a The Scripps Research Institute , San Diego , CA , USA.
b The Scintillon Institute , San Diego , CA , USA.
Amyloid. 2019 Jun;26(2):55-65. doi: 10.1080/13506129.2019.1575201. Epub 2019 Mar 24.
There have now been randomized controlled trials of four different therapeutics for hereditary amyloid polyneuropathy related to transthyretin (TTR) deposition and one for amyloidotic cardiomyopathy of both genetic and sporadic origin. It is likely that in the next few months those not already approved by either the US Food and Drug Administration (FDA) and/or the European Medicines Authority (EMA) will receive similar approvals for treatment for all or particular groups of patients. This is a far cry from circumstances less than 10 years ago when the only available therapy was gene replacement by liver transplant. The randomized controlled trials have shown that all the treatments (tafamidis, diflunisal, patisiran, and inotersen) are effective in the context of a clinical trial. However, we have very little idea of whether individual patients will respond in an equally positive way to all the drugs or whether there will be some who respond better to one or another or not respond at all, nor do we know whether combinations will be additive or synergistic. We lack validated markers of clinical response. While the small molecule TTR stabilizers increase serum TTR levels, the RNA-based drugs lower serum TTR. In the latter case, it is not clear that the reduction in serum TTR is related to the clinical response in a 1:1 fashion. Pharmaceutical companies have made substantial investments in the development of these agents and will clearly attempt to recoup those investments quickly. It is incumbent upon those of us who care for these patients to develop ways to assess the effects of therapy in the shortest possible time at the lowest possible cost. The better we are able to accomplish this the more likely it is that we will be able to treat the most patients in the most clinically efficient fashion regardless of their economic status. We now have the drugs we just have to figure out who should get them and when.
现在已经有四项针对转甲状腺素蛋白（TTR）沉积相关遗传性淀粉样多神经病的不同治疗药物和一项针对遗传性和散发性淀粉样心肌病的随机对照试验。很可能在接下来的几个月里，那些尚未获得美国食品和药物管理局（FDA）和/或欧洲药品管理局（EMA）批准的药物，将获得针对所有或特定患者群体的类似治疗批准。这与不到 10 年前的情况相去甚远，当时唯一可用的治疗方法是肝移植的基因替代。随机对照试验表明，所有治疗方法（塔法米迪、二氟尼柳、帕替沙尼和伊诺特沙尼）在临床试验中都是有效的。然而，我们几乎不知道个体患者是否会以同样积极的方式对所有药物产生反应，或者是否会有一些患者对一种或另一种药物反应更好，或者根本没有反应，我们也不知道联合用药是否会有叠加或协同作用。我们缺乏有效的临床反应标志物。虽然小分子 TTR 稳定剂可以提高血清 TTR 水平，但基于 RNA 的药物会降低血清 TTR。在后一种情况下，尚不清楚血清 TTR 的降低与临床反应是否呈 1:1 相关。制药公司在这些药物的开发上投入了大量资金，显然会试图尽快收回这些投资。我们有责任开发出在尽可能短的时间内以最低的成本评估治疗效果的方法。我们越能做到这一点，我们就越有可能以最具临床效率的方式治疗最多的患者，而不论其经济状况如何。我们现在有了药物，只需要弄清楚谁应该使用它们以及何时使用。
