Pharmacokinetics and Pharmacodynamics of Patisiran in Patients with hATTR Amyloidosis and with Polyneuropathy After Liver Transplantation.

BACKGROUND AND OBJECTIVE: Variants of the transthyretin (TTR) gene cause hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis (v for variant), which results from deposition of misfolded TTR protein as amyloid in organs and tissues. Patisiran is an RNA interference (RNAi) therapeutic that suppresses the hepatic production of TTR protein. Patisiran improves multiple clinical manifestations of hATTR amyloidosis in patients without liver transplantation (LT). Because the liver is the predominant source of circulating TTR, LT has been prescribed to eliminate the production of the variant TTR. However, the continued production of wild-type TTR can contribute to disease progression after LT. Patisiran could potentially address an unmet need in these affected patients. This clinical trial was conducted to evaluate the safety, efficacy, and pharmacokinetics (PK) and pharmacodynamics (PD) of patisiran in patients with hATTR amyloidosis with polyneuropathy progression after LT. In this paper, we describe the PK/PD of patisiran in post-LT patients and compare it with prior patisiran studies in healthy subjects and patients without LT. METHODS: In an open-label study, patients (N = 23) with hATTR amyloidosis with polyneuropathy progression after LT received 0.3 mg/kg patisiran intravenously every 3 weeks (q3w) for 12 months. As a post hoc analysis, the PK and PD results from the current study were compared with prior patisiran studies in healthy volunteers from a Phase 1 study and in patients with hATTR amyloidosis without LT from Phase 2 and 3 studies. RESULTS: The PK profile of patisiran siRNA (ALN-18328) and its 2 lipid excipients, DLin-MC3-DMA and PEG2000-C-DMG, in hATTR amyloidosis patients after LT was consistent with prior patisiran studies in non-LT subjects. Plasma PK profiles of ALN-18328 and DLin-MC3-DMA exhibited 2 phases, the first characterized by a short distribution half-life and the second by a minor peak and relatively long elimination half-life. The plasma concentrations of PEG2000-C-DMG reached Cmax at the end of infusion and declined in a multiphasic manner. There was no appreciable accumulation at steady state. Consistent with prior studies in non-LT subjects, the post-LT patients showed a robust, and sustained TTR reduction; with median TTR reduction from baseline of 91% (average of Month 6 and Month 12). No anti-drug antibodies were observed in any patient. CONCLUSIONS: The consistency of patisiran PK and PD between patients with and without LT suggests that neither LT nor concomitantly administered immunosuppressants influence hepatic uptake or RNAi activity of patisiran. The patisiran dosing regimen of 0.3 mg/kg q3w is appropriate for hATTR amyloidosis patients with or without LT. CLINICAL TRIAL REGISTRATION NO: NCT03862807.

Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial.

BACKGROUND: The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. METHODS: HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months. RESULTS: HELIOS-A enrolled 164 patients (vutrisiran, n = 122; patisiran reference group, n = 42); external placebo, n = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (p = 3.54 × 10-12), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths. CONCLUSIONS: Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile. CLINICALTRIALS.GOV: NCT03759379.

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

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).

Concept of a Radiofrequency Device for Osteopenia/Osteoporosis Screening.

Osteoporosis represents a major health problem, resulting in substantial increases in health care costs. There is an unmet need for a cost-effective technique that can measure bone properties without the use of ionizing radiation. The present study reports design, construction, and testing of a safe, and easy to use radiofrequency device to detect osteoporotic bone conditions. The device uses novel on-body antennas contacting the human wrist under an applied, operator-controlled pressure. For the dichotomous diagnostic test, we selected 60 study participants (23-94 years old, 48 female, 12 male) who could be positively differentiated between healthy and osteopenic/osteoporotic states. The band-limited integral of the transmission coefficient averaged for both wrists, multiplied by age, and divided by BMI has been used as an index. For a 100 MHz frequency band centered about 890-920 MHz, the maximum Youden's J index is 81.5%. Both the sensitivity and specificity simultaneously reach 87% given the calibration device threshold tolerance of ±3%. Our approach correlates well with the available DXA measurements and has the potential for screening patients at risk for fragility fractures, given the ease of implementation and low costs associated with both the technique and the equipment. The inclusion of radiofrequency transmission data does add supplementary useful information to the available clinical risk factors.

Re-evaluating osteoporosis and fracture risk in Crohn's disease patients in the era of TNF-alpha inhibitors.

INTRODUCTION: Patients with Crohn's disease (CD) are at increased risk for osteoporosis and fractures as compared to the general population. Recently, various cytokines including tumor necrosis factor (TNF)-alpha are found to play a major role in bone health. In this study, we aimed to gain a better understanding of the risk factors for osteoporosis and vitamin D deficiency in the era of TNF-alpha inhibitors. METHODS: We conducted a retrospective review of 464 consecutive patients with CD in our GI clinic between 2008 and 2015. Statistical analysis was performed using the student t-test and chi-square test. RESULTS: CD patients treated with TNF-alpha inhibitors (TNF) and those who are anti-TNF naïve (NB) had similar rates of vitamin D deficiency, insufficiency and normal vitamin D-25-OH levels. Similarly, rates of osteoporosis (16% vs 18%), osteopenia (53% vs 57%) and normal bone density (31% vs 25%) were comparable between the TNF and NB groups respectively. However, Z-scores at the spine (-0.47 vs -0.05) were significantly lower in the TNF group (p = .03). Interestingly, rates of osteoporosis in the NB group were drastically different before and after age 60 (3.6% vs 30%) with no major difference in the TNF group (15% vs 18%). Bone density was positively correlated with BMI (Pearson's R = 0.39) and negatively correlated with age and smoking status (R= -0.25). CONCLUSIONS: TNF group patients were diagnosed with osteoporosis from an earlier age compared to NB group but with a smaller increase in osteoporosis after menopause. Further prospective studies are necessary to further determine the role of anti-TNF medications in osteoporosis.

Management of adynamic bone disease in chronic kidney disease: A brief review.

The Kidney Disease: Improving Global Outcomes (KDIGO) work group released recommendations in 2006 to define the bone-related pathology associated with chronic kidney disease as renal osteodystrophy. In 2009, KDIGO released revised clinical practice guidelines which redefined systemic disorders of bone and mineral metabolism due to chronic kidney disease as chronic kidney disease-mineral and bone disorders. Conditions under this overarching term include osteitis fibrosa cystica, osteomalacia, and adynamic bone disease. We aim to provide a brief review of the histopathology, pathophysiology, epidemiology, and diagnostic features of adynamic bone disease, focusing on current trends in the management of this complex bone disorder.

Vitamin D deficiency and chronic lung disease.

Vitamin D deficiency is increasingly being recognized as a prevalent problem in the general population. Patients with chronic lung diseases such as asthma, cystic fibrosis, chronic obstructive lung disease and interstitial pneumonia appear to be at increased risk for vitamin D deficiency for reasons that are not clear. Several studies indicate that vitamin D possesses a range of anti-inflammatory properties and may be involved in processes other than the previously believed functions of calcium and phosphate homeostasis. Various cytokines, cellular elements, oxidative stress and protease/antiprotease levels appear to affect lung fibroproliferation, remodelling and function, which may be influenced by vitamin D levels. Chronic lung diseases such as asthma and chronic obstructive lung disease have also been linked to vitamin D on a genetic basis. This immune and genetic influence of vitamin D may influence the pathogenesis of chronic lung diseases. A recent observational study notes a significant association between vitamin D deficiency and decreased pulmonary function tests in a large ambulatory population. The present review will examine the current literature regarding vitamin D deficiency, its prevalence in patients with chronic lung disease, vitamin D anti-inflammatory properties and the role of vitamin D in pulmonary function.

New developments surrounding the safety of bisphosphonates.

PURPOSE OF REVIEW: Several new issues have been linked with the use of bisphosphonates in recent years. This has complicated the use of this important class of agents. This article reviews data surrounding these issues and discusses the impact on patient care. RECENT FINDINGS: Gastrointestinal toxicity has been a classic side effect of oral bisphosphonates. Newer issues such as osteonecrosis of the jaw have clearly been associated with bisphosphonate use, and adjustments to clinical practice need to be made to prevent and address this new complication. Atrial fibrillation has also been associated with bisphosphonates in recent years, but the literature is variable, and the connection is not clear. Limiting musculoskeletal pain is a rare side effect of bisphosphonates, but public awareness has been heightened by a recent Food and Drug Administration alert. Severe suppression of bone turnover is the most recent potential complication, and an increasing literature has made this a much more clinically relevant issue. SUMMARY: With all the public exposure regarding the various concerns associated with bisphosphonates, clinicians need to be keenly aware of the details surrounding these issues. Patients need to be presented with a digestible synopsis, such that risks and benefits can be evaluated, an informed decision regarding treatment can be made, and possible complications can be prevented or discovered early.

Vitamin D deficiency and osteoporosis in rehabilitation inpatients.

OBJECTIVE: To determine vitamin D status and bone mineral density (BMD) in patients admitted to a subacute rehabilitation facility. DESIGN: Cross-sectional cohort study. SETTING: Subacute rehabilitation facility. PARTICIPANTS: Fifty-three community-dwelling patients admitted from June through February 2005. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: BMD, 25-hydroxyvitamin D (25[OH]D), C-telopeptide (CTX), osteocalcin, and dietary milk intake. RESULTS: Prevalence of vitamin D deficiency (25[OH]D <20 ng/mL) was 49.1%, while a total of 83% of patients were either vitamin D deficient or insufficient (25[OH]D <30 ng/mL). The prevalence of osteopenia (T score, <-1) was 52.8%; osteoporosis (T score, <-2.5) was 17.0%. CTX (bone resorption marker) was elevated in 60.4% of patients. Osteocalcin (bone formation marker) was elevated in 13.2% of patients. Measurements of bone resorption and formation positively correlated (R2 = .22) indicating increased bone remodeling. CONCLUSIONS: Vitamin D deficiency and osteopenia and osteoporosis were highly prevalent in patients admitted for rehabilitation. Elevated bone resorption and remodeling were evident. This could be due to vitamin D deficiency that should be corrected before antiresorptive therapy is considered. The study emphasizes the need for vigilance for vitamin D status and BMD testing in patients admitted to rehabilitation facilities.

123I thyroid uptake and thyroid size at 24, 48, and 72 hours after the administration of recombinant human thyroid-stimulating hormone to normal volunteers.

CONTEXT: Recombinant human TSH (rhTSH) is used to evaluate thyroid carcinoma patients and off-label for (131)I thyroid ablation and nontoxic goiter therapy. OBJECTIVE: Our objective was to determine the optimal time for (131)I administration after rhTSH. PARTICIPANTS: Twenty-five euthyroid nongoitrous volunteers participated in the study. DESIGN: Baseline 24-h thyroid (123)I uptake (RAIU) was measured, and then 0.1 mg rhTSH was administered. (123)I was administered 24, 48, or 72 h after rhTSH, and a repeat 24-h RAIU was obtained. SETTING: The study was conducted at an academic research center. MAIN OUTCOME MEASURES: Thyroid function tests, thyroid ultrasounds, and electrocardiograms were measured before rhTSH, then daily for 4 d, and finally 7 d after rhTSH. RESULTS: Serum TSH concentrations 24 h after rhTSH increased from 1.7 +/- 0.5 muU/ml (mean +/- sd) to 13.3 +/- 4. The 24-h RAIUs rose from 25 +/- 5 to 47 +/- 8% (88% increase) when the (123)I was given at 24 h after rhTSH and from 29.8 +/- 7 to 40.5 +/- 13% (36% increase) when the (123)I was given at 48 h and were unchanged when the (123)I was given at 72 h. The post-rhTSH RAIU increase was greater at 24 than at 72 h (P < 0.005) and marginally greater than at 48 h (P = 0.057). Thyroid volumes significantly increased 48 h after rhTSH (10 +/- 3.8 vs. 11.1 +/- 3.7 ml; P < 0.009). Electrocardiograms were normal. CONCLUSIONS: Marked increases in RAIU occurred when (123)I was given 24 h after rhTSH administration to euthyroid volunteers. Smaller increases were observed at 48 h and none at 72 h.

A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas.

Pheochromocytomas are neural crest-derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1alpha. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1alpha activity in tumors.

A RET mutation with decreased penetrance in the family of a patient with a "sporadic" pheochromocytoma.

We present the case of a 38-yr-old man with a sporadic, multifocal pheochromocytoma and paraganglioma who was discovered to carry a Y791F germline mutation in exon 13 of the RET proto-oncogene. This mutation was found in his 65-yr-old mother and his 86-yr-old maternal grandmother. Neither of them had either biochemical evidence of pheochromocytoma or medullary thyroid carcinoma. The patient had a pro-phylactic thyroidectomy, which revealed mild C-cell hyperplasia. This case brings to discussion several issues: (1) the benefit of screening patients with apparently sporadic pheochromocytomas for genetic mutations; (2) the management of patients and families with "lower-risk" RET mutations; and (3) the possibility that lower-penetrance RET mutations may contribute to the list of causes of familial pheochromocytomas.