Future Treatment of hATTR Amyloidosis


Analysis of current and newer therapies for the treatment of hereditary ATTR amyloidosis.

John L. Berk, MD: Dr Brannagan, what is the therapeutic future that you foresee in the next 2 years? Then I’m going to ask Dr Witteles what the therapeutic future is in 10 years.

Thomas H. Brannagan III, MD: In the next 2 years, hopefully vutrisiran looks promising to be approved, and the cardiac studies hopefully should be completed and moved forward. As was mentioned, Ionis Pharmaceuticals, Inc has a monthly subcutaneous product that, with the data so far, is thought not to cause the platelet and glomerulonephritis that requires the frequent monitoring. I think there will be easier-to-use medications available in the next 2 of years.

John L. Berk, MD: Ten years from now, Dr Witteles?

Ronald Witteles, MD: There is interest in some more novel approaches. For example, there’s interest in gene editing because you have this disease that’s usually from a single point mutation, and if gene editing is going to work in anything, this might be where it is. There has been an early look into that. There are still some attempts with antibodies for amyloid removal. I would say as a rule, those efforts in amyloid disease have been relatively underwhelming to date, but they’re still being investigated. There might potentially be something there. But I think it’s going to be more about better and easier-to-take ways of these sorts of approaches that we see now. It’s going to be hard to beat the results that you saw with patisiran and inotersen, in the way that they were able to halt progression of the disease and perhaps even improve it. It is going to be more about early diagnosis, better ways of delivering the therapies, and hopefully much more cost effective; right now the cost is really high for all of these treatments.

John L. Berk, MD: Dr Polydefkis, you’ve got a PhD degree. Can you live without TTR?

Michael J. Polydefkis, MD: I don’t know if you can live without it, but you could live with a lot less than you have.

John L. Berk, MD: So you have no concerns about gene editing to eliminate or suppress its production. Do you have any concerns about TTR gene silencers over decades?

Michael J. Polydefkis, MD: We accept patients who have been on therapies for upward of 6 years. Very detailed investigations, including looking for evidence of vitamin A deficiency, have shown no signal of toxicity.

John L. Berk, MD: Dr Dyck, in wrapping up here, how would you guide neurologists who are concerned that maybe they’re missing the diagnosis of hereditary TTR, peripheral and autonomic neuropathy?

P. James B. Dyck, MD: We already touched on this, but I think the easiest thing for them to do is a gene test. That is certainly a way that they won’t be missing these patients. The question is should we be doing this in every single patient with neuropathy who walks through our door, or how often do we do it? My involvement in all these different studies really opened my eyes to the range of severity of the neuropathy. At its mildest, it’s a very nonspecific axonal neuropathy, and then at its severest, it can look like CIDP [chronic inflammatory demyelinating polyneuropathy]. It can be a motor polyradiculoneuropathy, it can be almost a pure autonomic neuropathy, or most commonly it is a mixed pain, numbness, weakness, autonomic with cachexia. It’s quite easy to see there, however early on it’s not easy to see; the easiest way to pick those up is genetic testing.

John L. Berk, MD: Dr Brannagan, do you have any advice for community neurologists?

Thomas H. Brannagan III, MD: There have been a couple of papers published that highlight red flags that I think are often useful to think about when considering who to test. There’s estimated to be 20 million people in the United States with peripheral neuropathy, and whether all of those 20 million people need to have genetic testing is unclear. I’m not sure I would advocate for that, but it definitely is a disease that gets missed. The red flag points are useful to think about: if there’s a family history; if there’s bilateral carpal tunnel syndrome; alternating diarrhea or constipation, which in my experience often doesn’t get put together with neuropathy; the heart failure with preserved ejection fraction. Also rapidly progressive neuropathies, or neuropathies that have failed previous attempts at treatment, are some of the points in those red flag papers, which I’ve found to be useful in communicating with people.

John L. Berk, MD: Dr Witteles, understanding that you’re not a neurologist but you do deal with patients with amyloid and carpal tunnel, what’s your advice for physicians in the community who are pursuing carpal tunnel release surgeries? Is there any other management of those procedures that might inform us about disease?

Ronald Witteles, MD: There have been a couple of nice studies that have now looked at this. If at the time of surgery a bit of ligamentous tissue is sent to pathology specifically for red staining, you can find amyloid deposition in maybe up to 10% of these cases, not all ATTR, although mostly ATTR and usually preceding any other clinical involvement of the heart, or nerves, etc. There’s certainly a case to be made to speak to your hand surgeons, or orthopedists, or whomever is doing it to say, “Hey, start making this standard practice.” Typically with most carpal tunnel release surgeries that are done, there’s nothing that is sent to pathology, and it could be missed. Again it’s low-hanging fruit; I’d say that isn’t widespread but hopefully may become that.

John L. Berk, MD: Well gentlemen, it’s been a real pleasure spending time with you. I look forward to having a beer when the pandemic is not such a challenge. Thank you very much for your thoughts, and stay well.

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Transcript Edited for Clarity

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