Recent Advances in hATTR Amyloidosis Treatment


Treatment overview of hereditary ATTR amyloidosis and considerations for using newer therapies such as patisiran or inotersen in appropriate patients.

John L. Berk, MD: Gentlemen, let’s turn to some therapeutics because that’s really the purpose of our discussion. The original intervention was orthotopic liver transplant. In a very simple and really courageous experiment, the idea being that the abnormal protein is being produced in the liver. If you change the factory, then you can change the course of disease. The earlier results were quite impressive: The abnormal protein was replaced by a normal protein, there was a normal TTR [transthyretin], and disease course seemed to stabilize.

The problem began about 5 years into the transplant experience when some ultrasonographers at BU [Boston University] reviewed data and found that hearts were progressing as if there had never been liver transplants; they looked like amyloid hearts. That spawned efforts to develop a medical approach to treatment of this disease. Through efforts and really the brilliance of Jeff Kelly, a physical biochemist in California, the idea of stabilizing TTR tetramers was born. By searching for thyroxine mimetics, developed some agents that are proven quite effective at altering the course of disease.

One problem is that while those agents rarely can fully stabilize disease, typically they simply slow it down. This has been evidenced not only in neuropathy experience but also in cardiomyopathy. That leads us to the primary discussion that we need to have: TTR gene-silencing drugs. Dr Brannagan, how do these TTR gene-silencing drugs work?

Thomas H. Brannagan III, MD: There are 2 medications: patisiran, which is a small interferon RNA treatment, and inotersen, which is an antisense oligonucleotide. They both stop the message RNA from translating the transthyretin protein, which is the protein that misfolds into amyloid. It actually stops the production not only of the mutated transthyretin but also the wild-type transthyretin.

John L. Berk, MD: Excellent. Dr Polydefkis, can you give us a review of the APOLLO data featuring patisiran? What struck you about that study?

Michael J. Polydefkis, MD: This was an 18-month trial of 225 people randomized 2:1 patisiran to placebo; it showed a dramatic treatment effect. The primary outcome measure was a very rigorous neuropathy score that encompassed exam, nerve conduction, and other test results. It was wildly positive. The placebo group progressed 28 points on this scale of 304 points, and the treatment on the patients receiving patisiran improved by 6 points; that’s a big difference. A host of other secondary measures: the Norfolk Quality of Life [Questionnaire-Diabetic Neuropathy], walk speed, autonomic scores were also positive. In the world of peripheral neuropathy, this is really a remarkable test result, a wildly positive treatment effect. It spanned many domains of the disease.

John L. Berk, MD: That’s a great review. Dr Brannagan, you have been instrumental in the development and validation of inotersen. What results should we be most impressed by with that study? How does it compare with the APOLLO patisiran experience?

Thomas H. Brannagan III, MD: The studies were very similar. Patients were randomized 2:1 to the active drug, inotersen, compared with placebo. The placebo arm in that study, the patients progressed very rapidly. The outcome measures were very similar; both studies used the Norfolk Quality of Life score, and both studies used the modified Neuropathy Impairment Score + 7, even though they were slightly different scales. As Dr Polydefkis said, the modified Neuropathy Impairment Score + 7 was developed initially by Peter Dyck, the father of James Dyck on our call. It measures strength, sensation, and reflexes and also includes nerve conductions and quantitative sensory testing.

If you look at the study, the patients on placebo progressed rapidly on both the modified Neuropathy Impairment Score plus the Diabetic Neuropathy Quality of Life score, which has been validated in hereditary TTR amyloid. Patients who were on the active drug did much better compared with the progression. There was some worsening in the totality of the patients, though. I believe 36% of patients not only stabilized but improved on the Neuropathy Impairment Score, and about half of patients improved on the Quality of Life score.

John L. Berk, MD: Thank you for watching this NeurologyLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box.

Transcript Edited for Clarity

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