Patisiran: Post-Orthotopic Liver Transplant

 Patisiran: Post-Orthotopic Liver Transplant

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 Summary

 Index

Clinical Data – Global Safety Database – Case Reports –Abbreviations –References

 Clinical data

Open-Label Study of Patisiran in Patients with hATTR Post-OLT

Overview and Design

A phase 3b, open-label study was conducted to evaluate the safety, efficacy, and PK of patisiran in patients with hATTR who had polyneuropathy progression post-OLT. Patients in the study (N=23) received IV patisiran 0.3 mg/kg every 3 weeks for 12 months.

Key inclusion and exclusion criteria for the study are presented in Table 1.3

Table 1. Key Inclusion and Exclusion Criteria.3

The primary endpoint assessed was the average of Month 6 and Month 12 serum TTR percent reduction from baseline. Secondary endpoints were change from baseline to Month 12 in NIS, Norfolk QOL‑DN, COMPASS‑31, R‑ODS, and mBMI.3

Patient Demographics and Baseline Characteristics

A total of 23 patients across 7 European countries were enrolled and received patisiran. Baseline demographics of the patients enrolled are summarized in Table 2.3

Table 2. Baseline Demographics and Characteristics.3

Prior to initiation of patisiran treatment, the majority of patients (56.5%) had a PND score of IIIA/B. The first documented PND score was either the most recent PND score prior to OLT, or the first post-OLT PND score if no PND score was recorded prior to the OLT. Sixteen patients (69.6%) had experienced a 1‑unit increase from first documented PND score to study baseline, prior to patisiran treatment. Four patients (17.4%) experienced a 2-unit increase and three patients (13.0%) experienced a 3-unit increase in PND score (Table 3).3

Table 3. Increase from First Documented PND Score to PND Score at Baseline.3

Efficacy Results: Primary Endpoint

After 12 months of patisiran treatment, the median serum TTR percent reduction from baseline (average of Month 6 and Month 12) was 91.0% (95% CI: 86.1, 92.3; p<0.001) (Figure 1).3

Figure 1. Percentage Change in Serum TTR Through Month 12.3,a

Efficacy Results: Secondary Endpoints

For the secondary endpoint measures, data from the per protocol analysis set was analyzed (N=21), which included patients who met the criteria of ≤2 missing doses of patisiran due to COVID‑19. At 12 months, there was a decrease in observed mean total NIS score from baseline, indicating an improvement in neuropathy (mean [± SEM] from baseline -3.7 ± 2.7). Improvements were also seen at 12 months in quality of life and autonomic symptoms as indicated by a decrease in observed mean total Norfolk QOL‑DN score (-6.5 ± 4.9) and LS mean total COMPASS‑31 score (-5.0 ± 2.6), respectively, from baseline.3

Through 12 months, the measures of disability (total R‑ODS) and nutritional status (mBMI) were stable relative to baseline. Mean change [SEM] from baseline was -0.1 [1.1] for R-ODS and +4.4 [21.8] for mBMI.3

PK Endpoints

The PK profile of patisiran, including siRNA (ALN‑18328) and lipid excipients DLin‑MC3‑DMA and PEG2000‑C‑DMG, was assessed. PK samples were collected pre-dose, at end of infusion, at 4-hours, 24‑hours, and 72‑hours post-end of infusion on day 1 and week 54. Following the first dose administration of patisiran, the median tmax of ALN‑18328, DLin‑MC3‑DMA, and PEG2000‑C‑DMG were about 1.4 hours. At week 54 following q3w dosing, the PK of ALN‑18328 and PEG2000‑C‑DMG were similar to those observed after first dose. For DLin‑MC3‑DMA, a higher AUC but a lower Cmax was observed at week 54 compared to day 1. Table 4 presents a summary of select PK data obtained from the analysis.4

Table 4. Plasma PK Parameters of ALN‑18328, DLin‑MC3‑DMA, and PEG2000‑C‑DMG after Administration of Patisiran‑LNP 0.3 mg/kg q3w on Day 1 and Week 54.4

Safety Results

At 12 months, 23 patients (100%) experienced an AE, a majority of which were mild or moderate (Table 5). Common AEs were consistent with the Phase 3 APOLLO study. The most common AEs were diarrhea (34.8%) and IRRs (26.1%). Thirteen SAEs were reported in 5 patients (21.7%), 1 of which, an IRR, was considered related to patisiran. All 23 patients completed the study (1 patient discontinued treatment but completed the study). There were no discontinuations due to AEs, or deaths during the study.3

Table 5. Summary of Adverse Events.3

Liver transplant rejection occurred in 1 patient, which was deemed unrelated to patisiran by the investigator.3 This patient had a medical history of liver re-transplantation, and a liver biopsy 15 years after liver re-transplantation was consistent with mild acute cellular rejection likely due to inadequate immunosuppression. During the study, the patient’s immunosuppression regimen was modified, and LFTs remained stable, ranging from 1‑2x the ULN. The patient remained on study drug and completed the study.3,6

LFTs were normal in the majority of patients. Transient ALT elevation of >3x ULN associated with cholangitis in 1 patient was observed and deemed unrelated to patisiran by the investigator. There were no cases of platelet count < 50,000/mm3.3

 Global Safety Database

A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify any safety concerns regarding the use of patisiran in patients with a liver transplant. The use of patisiran in patients with hepatic disorders or moderate or severe hepatic impairment remains an important potential risk and will be closely monitored through routine pharmacovigilance activites.5

 Case Reports

The following information provides an overview of published case reports regarding patients receiving patisiran after liver transplantation. It is not intended to be an all-inclusive list of relevant publications, abstracts, and manuscripts.

Orthotopic Liver Transplant Case Reports

Seibert K, Wlodarski R, Sarswat N, et al. Progressive Multiple Mononeuropathy in a Patient With Familial Transthyretin Amyloidosis After Liver Transplantation. J Clin Neuromuscul Dis. 2022;23(3):143-147. doi:10.1097/CND.00000000000003687

      A case report detailed a 61‑year-old African American male, who presented with advanced biventricular heart failure and progressive numbness from the hands to the feet. The patient was diagnosed with hATTR, homozygous for the V122I variant. The patient underwent heart and liver transplantation for the management of hATTR.

      Over the 5 years following transplantation, the patient developed progressive weakness of the upper limbs, with increasing muscle atrophy in the hands. The patient was started on patisiran about 5.5 years post transplantation and maintained treatment for over 2 years, with reported stabilization of his neuropathy symptoms.

Bulinski C, Discher T, Rutsatz W, Assmus B, Krämer HH. Clinical improvement after change of therapy from tafamidis to patisiran in progressive TTR amyloidosis post-liver transplantation. J Neurol. 2022;269(7):3912-3914. doi:10.1007/s00415-022-10978-38

      A case report detailed a 36-year-old male patient diagnosed with hATTR with a Glu54Gly variant who was started on tafamidis a year after diagnosis. The patient underwent living split-liver transplantation, at which time tafamidis was discontinued.

      The patient experienced polyneuropathy progression 5 years post-transplant, and tafamidis was re-started. A year later, the patient required permanent assistance while walking and treatment with patisiran was started.

      After 18 months of patisiran treatment, the patient could walk independently with two dynamic peroneal splints and could climb 7‑8 stairs with assistance.

Gondi KT, Nazir S, Grande R, Hummel SL. Development of late amyloid cardiomyopathy following liver transplantation for hereditary Val30Met transthyretin amyloidosis. Amyloid. 2021;28(3):215-216. doi:10.1080/13506129.2021.19043919

      A case report detailed a 67-year-old male patient with Val30Met hATTR-PN who experienced cardiomyopathic disease progression after receiving an orthotopic liver transplant for polyneuropathy. The patient had no cardiac disease at the time of transplant and developed worsening fatigue, exertional dyspnea, cardiac arrhythmia, and reduced ejection fraction 22 years post-transplant.

      The patient had an ICD placed previously and therapy with patisiran was initiated; metoprolol succinate was continued. An improvement in exertional dyspnea and fatigue was observed within 2 months of starting patisiran treatment.

Domino Liver Transplant Case Reports

Nedkova-Hristova V, Donadeu L, Baliellas C, et al. Efficacy and safety of patisiran for the treatment of acquired amyloid polyneuropathy in domino liver transplant recipients. Ther Adv Neurol Disord. 2025;18:17562864251396030. Published 2025 Dec 10. doi:10.1177/1756286425139603010

      A prospective longitudinal study was conducted to evaluate the safety and efficacy of patisiran treatment for acquired amyloid polyneuropathy in DLT recipients.

      Four patients were enrolled in the study and initiated treatment with patisiran 0.3 mg/kg every 21 days. The primary endpoint was the change from baseline in NIS after 22 months of treatment. Secondary outcomes included the change in NIS-LL, neurophysiologic study, QST score, and 10MWT assessed after 22 months of treatment.

      The primary endpoint of change in NIS showed an average decrease of 3.75 points (95% CI ‑0.47, 7.97) from baseline at 22 months. Patients did not have evidence of cardiac amyloidosis on echocardiography or cardiac scintigraphy at the start of treatment. There were no serious adverse events during the follow-up period.

Ball HA, Stevens J, Gillmore JD. Peripheral neuropathy secondary to a 'domino' liver transplant: a case report. J Med Case Rep. 2023;17(1):291. Published 2023 Jun 29. doi:10.1186/s13256-023-04001-011

         A case report detailed a 74-year-old male patient with acquired ATTR after receiving DLT for non-alcoholic steatohepatitis. The donor of the liver had the Val30Met TTR mutation.

         About 8 years after transplant, the patient developed numbness and paresthesia in his feet, and weight loss. His symptoms continued to progress over 2 years.

      In consideration of the presence of transthyretin amyloid deposits and clinical symptoms of peripheral neuropathy, the patient began patisiran treatment at 0.3 mg/kg every 3 weeks. However, he then experienced a stroke resulting in impaired mobility and patisiran treatment was discontinued.

Tsamis KI, Mytilinaios D, Heneghan M, et al. Treatment of acquired transthyretin amyloidosis in domino liver transplantation. Clin Transplant. 2023;37(1):e14822. doi:10.1111/ctr.1482212

         A case report detailed a patient with acquired ATTR after receiving DLT for hepatocellular carcinoma. The donor underwent a transplant due to familial amyloidosis with a TTR Met 30 mutation.

         About ten years after transplant, the patient began to develop neurological symptoms, including distal limb paresthesia, tingling, and mild weakness. A nerve biopsy was conducted and confirmed the diagnosis of amyloid polyneuropathy.

      At the time of diagnosis, the patient was classified as FAP stage 1 and PND score 2, and was started on tafamidis. Two years later, the patient was classified as FAP stage 2 and PND score 3B and was started on patisiran treatment. Over the following months, the patient experienced a slow improvement of symptoms and was then classified as FAP stage 1 and PND score 2.

 Abbreviations

10MWT = 10-meter walk test; %CV = coefficient of variation; AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; ATTR = transthyretin amyloidosis; AUCτ = area under the concentration-time curve over a dosing interval; BL = baseline; BMI = body mass index; CI = confidence interval; CLss = systemic clearance at steady state; Cmax = maximum observed concentration; COMPASS‑31 = Composite Autonomic System Score‑31; COVID-19 = coronavirus disease 2019; DLT = domino liver transplantation; eGFR =  estimated glomerular filtration rate; FAP = Familial Amyloid Polyneuropathy; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; ICD = implantable cardioverter defibrillator; IRR = infusion‑related reaction; IV = intravenous; KPS = Karnofsky Performance Status; LFT = liver function test; LS = least squares; mBMI = modified body mass index; NIS = Neuropathy Impairment Score; NIS-LL = Neuropathy Impairment Score–Lower Limbs; Norfolk QOL‑DN = Norfolk Quality of Life-Diabetic Neuropathy; NYHA = New York Heart Association; OLT = orthotopic liver transplantation; PK = pharmacokinetic; PND = polyneuropathy disability; q3w = every 3 weeks; QST = quantitative sensory testing; R‑ODS = Rasch‑built Overall Disability Scale; SAE = serious adverse event; SD = standard deviation; SEM = standard error of the mean; siRNA = small interfering ribonucleic acid; t½ = half life; tmax = time to reach maximum concentration; TTR = transthyretin; ULN = upper limit of normal; Vdss = apparent volume of distribution at steady state; Wk = week.

Updated 26 August 2026

 References

1.  Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018;379(1):11-21. doi:10.1056/NEJMoa1716153

2.  Supplement to: Maurer MS, Kale P, Fontana M, et al. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389(17):1553-1565. doi:10.1056/NEJMoa2300757

3.  Schmidt HH, Wixner J, Planté‐Bordeneuve V, et al. Patisiran treatment in patients with hereditary transthyretin‐mediated amyloidosis with polyneuropathy after liver transplantation. Am J Transplant. 2022;22(6):1646-1657. doi:10.1111/ajt.17009

4.  Badri P, Habtemariam B, Melch M, et al. Pharmacokinetics and pharmacodynamics of patisiran in patients with hATTR amyloidosis and with polyneuropathy after liver transplantation. Clin Pharmacokinet. 2023;62(10):1509-1522. doi:10.1007/s40262-023-01292-w

5.  Alnylam Pharmaceuticals. Data on file. MED-ALL-PATI-2500013.

6.  Coelho T, Gillmore J, Adams D, et al. Open-label study of patisiran in patients with hATTR amyloidosis post-orthotopic liver transplant. Presented at: Peripheral Nerve Society (PNS) Annual Meeting; June 27-30, 2020; Virtual.

7.  Seibert K, Wlodarski R, Sarswat N, et al. Progressive multiple mononeuropathy in a patient with familial transthyretin amyloidosis after liver transplantation. J Clin Neuromuscul Dis. 2022;23(3):143-147. doi:10.1097/CND.0000000000000368

8.  Bulinski C, Discher T, Rutsatz W, Assmus B, Krämer HH. Clinical improvement after change of therapy from tafamidis to patisiran in progressive TTR amyloidosis post-liver transplantation. J Neurol. 2022;269(7):3912-3914. doi:10.1007/s00415-022-10978-3

9.  Gondi KT, Nazir S, Grande R, Hummel SL. Development of late amyloid cardiomyopathy following liver transplantation for hereditary Val30Met transthyretin amyloidosis. Amyloid. 2021;28(3):215-216. doi:10.1080/13506129.2021.1904391

10.  Nedkova-Hristova V, Donadeu L, Baliellas C, et al. Efficacy and safety of patisiran for the treatment of acquired amyloid polyneuropathy in domino liver transplant recipients. Ther Adv Neurol Disord. 2025;18. doi:10.1177/17562864251396030

11.  Ball HA, Stevens J, Gillmore JD. Peripheral neuropathy secondary to a ‘domino’ liver transplant: a case report. J Med Case Rep. 2023;17(1). doi:10.1186/s13256-023-04001-0

12.  Tsamis KI, Mytilinaios D, Heneghan M, et al. Treatment of acquired transthyretin amyloidosis in domino liver transplantation. Clin Transplant. 2023;37(1). doi:10.1111/ctr.14822