Current Series: Amyloidosis

John L. Berk, MD: I’d like to shift topics here and focus a little bit on therapy. Back in 1990, some creative and rather courageous transplant surgeons, recognizing that the liver is the primary source of the abnormal protein in the familial form of disease, undertook a rather straightforward intervention, in regard to transplant livers. This first happened in Sweden, shortly thereafter followed by liver transplants in Boston. For years, at least the next decade, it was the primary mode of treatment. But we recognize that there could be progressive amyloid cardiomyopathy despite a successful orthotopic liver transplant. And that’s what really led to the evolution of medical therapies.

The first therapy to come along was really the brainchild of Jeff Kelly, a brilliant biophysical chemist at The Scripps Research Institute [in La Jolla, California]. He came up with a philosophy, or a hypothesis, that you could restabilize misfolding TTR [transthyretin] by investigating and identifying small molecules that were thyroxine mimetics. And by introducing these, could result in TTR tetramer stabilization, which, in clinical trial, proved to inhibit the progression of neurological disease. Those TTR agents, diflunisal and tafamidis, are oral agents and have been through registration clinical trials. I think at this point, the proper perspective is that those agents slow but do not stop disease. And more recently, Michael and Jim have been involved in revolutionary phase III trials that investigate RNA-modifying agents. So I’d like to get your perspectives on these TTR gene-silencing agents. We are specifically talking about patisiran and inotersen. Jim, we’ll let you lead off here, regarding your observations. We will again rely on Akshay for perspectives on the potential application of these agents for familial amyloid cardiomyopathy. So Jim, what do you think?

P. James B. Dyck, MD: I think it’s a very exciting time for TTR amyloidosis. I think the liver transplant clearly was a step forward but not a cure. I think the work that you did—you’re being very modest; you were the big leader on the diflunisal study. The diflunisal study also was a large step forward, but these gene-silencing drugs, I think, really have essentially stopped progression of the neuropathy. They both are home runs as far as I see it. The neuropathy clearly is stabilized, maybe even improved to a little degree. The inotersen potentially has a platelet problem, but with monitoring I think that could be avoided. People ask me, “Which drug would you go on?” I think it really becomes a very practical thing for patients. One of them is an intravenous drug, the other is a subcutaneous drug. One of them needs more monitoring than the other, but I think both are very good drugs and that both should be used.

John L. Berk, MD: Michael?

Michael J. Polydefkis, MD: I have very similar sentiments to Jim. Liver transplant works fantastic, but not for everybody. There are some genetic variants that do better than others. So I think for certain patients who carry certain genetic variants, I’m certainly more hesitant to consider a liver transplant. I agree that the stabilizers seem to slow the rate of disease, but disease still progresses and the knock-down drugs, the silencers, seem to halt disease progression. And that’s been remarkable to witness on many levels. This is a familial disease. It’s inherited. So there are often generations affected. It could be quite emotional for patients to now see a different future. So it’s been remarkable to be a part of. In terms of which agent, patisiran versus inotersen, I think Jim summarized it accurately and eloquently. One is subcutaneous, and 1 is intravenous. One has some safety monitoring, while 1 has no safety monitoring. But both are home runs.