Neuropathy Impairment Score Research Articles

Indirect treatment comparison of the efficacy of patisiran and inotersen for hereditary transthyretin-mediated amyloidosis with polyneuropathy

ABSTRACT Introduction Patisiran and inotersen are two therapies approved for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy, a rapidly progressive disease with a substantial clinical burden. This analysis indirectly compares the efficacy of patisiran and inotersen on neuropathy and quality of life (QOL). Methods Published results from the NEURO-TTR study of inotersen and individual patient data from the APOLLO study of patisiran were used. Indirect comparisons were conducted for 15-month changes in neuropathy and QOL endpoints: modified Neuropathy Impairment Score +7 (mNIS+7Ionis,), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire, body mass index (BMI), and Polyneuropathy Disability (PND) score. Analyses were conducted under different assumptions about the impact of missing data and to adjust for baseline differences between studies. Results Patisiran showed significantly greater treatment effects than inotersen for mNIS+7Ionis (mean difference: −12.3 [95% confidence interval: −21.4, −3.3]), Norfolk QOL-DN (−11.3 [−19.8, −2.9]), and BMI (1.0 [0.4, 1.7]). The proportion of patients with improvement or no change from baseline on PND score was higher for patisiran-treated patients (odds ratio: 8.9 [4.6, 17.5]). Results were consistent and robust across analyses and methods. Conclusions Patisiran demonstrated greater treatment effects on neuropathy and QOL than inotersen in patients with hATTR amyloidosis with polyneuropathy.

MNIS+7 and lower limb function in inotersen treatment of hereditary transthyretin-mediated amyloidosis.

IntroductionInotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, demonstrated significant benefit versus placebo in the modified Neuropathy Impairment Score (NIS) +7 neurophysiologic tests (mNIS+7) in patients with hereditary TTR‐mediated amyloidosis (hATTR) with polyneuropathy. This analysis assessed the mNIS+7 components by anatomic location and the lower limb function (LLF) test.MethodsAdults with hATTR in the NEURO‐TTR trial (NCT01737398) were randomly assigned to receive weekly doses of subcutaneous inotersen 300 mg or placebo for 65 weeks. The mNIS+7 and LLF were assessed at 35 and 66 weeks.ResultsAll major mNIS+7 components (muscle weakness, muscle stretch reflexes, sensation) and the LLF showed significant efficacy in patients receiving inotersen versus placebo; however, NIS‐reflexes (upper limb), touch pressure (upper and lower limbs), and heart rate during deep breathing did not show significant effects.DiscussionThe results of this analysis reinforce the beneficial effect of inotersen on slowing neuropathy progression in patients with hATTR polyneuropathy.

Patisiran, an RNAi therapeutic for patients with hereditary transthyretin‐mediated amyloidosis: Sub‐analysis in Japanese patients from the APOLLO study

AbstractBackgroundHereditary transthyretin‐mediated (hATTR) amyloidosis is a rapidly progressive and fatal disease. Patisiran is an RNA interference therapeutic that inhibits synthesis of disease‐causing mutant and wild‐type transthyretin (TTR) protein in hATTR amyloidosis.AimThe efficacy and safety of patisiran were evaluated in the Phase 3 APOLLO study in patients with hATTR amyloidosis with polyneuropathy.MethodsIn total, 225 patients from 19 countries, including Japan (n = 16), received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks for 18 months. Patisiran halted or improved outcomes of polyneuropathy (measured by modified Neuropathy Impairment Score +7 [mNIS+7]) and improved quality of life (QOL) (measured by Norfolk Quality of Life‐Diabetic Neuropathy questionnaire). Present analyses assess the efficacy, safety, pharmacokinetic exposure, and pharmacodynamic effect of patisiran in the Japanese sub‐population of APOLLO.ResultsConsistent with the overall APOLLO population, patisiran significantly improved outcomes of polyneuropathy (mNIS+7) compared with placebo at 18 months in the APOLLO Japanese patients. Patisiran treatment also demonstrated benefit in QOL, motor strength, gait speed, nutritional status, and autonomic symptoms compared with placebo at 18 months in the Japanese sub‐population. Patisiran was generally well tolerated in Japanese patients, with most adverse events mild or moderate; safety profile was similar to the overall APOLLO population, and no deaths were observed. Patisiran pharmacokinetic exposures and TTR reduction were comparable to the overall population.ConclusionsData in the Japanese sub‐population were consistent with those from the overall APOLLO population and indicate a notable health benefit for patisiran treatment in Japanese patients with hATTR amyloidosis with polyneuropathy.

A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis

BackgroundPatisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score +7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup.ResultsTwenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (~ 82%), and sustained reduction of mean transthyretin levels over 24 months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24 months. Patisiran’s impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24 months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24 months.ConclusionsLong-term treatment with patisiran had an acceptable safety profile and was associated with halting/improvement of polyneuropathy progression in patients with hATTR amyloidosis.Trial registrationThe study was registered at ClinicalTrials.gov (identifier: NCT01961921) on October 14, 2013.

TTR gene silencing therapy in post liver transplant hereditary ATTR amyloidosis patients

Objective Patients with hereditary transthyretin (TTR) amyloidosis (hATTR) often experience disease progression after orthotopic liver transplant (POLT) due in part to wild type ATTR amyloid deposition. The management strategy is not defined. We propose that TTR gene silencing with an antisense oligonucleotide or a small interfering ribonucleic acid may be a treatment for these patients. Methods We reviewed the charts of hATTR patients POLT treated with a TTR gene silencing agent at 7 different Amyloid Clinics between 2018–2020. Results Nine hATTR patients with POLT were treated with TTR gene silencing therapy (Inotersen). The median age was 61 years. The median time from OLT to initiation of TTR gene silencing therapy was 7.5 years. The median duration of therapy was 12 months. Neuropathy impairment score remained stable or improved in all patients. Five patients stopped treatment: 3 because of thrombocytopenia, 2 because of reversible liver rejection. Three patients who discontinued treatment subsequently experienced worsening of their neuropathy. Conclusion TTR gene silencing therapy in hATTR patients with POLT could be a treatment option. Vigilant monitoring of renal, liver and bone marrow functions is necessary because of frequent complications. Further studies are needed to determine efficacy.

Pharmacological treatment for familial amyloid polyneuropathy.

Pharmacological treatment for familial amyloid polyneuropathy.

A study of diffusion tensor imaging of median nerve in diabetic peripheral neuropathy

ObjectiveTo evaluate the role of diffusion tensor imaging (DTI) in the evaluation of diabetic peripheral neuropathy (DPN) compared to clinical scores and nerve conduction studies (NCS).Patients and methodsWe included 30 patients with diabetes mellitus complaining of neuropathy symptoms and 15 healthy volunteers. All subjects underwent evaluation using 1.5-T DTI of median nerves and NCS. Patients underwent clinical evaluation using the Neuropathy Deficit Score (NDS), Neuropathy Impairment Score in the Lower Limbs (NIS-LL), and Diabetic Neuropathy Examination (DNE) score.ResultsWe found statistically significant differences between healthy volunteers and patients in fractional anisotropy (FA) of the distal segment (P = 0.016) and whole median nerve (P = 0.024), apparent diffusion coefficient (ADC) of proximal (P = 0.027) and distal (P < 0.001) segments, and whole median nerve (P = 0.019). Distal segment FA was significantly correlated with NDS (P = 0.003), DNEs (P = 0.003), sensory amplitude (P = 0.048), and motor CV (P = 0.020). Distal segment ADC was significantly correlated with NDS (P = 0.007), NIS-LL (P = 0.003), DNEs (P = 0.01), and sensory amplitude (P = 0.032). The best cut-off value of distal segment for FA was 0.45 (87% sensitivity, 80% specificity) and of distal segment ADC was 1.217 (80% sensitivity and specificity).ConclusionsOur results suggest that 1.5-T DTI examination of the median nerve can provide useful non-invasive information in patients with DPN.Trial registrationClinicalTrials.gov, NCT03934970. Registered on May 1, 2019

Responder Analysis for the Modified Neuropathy Impairment Score + 7 and the Norfolk-Quality of Life-Diabetic Neuropathy Questionnaire in Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy (4973)

Responder Analysis for the Modified Neuropathy Impairment Score + 7 and the Norfolk-Quality of Life-Diabetic Neuropathy Questionnaire in Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy (4973)

Follow-up in transthyretin familial amyloid polyneuropathy: Useful investigations

Patients with transthyretin amyloid polyneuropathy (TTR-FAP) and asymptomatic mutation-carriers have to be regularly followed-up in order to identify disease progression and the time point for starting or modifying therapy. In this case series we describe the potential suitability of different variables as progression markers.We retrospectively analyzed the follow-up charts of 10 TTR-FAP patients. Clinical examination included the Neuropathy Impairment Score of Lower Limb (NIS-LL), temperature perception thresholds, nerve conduction and autonomic function tests.The NIS-LL had the greatest value for a sensitive and correct follow-up for all TTR-FAP stages. All other examinations provided useful additional information but they were either less suited for advanced TTR-FAP, or had a higher test-retest variability.The results of this study provide preliminary evidence that a good clinical investigation is mandatory in TTR-FAP follow-up. Simple neuropathy scores like the NIS-LL might be as useful as technical investigations for TTR-FAP follow-up.

Improvement in Quality of Life in Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy and Cardiomyopathy Treated with Inotersen in the Phase 3 Study NEURO-TTR

Introduction Hereditary transthyretin (TTR) amyloidosis (hATTR) is a rare, progressive, and fatal disease. The disease is caused by misfolded TTR that builds up as amyloid in major organ systems, especially cardiac tissue and nerves, causing cardiomyopathy (CM) and polyneuropathy (PN), respectively. hATTR causes significant morbidity and a progressive decline in patient quality of life (QOL), severely limiting activities of daily living. Purpose To evaluate the effect of inotersen, an antisense oligonucleotide inhibitor of TTR protein production, on QOL of patients with hATTR with CM and PN. Methods NEURO-TTR (NCT01737398) is a global, randomised, double-blind, placebo-controlled phase 3 study. Adults (n=172) with hATTR-PN (stage 1 or 2) with or without CM were randomly assigned 2:1 and received 300-mg weekly subcutaneous inotersen or placebo for 15 months. CM was defined as diagnosis of hATTR-CM or =1.3 cm interventricular septum thickness (by echocardiography) at baseline. Primary endpoints were change from baseline to week 66 in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score and the modified Neuropathy Impairment Score+7 (mNIS+7). The Optum SF-36v2 Health Survey (SF-36v2) score was an exploratory outcome. Results At baseline, 69% of patients were male, mean age was 59 years (range, 27-81 years) and 63% (108/172) had CM. Of patients given placebo and inotersen, 55% (33/60) and 67% (75/112), respectively, had CM. Patients with CM had higher baseline mNIS+7 scores (higher scores indicate worse neuropathy), higher Norfolk QOL-DN total scores (higher scores indicate worse QOL) and lower SF-36v2 physical component summary scores (lower scores indicate worse QOL) than patients without CM. Inotersen-treated patients achieved highly statistically significant benefit compared with placebo in Norfolk QOL-DN total score (P=0.0006) and mNIS+7 (P Conclusion Significant improvement in Norfolk QOL-DN and SF-36v2 scores, which include several domains related to patient well-being and activities of daily living, suggest that inotersen improves the QOL of patients with hATTR-PN with CM, the hATTR population with the greatest disease burden.

Neuropathic pain as independent predictor of worse quality of life in patients with diabetic neuropathy

Background/Aim. The prevalence of diabetes mellitus in general population is constantly increasing. On the other hand, the number of diabetic patients with neuropathic pain is large. The aim of the study was to examine influence of neuropathic pain on quality of life (QoL) in patients with diabetic sensorimotor polyneuropathy (DSPN) who did not have any other diabetic complication or any other significant comorbidity. Methods. A total of 32 patients with DSPN and definitive neuropathic pain were compared with 32 patients with DSPN without neuropathic pain. The respondents were matched according to age, gender, and duration of illness. The following scales were used: the Pain Detect Questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs, Douleur Neuropathique EN 4 Questions, Hamilton depression and anxiety rating scales, Neuropathy Impairment Score of the Lower Limb (NIS-LL), and the Short Form 36 Health Survey Questionnaire (SF-36). Results. Patients with neuropathic pain had significantly more severe DSPN measured with NIS-LL (p &lt; 0.01). They were more likely to be engaged in physical work (p &lt; 0.05), and had more symptoms of depression (p &lt; 0.05) than patients without neuropathic pain. Patients with neuropathic pain had significantly lower QoL in both physical and mental domains (p &lt; 0.01). Independent predictors of worse QoL in DSPN were presence of depression (beta=-0.58, p &lt; 0.01) and presence of neuropathic pain (beta = -0.23, p &lt; 0.05) - R2adjusted = 0.48. Conclusion. Independent predictors of QoL in patients with DSPN were presence of depression and neuropathic pain, which signifies importance of their early recognition and early treatment.

Conjunctival lymphangiectasia as a biomarker of severe systemic disease in Ser77Tyr hereditary transthyretin amyloidosis

AimsTo investigate the relationship between the ophthalmic and systemic phenotypes in patients with hereditary transthyretin amyloidosis with the S77Y mutation (ATTRS77Y).MethodsIn this cross-sectional study, patients with genetically confirmed ATTRS77Y amyloidosis...

Leading RNA Interference Therapeutics Part 1: Silencing Hereditary Transthyretin Amyloidosis, with a Focus on Patisiran.

In 2018, patisiran was the first-ever RNA interference (RNAi)-based drug approved by the US Food and Drug Administration. Now pharmacology textbooks may include a new drug class thatresults in the effect firstdescribed by Fire and Mello 2 decades ago: post-transcriptional gene silencing by a small-interfering RNA (siRNA). Patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) present withmutations in the transthyretin (TTR) gene that lead to the formation of amyloid deposits in peripheral nerves and heart. The disease may also affect the eye and central nervous system. The formulation of patisiran comprises the RNAi drug encapsulated into a nanoparticle especially developed to deliver the anti-TTR siRNA into the main TTR producer: the liver. Hepatic cells contain apolipoprotein E receptors that recognize ApoE proteins opsonized in the lipid carrier and internalize the drug by endocytosis. Lipid vesicles are disrupted in the cell cytoplasm, and siRNAs are free to trigger the RNAi-based TTR gene silencing. The silencing processinvolves the binding of siRNA guide strand to 3'-untranslated region sequence of both mutant and wild-type TTR messenger RNA, which culminates in the TTR mRNA cleavage by the RNA-induced silencing complex (RISC)asthe first biochemical drug effect. Patisiran 0.3mg/kg is administered intravenously every 3weeks. Patients require premedication with anti-inflammatory drugs and antagonists of histamine H1 and H2 receptors to prevent infusion-related reactions and may require vitamin A supplementation. Following patisiran treatment, TTR knockdown remained stable for at least 2years. Adverse effects were mild to moderate with unchanged hematological, renal, or hepatic parameters. No drug-related severe adverse effects occurred in a 24-month follow-up phase II open-label extension study.At the recommended dosage of patisiran, Cmax and AUC values (mean ± standard deviation) were 7.15±2.14μg/mL and 184±159μg·h/mL, respectively. The drug showed stability in circulation with > 95% encapsulated in lipid particles. Metabolization occurred by ribonuclease enzymes, with less than 1% excreted unchanged in the urine. Patisiran ameliorated neuropathy impairment according to the modified Neuropathy Impairment Score + 7 analysis of the phase III study. The Norfolk Quality of Life-Diabetic Neuropathy score and gait speed improved in 51% of the patisiran-treated group in 18months. Additionally,the modified body mass index showed positive outcomes. Altogether, the data across phase I-III clinical trials points to patisiran as an effective and safe drug for the treatment of hATTR amyloidosis. It is hoped that real-world data from a larger number of patients treated with patisiran will confirm the effectiveness of this first-approved siRNA-based drug.

P.024 Long-term use of patisiran in patients with hereditary transthyretin amyloidosis (hATTR): 12 month efficacy &amp; safety data from a global open label extension (OLE) study

Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a multi-systemic, heterogenous, life-threatening disease. Patisiran resulted in significant improvement in neuropathy and QoL at 18-months compared to placebo, and was generally well-tolerated in the Phase 3 APOLLO study. Methods: Multi-center, OLE study to evaluate the efficacy and safety of long-term patisiran dosing for ≤ 5 years in hATTR amyloidosis patients with polyneuropathy who have completed the APOLLO study (NCT02510261). Endpoints include safety, tolerability and long-term efficacy of patisiran. Measures of clinical benefit are the same endpoints used in APOLLO including changes in mNIS+7 composite neuropathy impairment score and QoL (Norfolk QoL-DN) Results: As of December 2017, 184 of 186 (99%) patients who completed APOLLO and 25 patients from the Ph 2 OLE study enrolled in the Global OLE study. Baseline data for 211(APOLLO/placebo, n=49; APOLLO/patisiran, n=137 and patisiran Ph 2 OLE, n=25) patients included: median age 61 years (26-84); 74% males; 46% V30M. Interim safety data and 12-month efficacy results will be presented. Conclusions: The global OLE study includes a diverse population of hATTR amyloidosis patients. Interim data will include the long-term safety and maintenance of effect in patients continuing on patisiran, as well as the impact of treatment with patisiran on patients previously treated with placebo.

PRO59 ASSOCIATION BETWEEN CLINICAL OUTCOMES AND QUALITY OF LIFE IN PATIENTS WITH HEREDITARY TRANSTHYRETIN AMYLOIDOSIS

Hereditary transthyretin (hATTR) amyloidosis is a rare, systemic, progressive disease that often clinically manifests as polyneuropathy. The current analysis assesses associations of clinical outcomes with neuropathic-specific and generic health-related quality of life (HRQOL). Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a double-blinded, placebo-controlled randomized trial of inotersen in patients with hATTR accompanied by polyneuropathy. Clinical and patient-reported outcomes were assessed at baseline and week 66. Neuropathic-specific HRQOL was measured using the Norfolk QOL-diabetic neuropathy (DN) questionnaire, with the SF-36v2® Health Survey (SF-36v2) measuring generic HRQOL. Polyneuropathy symptoms and impairment were assessed by the polyneuropathy disability (PND) score (Stages I – IV, with higher stages indicating worse ambulatory disability), the modified Neuropathy Impairment Score+7 (mNIS+7), and the Neuropathy Symptoms and Change (NSC) questionnaire. Transthyretin (TTR) concentration was measured. Analysis of covariance models tested for differences in baseline HRQOL scores across baseline PND scores. Correlations measured associations between clinical outcomes and HRQOL measures at baseline. Ordinary least squares regression models tested associations between change-from-baseline HRQOL scores at week 66 and changes in clinical outcomes. Significantly worse scores in the majority of Norfolk QOL-DN and SF-36v2 scores were observed for patients in higher PND stages. mNIS+7 and NSC scores showed strong univariate correlations with Norfolk QOL-DN activities of daily living, large fiber neuropathy, and small fiber neuropathy domains, and SF36v2 physical functioning and role-physical domains. In multivariable regression models, decreases in NSC scores were associated with improvement in Norfolk QOL-DN domains, while decreases in both NSC scores and TTR concentration were associated with improvements in SF36v2 physical functioning and role-physical domains. Differences and changes in the severity of neuropathy predicted both neuropathic-specific and generic HRQOL. Decreased TTR concentration predicted improvement in generic HRQOL. Thus, treatments that reduce TTR and neuropathy should produce better HRQOL in patients with hATTR.

A population-based and cross-sectional study of the long-term prognosis in multifocal motor neuropathy.

A population-based, cross-sectional study of patients referred to the Danish hospital system between 1985 and 2006 was conducted to evaluate the long-term outcome in Danish patients treated for multifocal motor neuropathy (MMN). Thirty-four MMN patients were identified, three had died of unrelated diseases, 10 were excluded, one did not reply to study request and 20 were included. The median disease duration was 24 years (interquartile range: 18.5-31.0). Compared to 24 healthy matched control subjects, the Rasch-built Overall Disability Scale for Multifocal Motor Neuropathy was reduced by 9%, the Neuropathy Impairment Score showed a 3-fold increase, the isokinetic strength was reduced by 29%, the grip strength by 56%, the Timed 25-Foot Walk was prolonged by 13% and the EQ-5D-5 L-Index value was impaired by 20%. The isokinetic strength was significantly more impaired at the wrist and ankle as compared to the elbow and knee, and one patient had lost ambulation because of instability at the ankle. Patients were considerably more fatigued and had substantially impaired hand dexterity, while mood, aerobic capacity, social adjustment, and working capacity were not affected. Regression analysis showed that lag-time until start of initial therapy lead to impaired long-term outcome without any effect of disease duration. Long-term prognosis in treated MMN is characterized by moderate to severe impairment primarily affecting dexterity and stability at the ankle. Our observations support previous observations that the long-term impairment in MMN might be improved following earlier start of therapy and that an effect of disease duration cannot be demonstrated.

Upper limb onset of hereditary transthyretin amyloidosis is common in non-endemic areas.

The aim is to describe an uncommon phenotype of hereditary ATTR neuropathy with upper limb onset. The French TTR Familial Amyloid Polyneuropathy database was used for a retrospective evaluation of 32 consecutive patients with upper limb onset of the neuropathy (study group) and they were compared to 31 Portuguese early-onset patients and 99 late-onset patients without upper limb onset. Initial upper limb symptoms were mostly sensory. Lower limb symptoms began 2.3 ± 3 years after upper limb symptoms. Twenty-four (75%) patients were initially misdiagnosed, with 15 different diagnoses. More patients in the study group had a Neuropathy Impairment Score upper limb/lower limb ratio > 1 compared to the late-onset patient group. The study group had significantly more pronounced axonal loss in the median and ulnar motor nerves and the ulnar sensory and sural nerves. On radial nerve biopsies (n = 11), epineurial vessels were abnormal in six cases, including amyloid deposits in vessel walls (3/11), with vessel occlusion in two cases. Upper limb onset of hereditary ATTR neuropathy is not rare in non-endemic areas. It is important to propose early TTR sequencing of patients with idiopathic upper limb neuropathies, as specific management and treatment are required.

Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy

BackgroundEmerging evidence suggests that several factors can impact disease progression in transthyretin amyloid polyneuropathy (ATTR-PN). The present analysis used longitudinal data from Val30Met patients participating in the tafamidis (selective TTR stabilizer) clinical development program to evaluate the impact of baseline neurologic severity on disease progression in ATTR-PN.MethodsA linear mixed-effects model for repeated measures (MMRM) was constructed using tafamidis and placebo data from the intent-to-treat Val30Met population of the original registration study as well as tafamidis data from the two consecutive open-label extension studies. The second extension study is ongoing, but a prospectively-planned interim analysis involving a cleaned and locked database was conducted (cut-off: December 31, 2014). Val30Met patients are presented by treatment groups as those who received tafamidis during the registration and open-label studies (T-T group), or who received placebo during the registration study and were switched to tafamidis in the open-label studies (P-T group). Neurologic functioning was assessed at baseline and subsequent visits using the Neuropathy Impairment Score–Lower Limbs (NIS-LL). The analysis focused on the disease trajectory over the first 18 months of treatment.ResultsThe T-T (n = 64) and P-T (n = 61) cohorts were predominantly Caucasian and presented with early-stage neurologic disease (mean [standard deviation] baseline NIS-LL values were 8.4 [11.4] and 11.4 [13.5], respectively). The MMRM analysis demonstrated that baseline severity is an independent significant predictor of disease progression in addition to the treatment effect: patients with a lower baseline NIS-LL showed less progression than those with a higher baseline NIS-LL (p < 0.0001). Neurologic progression in the T-T group was less than in the P-T group across all levels of baseline NIS-LL (p = 0.0088), and the degree of separation increased over the 18-month period. Similar results were seen with the NIS-LL muscle weakness subscale.ConclusionsThis analysis of patients with Val30Met ATTR-PN demonstrates that neurologic disease progression strongly depends on baseline neurologic severity and illustrates the disease-modifying effect of tafamidis relative to placebo across a range of baseline levels of neurologic severity and treatment durations. These data also underscore the benefit of early diagnosis and treatment with tafamidis in delaying disease progression in ATTR-PN.Trial RegistrationNCT00409175, NCT00791492 and NCT00925002 registered 08 December 2006, 14 November 2008 (retrospectively registered), and 19 June 2009, respectively.

Long-Term Update from the Open-Label Extension of the NEURO-TTR Study in Patients with Hereditary Transthyretin Amyloidosis

Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, progressive, and fatal disease caused by the buildup of transthyretin-derived amyloid protein in major organs, predominantly affecting the peripheral nerves and heart. Inotersen, a second-generation antisense oligonucleotide targeting TTR mRNA, has shown efficacy and safety in patients with hATTR in a randomized, double-blind, placebo-controlled, phase 3 study, NEURO-TTR (ClinicalTrials.gov, NCT01737398; Benson NEJM 2018). Patients with hATTR amyloidosis who completed the NEURO-TTR study were eligible to receive inotersen for up to 5 years in a phase 3 open-label extension study (ClinicalTrials.gov, NCT02175004).Methods: In NEURO-TTR, patients were randomized 2:1 to receive inotersen (300-mg weekly subcutaneous doses) or placebo. In the open-label extension, patients continued inotersen (inotersen-inotersen) or switched from placebo to inotersen (placebo-inotersen). Evaluations included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7; higher scores indicate worse neuropathy), Norfolk Quality of Life-Diabetic Neuropathy questionnaire total score (Norfolk QoL-DN; higher scores indicate worse QoL), and adverse events (AEs). Cardiomyopathy (CM) was defined by a diagnosis of hATTR-CM at trial entry or by an interventricular wall thickness of 13 mm or more on transthoracic echocardiography at baseline, as ascertained by a central reader, or no known history of persistent hypertension (systolic blood pressure, ≥150 mm Hg) within 12 months before screening.Results: In the placebo-controlled, double-blind, phase 3 NEURO-TTR study, 112/172 patients were randomized and received inotersen. At baseline, patients were predominantly white (91.9%) males (68.6%) with a mean age of 59.2 years. A total of 67.4% had stage I (ambulatory) and 32.6% had stage II (ambulatory with assistance) disease. Inotersen-treated patients who had stage II disease had a longer duration of disease from diagnosis (40.9 vs 24.8 months, respectively) and from onset (72.6 vs 63.2 months, respectively) of hATTR polyneuropathy symptoms compared with placebo-treated patients who had stage II disease, indicating more advanced disease. A higher proportion of inotersen-treated patients had CM at baseline (67% vs 55%, respectively), and more severe CM, measured by higher NT-proBNP levels and longer duration of disease from hATTR-CM symptom onset, compared with placebo-treated patients. In the phase 3 open-label extension study as of Sept 15, 2017, 134 of 135 patients enrolled received ≥1 dose of inotersen. The mean age was 60.4 years and most patients were male (69.4%). Extended dosing with inotersen up to 27 months continued to improve mNIS+7 and Norfolk QoL-DN in the open-label extension compared to placebo-treated patients at week 66 in the double-blind NEURO-TTR study; mean changes from open-label extension baseline to open-label extension week 52 in the inotersen-inotersen group were 5.1 points for mNIS+7 (vs 25.5 for placebo-treated patients in the double-blind NEURO-TTR study) and 3.9 points for Norfolk QoL-DN (vs 10.7 for placebo-treated patients in the double-blind NEURO-TTR study). Initiation of inotersen in placebo-treated patients (placebo-inotersen) resulted in improvement in mNIS+7 and Norfolk QoL-DN by week 26. Few patients discontinued treatment because of AEs (inotersen-inotersen, 9%; placebo-inotersen, 4%). The rate of treatment-related serious AEs was low in both treatment groups (2% each). There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of exposure. We will present 2-year follow-up results from the open-label extension study.Conclusions: Results of the open-label extension show continued benefit, measured by mNIS+7 and Norfolk QoL-DN, and confirmed that earlier initiation of treatment is important for optimal clinical outcomes. No new safety concerns were identified. Results from the longer-term follow-up for the open-label extension will further elucidate how inotersen may benefit patients with hATTR amyloidosis. DisclosuresBrannagan:Alnylam: Honoraria, Other: Investigator, Speakers Bureau; Ionis: Other: Investigator. Wang:Ionis: Other: Investigator, Speakers Bureau. Coelho:Prothena: Consultancy, Honoraria; Ionis: Consultancy, Other: Investigator; Alnylam: Consultancy, Honoraria, Other: Investigator; Pfizer: Consultancy, Honoraria, Other: Investigator. Waddington Cruz:Ionis: Honoraria; Genzyme/Sanofi: Honoraria; Pfizer: Honoraria. Polydefkis:Pfizer: Honoraria; Alnylam: Honoraria. Dyck:Ionis: Consultancy; Alnylam: Consultancy. Plante-Bordeneuve:Alnylam: Consultancy; Pfizer: Consultancy, Other: reimbursement for travel and meeting; Ionis: Other: reimbursement for travel and meeting. Berk:Ionis: Honoraria, Other: Investigator; Alnylam: Honoraria, Other: Investigator; Pfizer: Other: Investigator. Barroso:Pfizer: Consultancy, Honoraria, Other: Thaos registry, Speakers Bureau; Alnylam: Honoraria, Other: Investigator. Conceição:Alnylam: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Hughes:Ionis: Employment. Kwoh:Ionis: Employment. Jung:Ionis: Employment. Guthrie:Akcea: Employment. Pollock:Akcea: Employment. Benson:Ionis: Other: Investigator, Research Funding. Gertz:janssen: Consultancy; Teva: Consultancy; spectrum: Consultancy, Honoraria; Alnylam: Honoraria; Ionis: Honoraria; Amgen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; celgene: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; Physicians Education Resource: Consultancy.

Patisiran, an investigational RNAi therapeutic for patients with hereditary transthyretin-mediated (hATTR) Amyloidosis : Results from the phase 3 APOLLO study

Introduction hATTR is a rare, multisystem, rapidly progressive, life-threatening disease caused by a mutation in the gene. Patients et methodes Objectifs : Patisiran, an investigational RNAi therapeutic, reducesproduction of mutant and wild-type TTR. This report describes the efficacy and safety of patisiran from phase 3 Apollo study. Multi-center, international, randomized (2 :1), DBPC study of patisiran 0,3 mg or placebo IV q3 W in patients with hATTR. Primary endpoint : change from baseline at 18 months in composite mNIS + 7 neuropathy impairment score. Secondary endpoints : QOL, motor strength, disability, gait speed, nutritional status and autonomic function. 225 patients enrolled (19 countries) mean age 61 years, 39 different TTR mutations, mean NIS 59,3 (6,0,141,6), 75 % PND > 1 (walking difficulties) and 56 % with cardiac involvement. Resultats At 18 months, mean change from baseline in mNIS + 7 demonstrated significant improvement with patisiran compared to placebo (p = 9,26,10–24). All secondary endpoints demonstrated statistically significant favorable differences in the patisiran arm compared to placebo (p Discussion Similar frequency of AEs (96,6 %, 97,4 %), SAEs (36,5 %, 40,3 %), and deaths (4,7 %, 7,8 %) in the patisiran and placebo groups, respectively. AEs reported in ≥ 10 % and more frequently with patisiran were peripheral edema and IRRs, both generally mild or moderate. Apollo is the largest, controlled study in hATTR amyloidosis and included a wide range of TTR genotypes and neuropathy severity and majority with cardiac involvement. Conclusion Use of patisiran resulted in significant improvement in motor, sensory and autonomic neuropathy, a significant reduction in disease symptoms, and favorable safety profile compared placebo.