GBT021601, a Next Generation HbS Polymerization Inhibitor: Results of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Adults Living with Sickle Cell Disease and Healthy Volunteers

Background: Sickle cell disease (SCD) is caused by polymerization of sickle hemoglobin (HbS), resulting in red blood cell (RBC) sickling, RBC destruction, vaso-occlusion and end-organ damage. GBT021601 is an oral, small molecule, next-generation HbS polymerization inhibitor. Similar to voxelotor, the first generation HbS polymerization inhibitor, GBT021601 increases hemoglobin-oxygen (Hb-O2) affinity and stabilizes hemoglobin (Hb) in the oxy-hemoglobin (oxyHb) state, thereby inhibiting polymerization of HbS in RBCs. The fraction of Hb bound to drug - (Hb occupancy) approximates the oxyHb molecules per RBC. Compared to voxelotor, GBT021601 has the potential to achieve higher Hb occupancies. GBT021601 achieves greater exposures per dose and is more potent as measured by improvements in hematological parameters in an in vivo SCD mouse model (Dufu, Kobina 2020). We hypothesized that GBT021601 would achieve a substantial reduction in RBC hemolysis and increase in hemoglobin while maintaining a favorable safety profile. We therefore explored safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in healthy volunteer participants (HVs) and adults living with SCD. Methods: Two studies are in progress: 1) the first in human (FIH), randomized, double-blind, placebo-controlled, parallel group phase 1 study for HVs ages 18-55 years; and 2) a single arm, intrapatient single dose and multiple ascending dose study in homozygous HbSS SCD patients ages 18-60 years with baseline Hb levels ≥5.5 g/dL and ≤10.5 g/dL and without vaso-occlusive crisis or transfusion within 30 days of screening. The HV study tests single ascending doses (SAD) with a 6:2 randomization ratio. Doses administered to HV cohorts ranged from 50 mg to 2200 mg. The SCD patient study tests a single dose (100 mg) followed by multiple ascending doses of the study drug in the same patients to reach a % Hb occupancy of >20-30% over 7 weeks. The primary endpoints for both studies are safety and tolerability. Secondary endpoints include PK and PD. For the patient study, additional secondary endpoints are confirmation of the relationship between time matched GBT021601 concentrations and the change from baseline of clinical measures of anemia and hemolysis. Hb occupancy is calculated as a percentage of the molar ratio of drug concentrations in RBCs to the estimated Hb concentrations (using MCHC) in RBCs. Results: As of July 22, 2021, 63 HVs and 6 adults with SCD were enrolled. Thirty-nine HVs completed the study; one discontinued due to moving to a new geographical area and 23 were in follow-up. GBT021601 was generally well-tolerated, most adverse events (AE) were Grade 1 and 2, there were no deaths, and there was one serious adverse event in a HV that was not related to the study drug. There were no AEs indicative of tissue hypoxia. GBT021601 showed linear PK, high partitioning into RBCs, and a dose dependent increase in percent hemoglobin occupancy in HVs (Figure 1). From single doses of 50 to 1400 mg, the mean preliminary % Hb occupancy ranged from 0.88 to 25%, respectively, exceeding the Hb occupancies reported for HV receiving single doses of voxelotor over a similar range (Putz, 2017). Six adults with SCD have received a single 100 mg dose of GBT021601 and the dose has been well tolerated. Multiple-dose data in adults will be presented. Conclusions: Single doses of GBT021601 are well tolerated in HV and adults with SCD. Given its drug exposure, GBT021601 has the capacity to achieve a targeted Hb occupancy and attain the desired hematological effect at low doses, therefore reducing pill burden and improving clinical outcomes for individuals living with SCD. Forthcoming multiple-dose data will help to evaluate GBT021601's potential as a best-in-class, oral, disease-modifying therapy for SCD. Funding: This study was supported by Global Blood Therapeutics. Figure 1 Figure 1. Disclosures Brown: Pfizer: Research Funding; Imara: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Forma Therapeutics: Research Funding; Novo Nordisk: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding. Redfern: Eisai: Other: Advisory Board; Linear Clinical Research: Current Employment; Pfizer: Other: Advisory Board; Novartis: Other: Advisory Board; Astra Zeneca: Other: Advisory Board; Roche: Other: Advisory Board. Lisbon: Global Blood Therapeutics: Current Employment. Washington: Global Blood Therapeutics: Consultancy. Agodoa: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Smith-Whitley: Global Blood Therapeutics: Current Employment.

Optimisation of CT protocols in PET-CT across different scanner models using different automatic exposure control methods and iterative reconstruction algorithms

Background A significant proportion of the radiation dose from a PET-CT examination is dependent on the CT protocol, which should be optimised for clinical purposes. Matching protocols on different scanners within an imaging centre is important for the consistency of image quality and dose. This paper describes our experience translating low-dose CT protocols between scanner models utilising different automatic exposure control (AEC) methods and reconstruction algorithms. Methods The scanners investigated were a newly installed Siemens Biograph mCT PET with 64-slice SOMATOM Definition AS CT using sinogram affirmed iterative reconstruction (SAFIRE) and two GE Discovery 710 PET scanners with 128-slice Optima 660 CT using adaptive statistical reconstruction (ASiR). Following exploratory phantom work, 33 adult patients of various sizes were scanned using the Siemens scanner and matched to patients scanned using our established GE protocol to give 33 patient pairs. A comparison of volumetric CT dose index (CTDIvol) and image noise within these patient pairs informed optimisation, specifically for obese patients. Another matched patient study containing 27 patient pairs was used to confirm protocol matching. Size-specific dose estimates (SSDEs) were calculated for patients in the second cohort. With the acquisition protocol for the Siemens scanner determined, clinicians visually graded the images to identify optimal reconstruction parameters. Results In the first matched patient study, the mean percentage difference in CTDIvol for Siemens compared to GE was − 10.7% (range − 41.7 to 50.1%), and the mean percentage difference in noise measured in the patients’ liver was 7.6% (range − 31.0 to 76.8%). In the second matched patient study, the mean percentage difference in CTDIvol for Siemens compared to GE was − 20.5% (range − 43.1 to 1.9%), and the mean percentage difference in noise was 19.8% (range − 27.0 to 146.8%). For these patients, the mean SSDEs for patients scanned on the Siemens and GE scanners were 3.27 (range 2.83 to 4.22) mGy and 4.09 (range 2.81 to 4.82) mGy, respectively. The analysis of the visual grading study indicated no preference for any of the SAFIRE strengths. Conclusions Given the different implementations of acquisition parameters and reconstruction algorithms between vendors, careful consideration is required to ensure optimisation and standardisation of protocols.

The Perioperative Quality Improvement Programme (PQIP Patient Study): Protocol for a UK Multicentre, Prospective Cohort Study to Measure, Report and Improve Quality and Outcomes of Major Surgery

Background Major surgery accounts for a substantial proportion of health service activity and resource consumption, due not only to the primary procedure, but also the short and long-term implications of perioperative complications. It is likely that both compliance with best practice processes and outcomes from major surgery vary substantially between hospitals and therefore could be targets for quality improvement. Methods The Perioperative Quality Improvement Programme (PQIP) patient study is a multi-centre prospective cohort study which recruits participants undergoing major inpatient non-cardiac surgery with three main aims: to measure and improve processes of care and outcome from major surgery; to implement and evaluate a complex intervention aiming to enhance the use of data for improvement by clinical teams; and to create a national database to support collaborative research and efficient study design. The prospective dataset combines variables for risk adjustment, process measures and both objective and patient reported outcome data. Longer-term outcomes are collected through linkage to national administrative datasets (mortality and readmissions). PQIP deploys a theoretically underpinned improvement methodology to support the use of data for improvement by perioperative clinicians, incorporating action research principles to enable changes to be made in response to user feedback. Dissemination of interim findings (non-inferential) form a part of the improvement methodology and are provided to participating centres at regular intervals, including near-real-time feedback of key process measures. Inferential analyses will be published in the peer-reviewed literature, supported by a multi-modal communications strategy to patients, public, policy makers and academic audiences as well as clinicians. Discussion PQIP is the first national effort in the UK to measure and report risk-adjusted complications, patient-reported outcome and mortality rates for patients undergoing major surgery across multiple surgical specialties in the UK. Its main limitation is the risk of sampling bias due to the requirement for patient consent, and because local resource constraints may lead hospitals to recruit a convenience sample, rather than a truly random sample. We will evaluate this risk by using Hospital Episode Statistics (HES) to identify all patients undergoing PQIP eligible procedures, and undertaking sensitivity analyses comparing common data points in the PQIP sample and the HES population. As the purpose of PQIP is to support quality improvement and research as opposed to quality assurance or institutional comparisons, even if they exist, such sampling biases are unlikely to materially affect the ability of the programme to achieve its aims.