Clinical outcomes of monoclonal antibody therapy during a COVID-19 outbreak in a skilled nursing facility-Arizona, 2021.

BACKGROUND: Adult residents of skilled nursing facilities (SNF) have experienced high morbidity and mortality from SARS-CoV-2 infection and are at increased risk for severe COVID-19 disease. Use of monoclonal antibody (mAb) treatment improves clinical outcomes among high-risk outpatients with mild-to-moderate COVID-19, but information on mAb effectiveness in SNF residents with COVID-19 is limited. We assessed outcomes in SNF residents with mild-to-moderate COVID-19 associated with an outbreak in Arizona during January-February 2021 that did and did not receive a mAb. METHODS: Medical records were reviewed to describe the effect of bamlanivimab therapy on COVID-19 mortality. Secondary outcomes included referral to an acute care setting and escalation of medical therapies at the SNF (e.g., new oxygen requirements). Residents treated with bamlanivimab were compared to residents who were eligible for treatment under the FDA's Emergency Use Authorization (EUA) but were not treated. Multivariable logistic regression was used to determine association between outcomes and treatment status. RESULTS: Seventy-five residents identified with COVID-19 during this outbreak met eligibility for mAb treatment, of whom 56 received bamlanivimab. Treated and untreated groups were similar in age and comorbidities associated with increased risk of severe COVID-19 disease. Treatment with bamlanivimab was associated with reduced 21-day mortality (adjusted OR = 0.06; 95% CI: 0.01, 0.39) and lower odds of initiating oxygen therapy (adjusted OR = 0.07; 95% CI: 0.02, 0.34). Referrals to acute care were not significantly different between treated and untreated residents. CONCLUSIONS: mAb therapy was successfully administered to SNF residents with COVID-19 in a large outbreak setting. Treatment with bamlanivimab reduced 21-day mortality and reduced initiation of oxygen therapy. As the COVID-19 pandemic evolves and newer immunotherapies gain FDA authorization, more studies of the effectiveness of mAb therapies for treating emerging SARS-CoV-2 variants of concern in high-risk congregate settings are needed.

Discovery of PG545: a highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis.

Increasing the aglycone lipophilicity of a series of polysulfated oligosaccharide glycoside heparan sulfate (HS) mimetics via attachment of a steroid or long chain alkyl group resulted in compounds with significantly improved in vitro and ex vivo antiangiogenic activity. The compounds potently inhibited heparanase and HS-binding angiogenic growth factors and displayed improved antitumor and antimetastatic activity in vivo compared with the earlier series. Preliminary pharmacokinetic analyses also revealed significant increases in half-life following iv dosing, ultimately supporting less frequent dosing regimens in preclinical tumor models compared with other HS mimetics. The compounds also displayed only mild anticoagulant activity, a common side effect usually associated with HS mimetics. These efforts led to the identification of 3ß-cholestanyl 2,3,4,6-tetra-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-sulfo-ß-d-glucopyranoside, tridecasodium salt (PG545, 18) as a clinical candidate. Compound 18 was recently evaluated in a phase I clinical trial in cancer patients.

Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth.

A series of polysulfated penta- and tetrasaccharide glycosides containing alpha(1-->3)/alpha(1-->2)-linked mannose residues were synthesized as heparan sulfate (HS) mimetics and evaluated for their ability to inhibit angiogenesis. The compounds bound tightly to angiogenic growth factors (FGF-1, FGF-2, and VEGF) and strongly inhibited heparanase activity. In addition, the compounds exhibited potent activity in cell-based and ex vivo assays indicative of angiogenesis, with tetrasaccharides exhibiting activity comparable to that of pentasaccharides. Selected compounds also showed good antitumor activity in vivo in a mouse melanoma (solid tumor) model resistant to the phase III HS mimetic 1 (muparfostat, formerly known as PI-88). The lipophilic modifications also resulted in reduced anticoagulant activity, a common side effect of HS mimetics, and conferred a reasonable pharmacokinetic profile in the rat, as exemplified by the sulfated octyl tetrasaccharide 5. The data support the further investigation of this class of compounds as potential antiangiogenic, anticancer therapeutics.

A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies.

PURPOSE: This study evaluated the safety, toxicity, pharmacological properties and biological activity of PI-88, a heparanase endoglycosidase enzyme inhibitor, with fixed weekly docetaxel in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: This was a phase I study to determine the maximal-tolerated dose of escalating doses of PI-88 administered subcutaneously for 4 days per week, along with docetaxel 30 mg/m(2) given on days 1, 8, 15 of a 28-day schedule. RESULTS: Sixteen patients received a total of 42 courses of therapy. No dose-limiting toxicities were observed despite escalation to the highest planned dose level of PI-88 (250 mg/day). Frequent minor toxicities included fatigue (38%), dysgeusia (28.5%), thrombocytopenia (12%), diarrhea (14%), nausea (12%), and emesis (10%) in the 42 courses. No significant bleeding complications were observed. One patient developed a positive anti-heparin antibody test/serotonin releasing assay with positive anti-platelet factor 4/PI-88 antibodies and grade 1 thrombocytopenia in cycle 5, and was withdrawn from the study without any sequelae. PI-88 plasma concentrations (mirrored by APTT) and urinary elimination were linear and dose-proportional. Docetaxel did not alter the pharmacokinetic (PK) profile of PI-88, nor did PI-88 affect docetaxel PK. No significant relationship was determined between plasma or urine FGF-2, or plasma VEGF levels and PI-88 dose/response. Although no objective responses were observed; 9 of the 15 evaluable patients had stable disease for greater than two cycles of therapy. CONCLUSION: PI-88 administered at 250 mg/day for 4 days each week for 3 weeks with docetaxel 30 mg/m(2) on days 1, 8 and 15, every 28 days, was determined to be the recommended dose level for phase II evaluation. This combination was well tolerated without severe toxicities or PK interactions.

PI-88 and novel heparan sulfate mimetics inhibit angiogenesis.

The heparan sulfate (HS) mimetic PI-88 is a promising inhibitor of tumor growth and metastasis expected to commence phase III clinical evaluation in 2007 as an adjuvant therapy for postresection hepatocellular carcinoma. Its anticancer properties are attributed to inhibition of angiogenesis via antagonism of the interactions of angiogenic growth factors and their receptors with HS. It is also a potent inhibitor of heparanase, an enzyme that plays a key role in both metastasis and angiogenesis. A series of PI-88 analogs have been prepared with enhanced chemical and biological properties. The new compounds consist of single, defined oligosaccharides with specific modifications designed to improve their pharmacokinetic properties. These analogs all inhibit heparanase and bind to the angiogenic fibroblast growth factor 1 (FGF-1), FGF-2, and vascular endothelial growth factor with similar affinity to PI-88. However, compared with PI-88, some of the newly designed compounds are more potent inhibitors of growth factor-induced endothelial cell proliferation and of endothelial tube formation on Matrigel. Representative compounds were also tested for antiangiogenic activity in vivo and were found to reduce significantly blood vessel formation. Moreover, the pharmacokinetic profile of several analogs was also improved, as evidenced primarily by lower clearance in comparison with PI-88. The current data support the development of HS mimetics as potent antiangiogenic anticancer agents.

A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors.

PURPOSE: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study. EXPERIMENTAL DESIGN: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2). RESULTS: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C(max) correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for >or=6 months. CONCLUSION: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.

In motion, out of place: the public space(s) of Tourette Syndrome.

According to Doris Humphrey, "Nothing so clearly or inevitably reveals the inner man [sic] than movement and gesture...the moment you move you stand revealed, for good or ill, for what you are" (The dance notebook, 1984). Tourette Syndrome, characterized by motor and vocal tics, elicits stigma for just this reason: the tics and movements it causes have revealed Touretters as something beyond the 'normal.' This paper examines the ways Touretters are perceived and received in public spaces, using published illness narratives and film documentaries to address the question of why the reactions TS invokes are so severe. We will demonstrate how the stigma surrounding the disorder stems from the perception of Touretters as disruptive to the order and health of public spaces. To describe the production of stigma and the violent reactions to TS individuals, we draw upon theories of bodies and performativity from feminist studies, Catherine Waldby's work with the imaginary anatomy, and geographical perspectives on the social construction of space. The geographic studies of space are used to illuminate discussions of people's life experiences by showing how body movements associated with illness produce stigma by transgressing the unwritten codes that govern particular public spaces. Our intention in this paper is not to introduce new empirical data, but rather to analyze the mechanisms of stigma formation produced by the complex relationships between the functioning of social spaces and individuals' experiences of illness.