Utilizing high-energy γ-photons for high-resolution ²¹³Bi SPECT in mice

The combined α-, γ-, and x-ray emitter 213Bi (half-life, 46 min) is promising for radionuclide therapy. SPECT imaging of 213Bi is challenging, because most emitted photons have a much higher energy (440 keV) than common in SPECT. We assessed 213Bi imaging capabilities of the Versatile Emission Computed Tomograph (VECTor) dedicated to (simultaneous) preclinical imaging of both SPECT and PET isotopes over a wide photon energy range of 25-600 keV. Methods: VECTor was equipped with a dedicated clustered pinhole collimator. Both the 79 keV x-rays and the 440 keV γ-rays emitted by 213Bi could be imaged. Phantom experiments were performed to determine the maximum resolution, contrast-to-noise ratio, and activity recovery coefficient for different energy window settings. Additionally, imaging of [213Bi-DOTA,Tyr3]octreotate and 213Bi-diethylene triamine pentaacetic acid (DTPA) in mouse models was performed. Results: Using 440 keV γ-rays instead of 79 keV x-rays in image reconstruction strongly improved the resolution (0.75 mm) and contrast-to-noise characteristics. Results obtained with a single 440 keV energy window setting were close to those with a combined 79 keV/440 keV window. We found a reliable activity recovery coefficient down to 0.240 MBq/mL with 30-min imaging time. In a tumor-bearing mouse injected with 3 MBq of [213Bi-DOTA,Tyr3]octreotate, tumor uptake could be visualized with a 1-h postmortem scan. Imaging a nontumor mouse at 5-min frames after injection of 7.4 MBq of 213Bi-DTPA showed renal uptake and urinary clearance, visualizing the renal excretion pathway from cortex to ureter. Quantification of the uptake data allowed kinetic modeling and estimation of the absorbed dose to the kidneys. Conclusion: It is feasible to image 213Bi down to a 0.75-mm resolution using a SPECT system equipped with a dedicated collimator.RST/Biomedical Imagin

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics