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1. Real world safety of methoxyflurane analgesia in the emergency setting: a comparative hybrid prospective-retrospective post-authorisation safety study

Author

Nawab Qizilbash, Himanshu Kataria, Heather Jarman, Ben Bloom, Michelle Bradney, Maggie Oh, Sue Anne Yee, Ana Roncero, Ignacio Mendez, and Stuart Pocock

Subjects
Analgesia, Emergency department, Hepatotoxicity, Nephrotoxicity, Safety, Special situations and conditions, RC952-1245, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Low-dose analgesic methoxyflurane (Penthrox®) was approved in Europe for emergency relief of moderate to severe pain in conscious adults with trauma in 2015. A comparative post-authorisation safety study (PASS) was conducted to assess the risk of hepatotoxicity and nephrotoxicity with methoxyflurane during routine clinical practice. Methods This was a comparative hybrid prospective-retrospective cohort study. The comparative cohorts consisted of adults who were given methoxyflurane (methoxyflurane cohort) or another analgesic (concurrent cohort) routinely used for moderate to severe trauma and associated pain in the emergency setting (ambulance and Emergency Department) in the UK between December 2016 and November 2018. Hepatic and renal events were captured in the ensuing 12 weeks. A blinded clinical adjudication committee assessed events. A historical comparator cohort (non-concurrent cohort) was identified from patients with fractures in the English Hospital Episode Statistics (HES) accident and emergency database from November 2013 and November 2015 (before commercial launch of methoxyflurane). Hepatic and renal events were captured in the ensuing 12 weeks via linkage with the Clinical Practice Research Datalink (CPRD) and HES hospital admissions databases. Results Overall, 1,236, 1,101 and 45,112 patients were analysed in the methoxyflurane, concurrent and non-concurrent comparator cohorts respectively. There was no significant difference in hepatic events between the methoxyflurane and concurrent cohorts (1.9% vs. 3.0%, P = 0.079) or between the methoxyflurane and non-concurrent cohorts (1.9% vs. 2.5%, P = 0.192). Renal events were significantly less common in the methoxyflurane cohort than in the concurrent cohort (2.3% vs. 5.6%, P

Published
2023
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2. First clinical study of a pegylated diabody 124I-labeled PEG-AVP0458 in patients with tumor-associated glycoprotein 72 positive cancers

Author

Peter J. Hudson, Pece Kocovski, Ian D. Davis, John Pedersen, Andrew M. Scott, Sze Ting Lee, Scott Williams, Fook-Thean Lee, Graeme O'Keefe, Tim Akhurst, Andrew Weickhardt, Hui K Gan, Michael Paul Wheatcroft, Maggie Oh, Marika Ciprotti, Fiona Scott, Sylvia J. Gong, Linda Mileshkin, Kunthi Pathmaraj, Nancy Guo, Declan G. Murphy, and Rodney J. Hicks

Subjects
0301 basic medicine, Male, Antibodies, Neoplasm, medicine.medical_treatment, PET imaging, Medicine (miscellaneous), Pharmacology, Iodine Radioisotopes, Mice, 0302 clinical medicine, first-in-human, Neoplasms, Positron Emission Tomography Computed Tomography, Antibodies, Bispecific, Tissue Distribution, Infusions, Intravenous, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), medicine.diagnostic_test, Recombinant Proteins, Positron emission tomography, TAG-72, 030220 oncology & carcinogenesis, Radioimmunotherapy, Female, Tumor-associated glycoprotein 72, Research Paper, Adult, Biodistribution, Biological Availability, Antineoplastic Agents, pegylated diabody, 03 medical and health sciences, Pharmacokinetics, Antigens, Neoplasm, Cell Line, Tumor, medicine, Animals, Humans, biodistribution, Dose-Response Relationship, Drug, business.industry, Cancer, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, PEGylation, Feasibility Studies, Radiopharmaceuticals, Ovarian cancer, business, Single-Chain Antibodies
Abstract

Through protein engineering and a novel pegylation strategy, a diabody specific to tumor-associated glycoprotein 72 (TAG-72) (PEG-AVP0458) has been created to optimize pharmacokinetics and bioavailability to tumor. We report the preclinical and clinical translation of PEG-AVP0458 to a first-in-human clinical trial of a diabody. Methods: Clinical translation followed characterization of PEG-AVP0458 drug product and preclinical biodistribution and imaging assessments of Iodine-124 trace labeled PEG-AVP0458 (124I-PEG-AVP0458). The primary study objective of the first-in-human study was the safety of a single protein dose of 1.0 or 10 mg/m2 124I-PEG-AVP0458 in patients with TAG-72 positive relapsed/ metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor uptake, pharmacokinetics and immunogenicity. Patients were infused with a single-dose of 124I labeled PEG-AVP0458 (3-5 mCi (111-185 MBq) for positron emission tomography (PET) imaging, performed sequentially over a one-week period. Safety, pharmacokinetics, biodistribution, and immunogenicity were assessed up to 28 days after infusion. Results: PEG-AVP0458 was radiolabeled with 124I and shown to retain high TAG-72 affinity and excellent targeting of TAG-72 positive xenografts by biodistribution analysis and PET imaging. In the first-in-human trial, no adverse events or toxicity attributable to 124I-PEG-AVP0458 were observed. Imaging was evaluable in 5 patients, with rapid and highly specific targeting of tumor and minimal normal organ uptake, leading to high tumor:blood ratios. Serum concentration values of 124I-PEG-AVP0458 showed consistent values between patients, and there was no significant difference in T½α and T½β between dose levels with mean (± SD) results of T½α = 5.10 ± 4.58 hours, T½β = 46.19 ± 13.06 hours. Conclusions: These data demonstrates the safety and feasibility of using pegylated diabodies for selective tumor imaging and potential delivery of therapeutic payloads in cancer patients.

Published
2020

3. Prior authorization restrictions on medications for opioid use disorder: trends in state laws from 2005 to 2019

Author

Barbara Andraka-Christou, Olivia Golan, Rachel Totaram, Maggie Ohama, Brendan Saloner, Adam J. Gordon, and Bradley D. Stein

Subjects
Buprenorphine, methadone, naltrexone, opioid use disorder, medication-assisted treatment, prior authorization, Medicine
Abstract

AbstractResearch objective Medications for opioid use disorder (MOUDs) – including methadone, buprenorphine, and naltrexone – are the most effective treatments for opioid use disorder (OUD). Historically, insurers have required prior authorization for MOUD, but prior authorization is often reported as a key barrier to MOUD prescribing. Some states have passed laws prohibiting MOUD prior authorization requirements. We sought to identify the frequency of MOUD prior authorization prohibitions in state laws and to categorize types of prohibitions.Methods We searched for regulations and statutes present in all U.S. states and Washington DC between 2005 and 2019 using MOUD-related terms in Westlaw legal software. In qualitative software, we coded laws discussing MOUD prior authorization using template analysis – a mixed deductive/inductive approach. Finally, we used coded laws to identify frequencies of states with prior authorization prohibitions, including changes over time.Results No states had laws prohibiting MOUD prior authorization between 2005 and 2015, with the first prohibition appearing in 2016. By 2019, fifteen states had MOUD prior authorization prohibitions. States varied significantly in their approach to prohibiting MOUD prior authorization. In 2019, it was more common for states to have MOUD prior authorization prohibitions applying to all insurers (n = 10 states) than to only Medicaid (n = 7 states) or only non-Medicaid insurers (n = 1 state). In 2019, general prior authorization prohibitions (n = 10 states) were more common than prohibitions only applicable to medications on the formulary, prohibitions only applicable to medications on the preferred drug list, prohibitions only applicable during the first 5 days of treatment, and prohibitions only applicable during the first 30 days of treatment.Conclusions The number of states with an MOUD prior authorization law prohibition increased in recent years. Such laws could help expand access to life-saving OUD treatments by making it easier for clinicians to prescribe MOUD.KEY MESSAGESNo states had MOUD prior authorization prohibitions between 2005 and 2015 in state statutes or regulations, and only one state had such a prohibition in 2016.By 2019, fifteen states had an MOUD prior authorization prohibition law.States varied significantly in their approach to prohibiting MOUD prior authorization, including with respect to the insurer type, duration of the prohibition, and applicable medication.

Published
2023
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4. Abstract CT238: Phase I safety and biodistribution study of 124I-PEG-AVP0458 diabody in patients with TAG-72 positive ovarian and prostate cancer

Author

Ian D. Davis, Rod Hicks, Fook-Thean Lee, Scott Williams, Hui K Gan, Graeme O'Keefe, Andrew M. Scott, Linda Mileshkin, Maggie Oh, Kunthi Pathmaraj, Declan G. Murphy, Nancy Guo, Sze Ting Lee, Tim Akhurst, Pece Kocovski, Andrew Weickhardt, Marika Ciprotti, Sylvia J. Gong, Peter J. Hudson, and Michael Paul Wheatcroft

Subjects
Oncology, Cancer Research, Biodistribution, Pathology, medicine.medical_specialty, business.industry, Immunogenicity, Cancer, medicine.disease, Prostate cancer, medicine.anatomical_structure, Pharmacokinetics, In vivo, Prostate, Internal medicine, medicine, Ovarian cancer, business
Abstract

Background: The development of antibody therapeutics for imaging and payload delivery is complex, and intact IgG have long half-lives that impact on tumor:blood ratios and tumor penetrance. Smaller molecular weight antibody constructs (eg diabodies) have been developed for improved penetrance into tumor, faster blood clearance, and enhanced tumor: normal tissue uptake, however renal uptake may impact on imaging and therapeutic effects. Through a novel pegylation strategy to surface disulphides, a diabody to TAG-72 (AVP0458) has been generated, and produced under cGMP for a first-in-human clinical trial. Materials and Methods: We have conducted a phase I, open label, first-in-human trial of PEG-AVP0458. The primary study objective was the safety of single dose of I-124 PEG-AVP0458 in patients (pts) with TAG-72 +ve relapsed / metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor targeting, pharmacokinetics (PK) and immunogenicity of I-124 PEG-AVP0458. Pts were infused with I-124 PEG-AVP0458 (3-5mCi) at one of two dose levels (1mg/m2 and 10mg/m2), and imaged sequentially over a one week period. Safety, PK, and immunogenicity was assessed up to 30 days post infusion. Results: Six pts (1F:5M; age range 62-85yrs; 1 ovarian cancer, 5 prostate cancer) were entered into the study, 3 at each dose level. I-124 PEG-AVP0458 was well tolerated, with no infusion-related adverse events, and no serious adverse events observed. There was consistent biodistribution on PET imaging of I-124 PEG-AVP0458, with no normal tissue uptake. High tumor uptake was evident in metastatic disease in liver and lymph nodes, with lesion uptake seen within 1-2 days post injection. PK analysis showed a T½β of 46.8 ± 12.4 hrs. There was no impact of protein dose on biodistribution, tumor uptake or PK. No immunogenicity to PEG-AVP0458 was evident. Conclusions: I-124 PEG-AVP0458 is safe, and demonstrates excellent, rapid targeting of tumor in vivo, with no specific normal organ uptake, and high tumor: blood ratios. This data demonstrates the feasibility of using pegylated diabodies for imaging and for delivery of radioisotopes (RIT) or cytotoxic drug payloads (ADC) in cancer patients. Citation Format: Andrew M. Scott, Timothy Akhurst, Fook-Thean Lee, Marika Ciprotti, Ian Davis, Andrew Weickhardt, Hui Gan, Pece Kocovski, Nancy Guo, Linda Mileshkin, Scott Williams, Declan Murphy, Rod Hicks, Kunthi Pathmaraj, Sze Ting Lee, Graeme O'Keefe, Sylvia Gong, Maggie Oh, Michael Wheatcroft, Peter J. Hudson. Phase I safety and biodistribution study of 124I-PEG-AVP0458 diabody in patients with TAG-72 positive ovarian and prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT238. doi:10.1158/1538-7445.AM2015-CT238

Published
2015

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