Associate professor of medicine; director, Clinical Trials for Familial Amyloidosis; and d

, Localized Amyloid Clinic, Boston University School of Medicine

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.

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.

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.

Dr Polydefkis, you’ve got a PhD degree. Can you live without TTR?

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

So you have no concerns about gene editing to eliminate or suppress its production. Do you have any concerns about 

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.

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?

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.

Dr Brannagan, do you have any advice for community neurologists?

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.

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?

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.

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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Videos

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

Future Treatment of hATTR Amyloidosis

There has been some exciting top of the line results shared by Alnylam Pharmaceuticals, Inc on a study named HELIOS-A looking at a drug called vutrisiran, which is a second-generation 

gene silencer. There is hope for it to be the new and improved patisiran. Dr Brannagan, what were your thoughts about the press release for vutrisiran?

It seemed like exciting data; I would like to see more of it, but at 9 months there was already a difference between the placebo arm and the active drug. This was true of patisiran as well as inotersen. They also reported that there was a very good safety profile. It was thought at the time of the study that is was unethical to have a placebo arm, therefor the study compared the drug to the historical placebo from the patisiran APOLLO study. However, there was an active comparator arm with patisiran, and I did not see data in the press release about how the new drug compared to patisiran; I would be interested in that.

Dr Polydefkis, let’s say you’ve got patients who are on patisiran and they’re getting intravenous infusions every 3 weeks. Vutrisiran sails along and meets FDA approval; what’s the future for your patients on patisiran?

 First, we’ve been a little bit spoiled. Here’s this terrible progressive disease, and we have yet another drug that I would characterize as another grand slam. We’re becoming spoiled with all this success. The data that were announced are not complete, but it does look remarkable. The difference at 9 months was on par with what we see in the APOLLO-B study; it looks very similar. Would I switch patients? Again, I think it’s a discussion with the patient. However, the once every 3 months subQ [subcutaneous] injection does sounds better than an infusion every 3 weeks.

Reported were quality of life, gait speed, and the neuropathic measures. Dr Witteles, I’m really going to stretch you on this one. There was a mention in the press release that NT-proBNP [N-terminal pro-B-type natriuretic peptide] improved, or that there was movement in an improving direction. Is that surprising to you? How does that fit with your concepts of TTR protein stabilization with tafamidis?

It’s certainly not surprising in the context that patisiran clearly did that in the APOLLO trial. In the APOLLO trial they had a subset of patients who had clear evidence of cardiac involvement who were preidentified. On average in the placebo arm, their NT-proBNP went from about 700 to 1100 [pg/mL]. In the patisiran arm, it went from about 700 to 600 [pg/mL]. Frankly, it would have been surprising just based on mechanism if the vutrisiran showed anything different. In the cardiac world, there are phase 3 studies with vutrisiran as well as the next-generation form of inotersen going on as we speak. I believe all of us are extremely excited about their potential for the cardiac form of the disease based on how the disease works; it would be shocking if they weren’t effective

Expert discussion on the recent topline results released for vutrisiran in the HELIOS-A trial. 

Evaluating the Potential of Vultrisiran 

Dr Polydefkis, Dr Witteles suggested that the earlier the better with most effective therapy, alluding to 

 gene silencers. Let’s say I have fairly advanced, previously undiagnosed TTR amyloid neuropathy. I’m seeking your advice; am I out of luck in terms of getting benefits from the 

No. It’s been shown that irrespective of neuropathy severity, you’ll still experience a benefit from silencer therapy. This means that your disease will be likely halted. You may not improve dramatically, you may not go from a cane to running marathons, but you won’t regress to 2 canes or to a wheelchair.

Discussion on the role of TTR protein stabilizers and gene silencers for treating hereditary ATTR amyloidosis. 

Benefits of TTR Gene Silencers 

 Dr Dyck, help us here. Dr Polydefkis said there was a 28-point worsening of neuropathy in the placebo group of the APOLLO study and a 6-point actual improvement of scores from beginning to end of study in the treated group. What does that mean? How do we interpret the complex and comprehensive scoring system?

The Neuropathy Impairment Score [NIS] troubles people because they don’t know what it means. Simply, it is a measurement of patients’ deficits on a neurological examination. It’s weakness, it’s reflex changes, and it’s sensory loss, and it’s adding those together into a score. An NIS score of 50 is a moderate neuropathy; 100 is a severe neuropathy. A worsening of 28 points is a big deal. That was part of the point I was making earlier: The reason these studies were able to be effective is that patients with this disease worsen fairly dramatically over time.

Can you give us an idea of what the difference would functionally be if I’m in the study and I worsen by 28 points?

That might mean that you went from walking independently to not walking; it is a big difference. Improvement of 6 points is a real improvement. People always want to make head-to-head comparisons between these 2 studies. I always try to avoid doing that. The reason is 1 study went for 18 months; the other went for 15 months. They also used slightly different end points, and they allowed slightly different degrees of severity in neuropathy of the patients who went in there. It is a mistake to say that 1 drug is better than the other because there are these differences in the studies.

The thing that is very clear about both studies is that they’re both home runs. Both drugs work incredibly well. Both not only stop progression of neuropathy but had sizable numbers of patients in the study actually having improvement. To me, the big difference really has to do with the adverse-effect profile. One advantage of inotersen is that it’s a subcutaneous drug; patisiran is an intravenous drug. Inotersen had the thrombocytopenia, so that was a real potential problem. Since they have begun a surveillance program, they really stopped that problem with the thrombocytopenia. From my perspective, it really comes down to patients’ convenience about which of these drugs is better. If a subcutaneous drug is better for you, you might want to go with inotersen. If you’re not bothered by the intravenous route, you have less monitoring and fewer potential adverse effects with patisiran.

Dr Polydefkis, how do you decide between these 2 agents when prescribing TTR [transthyretin] gene silencer?

It is a discussion with the patient. We talk about many of the things Jim just touched upon: the route of administration, subcutaneously vs intravenously; the frequency, weekly versus every 3 weeks; and the need for monitoring. That discussion leads to a mutual decision.

On the West Coast, Dr Witteles, even though you’re a cardiologist, you’re an honorary neurologist because you’re codirector. How do you guys differentiate between these 2 agents? Or do you simply leave it up to the patient?

I’d follow somewhere in between that vs paftisiran clearly being superior. I agree that they were different trials. Unless you have head-to-head in a given trial, there’s never going to be a perfect comparison. We have the data that we have. You can even extend it to some of the substudies like the cardiac side. In APOLLO you did see some clear improvement from a cardiac side, which was not so clear in the inotersen study. When you look at it all, if you had to bet if 1 of them was a bit more efficacious than the other, the answer would be yes; it seems like patisiran was a bit more efficacious. Is that as good as a head-to-head study? Of course not, but those are the data we have.

Then you do have those safety issues: the thrombocytopenia, glomerulonephritis, and a little imbalance that wasn’t statistically significant but that was still notable on deaths. I put all those together. Though I discuss both options with patients, I generally recommend patisiran for them unless the IV [intravenous] infusion or the premeds are going to be a specific problem. For the big picture, I agree entirely with Dr Dyck. The big takeaway is not which is better. It’s that, my lord, these were both grand slams, not just home runs. They were both incredible, and the biggest thing is to get somebody on 1 of these 2 agents as soon as you can when you make the diagnosis.

Dr Brannagan, do you use any TTR protein stabilizers for your patients with neuropathy? Dr Witteles is saying that’s a waste of time.

Hold on, I didn’t say that. No, I don’t believe that at all.

I do certainly have patients who are on these medications, and I work closely with our cardiologists. There are some data that have shown a survival benefit with stabilizing drugs. I have to say, I’m not entirely certain that combining a silencer and a stabilizer is necessarily more beneficial. However, there are not survival data with the RNA silencers, and there are, including your own work, with the stabilizing drugs. I certainly have people who are combined. We also sometimes use the stabilizers, particularly diflunisal, when people don’t have neuropathy and don’t have cardiomyopathy but do have carpal tunnel, which is from amyloid, as a preventive medication. We usually discuss with them that there are no clear-cut data, but that it’s potentially a treatment. Studies on this area need to be done, but at this moment when we don’t have studies, we sometimes do that.

I want to interrupt here because I know Dr Berk is not going to toot his own horn. I’m going to toot his horn. He did a very nice study with my father on the use of diflunisal in hATTR [hereditary transthyretin-mediated amyloidosis]. He showed, very convincingly, with the modified Neuropathy Impairment Score + 7 that diflunisal slows the progression of hATTR polyneuropathy. It’s a very important study, and I do think the role of membrane stabilizers should still be considered. Some sort of cocktail may be the ultimate answer, but we don’t have that data. We should not abandon diflunisal or tafamidis.

I agree with that entirely. In fact, we try to get most of the patients on a stabilizer who are on patisiran or inotersen as well if they have clear cardiac involvement, as long as they can have it paid for and it’s not huge out-of-pocket expense. I do tend to try to get them on both a stabilizer and a silencer, so tafamidis plus most of the time patisiran or inotersen. In the absence of being able to do so, unless they have a contraindication, I do usually put them on diflunisal. As was said, do we know that diflunisal plus a silencer is better than a silencer alone? No. For people who have real phenotypic neurological involvement and cardiac involvement, if it’s 1 of 2 I can choose, I will definitely go the silencer route because we know that the difference in the progression of their neuropathy is so much dramatically better with a silencer vs the stabilizers.

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Clinicians elaborate on key trial data revealed through the APOLLO and NEURO-TTR studies in hereditary ATTR amyloidosis. 

John L. Berk, MD

Articles

Future Treatment of hATTR Amyloidosis

Evaluating the Potential of Vultrisiran

Benefits of TTR Gene Silencers

Evaluating hATTR Amyloidosis Therapy