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Management of transthyretin (ATTR) amyloidosis has undergone a multitude of notable changes in recent decades.
More recently, new data from the APOLLO-B trial has reignited discussions about gaps in management of ATTR amyloidosis. Data from the trial, which Alnylam Pharmaceuticals announced will be used in a supplemental new drug application for patisiran, suggested the small interfering RNA reached both its primary and first secondary end points, with the agent providing a statistically significant improvement in 6-minute walk test and a statistically significant improvement in quality of life at 12 months with patisiran compared to placebo.
To learn more about the current state of management for ATTR amyloidosis, particularly, ATTR amyloidosis with cardiomyopathy, Practical Cardiology reached out to Srinivas Murali, MD, professor of medicine and chair of the Department of Cardiovascular Medicine at Allegheny Health Network, to take part in a Q&A on the subject.
Practical Cardiology: Can you discuss the largest current gaps in management of ATTR amyloidosis with cardiomyopathy?
Murali: First and foremost, the biggest gap, which has really narrowed substantially, is the gap in diagnosis. Before we talk about treatment gaps we should first talk about the gaps in diagnosis. Roughly 1 out of every 6000 people have ATTR and that gives you a pretty good number of patients who likely have this condition. So, up until a few years ago, the only way to be absolutely certain with the diagnosis of amyloidosis was a biopsy of the organ and biopsy of the heart. This, in particular, is not a slam dunk procedure—it is somewhat risky to go in and get a piece of the heart muscle from somebody. So, heart biopsy was a rate-limiting step in diagnosis because it was not widely available. Then the pathologic examination requires a skilled pathologist who can make the pathologic diagnosis that there is ATTR amyloidosis.
Due to the lack of access to easy diagnostic testing and the special skills necessary to make the diagnosis it was often missed— people would never know they had amyloidosis unless they happen to go see one of those few specialists, but in the past several years there has been a noninvasive diagnostic test that is widely available, which is the cardiac PYP scan and was introduced around 2013-2014. The specificity of this test is pretty high, and the sensitivity is high as well.
So, the gap in diagnosis has significantly narrowed. Now, we are focused on developing a much better understanding of the true prevalence of the disease because more and more patients are getting diagnosed.
Practical Cardiology Can you provide an overview of treatment options and strategies?
Murali: In the treatment of ATTR amyloidosis you want to do several things and there are several places where we can attack this disease. One is we can block the production of this protein in the liver. So, we say 'okay, I'm going to make sure your liver doesn't manufacture this abnormal protein. Let's just shut off the production'. Another treatment strategy is to say 'Okay, we can’t block the production, but let's make sure that when the abnormal protein is misfolded, we stabilize it'. That is another strategy and these drugs are called TTR stabilizers. With the third treatment we are trying to extract that abnormal protein from your heart or other tissues and eliminate it in the body so the organs can recover on their own. So, those are the 3 primary strategies. Obviously, the most drastic treatment for ATTR amyloidosis is to do a liver transplant, but that is a pretty drastic step. So, it is certainly not a practical approach.
Practical Cardiology: When discussing pharmacologic management, how effective are current treatment options?
Murali: The TTR stabilizers were the first class approved by the US FDA. What the studies have showed is that, if you take this medication, your heart failure does not deteriorate, you may start to have some stabilization of your symptoms, and you stay out of the hospital. We don't know yet, but we think people could possibly live longer with this strategy as well. They also seem to work in both hereditary ATTR amyloidosis and the wild type.
The second category of drugs are drugs that block the synthesis of block the production of the abnormal protein in the liver. And there are two drugs in the market. One is patisiran and one is called inotersen. Both of these agents are they are called RNA silencers, which means they block the messenger RNA that is giving orders to the liver to produce this protein.
So, these drugs don't get rid of the protein that's already in your tissues, but it prevents production of new proteins. Initially these drugs were evaluated in amyloid neuropathy. More recently, the APOLLO-B data showed that patients with ATTR amyloid cardiomyopathy also seem to have benefits with patisiran. Their heart failure symptoms appeared to stabilize, there is disease progression is diminished, and there was less risk for hospitalization, etc.
Editor’s note: This transcript has bee edited for length and clarity.