TTR Gene Silencing Drugs in hATTR Amyloidosis: Trial Data

John L. Berk, MD: There have been some innovative trials that have recently been concluded, leading to FDA approval of these dramatic agents. There’s the APOLLO trial, sponsored by Alnylam [Pharmaceuticals, Inc], featuring patisiran, and then the inotersen NEURO-TTR trial, which is sponsored by Ionis [Pharmaceuticals, Inc] and Akcea Therapeutics, [Inc]. Jim, can you give us a little bit of an overview on the design of the APOLLO study?

P. James B. Dyck, MD: Sure. So in the APOLLO study, the patisiran study, their main end point was the modified Neuropathy Impairment Score mNIS + 7, which is essentially a neurological examination and then some nerve conduction abnormalities, the amplitudes of motor and sensory responses. And they also had a quantitative sensory study component built in, which is somatic smart QST [quantitative sensory testing]. These are all different ways of looking at motor deficits, sensory deficits, and some autonomic deficits, although the autonomic was a bit lacking. Then there were many secondary end points. The study showed that by using patisiran given intravenously every 3 weeks, there was a very robust change in the modified Neuropathy Impairment Score + 7 in the patisiran versus placebo. And in many patients, there was actually improvement in that score.

John L. Berk, MD: So there was a big difference in the change over time in this neuropathy composite scoring system.

P. James B. Dyck, MD: There was.

John L. Berk, MD: But what does that mean clinically? Was that meaningful?

P. James B. Dyck, MD: I think a lot of people find this modified Neuropathy Impairment Score + 7 to be very confusing. Essentially, it’s the neurological exam. So it’s patients’ weakness, sensory changes, reflex changes, and a nerve conduction study. That has real meaning to people’s lives. If you develop weakness, you can’t walk. You can’t use your hands. You can’t dress. If you develop numbness, you can’t feel the floor. You may become ataxic. If you have a lot of autonomic involvement, you have GI [gastrointestinal] dysmotility, diarrhea, light-headedness. So this large magnitude change in the score has huge clinical implications and can lead to big differences in people’s quality of lives.

John L. Berk, MD: And for those people who have a hard time understanding or implementing evaluations with the modified NIS + 7, would drug effect be demonstrated by just using the Neurology Impairment Score, which is the neurologist’s direct assessment?

P. James B. Dyck, MD: I think the thing that was really impressive in these studies is that the different components, by themselves, showed effect. This was a home run, as I’ve said. This was a real big difference. So yes, the neurologic examination by itself, without all the other fancy bells and whistles, shows an absolute effect.

John L. Berk, MD: Can a neurologist feel comfortable using their examination in a strict fashion that is reproducible?

P. James B. Dyck, MD: I think a neurologist can use whatever scale he or she uses and just follow along and show that the neuropathy is not getting worse, as long as they are a thoughtful, compulsive neurologist who scores things and pays attention. This isn’t overly fancy. A good neurological exam is a very powerful tool.

John L. Berk, MD: Michael, the inotersen study: Can you give us a little bit of an overview on the design of that study? Did it have the same end points? And what is your perspective on the composite scoring system versus the trimmed-down NIS alone?

Michael J. Polydefkis, MD: The inotersen study was a little peculiar. It was 15 months versus 18 months. It also was randomized 2:1, so 2 patients were on the drug for every 1 on placebo. And at 15 months, there was a highly significant difference between treatment and placebo in the mNIS + 7 score as well as a coprimary quality-of-life score, which took into account different physical domains—physical functioning, motor strength, pain, things like that. And so this was highly significant across both measures.

John L. Berk, MD: In your opinion, is a neurologist evaluation, effectively the Neurology Impairment Score, sufficient without the bells and whistles to detect change over time in neuropathy?

Michael J. Polydefkis, MD: Yes. So in this disease, it was shown to be true. As Jim said, if you stripped away different components of the mNIS + 7, just the NIS part, just the nerve conduction with different components of the NIS, they were all significant. So I do think a good compulsive community neurologist can do an exam that’s meaningful and track this disease.

John L. Berk, MD: OK. Again, the thing that seems to most distinguish these agents from the oral TTR [transthyretin] protein stabilizers: These agents more reliably stop disease, and there’s a signal of some sensory improvement in both trials.

Michael J. Polydefkis, MD: Yeah.

P. James B. Dyck, MD: One other thing I just want to add to this discussion is part of the reason we can show this big difference is that hATTR [hereditary transthyretin] amyloidosis for early amyloid polyneuropathy is such a devastating disease. Once it starts, it progresses rapidly. So in diabetic polyneuropathy, we’ve been unable to show effective, different agents. I don’t know if it’s because they don’t work or because the neuropathy progresses so slowly. In familial amyloid polyneuropathy, the neuropathy progresses very rapidly and very severely.