TTR Gene Silencers as Cardiomyopathy Treatment

John L. Berk, MD: Dr Witteles, there were 2 New England Journal of Medicine articles in 2018 regarding the success of TTR [transthyretin] gene silencers—inotersen and patisiran, both of which effectively stopped the generation of TTR mRNA by targeting a sequence in the 3’ prime untranslated region, which results in reductions in TTR, regardless of whether it’s a variant or wild-type.

So, the cardiac findings in these trials are quite limited. But is there something we can glean from the inotersen experience or the patisiran that might suggest that these TTR gene silencers have potential for promise of better therapeutic outcomes in cardiomyopathy than the TTR gene, than the TTR tetramer stabilizers?

Ronald Witteles, MD: Yes, I would say there’s tremendous excitement about the silencers for TTR cardiomyopathy. They are, of course, not approved for that indication yet because both of the trials you are referring to were specifically for the hereditary or variant TTR or polyneuropathy indications. Now as everybody on this panel knows very well, the idea that there’s a clear distinction between patients with variant TTR and those with polyneuropathy and cardiomyopathy is not true. It’s a spectrum, and particularly when you get into a lot of the mutations that lead to a predominantly polyneuropathy phenotype, many, if not most, will have some degree of overt cardiac involvement as assessed by imaging and/or biomarkers.

So, specifically for patisiran, there was a follow-up study where there were good data that were released from a cardiac subgroup that had been predefined from the APOLLO Trial, which pretty clearly showed a benefit in terms of echocardiographic parameters as well as from NT-proBNP, for the group who’s on patisiran versus placebo.

Now, it’s worth saying that the results of these studies, even more so with patisiran, but to a real extent with both of them, were absolutely unbelievable good results from a polyneuropathy standpoint. I mean, a P value in 1 of the trials, I believe in the 10-23 level with a couple hundred patients enrolled. That’s how big the treatment difference was and how consistent the difference was.

So, it would be utterly shocking knowing how, what the pathophysiology of the disease is if you could see that sort of result in neuropathy and not end up seeing that sort of result in cardiomyopathy.

There were some safety concerns, more so with inotersen. There’s a little bit about the patisiran arm that was brought up because there seemed to be more cardiovascular deaths potentially in the patisiran arm. But overall, there was actually fewer in the patisiran arm, and we’re talking about small numbers, so it probably wasn’t real. With inotersen, there was a trend toward a little more deaths in the inotersen arm. And there were issues with renal dysfunction and thrombocytopenia that give people some pause with it that hopefully will be different with next-generation forums.

In the big picture, there is tremendous excitement for the silencers and both companies have agents that are now either starting or about to start clinical trials for cardiomyopathy.