Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels.

Importance: Lipoprotein(a) (Lp[a]) is an important risk factor for atherothrombotic cardiovascular disease and aortic stenosis, for which there are no treatments approved by regulatory authorities. Objectives: To assess adverse events and tolerability of a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a) and to assess associated changes in plasma concentrations of Lp(a) at different doses. Design, Setting, and Participants: A single ascending dose study of SLN360, an siRNA targeting apolipoprotein(a) synthesis conducted at 5 clinical research unit sites located in the US, United Kingdom, and Australia. The study enrolled adults with Lp(a) plasma concentrations of 150 nmol/L or greater at screening and no known clinically overt cardiovascular disease. Participants were enrolled between November 18, 2020, and July 21, 2021, with last follow-up on December 29, 2021. Interventions: Participants were randomized to receive placebo (n = 8) or single doses of SLN360 at 30 mg (n = 6), 100 mg (n = 6), 300 mg (n = 6), or 600 mg (n = 6), administered subcutaneously. Main Outcomes and Measures: The primary outcome was evaluation of safety and tolerability. Secondary outcomes included change in plasma concentrations of Lp(a) to a maximum follow-up of 150 days. Results: Among 32 participants who were randomized and received the study intervention (mean age, 50 [SD, 13.5] years; 17 women [53%]), 32 (100%) completed the trial. One participant experienced 2 serious adverse event episodes: admission to the hospital for headache following SARS-CoV-2 vaccination and later for complications of cholecystitis, both of which were judged to be unrelated to study drug. Median baseline Lp(a) concentrations were as follows: placebo, 238 (IQR, 203-308) nmol/L; 30-mg SLN360, 171 (IQR, 142-219) nmol/L; 100-mg SLN360, 217 (IQR, 202-274) nmol/L; 300-mg SLN360, 285 (IQR, 195-338) nmol/L; and 600-mg SLN360, 231 (IQR, 179-276) nmol/L. Maximal median changes in Lp(a) were -20 (IQR, -61 to 3) nmol/L, -89 (IQR, -119 to -61) nmol/L, -185 (IQR, -226 to -163) nmol/L, -268 (IQR, -292 to -189) nmol/L, and -227 (IQR, -270 to -174) nmol/L, with maximal median percentage changes of -10% (IQR, -16% to 1%), -46% (IQR, -64% to -40%), -86% (IQR, -92% to -82%), -96% (IQR, -98% to -89%), and -98% (IQR, -98% to -97%), for the placebo group and the 30-mg, 100-mg, 300-mg, and 600-mg SLN360 groups, respectively. The duration of Lp(a) lowering was dose dependent, persisting for at least 150 days after administration. Conclusions and Relevance: In this phase 1 study of 32 participants with elevated Lp(a) levels and no known cardiovascular disease, the siRNA SLN360 was well tolerated, and a dose-dependent lowering of plasma Lp(a) concentrations was observed. The findings support further study to determine the safety and efficacy of this siRNA. Trial Registration: ClinicalTrials.gov Identifier: NCT04606602; EudraCT Identifier: 2020-002471-35.

Iron parameters in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based phosphate binders: Results from a phase 3, randomized open-label study.

OBJECTIVES: The recent availability of iron-based phosphate binders has raised some concerns about iron overload in patients with end-stage renal disease. This study evaluated iron parameters in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based phosphate binders. METHODS: This analysis used 2-year follow-up data from an open-label, multicentre, randomized, active-controlled, parallel-group, phase 3 trial of lanthanum carbonate (SPD405-307). After a washout period, if patients' serum phosphate levels exceeded 5.9 mg/dL, they were randomized 1:1 to receive lanthanum carbonate (375-3000 mg/day) or non-iron-based standard therapy during a 6-week dose titration period. Patients achieving control of serum phosphate levels (⩽5.9 mg/dL) received maintenance therapy with lanthanum carbonate or standard therapy for up to 24 months. RESULTS: No clinically relevant changes in mean (standard deviation) iron parameters between the treatment groups (lanthanum carbonate, n = 682; standard therapy, n = 677) from baseline to month 24/final visit were observed: iron (µg/dL), -1.1 (41.8) versus 1.0 (38.7); ferritin (ng/mL), 208.4 (445.1) versus 262.4 (505.5); transferrin saturation (%), 2.8 (18.0) versus 2.8 (17.3); and haemoglobin (g/dL), 0.4 (1.9) versus 0.3 (1.7), respectively (all, p > 0.1). There were no clinically relevant changes in the percentage of patients receiving any anti-anaemic preparation in either treatment group (pre- vs post-randomization: lanthanum carbonate, 94.9% vs 97.8%; standard therapy, 95.1% vs 98.8%, respectively). This is in contrast to the study by Lewis and colleagues, which found significant increases in ferritin and transferrin saturation levels in patients receiving ferric citrate versus active control (calcium acetate and/or sevelamer carbonate) after 52 weeks of therapy. Although serum ferritin and transferrin saturation are the recommended iron indices by the Kidney Disease Outcome Quality Initiative, they are indirect indicators of iron status. Longer-term studies are required to understand fully the potential risks associated with iron overload. CONCLUSION: No evidence of iron accumulation was found in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based binders.

Elemental calcium intake associated with calcium acetate/calcium carbonate in the treatment of hyperphosphatemia.

BACKGROUND: Calcium-based and non-calcium-based phosphate binders have similar efficacy in the treatment of hyperphosphatemia; however, calcium-based binders may be associated with hypercalcemia, vascular calcification, and adynamic bone disease. SCOPE: A post hoc analysis was carried out of data from a 16-week, Phase IV study of patients with end-stage renal disease (ESRD) who switched to lanthanum carbonate monotherapy from baseline calcium acetate/calcium carbonate monotherapy. Of the intent-to-treat population (N=2520), 752 patients with recorded dose data for calcium acetate (n=551)/calcium carbonate (n=201) at baseline and lanthanum carbonate at week 16 were studied. Elemental calcium intake, serum phosphate, corrected serum calcium, and serum intact parathyroid hormone levels were analyzed. FINDINGS: Of the 551 patients with calcium acetate dose data, 271 (49.2%) had an elemental calcium intake of at least 1.5 g/day at baseline, and 142 (25.8%) had an intake of at least 2.0 g/day. Mean (95% confidence interval [CI]) serum phosphate levels were 6.1 (5.89, 6.21) mg/dL at baseline and 6.2 (6.04, 6.38) mg/dL at 16 weeks; mean (95% CI) corrected serum calcium levels were 9.3 (9.16, 9.44) mg/dL and 9.2 (9.06, 9.34) mg/dL, respectively. Of the 201 patients with calcium carbonate dose data, 117 (58.2%) had an elemental calcium intake of at least 1.5 g/day, and 76 (37.8%) had an intake of at least 2.0 g/day. Mean (95% CI) serum phosphate levels were 5.8 (5.52, 6.06) mg/dL at baseline and 5.8 (5.53, 6.05) mg/dL at week 16; mean (95% CI) corrected serum calcium levels were 9.7 (9.15, 10.25) mg/dL and 9.2 (9.06, 9.34) mg/dL, respectively. CONCLUSION: Calcium acetate/calcium carbonate phosphate binders, taken to control serum phosphate levels, may result in high levels of elemental calcium intake. This may lead to complications related to calcium balance.

Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: Results from an Open-Label Extension Study.

BACKGROUND: Drisapersen induces exon 51 skipping during dystrophin pre-mRNA splicing and allows synthesis of partially functional dystrophin in Duchenne muscular dystrophy (DMD) patients with amenable mutations. METHODS: This 188-week open-label extension of the dose-escalation study assessed the long-term efficacy, safety, and pharmacokinetics of drisapersen (PRO051/GSK2402968), 6 mg/kg subcutaneously, in 12 DMD subjects. Dosing was once weekly for 72 weeks. All subjects had a planned treatment interruption (weeks 73-80), followed by intermittent dosing (weeks 81-188). RESULTS: Subjects received a median (range) total dose of 5.93 (5.10 to 6.02) mg/kg drisapersen. After 177 weeks (last efficacy assessment), median (mean [SD]) six-minute walk distance (6MWD) improved by 8 (-24.5 [161]) meters for the 10 subjects able to complete the 6MWD at baseline (mean age [SD]: 9.5 [1.9] years). These statistics include 2 subjects unable to complete the test at later visits and who scored "zero". When only the 8 ambulant subjects at week 177 were taken into account, a median (mean [SD]) increase of 64 (33 [121]) meters in 6MWD was observed. Of 7 subjects walking ≥330 m at extension baseline, 5 walked farther at week 177. Of 3 subjects walking <330 m, 2 lost ambulation, while 1 declined overall but walked farther at some visits. Over the 188 weeks, the most common adverse events were injection-site reactions, raised urinary α1-microglobulin and proteinuria. Dystrophin expression was detected in all muscle biopsies obtained at week 68 or 72. CONCLUSION: Drisapersen was generally well tolerated over 188 weeks. Possible renal effects, thrombocytopenia and injection-site reactions warrant continued monitoring. Improvements in the 6MWD at 12 weeks were sustained after 3.4 years of dosing for most patients. For a small, uncontrolled study, the outcomes are encouraging, as natural history studies would anticipate a decline of over 100 meters over a 3-year period in a comparable cohort. TRIAL REGISTRATION: ClinicalTrials.gov NCT01910649.

Lanthanum carbonate: safety data after 10 years.

Despite 10 years of post-marketing safety monitoring of the phosphate binder lanthanum carbonate, concerns about aluminium-like accumulation and toxicity persist. Here, we present a concise overview of the safety profile of lanthanum carbonate and interim results from a 5-year observational database study (SPD405-404; ClinicalTrials.gov identifier: NCT00567723). The pharmacokinetic paradigms of lanthanum and aluminium are different in that lanthanum is minimally absorbed and eliminated via the hepatobiliary pathway, whereas aluminium shows appreciable absorption and is eliminated by the kidneys. Randomised prospective studies of paired bone biopsies revealed no evidence of accumulation or toxicity in patients treated with lanthanum carbonate. Patients treated with lanthanum carbonate for up to 6 years showed no clinically relevant changes in liver enzyme or bilirubin levels. Lanthanum does not cross the intact blood-brain barrier. The most common adverse effects are mild/moderate nausea, diarrhoea and flatulence. An interim Kaplan-Meier analysis of SPD405-404 data from the United States Renal Data System revealed that the median 5-year survival was 51.6 months (95% CI: 49.1, 54.2) in patients who received lanthanum carbonate (test group), 48.9 months (95% CI: 47.3, 50.5) in patients treated with other phosphate binders (concomitant therapy control group) and 40.3 months (95% CI: 38.9, 41.5) in patients before the availability of lanthanum carbonate (historical control group). Bone fracture rates were 5.9%, 6.7% and 6.4%, respectively. After more than 850 000 person-years of worldwide patient exposure, there is no evidence that lanthanum carbonate is associated with adverse safety outcomes in patients with end-stage renal disease.

Real-world dose-relativity, tablet burden, and cost comparison of conversion between sevelamer hydrochloride/carbonate and lanthanum carbonate monotherapies.

PURPOSE: Sevelamer hydrochloride/carbonate (SH/C) and lanthanum carbonate (LC) are noncalcium-based phosphate binders used for the management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objectives of this study were to examine the dose-relativity, tablet burden, and cost difference of bidirectional conversion between SH/C and LC monotherapy in a large cohort of real-world patients with ESRD. METHODS: This retrospective cohort study included three 30-day preconversion periods (days -90 to -61, -60 to -31, and -30 to -1) followed by three 30-day postconversion periods (days 1 to 30, 31 to 60, and 61 to 90); day 0 was the index date of conversion. The full analysis population (FAP) comprised two cohorts: SH/C to LC (S-L) converters and LC to SH/C (L-S) converters. The SH/C:LC dose-relativity ratio was assessed in the dose-relativity subset, defined as patients whose serum phosphate levels fell within a caliper range of ± 0.5 mg/dL in the final preconversion (days -30 to -1) and postconversion (days 61 to 90) periods. Tablet burden and phosphate binder costs were assessed in the FAP. Phosphate binder costs were based on average wholesale prices. FINDINGS: The FAP contained a total of 303 patients, comprising the S-L (128 patients) and L-S (175 patients) converter cohorts. The dose-relativity subset contained 159 patients, 72 from the S-L cohort and 87 from the L-S cohort. The overall mean SH/C:LC dose-relativity ratio was 2.27 (95% CI, 2.04 to 2.52). In SH/C dose strata >800 to 2400, >2400 to 4800, >4800 to 7200, and >7200 mg/d, overall mean dose-relativity ratios were 0.79 (95% CI, 0.57 to 1.10), 1.45 (95% CI, 1.20 to 1.75), 2.05 (95% CI, 1.75 to 2.39), and 3.24 (95% CI, 2.89 to 3.66), respectively. The overall mean tablet burden was 6.6 tablets per day lower with LC monotherapy than with SH/C monotherapy (95% CI, -7.1 to -6.0; P < 0.0001). The overall mean binder cost/patient per month was $1080.40 for SH/C compared with $1006.20 for LC, corresponding to a mean binder cost saving for LC of $74.20/patient per month (95% CI, -141.80 to -6.63; P = 0.032). SH/C >7800 mg/d was the inflection point at which conversion to LC resulted in mean cost savings. Patients requiring SH/C >7800 mg/d comprised 50% of the FAP. IMPLICATIONS: Converting patients with ESRD and hyperphosphatemia from SH/C to LC monotherapy offers potential drug cost savings and a significant reduction in the daily tablet burden, without compromising the effective management of serum phosphate levels.

Cost-minimization analysis of lanthanum carbonate versus sevelamer hydrochloride in US patients with end-stage renal disease.

PURPOSE: Sevelamer hydrochloride (SH) and lanthanum carbonate (LC) are calcium-free phosphate binders used in the clinical management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objective of this analysis was to assess the cost-effectiveness of LC monotherapy compared with SH monotherapy in US patients with ESRD in a clinical practice setting. METHODS: This was a post hoc assessment of phosphate binder costs among US patients with ESRD who converted from SH to LC monotherapy in a previously published, 16-week, Phase IV, real-world study. Calculations of drug costs used both average wholesale price (AWP) and wholesale acquisition cost (WAC). FINDINGS: There were 953 patients with available baseline SH dose data; 950 also had a recorded LC dose >0 mg at baseline, and 691 had dose data available for both SH at baseline and LC at week 16 (post hoc analysis population). Baseline demographic characteristics were similar in excluded patients and the post hoc analysis population. Mean (SD) serum phosphate levels were 5.91 (1.66) mg/dL at baseline and 5.93 (1.85) mg/dL after conversion to LC monotherapy for 16 weeks. Mean AWP costs were US$35.72 (16.89) per day at baseline and US$24.69 (8.28) per day at week 16, yielding an overall mean cost change (defined as LC cost - SH cost) of -US$11.03 (16.37) per day in favor of LC. The overall mean WAC cost change was -US$9.17 (13.64) per day. Within baseline SH dose subgroups 2400 to 4800, >4800 to 7200, >7200 to 9600, and >9600 mg/d, the mean AWP cost change ranged from US$2.78 (9.26) per day in favor of SH for the 2400- to 4800-mg/d subgroup to -US$33.15 (12.58) per day in favor of LC for the >9600-mg/d subgroup. Mean WAC cost changes showed a similar trend, ranging from US$2.33 (7.72) per day to -US$27.59 (10.48) per day. Linear regression analyses revealed that the inflection SH doses corresponding to a mean cost change of zero were 4905 mg/d (AWP) and 4908 mg/d (WAC). For the 455 (66%) patients in the post hoc analysis population who had baseline SH doses at least as high (≥ 5600 mg/d) as these point estimates, the mean SH:LC tablet ratio was ≥ 3.7, indicating a mean reduction in the tablet burden after conversion to LC of ≥ 73%. IMPLICATIONS: This real-world assessment of comparative phosphate binder drug costs between SH and LC among US patients with ESRD indicates that average cost savings with LC use increased with increasing SH doses. Conversion to LC from SH ≥ 5600 mg/d reduced drug costs and tablet burden while maintaining serum phosphate levels.

The real-world dose-relativity of sevelamer hydrochloride and lanthanum carbonate monotherapy in patients with end-stage renal disease.

INTRODUCTION: Sevelamer hydrochloride (SH) and lanthanum carbonate (LC) are calcium-free phosphate binders used for the management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objective of this analysis was to evaluate the real-world dose-relativity between SH and LC monotherapy in US patients with ESRD. METHODS: This was a post hoc analysis of a 16-week, real-world study (Vemuri et al. in BMC Nephrol 12:49, 2011) of the efficacy of conversion to LC monotherapy from other phosphate binders. The SH:LC dose-relativity ratio, based on the mean daily dose, was calculated in the subset of patients from the Vemuri study who converted from SH to LC monotherapy and had available SH and LC dose data. RESULTS: A total of 950 patients converted from SH to LC monotherapy and had recorded dose data. The post hoc analysis population comprised 691 patients with available dose data for both SH at baseline and LC at week 16. The mean (SD) serum phosphate level at baseline was 5.91 (1.66) mg/dL. After conversion to LC monotherapy for 16 weeks, the mean (SD) serum phosphate level was 5.93 (1.85) mg/dL. The mean (SD) daily baseline SH dose was 7,703 (3,642) mg and the mean (SD) daily LC dose at week 16 was 2,800 (939) mg (9.6 versus 2.8 tablets, respectively; P < 0.0001), resulting in a SH:LC dose-relativity ratio of 2.8. The median individual patient SH:LC dose-relativity ratio was 2.6 (95% CI 2.6-2.8). Across baseline SH dose subgroups (2,400-4,800, >4,800-7,200, >7,200-9,600, and >9,600 mg/day), the mean daily SH dose was 4,051, 7,047, 9,253, and 13,150 mg, respectively. In comparison, the mean daily LC dose was 2,445-3,156 mg. Thus, patients requiring baseline SH doses >7,200 mg/day (41% of the analysis population) had higher SH:LC dose-relativity ratios of 3.1-4.2 (median individual patient ratios 3.1-4.0). CONCLUSION: In this post hoc analysis of real-world dose-relativity, the overall SH:LC dose-relativity ratio was 2.8 (median individual patient ratio 2.6 (95% CI 2.6-2.8). These findings are consistent with the World Health Organization-defined daily dose and previous studies of the relative phosphate binding capacity of the two drugs. Patients requiring SH doses >7,200 mg/day had higher SH:LC dose-relativities of 3.1-4.2 (median individual patient ratios 3.1-4.0). These findings have implications for the tablet burden and cost-effectiveness of SH and LC in the treatment of hyperphosphatemia.

Lanthanum carbonate versus placebo for management of hyperphosphatemia in patients undergoing peritoneal dialysis: a subgroup analysis of a phase 2 randomized controlled study of dialysis patients.

BACKGROUND: This short-term study assessed the efficacy and safety of lanthanum carbonate in the treatment of hyperphosphatemia in dialysis patients; here, we report a prespecified subgroup analysis of patients undergoing peritoneal dialysis. METHODS: Men and women (n=39) who had received continuous ambulatory peritoneal dialysis for chronic kidney disease for 6 months or more were enrolled in eight renal medicine departments in the United Kingdom. A 2-week washout period was followed by a 4-week dose-titration phase during which patients received lanthanum carbonate titrated up to 2250 mg/day. This was followed by a 4-week, randomized, placebo-controlled, parallel-group phase during which patients continued to receive either lanthanum carbonate at the titrated dose, or a matched dose of placebo. The main outcome measure was control of serum phosphate levels (1.3-1.8 mmol/l) at the end of the parallel-group phase. RESULTS: Serum phosphate was controlled in 3/39 (8%) patients at the beginning of the dose-titration phase (after washout) and in 18/31 (58%) patients treated with lanthanum carbonate at its end. After the parallel-group phase, 60% of lanthanum carbonate-treated patients and 10% of those receiving placebo had controlled serum phosphate. There was no difference in mean (95% confidence interval) serum phosphate levels between groups at randomization: lanthanum carbonate, 1.57 (1.34-1.81) mmol/l; placebo, 1.58 (1.40-1.76) mmol/l (p=0.96). However, a difference was seen at the end of the parallel-group phase: lanthanum carbonate, 1.56 (1.33-1.79) mmol/l; placebo, 2.25 (1.81-2.68) mmol/l (p=0.0015). There were no clinically important changes in nutritional parameters and no serious treatment-related adverse events were recorded. CONCLUSIONS: At doses up to 2250 mg/day, lanthanum carbonate is well tolerated and controls hyperphosphatemia effectively. Treatment with higher doses of lanthanum carbonate may allow patients undergoing peritoneal dialysis the potential to increase their dietary protein intake without compromising their phosphate control.