Challenges in Diagnosing and Treating hATTR Amyloidosis Polyneuropathy

P. James B. Dyck, MD

In 2018, the FDA approved 2 treatments for hereditary ATTR (hATTR) amyloidosis polyneuropathy, a disease which was previously treatable only with organ transplantation. The advent of patisiran (Onpattro®, Alnylam Pharmaceuticals) and inotersen (Tegsedi^TM, Ionis/Akcea Therapeutics) markedly changed the treatment landscape for this debilitating disease; however, challenges in diagnosis and treatment are still apparent. To better understand current challenges being faced in the clinic, NeurologyLive spoke with P. James B. Dyck, MD, professor of neurology at Mayo Clinic in Rochester, Minnesota and an expert in neuropathy.

NeurologyLive: What types of challenges do you encounter in diagnosing hATTR amyloidosis?

P. James B. Dyck, MD: Diagnosing familial polyneuropathy hATTR is a challenge. What one thinks about typically in diagnosing this disease is that it is a neuropathy that involves motor, sensory, and autonomic systems; it is associated with weight loss, and if that is associated with carpal tunnel syndrome, you are pretty sure you have somebody with amyloidosis. Now that does not necessarily distinguish that from light chain AL amyloidosis versus inherited TTR amyloidosis, so if the patient develops progressive weakness, sensory loss, pain, autonomic symptoms such as erectile dysfunction, lightheadedness, GI disturbance, diarrhea, or constipation, those are big clues.

The real issue is seeing patients early in the disease, and being involved with the patisiran and inotersen studies really brought this home for me. There is a large diversity in how these can develop and early on in the disease, these neuropathies don't look that much different than other neuropathies. I myself do a fat aspiration for essentially every neuropathy I see, and that will tell me if they have amyloid or not in 50% [of patients], so it's not a very great screening test but it's better than not doing it. I've debated whether I should do a genetic test in every neuropathy I see; I don't necessarily do that at this point but if I do have any sort of index of suspicion I will do the genetic test.

There has been a lot of interest recently in CIDP [chronic inflammatory demyelinating polyneuropathy] looking like hATTR. In some cases it does, in most cases it really doesn't but neurologists around the world want to have a treatment and one of the few neuropathies that is treatable is CIDP, which is treatable with IVIG, steroids, or plasma exchange. Many patients with neuropathy will get put on IVIG with the presumption that it's CIDP, but many of those patients don't have CIDP. I don't think it's that TTR amyloidosis looks so much like CIDP, it’s that neurologists over-diagnose CIDP for all causes of neuropathy.

Now that there are effective therapies available, how do you decide on treatment course?

A lot of that really depends on the patient. If the patient is living in some rural area where a subcutaneous route of administration is going to be superior, I think they may prefer to take inotersen; if they have platelet issues to begin with or something like that, I think they may prefer to take patisiran. I think that a lot of it really comes down to what the patient's individual needs are. Both drugs were absolutely very effective and I don't think one can say that one is better than the other; I think they are both very good treatment options and I think there's a place for both drugs.

What are the ongoing challenges in treating hATTR amyloidosis?

I think the biggest challenge is going to be actual coverage. These drugs cost $450,000 a year; that's a lot of expense, but I don't hold it against the pharmaceutical companies for that cost either, as there is a huge amount of money that goes into development of these drugs for a small number of patients who have these diseases. I think that this is the real question for the country and the world: Now that there are so many different orphan diseases that potentially could have treatments, how can we afford this? I don't have the answer for that.

So what do you do with the patient who has some symptoms but doesn't have evidence of neuropathy on examination? I'm not going to put that patient on treatment; what I would do though is see them back on a regular basis and look for development of neuropathy. Once they develop neuropathy, then I would put them on treatment. Addressing the asymptomatic or early symptomatic patient is going to have to be sorted out. I think we should do clinical trials in asymptomatic patients to see if we can delay onset of disease, but that's hard because you don't know when the disease is going to start. How long are you going to run that study for to really show that effect? That is only one of many difficulties in designing such a trial that I am quite aware of.

Transcript edited for clarity