Phase I IND-enabling studies for the amyloid-imaging peptide p5+14 (Api1832) - a novel agent for the detection of systemic amyloidosis

• Published in: The Journal of nuclear medicine (1978) Vol. 59; p. 1804
• Main Authors: Stuckey, Alan, Williams, Angela, Richey, Tina, Moody, Carmella, Kennel, Steve, Wall, Jonathan
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01-05-2018
• Subjects: Acetonitrile; Amino acids; Amyloidosis; Ascorbic acid; Biological activity; Computed tomography; Diagnosis; Fibrils; Gas chromatography; High performance liquid chromatography; Human serum albumin; Liquid chromatography; Medical diagnosis; Medical imaging; Patients; Peptides; Positron emission; Proteins; Safety; Serum albumin; Substrates; Systemic diseases; Tomography; β-Amyloid; United States > US
• ISSN: 0161-5505; 1535-5667

Objectives: here are approximately 4,500 new cases each year of systemic amyloidosis in the US. Despite decades of active research that have increased our understanding of this devastating disease, systemic amyloidosis remains a poorly-diagnosed and, for this reason, a generally incurable disease. Due to the complexity of the disease and its low prevalence in the population, a correct diagnosis of amyloidosis can take many years. Consequently, the prognosis for patients is poor with a median survival of three years or less from diagnosis. Presently there are no FDA approved methods for imaging systemic amyloidosis in these patients although in major imaging centers Aβ amyloid imaging agents are being employed with variable efficacy. To address this we have developed a synthetic 45 all-L-amino acid peptide that, in preclinical studies binds many of the 30 diverse forms of systemic amyloidosis (Molecules. 2015; 20(5):7657-82). In preparation for an investigational new drug (IND) application to the US FDA for a single-site Phase I PET/CT imaging study of 124I-labeled peptide p5+14 we have characterized the peptide in preparation for developing appropriate release criteria for efficacy and safety. Peptide p5+14 drug substance, synthesized by Ambiopharm Inc, is ~95% pure based on HPLC profiling. The peptide was deemed safe In a single IV dose safety study in male and female rats using 50x and 100x the human equivalent dose. No adverse events were seen and the MTD and NOAEL were considered to be >17.6 mg/Kg. Peptide was radiolabeled using 2 mg of peptide and 5 mCi to yield a mono-iodonated preparation with a specific activity of <2.5 mCi/mg. Chromatographic evaluation of the drug intermediate, following sterile filtration, was used to determine the peptide concentration. The preparation was >90% pure and eluted as a single radioactive species with >90% radiopurity. Residual acetonitrile was <410 ppm by gas chromatography. The formulated peptide (in sterile PBS with 5% human serum albumin and 0.5 mg/mL ascorbic acid) was shown to be sterile (TSB and FTM media), particulate free, and with an endotoxin level of <175 EU/dose. Bioactivity of the formulated drug product was evidenced by >60% reactivity in a pull-down assay using synthetic human amyloid fibrils as the substrate and was deemed compatible with storage and delivery systems in a hold-up assay. The process we have developed for the production of 124I-p5+14 peptide drug product results in a sterile, endotoxin-free, mono-iodinated species with peptide carrier. The drug is bioactive with >90% radiopurity and peptide purity. We anticipate beginning the Phase I PET/CT exploratory study in patients with diverse forms of systemic amyloidosis in April 2018.