Dr. Short is a toxicologist and toxicologic pathologist. He has contributed to over 100 regulatory submissions in the US, EU, Australia and Japan, coauthored over 40 peer review publications, and been a Diplomate of the American College of Veterinary Pathology since 1985. With over 17 years of ocular pharmaceutical and biotechnology development experience at Allergan, Dr. Short has directed Pathology and Toxicology departments and provided guidance for interpretation of results of safety studies including pathology peer review, risk assessments, positioning adverse findings, evaluation of in-licensing candidates and review of nonclinical development plan strategies. He has led nonclinical development teams regarding an intravitreal anti-angiogenic biologic (DARPin) for the neovascular form of age-related macular degeneration and an intravitreal implant (brimonidine) for neuroprotection in geographic atrophy. He has contributed to global marketing approval for many ophthalmic drugs or devices (Restasis®, Lumigan®, Alphagan®, Ozurdex®, Trivaris®, and Refresh/Optive®) as well as neurologic (BOTOX®) and dermal (Aczone®, Tazorac®) drugs.
Selected Aspects of Ocular Toxicity Studies With a Focus on High-Quality Pathology Reports: A Pathology/Toxicology Consultant's Perspective.
Toxicol Pathol. 2020 Aug 20;:192623320946712
Authors: Short B
Ocular toxicity studies are the bedrock of nonclinical ocular drug and drug-device development, and there has been an evolution in experience, technologies, and challenges to address that ensures safe clinical trials and marketing authorization. The expectations of a well-designed ocular toxicity study and the generation of a coherent, integrative ocular toxicology report and subreports are high, and this article provides a pathology/toxicology consultant's perspective on achieving that goal. The first objective is to cover selected aspects of study designs for ocular toxicity studies including considerations for contract research organization selection, minipig species selection, unilateral versus bilateral dosing, and in-life parameters based on fit-for-purpose study objectives. The main objective is a focus on a high-quality ocular pathology report that includes ocular histology procedures to meet regulatory expectations and a report narrative and tables that correlate microscopic findings with key ophthalmic findings and presents a clear interpretation of test article-, vehicle-, and procedure-related ocular and extraocular findings with identification of adversity and a pathology peer review. The last objective covers considerations for a high-quality ophthalmology report, which in concert with a high-quality pathology report, will pave the way for a best quality toxicology report for an ocular toxicity study.
PMID: 32815474 [PubMed - as supplied by publisher]
Toxicology Evaluation of Drugs Administered via Uncommon Routes: Intranasal, Intraocular, Intrathecal/Intraspinal, and Intra-Articular.
Int J Toxicol. 2017 Jan 01;:1091581817741840
Authors: Emami A, Tepper J, Short B, Yaksh TL, Bendele AM, Ramani T, Cisternas AF, Chang JH, Mellon RD
As the need for nasal, ocular, spinal, and articular therapeutic compounds increases, toxicology assessments of drugs administered via these routes play an important role in human safety. This symposium outlined the local and systemic evaluation to support safety during the development of these drugs in nonclinical models with some case studies. Discussions included selection of appropriate species for the intended route; conducting nonclinical studies that closely mimic the intended use with adequate duration; functional assessment, if deemed necessary; evaluation of local tissues with special histological staining procedure; and evaluations of safety margins based on local and systemic toxicity.
PMID: 29264927 [PubMed - as supplied by publisher]
Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.
N Engl J Med. 2017 09 28;377(13):1228-1239
Authors: Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, Chan JC, Choi J, Gustavson SM, Iqbal N, Maggioni AP, Marso SP, Öhman P, Pagidipati NJ, Poulter N, Ramachandran A, Zinman B, Hernandez AF, EXSCEL Study Group
BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.
METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.
RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.
CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .).
PMID: 28910237 [PubMed - indexed for MEDLINE]
Recommendations from a global cross-company data sharing initiative on the incorporation of recovery phase animals in safety assessment studies to support first-in-human clinical trials.
Regul Toxicol Pharmacol. 2014 Oct;70(1):413-29
Authors: Sewell F, Chapman K, Baldrick P, Brewster D, Broadmeadow A, Brown P, Burns-Naas LA, Clarke J, Constan A, Couch J, Czupalla O, Danks A, DeGeorge J, de Haan L, Hettinger K, Hill M, Festag M, Jacobs A, Jacobson-Kram D, Kopytek S, Lorenz H, Moesgaard SG, Moore E, Pasanen M, Perry R, Ragan I, Robinson S, Schmitt PM, Short B, Lima BS, Smith D, Sparrow S, van Bekkum Y, Jones D
An international expert group which includes 30 organisations (pharmaceutical companies, contract research organisations, academic institutions and regulatory bodies) has shared data on the use of recovery animals in the assessment of pharmaceutical safety for early development. These data have been used as an evidence-base to make recommendations on the inclusion of recovery animals in toxicology studies to achieve scientific objectives, while reducing animal use. Recovery animals are used in pharmaceutical development to provide information on the potential for a toxic effect to translate into long-term human risk. They are included on toxicology studies to assess whether effects observed during dosing persist or reverse once treatment ends. The group devised a questionnaire to collect information on the use of recovery animals in general regulatory toxicology studies to support first-in-human studies. Questions focused on study design, the rationale behind inclusion or exclusion and the impact this had on internal and regulatory decisions. Data on 137 compounds (including 53 biologicals and 78 small molecules) from 259 studies showed wide variation in where, when and why recovery animals were included. An analysis of individual study and programme design shows that there are opportunities to reduce the use of recovery animals without impacting drug development.
PMID: 25078890 [PubMed - indexed for MEDLINE]
Meeting report: Urinary Pathology; sixth Research Triangle Park Rodent Pathology Course.
Vet Pathol. 2013 May;50(3):563-8
Authors: Boyle MC, Boyle MH, Sixth Rodent Pathology Course Committee
Urinary system toxicity is a significant concern to pathologists in the hazard identification, drug and chemical safety evaluation, and diagnostic service industries worldwide. There are myriad known human and animal urinary system toxicants, and investigatory renal toxicology and pathology is continually evolving. The system-specific Research Triangle Park (RTP) Rodent Pathology Course biennially serves to update scientists on the latest research, laboratory techniques, and debates. The Sixth RTP Rodent Pathology Course, Urinary Pathology, featured experts from the government, pharmaceutical, academic, and diagnostic arenas sharing the state of the science in urinary pathology. Speakers presented on a wide range of topics including background lesions, treatment-related non-neoplastic and neoplastic lesions, transgenic rodent models of human disease, diagnostic imaging, biomarkers, and molecular analyses. These seminars were accompanied by case presentation sessions focused on usual and unusual lesions, grading schemes, and tumors.
PMID: 23645617 [PubMed - indexed for MEDLINE]
Society of Toxicologic Pathology position paper on best practices on recovery studies: the role of the anatomic pathologist.
Toxicol Pathol. 2013;41(8):1159-69
Authors: Perry R, Farris G, Bienvenu JG, Dean C, Foley G, Mahrt C, Short B, Society of Toxicologic Pathology
This article reviews the regulatory guidelines that provide for the inclusion of recovery groups in toxicology studies, presents the challenges in the design and interpretation of nonclinical recovery studies, and summarizes the best practices for the role of an anatomic pathologist regarding toxicology studies with recovery groups. Evaluating the potential recovery of histopathologic findings induced by a biopharmaceutical requires the active participation of one or more anatomic pathologists. Their expertise is critical in risk assessment regarding the potential for recovery as well as providing scientific guidance in the design and evaluation of studies with recovery groups.
PMID: 23531793 [PubMed - indexed for MEDLINE]
RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027.
Am J Ophthalmol. 2010 Jul;150(1):33-39.e2
Authors: Kaiser PK, Symons RC, Shah SM, Quinlan EJ, Tabandeh H, Do DV, Reisen G, Lockridge JA, Short B, Guerciolini R, Nguyen QD, Sirna-027 Study Investigators
PURPOSE: To assess the safety, tolerability, pharmacokinetics, and dose-limiting toxicity of single intravitreal injection of Sirna-027, a small interfering RNA targeting vascular endothelial growth factor receptor-1, in patients with choroidal neovascularization (CNV) resulting from neovascular age-related macular degeneration (AMD). Secondary objectives included assessment of anatomic changes in retinal thickness, size of CNV, and changes in visual acuity.
DESIGN: Prospective, open-label, single-dose, dose-escalation phase 1 study.
METHODS: Twenty-six eyes of 26 patients with a median age of 82 years and CNV resulting from AMD who had previous treatments with other therapies were treated at 2 academic retinal practices. Patients received a single dose of Sirna-027 (100, 200, 400, 800, 1200, or 1600 microg/eye). Blood was sampled for pharmacokinetic analysis at 1, 4, and 24 hours after injection and on day 7. Patients underwent ophthalmic examinations including visual acuity, fluorescein angiography, and optical coherence tomography at screening and days 7, 14, 28, and 84. The main outcome measures were adverse reactions and dose-limiting toxicities.
RESULTS: Intravitreal injection of a single dose of Sirna-027 from 100 to 1600 microg was well tolerated in patients with AMD, with no dose-limiting toxicity found. Adverse events were mild to moderate in severity. Adjusted mean foveal thickness decreased within 2 weeks after study treatment. The decrease was most pronounced in the 100- and 200-microg doses.
CONCLUSIONS: A single intravitreal dose of Sirna-027 up to 1600 microg/eye was well tolerated in patients with CNV resulting from neovascular AMD that had been refractory to other therapies. Stabilization or improvement in visual acuity and foveal thickness was observed. No dose-response or dose-limiting effects were noted.
PMID: 20609706 [PubMed - indexed for MEDLINE]
Carcinogenicity assessments of biotechnology-derived pharmaceuticals: a review of approved molecules and best practice recommendations.
Toxicol Pathol. 2010 Jun;38(4):522-53
Authors: Vahle JL, Finch GL, Heidel SM, Hovland DN, Ivens I, Parker S, Ponce RA, Sachs C, Steigerwalt R, Short B, Todd MD
An important safety consideration for developing new therapeutics is assessing the potential that the therapy will increase the risk of cancer. For biotherapeutics, traditional two-year rodent bioassays are often not scientifically applicable or feasible. This paper is a collaborative effort of industry toxicologists to review past and current practice regarding carcinogenicity assessments of biotherapeutics and to provide recommendations. Publicly available information on eighty marketed protein biotherapeutics was reviewed. In this review, no assessments related to carcinogenicity or tumor growth promotion were identified for fifty-one of the eighty molecules. For the twenty-nine biotherapeutics in which assessments related to carcinogenicity were identified, various experimental approaches were employed. This review also discusses several key principles to aid in the assessment of carcinogenic potential, including (1) careful consideration of mechanism of action to identify theoretical risks, (2) careful investigation of existing data for indications of proliferative or immunosuppressive potential, and (3) characterization of any proliferative or immunosuppressive signals detected. Traditional two-year carcinogenicity assays should not be considered as the default method for assessing the carcinogenicity potential of biotherapeutics. If experimentation is considered warranted, it should be hypothesis driven and may include a variety of experimental models. Ultimately, it is important that preclinical data provide useful guidance in product labeling.
PMID: 20472697 [PubMed - indexed for MEDLINE]
Alternative mouse models for carcinogenicity assessment: industry use and issues with pathology interpretation.
Toxicol Pathol. 2010 Jan;38(1):43-50
Authors: Long GG, Morton D, Peters T, Short B, Skydsgaard M
The Carcinogenicity Alternative Mouse Models (CAMM) Working Group of the Society of Toxicologic Pathology (STP) surveyed the membership to define current practices and opinions in industry regarding the use of alternative mouse models for carcinogenicity testing. The results of the survey indicated that CAMM are used most often to fulfill a regulatory requirement (e.g., to replace the two-year mouse bioassay) and are being accepted by regulatory agencies. Alternative models are also sometimes used for internal decision making or to address a mechanistic question. The CAMM most commonly used are the p53+/- and rasH2. The rasH2 appears to be the currently accepted model for general carcinogenicity testing. Problems with study interpretation included lack of historic background data, unexpected tumor finding, and tumor identification/characterization of early lesions. Problems with implementation or conduct of the study included extent of the pathology evaluation, numbers of animals, survival, and study duration. Recommendations were developed for, frequency and type of positive control testing, extent of histopathologic examination of test article-treated and positive control animals, current use and future development of diagnostic criteria; increased availability and use of historic data, and use of other genetically modified mice in carcinogenicity testing.
PMID: 19915137 [PubMed - indexed for MEDLINE]