John L. Berk, MD: Ten years ago, we had liver transplantation. Now there are 2 oral TTR [transthyretin] tetramer protein stabilizers. There are 2 RNA-modifying agents. How do you guys use these agents? And then I’ve got an even tougher question after that. So Jim, why don’t you start off? How do you use these agents? When do you use one versus the other?
P. James B. Dyck, MD: I really talk to the patients about patisiran versus inotersen. I explain to them the way we’re going to give it, explain to them the adverse effects, and essentially let the patients decide which one they will go with. Insurance companies may also have a say on which they’ll pay for and which they won’t pay for, so it may not entirely be the patient’s decision. I also think diflunisal with these agents potentially has a role—using a stabilizer and a knockdown therapy together.
John L. Berk, MD: Why would you use combined therapy?
P. James B. Dyck, MD: One of them is knocking down TTR by about 80%, but there is still going to be 20% of TTR remaining in that patient. And so stabilizing that so it’s not going to form amyloid, theoretically, makes sense to me.
John L. Berk, MD: Is there any role for a TTR tetramer stabilizer independent of a gene silencer?
P. James B. Dyck, MD: I absolutely think there’s a role for that, because there will be people without insurance. Again, these are very expensive drugs. Diflunisal is a relatively inexpensive drug. So I think that there is a role for that, absolutely.
John L. Berk, MD: Michael?
Michael J. Polydefkis, MD: I think diflunisal is the perfect solution for somebody who is early on, who’s having symptoms, but neither I nor the patient are sure what they mean, which means that there’s no objective neuropathy. Their exam is quite good. So it’s not clear if they’ve begun the cascade of amyloid deposition. That’s a great patient to put on diflunisal, because we’re potentially stalling or delaying the development of symptomatic disease. In terms of a symptomatic patient with hATTR [hereditary amyloid transthyretin amyloidosis], I think that a silencer or knockdown drugs are the way to go. Not considering cost or other issues, the data look better. Now, if there’s a patient who might experience some progression, or if you want to be extra conservative, adding a stabilizer drug would make sense.
John L. Berk, MD: If I’m getting this correct from you both, the feeling is that when symptomatic, TTR gene silencing therapy is mandatory.
P. James B. Dyck, MD: Mandatory is a strong word, but I think it’s certainly preferable.
John L. Berk, MD: Advised.
P. James B. Dyck, MD: Yes, advised.
Michael J. Polydefkis, MD: I agree. The data from the trials suggest that the neuropathy is stopped or even improved a little.
John L. Berk, MD: Ah, improved.
P. James B. Dyck, MD: Yes. John, I know that you’d had this beautiful study in JAMA about diflunisal. In no way am I trying to detract from the work that you have done, in supporting the gene silencing drugs, but they both showed that a sizable number of patients actually stabilized or even improved. Now, Alnylam [Pharmaceuticals], APOLLO study, patisiran had slightly more. And so, I think that company likes to tout that. Again, I would advise not to make too much of that. But I think it’s very exciting that in both studies there was improvement in some of the patients.
John L. Berk, MD: Michael?
Michael J. Polydefkis, MD: I agree.
John L. Berk, MD: OK. So the only editorial comment I have is that in the diflunisal trial, for the people who took diflunisal for a full 24 months, 30%—actually, 29%, but we’ll round up to 30%—had no progression of neuropathy by complex composite scoring. P. James B. Dyck, MD: I think diflunisal is a great option for people without insurance.
John L. Berk, MD: I don’t know how these drugs will be best used, although I think you could make an argument that in people who are early in disease, you could start them on an oral agent and monitor them. If they demonstrate any neurologic progression, then you would be on solid grounds to augment or completely change therapies. So I think you both make excellent points.
Now, the more difficult topic: You know people who are geno-positive for a mutation for which if it manifests, has devastating effects. Do you put people on treatment prophylactically without any evidence of neuropathy or cardiomyopathy?
P. James B. Dyck, MD: I’ve talked to the companies, both of them, about this issue, because I think this is the place to do studies. To me, that’s research and I think it’s a great study to do. They ought to, similarly to the way they’ve done these other studies, put a group of patients on treatment and another group on placebo and see if they can show that they can delay or abort onset of cardiomyopathy or neuropathy by doing that.
John L. Berk, MD: Michael?
Michael J. Polydefkis, MD: I agree it’s a great trial and a great study to be done. In today’s world, it’s difficult to prescribe these drugs for asymptomatic patients. If you could get it approved, which is a big “if,” I think it’s difficult to do. So you have to decide if they will develop the disease, ever, and if they will, when they’ll develop it.
Akshay S. Desai, MD, MPH: It’s a tough trial to design, isn’t it?
Michael J. Polydefkis, MD: Yes.
Akshay S. Desai, MD, MPH: You’d need a large number of patients, variable penetrance. It would take a long time of follow-up to basically ascertain that.
P. James B. Dyck, MD: It’s a very hard study to do. Again, one would probably take family history and see when parents became involved. But as we’ve talked about, there’s variable penetrance, so that would be imperfect too.