Tafamidis for Transthyretin Amyloid Cardiomyopathy: The Solution or Just the Beginning of the End?

Rodney H. Falk


Eur Heart J. 2019;40(12):1009-1012. 

In This Article

Responders and Non-responders

If tafamidis is approved for ATTR cardiomyopathy, will everyone with TTR amyloid cardiomyopathy benefit from the drug, and should it therefore be widely prescribed? Patients in New York Heart Association (NYHA) Class 1 were a small minority in the study and were analysed together with NYHA Class 2 patients. This combined group drove the positive outcome and, doubtless, the drug should be given as early as possible after diagnosis. Early use may have particular relevance to patients with a mutant TTR gene, as screening of relatives may pick up asymptomatic cardiac disease, and such patients should be treated. It is unlikely that a trial could ever be done in asymptomatic gene-positive patients with evidence of early cardiac involvement by noninvasive cardiac imaging, but post-marketing data collection may determine whether TTR stabilization in this population can prevent the onset of symptoms. In contrast to patients classified as NYHA 1 and 2, those in Class 3, as a group, showed no response to therapy. It is in these patients that the benefits of therapy can be questioned, and it is this question that leads to another—why did they not respond to therapy in the ATTR-ACT trial? There are two possible, but not mutually exclusive, answers. Either the degree of TTR stabilization in more advanced disease was inadequate to prevent disease progression over the 30-month study period, or there is a 'point of no return' in patients with more advanced disease, in whom the degree of cardiac dysfunction at the time of treatment drives the outcome, regardless of reduction in further amyloid deposition. If more intense TTR stabilization than can be achieved by tafamidis is needed in more advanced disease, then there be may a role for 'next generation' TTR stabilizers currently in development that show a stronger effect in vitro. Such drugs include AG10,[5] currently in phase 2 clinical trials. Alternatively, the TTR silencers inotersen and patisiran, both of which reduce TTR levels by >70% and which are highly effective in slowing the progression of both early and advanced TTR familial amyloid polyneuropathy,[9,10] may prove to be a more effective approach, used either as single agents or as part of a dual 'suppress and stabilize' approach. There is certainly room for comparative trials of these approaches, which hopefully can soon be initiated.

Given the subjective nature of the NYHA class, it would seem inappropriate at present to limit tafamidis to Class 1 and 2 patients only, but it might be possible to distinguish responders and non-responders more precisely by application of recently-published staging systems which, despite the limitations of a binary analysis offer a better approach than NYHA class for prognostication.[11,12] If a group of non-responders can be more precisely defined, they may benefit from a different approach, other than tafamidis. Specifically, there are antibodies in development, either targeted against transthyretin or against serum amyloid P component, an obligatory component of all types of amyloid fibrils.[13] Such therapies are designed to reduce amyloid burden in the heart but are currently only in preclinical and early stage clinical trials.