic sites consistent with the presence of amyloid in patients with systemic AL. The dosimetry estimates established in this cohort are acceptable for whole-body PET/CT imaging. Pharmacokinetic parameters are heterogeneous and consistent with uptake of the tracer in an amyloid compartment. PET/CT imaging of 124I-p5+14 may facilitate non-invasive detection of amyloid in multiple organ systems.

Acetabular and femoral remodeling after varus derotational osteotomy in cerebral palsy: the effect of age and Gross Motor Function Classification Level.

UNLABELLED: This study investigated the degree of acetabular and femoral remodeling after isolated varus derotation osteotomy (VDRO) in children with cerebral palsy. This retrospective review investigated 56 children (103 hips) who underwent VDROs for spastic hip displacement between 1994 and 2007. The average age of the patients at surgery was 7.7 years and the follow-up duration was 7.8 years (range 5-11 years). The acetabular index showed a significant linear decrease (P<0.001), with children of less than 6 years showing the greatest correction (P<0.001). VDRO without pelvic osteotomy does result in a mild improvement in acetabular dysplasia over time, with greater rates of correction found in children of less than 6 years old. LEVEL OF EVIDENCE: Therapeutic Study - Level IV.

Proximal Femoral Varus Derotation Osteotomy in Children with Cerebral Palsy: The Effect of Age, Gross Motor Function Classification System Level, and Surgeon Volume on Surgical Success.

BACKGROUND: The purpose of this study was to evaluate mid-term results of proximal femoral varus derotation osteotomy (VDRO) in children with cerebral palsy and determine what effect age, Gross Motor Function Classification System (GMFCS) level, and surgeon volume had on surgical success. METHODS: We analyzed a cohort of children with cerebral palsy who underwent VDRO for hip displacement at a tertiary-level pediatric hospital between 1994 and 2007. Age, sex, GMFCS level, preoperative radiographic parameters, previous botulinum toxin administration or soft-tissue release, adjunctive pelvic osteotomy, the performance of bilateral surgery at the index VDRO, and surgeon volume (the number of procedures performed) were recorded. Results were analyzed via univariate and multivariate analyses for association with the need for revision hip surgery. Kaplan-Meier survivorship curves were generated, determining the time from index surgery to failure (defined as the need for subsequent surgical procedures on the hip and/or pelvis, or a hip migration percentage of >50% at the time of final follow-up), and were further stratified according to osseous versus soft-tissue revision. RESULTS: A total of 567 VDROs were performed in 320 children (mean age [and standard deviation], 8.2 ± 3.8 years). The mean follow-up was 8.3 years (range, three to eighteen years). Of the initial 320 patients, 117 (37%) were considered to have had failure. Multivariate Cox regression analysis confirmed that younger age at surgery (p < 0.001), increased GMFCS level (p = 0.01), and lower annual surgical hip volume (p = 0.02) were significant independent predictors of any type of surgical revision. Furthermore, soft-tissue release at VDRO was protective against revision (p = 0.02). Five-year survivorship analysis revealed a 92% success rate for children classified as GMFCS levels I and II compared with a 76% success rate for those of GMFCS level V (p < 0.01). CONCLUSIONS: This study demonstrated a 37% failure rate after VDRO in children with cerebral palsy. Older age, lower GMFCS level, and increased surgeon volume were strong predictors of surgical success.