John L. Berk, MDJohn L. Berk, MD
Just one year ago, the treatment landscape for ATTR amyloidosis was nearly bare. Patients with the disease, which in its worst form can resemble amyotrophic lateral sclerosis, now have 3 therapeutic options available to them based on the stage of their disease. We sat down with John L. Berk, MD, associate professor of medicine, director, Localized Amyloid Clinic, and director, Clinical Trials for Familiar Amyloidosis at Boston University, to talk about next steps in therapeutic development for amyloidosis.

NeurologyLive: What does the current clinical trial landscape for amyloidosis look like?

John L. Berk, MD: I've been involved in TTR drug development since 2004. I designed and sponsored the diflunisal trial, so it's been a really enjoyable ride over the past 15 years, and in that time 2 oral TTR tetramer protein stabilizers have had successful trials and now we're moving into TTR gene silencing, which has been remarkably impactful. What we know about the TTR gene silencers is that they work for neuropathy; the open-ended question is whether that's true of other major end organs such as the heart.

We've learned quite a lot from the TTR gene silencing trials as they involved over 60% of people who had significant TTR amyloid cardiomyopathy. and in those trials inotersen demonstrated stability over a 15-month period and patisiran had signals of cardiac remodeling which we've never seen with any of the other agents, and that was both on a structural and a biomarker level.
The data were not sufficient to gain approval for indication from the FDA, but certainly whet the appetite for upcoming trials. The upcoming trials then will examine the effect of these TTR gene silencing agents on TTR amyloid cardiomyopathy and that'll be in both hereditary and wild-type TTR.

There will be new generation agents or for both the RNAi and for the antisense oligonucleotide RNA-modifying agents and those trials are either underway or about to be underway, so in the space of the next 5 years, we anticipate that there are going to be even better RNA-modifying agents available: there is going to be less toxicity; they will be more practical agents where you will probably have subcutaneous injections 4 times a year as opposed to either a 21-day recurring infusion or a weekly injection; and there will be less, if any, issues with thrombocytopenia and renal dysfunction. So, the landscape is going to change, the agents are going to definitely be better, and there's going to be more competition between the pharmaceuticals, which will probably bring price down.

Now that we have effective treatments, what is the next therapeutic goal?

What we know is that these agents modify disease course from time of diagnosis; that means disease is active and ongoing. It begs the question whether the next leap in therapeutics is going to be applying these agents to people in anticipation of disease onset and how you demonstrate that. There has been some discussion about the impact of a study in which you would try to determine whether initiating therapy when people are simply geno-positive and don't have disease demonstrated [delays disease onset]; I think that would be extremely difficult and I don't see how a pharmaceutical could do that, particularly with penetrance being an issue. So, I don't think that's going to be on the near horizon, but if we did have a blood test that told us when protein was beginning to misfold, that could key a lot of therapeutics and not only could it tell us when to start, but it could tell us when therapies were insufficient, so I think that's the next major push to develop that therapeutic.

Do you see an ongoing role for diflunisal in this developing treatment landscape?

I absolutely do. The reason is that I view TTR disease as sort of a spectrum; where someone is at the time of diagnosis really should determine what therapies are best for them. If they are at the very beginning of their journey, then treating with an oral agent which is easy and less disruptive in life, is to my mind the thing to do. At this point are saddled with following end organ changes and even with that, you can safely follow someone on an annual basis and determine whether there is any progression. If there is progression, in my paradigm there would need to be therapeutic acceleration: either the introduction of a TTR gene silencer to the oral TTR protein stabilizer, or simply switching out agents. So yes, I think there is a role for diflunisal as a single agent; as people approach what I refer to as the tipping point in disease, then they really need to stop disease and that is when TTR gene silencers become imperative.