Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation

Abstract

Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%-92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, -3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, -6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, -5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807).

Keywords: clinical research/practice; clinical trial; liver allograft function/dysfunction; liver transplantation/hepatology; molecular biology: small interfering RNA; neurology; patient survival; pharmacology.

FIGURE 1

Treatment of ATTRv amyloidosis with LT and with patisiran post‐LT. The liver is the predominant source of circulating TTR protein. While unstable, variant TTR protein drives the pathogenesis of ATTRv amyloidosis, both variant and wt TTR protein form the amyloid deposits in multiple tissues. LT eliminates the hepatic production of variant TTR. However, ongoing deposition of wt TTR contributes to disease progression. Patisiran suppresses the production of variant and wt TTR, whether as first‐line therapy (native) or after LT (transplanted), thus allowing for the stabilization or improvement in the manifestations of ATTRv amyloidosis. ATTRv, hereditary transthyretin (v for variant); LT, liver transplantation; TTR, transthyretin; wt, wild‐type

FIGURE 2

Percent change in serum TTR through Month 12 (Safety analysis set). BL, baseline; CI, confidence interval; SEM, standard error of the mean; TTR, transthyretin; Wk, week

FIGURE 3

Mean change from baseline through Month 12 in secondary efficacy endpoints of NIS, Norfolk QOL‐DN, COMPASS‐31, R‐ODS, and mBMI. Graphs show mean score ± SEM for the per protocol analysis set. COMPASS‐31 graph shows LS mean score ± SEM for the per protocol analysis set and was analyzed using an MMRM approach. LOCF was used to impute missing assessments at or after Month 6 for mBMI. LOCF was not used for Month 12 assessment summaries for NIS, Norfolk QOL‐DN, and R‐ODS since all patients either had complete data at Month 12 or had no available post‐baseline data for LOCF imputation. COMPASS‐31, Composite Autonomic Symptom Score‐31; LOCF, last observation carried forward; LS, least‐squares; mBMI, modified body mass index; MMRM, mixed‐effects model for repeated measures; NIS, Neuropathy Impairment Score; Norfolk QOL‐DN, Norfolk Quality of Life‐Diabetic Neuropathy questionnaire; R‐ODS, Rasch‐built Overall Disability Scale; SEM, standard error of the mean