Technetium (99mTc) Pyrophosphate

124I-evuzamitide shown to be highly accurate for detection of cardiac amyloid across two independent investigator-initiated studies.124I-evuzamitide detects multiple types of systemic amyloidosis.124I-evuzamitide may be more sensitive than standard diagnostics, with cardiac uptake shown in ATTR patients who had negative 99mTc-PYP scans.Moderate-to-strong correlations were observed with 124I-evuzamitide uptake and structural and functional cardiac imaging measures, health related quality of life (HRQoL), and cardiac biomarkers. SAN FRANCISCO, Nov. 07, 2023 (GLOBE NEWSWIRE) -- Attralus, Inc., a clinical stage biopharmaceutical company developing transformative medicines to improve the lives of patients with systemic amyloidosis, today announced the publication of results from two Attralus-funded investigator-initiated studies of 124I-evuzamitide, the company’s investigational pan-amyloid radiotracer under development for the diagnosis and management of systemic amyloidosis. The manuscripts from Brigham and Women’s Hospital (BWH) and from the University of Tennessee Graduate School of Medicine were published in the Journal of American College of Cardiology – Cardiovascular Imaging (JACC CV Imaging). The manuscripts, entitled “Cardiac Amyloid Quantification Using 124I-Evuzamitide (124I-P5+14) Versus 18F-Florbetapir” and “Cardiac Amyloid Detection by PET/CT Imaging of Iodine (124I) Evuzamitide (124I-p5+14): A Phase 1/2 Study,” have been published online. These two manuscripts were also accompanied by an editorial entitled “Shining a Radiant Light on Cardiac Amyloidosis with Novel 124I-Evuzamitide PET Imaging.” All three articles can be found online here. The key data reported in the publications show PET/CT imaging of patients with diverse types of systemic amyloidosis with visually appreciable uptake in the heart with high sensitivity and other organs suspected of amyloid involvement and highlighted that 124I-evuzamitide imaging may detect cardiac amyloid prior to clinical manifestation. Furthermore, 124I-evuzamitide was shown to accurately discriminate amyloid cardiomyopathy (CMP) from controls. In patients with ATTRwt-CMP, performance may be better with 124I-evuzamitide, as evidenced by significantly higher uptake than 18F-florbetapir, and higher uptake than in AL patients aligning with literature that ATTR patients have a higher cardiac amyloid load. Moderate-to-strong correlations between 124I-evuzamitide uptake and cardiac structural and functional measures utilizing echocardiography and cardiac magnetic resonance imaging, health related quality of life (HRQoL) metrics, and cardiac biomarkers were observed. The results also support the potential of 124I-evuzamitide as a pan-amyloid imaging agent, with positive cardiac uptake also seen in AApoAIV, AApoA1 and ALys amyloidosis patients. Infusion of 124I-evuzamitide was generally safe and well tolerated in these studies. These studies suggest that 124I-evuzamitide is a promising novel radiotracer to detect and quantify cardiac amyloid in multiple types of amyloidosis. Furthermore, the authors from BWH study stated that the ability of 124I-evuzamitide to specifically bind to amyloid deposits is promising for the ongoing Phase I trial investigating a monoclonal antibody fusion protein incorporating a similar amyloid-binding peptide, which targets amyloid deposits to trigger their removal. “Cardiac amyloidosis is an underdiagnosed condition. Despite recent improvements, diagnosis continues to be a challenge. There is an unmet need for more sensitive and specific diagnostics” said Professor Sharmila Dorbala MD, MPH, Harvard Medical School, Cardiovascular Medicine, and lead author of the BWH study. “In our study, I-124 evuzamitide perfectly discriminated between healthy subjects and both AL and ATTR cardiac amyloidosis patients. In ATTR patients, myocardial uptake was significantly higher with I-124 evuzamitide than with F18-florbetapir, suggesting that diagnostic performance may be better with I-124 evuzamitide. Although not evaluated in this study, direct amyloid quantification with I-124 evuzamitide may be useful for diagnosis of early disease and for monitoring disease progression or response to treatment. We were particularly encouraged by the moderate to strong correlations between amyloid quantitation by I-124 evuzamitide and health-related quality of life metrics, cardiac biomarkers, and standard imaging measures of structure and function.” “Detection and quantification of amyloid burden in the heart is an unmet clinical need for patients with diverse types of systemic amyloidosis,” said Jonathan Wall, Ph.D., Distinguished Professor, University of Tennessee Graduate School of Medicine. “The iodine-124 evuzamitide radiotracer has the potential to be an invaluable tool to both detect early cardiac and extracardiac deposits and to quantify amyloid burden.” Summary of Published ResultsBWH studyThis pilot study enrolled 26 patients with systemic amyloidosis (12 AL, 12 ATTR and 2 other types) and 12 healthy volunteers (HVs). Eight additional HVs were included in the publication from a 18F-florbetapir study to compare the accuracy of 18F- florbetapir to 124I-evuzamitide. The BWH study is the first to systematically evaluate myocardial uptake of 124I-evuzamitide compared to standard imaging modalities, clinical metrics, and HRQoL parameters in a cohort of participants with amyloid CMP, and the first to compare it to 18F- florbetapir. The study evaluated the quantitative myocardial uptake of 124I-evuzamitide and measured correlations between 124I-evuzamitide and clinical markers of amyloid CMP. All patients received an IV infusion of 1 mCi of 124I-evuzamitide and images were acquired at 5 hours post injection. Quantitative uptake of 124I-evuzamitide perfectly discriminated all cases of known AL-CMP and ATTRwt-CMP from controls, using measures of left ventricular % injected dose (LV %ID), cardiac amyloid activity (CAA), and target to background ratio (TBR).When comparing radiotracers, 124I-evuzamitide consistently showed higher myocardial uptake in patients with ATTRwt amyloidosis, suggesting that it may perform better in these patients. The performance was similar to 18F- florbetapir in AL Amyloidosis.Furthermore, among AL and ATTRwt participants, 124I-evuzamitide LV %ID was moderately to strongly correlated with indirect metrics of amyloid burden, both structural and functional (interventricular septum thickness, LV mass index, MCF, GLS, ECV), assessed using standard echocardiographic and MRI techniques, suggesting valid amyloid burden quantitation.Cardiac uptake of 124I-evuzamitide strongly correlated with cardiac-related serum biomarkers (NT-proBNP and troponin), and moderately to strongly correlated with clinical and HRQoL measures, suggesting meaningfulness to patients. The results also include a case in which an ATTRwt patient showed positive cardiac uptake of 124I-evuzamitide, a negative 99mTc-PYP scan, with an amyloid positive cardiac biopsy, suggesting 124I-evuzamitide may be more sensitive than 99mTc-PYP.No cardiac uptake was observed in HVs. The results suggest that 124I-evuzamitide can accurately detect and quantify cardiac amyloid burden. With further validation, quantitative 124I-evuzamitide uptake may be particularly useful to diagnose early disease or to monitor disease progression or response to therapy in subjects with cardiac amyloidosis. UT studyThe first in human Phase 1/2 trial evaluated the ability of 124I-evuzamitide to detect amyloid deposits by PET/CT imaging in patients with diverse forms of systemic amyloidosis. The trial enrolled 50 systemic amyloidosis pts (23 AL, 20 ATTR and 7 other types) and 5 HVs. All patients received an IV infusion of <2 mg of 124I-evuzamitide (≤2 mCi of I-124) and images were acquired at ~5 hours post injection. Efficacy endpoints included patient- and organ-based sensitivity of 124I-evuzamitide uptake in the heart, liver, spleen, and kidney. Cardiac uptake of the radiotracer was observed in 100% of patients with ATTR in whom clinical evidence supported a diagnosis of amyloid CMP.Positive cardiac PET/CT imaging was observed in six patients with a diagnosis of ATTR amyloidosis but no clinical evidence of cardiac involvement, with negative 99mTc-PYP imaging and normal serum NTproBNP levels. At least one of these subjects had a confirmatory cardiac biopsy confirming ATTR amyloidosis in the heart.Of the major abdominothoracic organs, the sensitivity (positive percent agreement) between clinical findings and 124I-evuzamitide imaging was strongest for the heart (96.2%; 95% CI: 80.4-99.9; n=25/26). PET/CT imaging of 124I-evuzamitide in patients with ATTR and AL amyloidosis exhibited diverse anatomic uptake involving e.g., the lung, liver, kidney, pancreas, spheroid joints, spine, and abdominal fat, consistent with the systemic nature of these diseases, and with previously published autopsy findings. These data suggest that 124I-evuzamitide imaging can detect not only cardiac amyloidosis, but also extracardiac disease.No cardiac uptake was observed in HVs. The data from this first-in-human study supports the overall safety and efficacy of 124I-evuzamitide for detecting cardiac amyloidosis, as well as systemic amyloid deposits. About Systemic Amyloidosis Systemic amyloidosis encompasses a diverse group of rare diseases that occur due to accumulation of toxic amyloid deposits in tissues and organs, a consequence of aberrant protein misfolding events. These diseases are progressive, debilitating and often fatal. Systemic amyloidosis is significantly underdiagnosed due to low awareness, lack of specific symptoms, and no current disease-specific diagnostics. The two most common forms of systemic amyloidosis are immunoglobulin light-chain-associated (AL) amyloidosis and transthyretin-associated amyloidosis (ATTR). There is a significant unmet need for new therapies and diagnostics in systemic amyloidosis. About I-124-EVUZAMITIDE Pan-Amyloid Diagnostic (Also known as AT-01)I-124-EVUZAMITIDE (iodine-124 Evuzamitide) utilizes the company’s pan-amyloid binding peptide as an amyloid-specific imaging agent to image all types of systemic amyloidosis by PET/CT imaging. In initial clinical trials, I-124-EVUZAMITIDE has been shown to detect multiple types of amyloid deposits, including AL and ATTR, in major organs such as the heart, kidney, liver and spleen. Attralus obtained exclusive rights to commercialize I-124-EVUZAMITIDE under a commercial license agreement with the University of Tennessee Research Foundation. The same PAR-peptide technology is utilized in AT-02 and AT-04, two of the company’s therapeutic candidates. About Attralus Attralus is a clinical stage biopharmaceutical company focused on creating transformative medicines to improve the lives of patients with systemic amyloidosis. The company’s proprietary pan-amyloid removal (PAR) therapeutics are designed to directly bind to and remove toxic amyloid in organs and tissues. By targeting the universal disease-causing pathology in systemic amyloidosis diseases, PAR therapeutics have the potential to treat and reverse disease in patients with all types and stages of systemic amyloidosis. Attralus was founded by scientific experts in the field of amyloidosis and the company is headquartered in San Francisco. Forward-Looking Statements This press release contains forward-looking statements, including statements related to the efficacy, continued development, and potential of the Company’s product candidates. Words such as “novel,” “developing,” “first and only,” “potential,” “shown” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Attralus' current expectations. Forward-looking statements involve risks and uncertainties. Attralus' actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties. Attralus expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in Attralus' expectations with regard thereto or any change in events, conditions, or circumstances on which any such statements are based. Contact:Krishna Gorti, MD FRCSCorporate Development‍(212) 489-4351kgorti@attralus.com

结直肠癌是全世界最常见的恶性肿瘤之一，在全世界的恶性肿瘤排名中位于第三位。2015年我国有38.7万例新确诊的结直肠癌患者，其中2%~5%可归因于Lynch综合征（Lynch syndrome，LS）[1]。Lynch综合征（LS）是由于DNA错配修复（MMR）引起的常染色体显性遗传病。它能够增加了许多类型癌症的风险，包括结直肠癌、子宫内膜癌，卵巢癌，胃癌，胰腺癌，胆管癌，泌尿道癌，脑癌和皮肤癌等。随着肿瘤免疫的发展，Lynch综合征相关结直肠癌逐步成为研究的热点。1999年，英国启动了癌症预防计划试验2（The Cancer Prevention Programme 2，CAPP2），通过长达10年的随访和基于登记的20年数据表明阿司匹林可以显著降低Lynch综合征患者结直肠癌发病率[2]。那么是否除了阿司匹林外的其他因素也具有类似效果呢？7月25日，英国纽卡斯尔大学转化与临床医学研究所约翰·伯恩教授团队在《CANCER PREVENTION RESEARCH》发表了题为《Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial: Planned 10-Year Follow-up》的研究性论文，文章在CAPP2的基础上评估了抗性淀粉对于预防Lynch综合征相关结直肠癌的效果。已有大量研究表明较高的膳食纤维（DF）摄入量可以预防结肠直肠癌和其他肠道疾病[3]。而在膳食纤维的构成中，抗性淀粉（Resistant Starch，RS）被认为是一种具有抗癌潜力的物质（生板栗抗性淀粉占总淀粉含量78%）。此外，抗性淀粉拥有比其他膳食纤维成分更好的口感和风味，因此在近年来成为食品卫生方面的研究热点。Fig.1 Trial profile showing distribution of participants by randomisation group and length of follow-up together with counted outcomes of cancer diagnoses among participants; CRC, colorectal cancer; LS Ca, Lynch syndrome associated cancers (other than colorectal cancer).为了探究抗性淀粉的抗癌作用。研究人员招募了曾参加CAPP2研究的937名LS患者（平均年龄45岁），并随机分为四组：1）阿司匹林+抗性淀粉组；2）阿司匹林安慰剂+抗性淀粉组；3）阿司匹林+抗性淀粉安慰剂组（玉米淀粉）；4）阿司匹林安慰剂+抗性淀粉安慰剂组（玉米淀粉）。实验周期为1999年-2007年。在937名参与者中，463人被分配到抗性淀粉组，455人被分配到玉米淀粉安慰剂组。抗性淀粉的服用剂量为每日30 g。Fig.2 Time to first colorectal cancer and time to any LS cancer in CAPP2 study participants from England, Finland and Wales with up to 20 years.首先，研究人员选取了整个CAPP2队列以及英格兰，芬兰和威尔士共计20年的数据作为目标进行分析。结果发现在随机分配到抗性淀粉组（n=463）和安慰剂组（n=455）的参与者中，2年和10年的随访表现结果相似，没有显著差异。表明短期内服用抗性淀粉效果并不明显。Fig.3 Cox proportional hazards and negative binomial regression analyses of cancer incidence.研究人员在调查中发现52名和53名参与者分别在抗性淀粉组和安慰剂组中发展为结肠直肠癌。而ITT分析（所有随机分配入组的受试者，以最小的和合理的方法剔除后所获得的数据进行的分析的方法）和PP分析（只对随机化入组后按规定完成了整个试验的观察对象的数据进行分析的方法）均显示抗性淀粉组对结直肠癌发病率没有影响。此外，研究人员还发现阿司匹林和抗性淀粉之间不存在任何相互作用，表明对于Lynch综合征这是两个独立的作用因素。Fig.4 Pigurez Time to first colorectal cancer and time to first non-colorectal cancer Lynch syndrome cancer inall CAPP2 study participants followed up for 10 years and for 20 years in England, Finland, and Wales.进一步地，研究人员猜测上述结果的无效性是因为观测时间太短，而抗性淀粉是一个长期的保护作用。因此，他们对参与者进行了长达20年的随访。结果当研究人员使用ITT和PP分析后，发现在Lynch综合征患者后续的10年的随访期间，无论是结直肠癌，还是其他类型的癌症，抗性淀粉组都有着更低的发病率，表明其良好的保护效果，其中消化道相关癌症最为明显（如胃癌，十二指肠癌，胆管癌和胰腺癌）。最后，研究人员对抗性淀粉的这种长期效果进行了分析，抗性淀粉可以有效调节肠道代谢，促进肠道内益生菌的繁殖而产生良好的健康保护作用。总的来说，这项研究让我们看到膳食纤维要想发挥作用，短期内可能比较困难的。只有长时间坚持良好的饮食习惯，才能从中获益。所以，以后买板栗吃，又多了一个理由！参考文献：1.国家癌症中心中国结直肠癌筛查与早诊早治指中国结直肠癌筛查与早诊早治指南.北京2021，30（1）：1-28.2.Burn, John, et al. "Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial." The Lancet 395.10240 (2020): 1855-1863.3.Burkitt DP.et al. Effect of dietary fibre on stools and the transit-times, and its role in the causation of disease. Lancet 1972;:1408-12.4.John Burn. et al. Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial: Planned 10-Year Follow-up. Cancer prevention research.2022.撰文｜安小猪编辑｜小耳朵上万科研人员交流基地，扫码加入“科研交流群”，找到组织，让科研更轻松！