University College London, Gower Street, Bloomsbury, London, WC1E 6BT, UK.
Institutionen för Medicinska Vetenskaper, Uppsala University, Uppsala, Sweden.
BMC Cardiovasc Disord. 2022 Feb 13;22(1):49. doi: 10.1186/s12872-021-02407-6.
In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis.
Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [Zr]Zr-dezamizumab cardiac uptake assessed via PET.
Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks.
Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).
在一项 I 期研究中，血清淀粉样蛋白 P 成分（SAP）耗竭剂米利德萨普联合 SAP 单克隆抗体（地塞米单抗）治疗系统性淀粉样变性患者，可清除肝脏、脾脏和肾脏中的淀粉样物质。我们报告了一项 II 期研究和同时进行的免疫正电子发射断层扫描（PET）研究的结果，该研究评估了在心脏淀粉样变性患者中采用相同干预措施后，地塞米单抗的疗效、药效动力学、药代动力学、安全性和心脏摄取（地塞米单抗）。
两项研究均为非对照开放性研究。米利德萨普清除 SAP 后，II 期试验中患者接受≤6 次地塞米单抗治疗（n=7），免疫 PET 研究中患者接受≤2 次非放射性标记的地塞米单抗加[Zr]Zr-地塞米单抗（第 1 次治疗 80mg，第 2 次治疗 500mg）（n=2）。II 期研究的主要终点为心脏磁共振成像（CMR）评估的左心室质量（LVM）从基线到随访（8 周）的变化以及安全性。免疫 PET 研究的主要终点为通过 PET 评估[Zr]Zr-地塞米单抗的心脏摄取。
地塞米单抗在 II 期研究中未产生可察觉或一致的 LVM 降低，也未改善心脏功能。在免疫 PET 研究中，尽管两名患者均观察到可测量的[Zr]Zr-地塞米单抗心脏摄取，但摄取程度为中度至低度。在 LVM 较高的患者中，摄取明显较低。两项研究中均观察到与治疗相关的皮疹伴皮肤小血管血管炎。在接受免疫球蛋白轻链淀粉样变性的第一位 II 期研究患者中，在初始地塞米单抗（300mg）给药后发生腹部大动脉血管炎。静脉注射甲基强的松龙和地塞米单抗停药后，症状几乎完全缓解；8 周时腹部计算机断层扫描显示血管炎缓解。
与之前观察到的内脏淀粉样物质减少不同，在这项 II 期试验中，心脏淀粉样变性患者中没有明显的淀粉样物质清除证据，这可能与免疫 PET 研究中观察到的地塞米单抗心脏摄取有限有关。在发生大动脉血管炎后，对地塞米单抗在心脏淀粉样变性中的获益-风险评估被认为不利，该适应证的开发已终止。试验注册 NCT03044353（2017 年 2 月 2 日）和 NCT03417830（2018 年 1 月 25 日）。
