Current Series: Amyloidosis

John L. Berk, MD: We have a few minutes left, and I’d like to discuss what you, the panelists, think of the unmet needs here. We have some really revolutionary agents that have come about over the past year, in terms of FDA approval. As you think about their shortcomings, what do you anticipate in terms of second-generation agents or other modalities that we can look forward to, Michael?

Michael J. Polydefkis, MD: I think one frustration I’ve had is that right now these drugs are approved for hATTR [hereditary transthyretin amyloidosis] neuropathy, but they’re not necessarily approved for cardiomyopathy or even wild-type disease. But certainly, I view hereditary TTR disease as 1 disease. I don’t view it as neuropathy or cardiomyopathy. Maybe we can even take a step back, and all TTR disease is similar. And so that’s a struggle I have in speaking with patients who may have hATTR cardiomyopathy but may have no neuropathy and can’t get these therapies.

John L. Berk, MD: That’s a very important point. Akshay, if you can give us your perspective on the secondary data that’s been generated from both the patisiran and inotersen studies and your perspective on the capacities of these revolutionary agents to treat and impact ATTR amyloid cardiomyopathy?

Akshay S. Desai, MD, MPH: I think the point is critically important: In some ways, the burden of TTR disease far exceeds the burden of hereditary amyloid polyneuropathy, particularly as it relates to the heart. And so, I think the ability to expand these therapies to the broader population with TTR amyloid is an important next step. When we think about the data that are available, we have data from APOLLO from a prespecified subgroup of patients with cardiomyopathy, defined as having a wall thickness of more than 13 mm. That population of patients, which is as you mentioned, about 60% of the total population in the study, was followed for the full duration of the 18-month follow up. The population of patients had echocardiographic surveillance over time as well as biomarker assessments.

And what we know is that the patisiran-treated patients, compared with the placebo-treated patients, had less progression in ventricular hypertrophy, improvements in longitudinal strain that is a marker of cardiac systolic function, and improvements in cardiac biomarkers, particularly natriuretic peptides. And in post hoc analyses that were not prespecified, there were also numerical reductions in the rates of hard clinical outcomes, including heart failure hospitalizations and death. So I think the impressive thing is that there does appear, in parallel with the reduction in progression of neuropathy, to be some decline in the progression of important markers of cardiac disease progression and certainly of incident heart failure, which is a lot less in the trial.

For the inotersen trial, we have a shorter follow up—at 15 months. There is less robust data from echocardiographic parameters, but again, the same signals with reduction in wall thickness. There is not a signal with regard to longitudinal strain. I think comparison across trials is a little difficult since, as was mentioned, the trial inclusion criteria are a little different. The severity of disease may have been a bit different between the trials. But still, about 60% of patients in the inotersen trial also had clinically apparent cardiac involvement. So I think there are some really positive signals of stalling of cardiomyopathy progression, reduction in incident heart failure, and a potentially significant impact on hard clinical outcomes that are really enticing. I think we need more data.

John L. Berk, MD: Jim?

P. James B. Dyck, MD: One of the concerns I have, and I don’t know how we get around this, is the cost. These drugs are $450,000 a year, per patient. We talk about 50,000 patients in the world, but it probably is much greater than that. How are we going to pay for that? How do we get these drugs out to the third world countries? I don’t have any easy answer for that. But it seems that these drugs really are going to change the future for people with hATTR, and we have some sort of responsibility, as a society, to try to treat people.