Real‐life experience with inotersen in hereditary transthyretin amyloidosis with late‐onset phenotype: Data from an early‐access program in Italy

Abstract

Background and purpose Hereditary transthyretin (TTR) amyloidosis (ATTRv) is a dominantly inherited, adult‐onset, progressive, and fatal disease caused by mutations in the transthyretin gene. Therapeutic agents approved for this disease include the TTR stabilizer tafamidis and the gene‐silencing drugs patisiran and inotersen. Inotersen is an antisense oligonucleotide that suppresses the hepatic production of transthyretin. After European Medical Agency approval in 2018, an early‐access program was opened in Italy, and in this article, we present the long‐term outcome of a cohort of Italian ATTRv patients who received inotersen within this program. Methods This is a multicenter, observational, retrospective study of patients affected by ATTRv that started inotersen during the early‐access program. The primary end point was safety. Secondary end points included change from baseline in familial amyloid polyneuropathy (FAP) stage, Polyneuropathy Disability, Neuropathy Impairment Scale, Compound Autonomic Dysfunction Test, Norfolk Quality of Life–Diabetic Neuropathy, troponin, N‐terminal pro–brain natriuretic peptide, interventricular septum thickness, and body mass index. Results In total, 23 patients were enrolled. No patient permanently discontinued the treatment because of thrombocytopenia, and no cases of severe thrombocytopenia were observed. Five patients discontinued the treatment permanently because of voluntary withdrawal (two patients), renal failure after infective pyelonephritis, not related to inotersen, drug‐related hypotension, and amyloid‐negative crescentic glomerulonephritis. In seven patients, dosing frequency was reduced to every 2 weeks due to recurrent thrombocytopenia. Considering the FAP stage, only two patients worsened, whereas the other 21 patients remained stable until the last follow‐up available. Conclusions The long‐term safety profile of inotersen is favorable. Neurologic disease severity at baseline is the main factor associated with progression.

Quantitative Sensory Testing in Late-Onset ATTRv Presymptomatic Subjects: A Single Center Experience

“…In the last decade, different therapies (TTR tetramer stabilizer and gene silencers) were approved for treating ATTRv disease [ 7 , 8 , 9 ] and they have drastically changed disease natural history. Nevertheless, the available anti-amyloid therapies can be prescribed only in patients with demonstrated polyneuropathy.…”

Nerve Conduction Studies of Dorsal Sural Nerve: Normative Data and Its Potential Application in ATTRv Pre-Symptomatic Subjects

“…In ATTRv, early detection of peripheral nerve damage is crucial to start a disease-modifying treatment [ 11 ]. ATTRv is generally a length-dependent polyneuropathy, and the most distal sensory fibers are affected first [ 12 ].…”

“…The disease results from an extracellular deposition of amyloid fibrils in a variety of organs, leading to a multisystemic condition with a prevalent involvement of the peripheral nervous system (transthyretin amyloid polyneuropathy, ATTR-PN) and heart (transthyretin amyloid cardiomyopathy, ATTR-CM), but kidney, ocular vitreous, liver, and gastrointestinal tract may also be involved [ 3 , 4 , 5 , 6 ]. In the past decades, significant advances have been achieved in the treatment of ATTRv amyloidosis as several therapies with the potential to delay the disease progression have emerged [ 7 , 8 , 9 , 10 ], especially if started early during the course of the illness [ 11 ]. Depending on the geographic areas, a wide variation in age at onset and clinical presentation of the disease is described.…”

Trajectories of Kidney Function in Patients with ATTRv Treated with Gene Silencers

“…eGFR slope in the inotersen group is stackable to the patisiran one, so the renal complications observed in the NEURO-TTR trial seem to be really rare in real-life experience [ 17 ], although a regular monitoring of renal function in these patients is always recommended.…”