An Association of SLC2A9 variant rs7442295 with Uric Acid at Baseline and in Interaction with Iloperidone

doi:10.21203/rs.3.rs-3989769/v1

Uric acid concentrations are routinely measured during clinical laboratory evaluations, given serum urate levels correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Circulating levels of uric acid are influenced by a complex mix of intrinsic and environmental factors, including genetics, diet, and drugs. We analyzed levels of uric acid in a recent phase 3 clinical trial of patients with bipolar mania treated with 24mg/day (12mg twice daily) of the antipsychotic iloperidone or placebo. Initial results revealed iloperidone treatment was associated with increases in uric acid from baseline, consistent with a similar, previous phase 3 study of iloperidone treatment of schizophrenia in adults. Pharmacogenetic analysis examining the urate transporter SLC2A9 revealed iloperidone associated increases were linked to a genetic variant (rs7442295), correlating with both urate levels at baseline and in interaction with iloperidone vs placebo. Further investigation suggested potentially clinically relevant sex differences associated with this variant, with male GG genotype patients exhibiting more frequent shifts from above the upper limit of normal for iloperidone-treated patients in comparison to female, AG/AA, and placebo groups. A pronounced increase of 35.91 µmol/L (0.674 mg/dL) was seen in iloperidone-treated patients homozygous for the for the rs7442295 (G) allele at the SLC2A9 gene, compared to a decrease of -16.5 µmol/L in the corresponding GG placebo group. Overall, the mechanism of this iloperidone-induced increase in serum urate levels is likely due to decrease in clearance of urate through interaction with the SLC2A9 urate transporter protein.

Biological sciences/Genetics/Clinical genetics/Disease genetics

Biological sciences/Genetics/Genetic association study/Genome wide association studies

Health sciences/Urology/Urological manifestations

Biological sciences/Drug discovery/Pharmaceutics

Health sciences/Diseases/Psychiatric disorders/Bipolar disorder

Uric acid is the end product of purine metabolism in humans and primates, which lack the enzyme uricase to further oxidize the heterocyclic compound. Under normal conditions the urate anion is generated after breakdown of excess purine nucleosides in the liver and the majority of the molecule is then excreted through the kidneys via urine. Circulating levels of uric acid the blood (i.e., blood uric acid or serum urate) correlate with disease states including high blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease¹. Accordingly, serum uric acid testing is routinely conducted in clinical settings, where the practice facilitates diagnosis of hyperuricemia, renal or kidney impairment, and rare inherited conditions².

The concentration of serum urate in an individual is influenced by multiple, overlapping factors, including diet, medications, genetic polymorphisms. For example, mutations identified in renal solute transporters have been identified as a major contributor to an individual’s baseline serum urate levels due to loss or gain of function in uric acid reabsorption^3,4, whereas anti-tubercular drugs such as pyrazinamide increase reabsorption while decreasing secretion of uric acid, which can cause hyperuricemia and gout⁵.

Several pharmacological interventions have been linked to clinically relevant changes in serum urate, for instance, use of low-dose acetylsalicylic acid (aspirin) on two consecutive days is associated with an increased risk of recurrent gout attacks⁶. In another example, diuretics, particularly of the thiazide class, are associated with an increase in serum urate levels, despite being indicated for treatment of hypertension⁶. These drug interactions represent direct mechanisms through which transport of uric acid can be impacted by drug interactions with various transporters and have led to inclusions of warnings and recommendations in physician prescribing guidelines regarding those drug’s risks for hyperuricemia and gout during treatment.

One critical player mediating circulating levels of uric acid is the integral membrane protein GLUT9, a high-capacity hexose-urate transporter encoded by the gene SLC2A9. GLUT9 is primarily expressed in the basolateral membrane kidneys, where it mediates reabsorption of uric acid from the proximal tubule into the bloodstream⁷. Genome-wide association studies previously identified associations between SLC2A9 and serum urate concentrations⁸, including loss of function variants in SLC2A9 associated with elevated levels of serum urate⁹. Access to commercial genetic testing has consistently expanded, facilitating diagnosis of renal pathology in clinical settings¹⁰, including for SLC2A9 variants associated with hyperuricemia¹¹. Accordingly, understanding iatrogenic hyperuricemia in the context of such polymorphisms in these transporters can enable health care providers to tailor treatment to individual patients and improve outcomes through precision medicine.

Iloperidone is an antipsychotic medication approved by the FDA for the treatment of schizophrenia in 2009. Here, we report analyses of blood uric acid concentrations obtained as part of routine clinical laboratory evaluations in two large, blinded, phase 3, randomized clinical trials of iloperidone treatment in two psychiatric patient populations (schizophrenia and bipolar mania, refer to Cutler et. al. 2008¹² and Torres et. al. 2024¹³). Iloperidone was associated with increases in serum urate compared to placebo or active comparator treatments in both studies. This observation led to investigation of genetic associations for this phenomenon, and revealed iloperidone associated increases in serum urate are greatest in patients who were homozygous (GG) for the rs7442295 (G) allele at the SLC2A9 gene. In particular, iloperidone treated male patients with the GG genotype were observed to have serum urate concentrations above the upper limit of normal at study endpoint more frequently compared placebo group. Ultimately, these results support sex and rs7442295 genotype can be used define subgroups of patients with differential propensities for iatrogenic elevations in serum urate following iloperidone treatment, which may be clinically relevant for individuals with hyperuricemia.

Iloperidone treatment was associated with serum urate increases in two placebo controlled phase 3 clinical studies

Clinical laboratory evaluations are routinely conducted during clinical trials and are relevant in populations of patients with neuropsychiatric disorders who are at increased risk of disorder associated comorbidities (e.g., obesity, diabetes, and metabolic syndrome)¹⁴. To evaluate the efficacy of the antipsychotic iloperidone, we conducted two separate four-week blinded, randomized, placebo controlled studies: one trial in patients with schizophrenia¹² (hereafter, Study 3101) and, more recently, one trial in patients with bipolar mania¹³ (hereafter, Study 3201) (Figure 1A). Both trials had similar fixed designs: patients were titrated over approximately 1 week to a dose of 12mg twice daily of iloperidone or placebo and treated at this dose for 3 consecutive weeks. Iloperidone showed a statistically significant benefit compared to placebo in each study’s respective primary endpoints, which measured reduction in symptoms associated schizophrenia or bipolar mania (for topline efficacy, safety, disposition, and methods reporting for each study, refer to Cutler et. al. 2008¹² and Torres et. al. 2024¹³, respectively).

Analysis of clinical laboratory results revealed iloperidone treated patients in both studies had statistically significant increases in serum urate from baseline to endpoint (day 28) as compared to placebo (and also for active control ziprasidone for Study 3101). (Figure 1B and C, and Table 1 and 2). In Study 3201 iloperidone patients had 4-fold greater increases in serum urate from baseline compared to placebo groups (33.4 μmol/L change for iloperidone and 4.2 μmol/L in placebo groups, respectively) (Table 1). This finding was replicated in Study 3101, with a roughly 4-fold greater increase in blood levels of uric acid for iloperidone compared to placebo treatment groups, and more than twice the change from baseline observed for iloperidone versus ziprasidone treated individuals (28.0 μmol/L, 4.2 μmol/L, and 13.1 μmol/L for iloperidone, placebo, and ziprasidone groups, respectively) (Table 2).

In both studies, significant differences in uric acid iloperidone vs placebo groups were detectable as early as 14 days (Table 1 and 2). At endpoint (day 28) in Study 3201, blood uric acid LS mean change was 27.2 μmol/L for iloperidone groups and 0.1 μmol/L for placebo groups (ANCOVA, p<0.0001, adjusting for covariates) (Figure 1C). Similarly, LS mean change in Study 3101 was 28.0 μmol/L for iloperidone treatment group compared to 4.2 μmol/L in placebo group (p=0.0014, Figure 1C), providing further confirmatory evidence that acute iloperidone treatment is associated with increases in circulating levels of uric acid.

SLC2A9 variant rs7442295 was associated with different baseline levels of serum urate in two separate psychiatric patient populations

We routinely collect genetic information during our clinical trials for exploratory pharmacogenetic analysis, and patients in both studies provided blood samples for DNA extraction, whole genome sequencing, and analysis (see methods). Polymorphisms in renal transport proteins can affect rates of uric acid reabsorption and secretion, impacting levels of serum urate in various genetic subgroups in the general population⁸. We hypothesized that genes encoding transporter proteins may be associated with observed baseline levels of serum urate in our patients as well.

To characterize the relationship between patient genetic compositions and serum urate levels prior to treatment, we used a linear regression model for serum urate, adjusting for age, sex, and principal components. One of the most significant variants identified was rs7442295 (p-value 10^-5 (BETA= -23.12) (Figure 2A). Our results are similar to previous reports associating variant rs7442295 and baseline serum urate levels, including the observation of an intermediary phenotype in heterozygous individuals⁹. Interestingly, male carriers were broadly observed to have a higher baseline level of uric acid compared to females (beta = 24.08 per G allele, p=0.04) (Figure 2B), consistent with prior work supporting a sex-specific effect for this variant¹⁵.

Additionally, we performed a full GWAS on these samples, and SLC2A9 variants were the strongest hits detected. Variant rs7442295 is in a strong LD with a coding nonsynonymous variant rs16890979 (Val253Ile), shown in Supplementary Figure 1, which was previously associated with serum uric acid levels where the minor allele, rs16890979 T allele was associated with a decrease of 0.47 mg/dl in the uric acid level (CI: 0.31-0.63, p = 1.43 x 10e^-11). The rs7442295 variant has a global MAF (GnomAD) of 0.24 with the highest MAF reported in patients of African/African American ancestry (MAF=0.40), which was nearly twice the MAF reported for non-Finnish Europeans of (MAF=0.20) (Figure 2C).

Variant rs7442295 was associated with changes in serum urate levels in iloperidone treated individuals

Applying pharmacogenetic analysis to predict the clinical effects of drugs in different patient subgroups remains a critical goal in pharmaceutical research and development. Accordingly, based on the strong associations detected for SLC2A9 variants at baseline, we hypothesized that there may be a relationship between carrier status of variant rs7442295 and serum urate changes observed during iloperidone treatment. We analyzed clinical laboratory results according to genotype status in Study 3201 for variant rs7442295. Remarkably, for iloperidone-treated patients homozygous for the rs7442295 (G) allele, we observed a pronounced increase of 40.9 μmol/L (0.674 mg/dL) compared to a decrease of -16.86 μmol/L in the corresponding GG placebo group (Figure 3A Figure 3B and Table 3).

Given we observed a sex effect for genotype and baseline serum urate levels, we further analyzed the effect of this variant on serum urate change from baseline in Study 3201, using linear regression models stratified by sex and treatment. Changes from baseline in serum urate in individuals with the GG genotype were particularly pronounced in the male subgroup (Figure 3C and Table 4), with a 65.61 μmol/L increase in serum urate in iloperidone treated GG males compared to a -37.35 μmol/L decrease in the corresponding placebo group, further supporting a sex effect for males with the GG genotype.

To address the extent to which iloperidone treatment interacts with these different subgroups, we analyzed the effect of this variant on serum urate change from baseline using linear regression models stratified by sex and treatment. Among male placebo group, each additional G allele increased the serum urate change by 1.82 μmol/L. This effect was dramatically larger in the iloperidone treated subgroup, with an increase of 27.64 μmol/L (p-value=1.54e-3).

Since sex was not balanced in this study, we conducted sample matching to fit a linear regression model in iloperidone group with a gene-by-sex interaction term. In iloperidone group males, each additional rs7442295 G allele increased the urate change by 29.13 (p-value=5.83e-3).

Clinically relevant serum urate levels following iloperidone treatment, according to genotype, drug, and sex

Females have lower circulating levels of uric acid compared to males; a phenomenon hypothesized to be driven by differences in the sex hormone estradiol¹⁶. Sex differences in serum urate are reflected in laboratory ranges used to evaluate clinical laboratory results. Lab specified upper limits of normal (ULN) was >453 μmol/L (7.62 mg/dL) for males and >394 μmol/L (6.46 mg/dL) for female patients in Study 3201, in alignment with clinical guidelines for interpreting uric acid blood tests for hyperuricemia defined as approximately 6 mg/dL for women and 7 mg/dL for men¹⁷. A key goal of clinical research is to characterize the safety profile of medications studied, including which patient subgroups have differential risk for adverse events. Accordingly, to further characterize the clinical relevance of serum urate changes following iloperidone treatment, we evaluated the proportions of patients who had concentrations of serum urate exceeding ULN at baseline compared to endpoint in Study 3201 according to treatment, sex, and genotype (Table 5). Subgroups of iloperidone treated patients had concentrations of serum urate above the upper level of normal range more frequently than placebo.

Consistent with the results for a strong interaction with G-allele and male subgroups, iloperidone-associated increase in serum urate above the upper limit normal (ULN) was largest in males with homozygous (GG) genotype for rs7442295. Treatment with iloperidone resulted in an approximately 4-fold increase in the proportions of GG males with lab results above the ULN for serum urate (baseline, 8.3%; EOS, 33.3%, respectively). Conversely, the percentage of placebo treated GG males above the ULN decreased (baseline, 14.3%; EOS, 0.0%, respectively). Consistent with the compounding effect for G allele for the variant observed in previous sections, proportions of patients with laboratory values above the ULN increased for iloperidone treated with AG genotype (baseline, 2.4% and EOS ~13.5%), while the proportion of patients in the corresponding placebo group remained essentially the same (baseline, 14.9%; EOS, 15.5%). Analysis using Fisher’s exact test combining GG+AG genotypes vs baseline was significant for iloperidone versus placebo groups, (p-value = 0.03, OR=5.73), supporting that patients are more likely to be above the ULN following four weeks of treatment.

We report here that iloperidone treatment was associated with statistically significant increases in uric acid compared to placebo groups in two independent clinical trials, conducted in two different psychiatric patient populations.

In both studies, participants received 24mg/day (12mg b.i.d.) iloperidone, the highest therapeutic dosage currently approved for acute and maintenance treatment of schizophrenia¹⁸. Increases in serum urate levels were nearly twice as large in iloperidone-treated patients homozygous for the common variant rs7442295 (G) in the SLC2A9 transporter gene. The GG genotype is carried by 7.6% of the general population, where it is most common in in African/African Americans (16.5%) and in Latino/Admixed Americans (14.2%), while being less common non-Finnish Europeans (3.9%) and is nearly absent in the South and East Asians (0%).

Based on the existing study data this observed effect of increased serum urate in the GG genotype population in association with iloperidone is particularly pronounced in males. Male patients are observed to exceed the upper limit normal after iloperidone treatment more frequently for individuals that are homozygous (GG) for the rs7442295 (G) allele at the SLC2A9 gene and had 4-fold higher increases in serum urate compared to placebo treated groups.

We observe a baseline effect consistent with the effect previously reported in literature by Wallace et al.¹⁹: in 1900 hypertensive Caucasian Europeans, the more common allele rs7442295(A) allele was associated with higher serum urate and hyperuricemia with a reported odds ratio of 1.89 (CI: 1.36–2.61, p = 5 x 10^− 5) cite. Overall, 79% of Europeans carry one or two alleles leading to higher serum urate levels. Each copy leads to an average increase of 20 µmol/L, and an approximate doubling of risk for hyperuricemia⁸.

There are many factors which influence reabsorption and excretion of uric acid in the blood, including the GLUT9 protein. Based on our findings, iloperidone-induced increase in serum urate levels is likely due to a decrease in clearance of urate through interaction with the SLC2A9 gene encoding for this urate transporter protein. Future work should explore potential drug-protein interactions between iloperidone and GLUT9 isoforms based on this variant, as well as investigation of the long term impacts of iloperidone exposure on serum urate levels in patients

Commercial tests are available to determine patient genotypes for this variant and could support physician decisions in individuals with preexisting hyperuricemia. Ultimately, our results hold clinical relevance for patients receiving iloperidone treatment, history of gout, and carriers of the variants of interest, are monitored for serum urate levels as they may need to increase the doses of their urate lowering treatments.

Clinical trial methods

Study VP-VYV-683-3102

Torres, R., Czeisler, E. L., Chadwick, S. R., Stahl, S. M., Smieszek, S. P., Xiao, C., ... & Polymeropoulos, M. H. (2024). Efficacy and Safety of Iloperidone in Bipolar Mania: A Double-Blind, Placebo-Controlled Study. The Journal of Clinical Psychiatry, 85(1), 51087.

Study VP-VYV-683-3101

Cutler, A. J., Kalali, A. H., Weiden, P. J., Hamilton, J., & Wolfgang, C. D. (2008). Four-week, double-blind, placebo-and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. Journal of clinical psychopharmacology, 28(2), S20-S28.

ClinicalTrials.gov identifier: NCT04819776; EudraCT: 2020–000405-83

Pharmacogenetic sample obtainment and analysis

Study VP-VYV-683-3101

In Study 3101 (Schizophrenia), patient genotypes were obtained via through a commercial 500k SNP Gene Chip Human Mapping Array.

Study VP-VYV-683-3102

In Study 3201 (Bipolar Mania), whole genome sequencing was conducted from blood samples, and genotype status was obtained through whole genome sequencing.

Pharmacogenetics

Incoming nucleic acid samples are quantified using fluorescent-based assays (PicoGreen) to accurately determine whether sufficient material is available for library preparation and sequencing. DNA sample size distributions are profiled by a Fragment Analyzer (Advanced Analytics) or BioAnalyzer (Agilent Technologies), to assess sample quality and integrity. HumanCoreExome 24v1.3 array was performed on all human DNA samples sequenced. Whole genome sequencing (WGS) libraries were prepared using the Truseq DNA PCR-free Library Preparation Kit. Whole Genome data were processed on NYGC automated pipeline. Paired-end 150 bp reads were aligned to the GRCh37 human reference (BWA-MEM v0.7.8) and processed with GATK best-practices workflow (GATK v3.4.0). The mean coverage was 35.8, it reflects the samples average. All high quality variants obtained from GATK were annotated for functional effects (intronic, intergenic, splicing, nonsynonymous, stopgain and frameshifts) based on RefSeq transcripts using Annovar31. Additionally, Annovar was used to match general population frequencies from public databases (Exac, gnomAD, ESP6500, 1000 g). Linear models adjusted for PC, age and sex were conducted in PLINK.

Statistical Analysis

Linear regression was used for all genetic association analysis, with adjustment of participants’ age, sex, and genetically derived principal components (PCs), wherever they are available. Genotypes were additively coded as the count of the alternative allele to represent a dosage effect. Gene-by-sex and gene-by-treatment analyses were conducted by adding a genotype-sex or genotype-treatment 2-way interaction term into the regression model. All regression analyses were performed using R statistical language (version 4.3.2).

Since sex ratio is not balanced in this study, a sample matching by sex was performed prior to the analysis stratified by treatment. The sample matching step was done by using R package Matchit with nearest neighbor matching method and a ratio of 1 to ensure a balanced sex ratio. Analysis of covariance (ANCOVA) was conducted using SAS

Data Availability

Vanda is committed to sharing with qualified external researchers access to patient- level data and supporting clinical documents from eligible studies. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. Contact the corresponding author regarding data requests.

Ethics Declaration

All methods were carried out in accordance with relevant guidelines and regulations.

The study protocol and all amendments were reviewed by the Independent Ethics Committee or Institutional Review Board for each center. The study from which samples were obtained was conducted according to the ethical principles of the Declaration of Helsinki. Informed consent was obtained from each patient in writing before any study-specific procedures were performed. Informed consent was obtained from all subjects and/or their legal guardian. The study was approved by Advarra IRB located in Washington DC.

Funding

This study was funded by Vanda Pharmaceuticals, Inc. (Washington, DC).

Author Information

Authors and Affiliations

See title/cover page.

Contributions

S.S made the initial discovery. S.S., S.C., E.C., H.B., and C.X. analyzed the data. S.S. and S.C. created the figures and wrote the manuscript with input from the other authors. R.T. and E.C. conceived and conducted Study 3201 with input from C.P., G.B., and M.P., who oversaw the research and study conduct. All authors were involved in writing and editing the manuscript. S.S. and S.C. contributed equally to the manuscript.

Corresponding author

Correspondence to Sandra P. Smieszek.

Competing interests

See title/cover page.

Funding/support

This study was funded by Vanda Pharmaceuticals, Inc. (Washington, DC).

Role of the sponsor

The sponsor was responsible for the design, analysis, interpretation, and publication of the clinical trials. Final approval for the decisions to submit the manuscript was the sole decision of the authors.

Relevant financial relationships

Drs Smieszek, Chadwick, Bai, Torres, Dr. Bai Xiao, C. Polymeropoulos, M. Polymeropoulos, Mr Birznieks and Ms Czeisler are full time employees of Vanda Pharmaceuticals Inc. and may hold company stock and/or stock options.

Previous presentations

Posters presented at the [ASHG meeting, Washington, DC, September 2023; meeting, city, date/year].

Acknowledgements

Vanda Pharmaceuticals and the authors thank the patients, study sites, and investigators who participated in these clinical trials.

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Table 1: Study 3201 (Bipolar Mania) LS Mean Change from Baseline for Serum Urate for Iloperidone vs Placebo Treatment Groups (μmol/L)

Visit	Iloperidone	Placebo	LS Mean Difference	p-value
Visit	LS Mean Change (SE), n	LS Mean Change (SE), n	(95% CI)	p-value
Baseline	323.0 (77.13), 206	328.5 (84.6), 208	-	-
Day 7	-2.7 (-4.07), 199	-4.0 (-4.11), 196	1.3 (-9.29, 11.88)	=0.8098
Day 14	12.6 (-4.28), 173	-2.7 (-4.24), 186	15.3 (4.50, 26.15)	=0.0057
Day 21	19.1 (-5.24), 157	-1.9 (-5.07), 166	21.0 (8.91, 33.18)	=0.0007
Day 28	27.2 (-4.93), 142	0.1 (-4.77), 154	27.1 (14.94, 39.20)	<0.0001

Baseline shown as mean (SD). LS mean change shown for each evaluation for serum urate in Study 3201 (Bipolar Mania). ANCOVA = Analysis of Covariance. CI = Confidence Interval. LS = Least Squares. SE=Standard Error. SD=Standard Deviation. Baseline is defined as the latest non-missing observation across all the visits in the Screening Phase before the first dose of study medication. LS means, CIs, and p-values are based on ANCOVA model with main effects of treatment group and pooled site, and baseline as a covariate. All p values represent the difference between iloperidone and placebo.

Table 2: Study 3101 (Schizophrenia) LS Mean Change from Baseline for Serum Urate for Iloperidone vs Placebo Treatment Groups (μmol/L)

Visit	Iloperidone	Placebo	LS Mean Difference	p-value
Visit	LS Mean Change (SE), n	LS Mean Change (SE), n	(95% CI)	p-value
Day 0	318.3 (73.96), 300	313.6 (79.61), 147	-	-
Day 14	15.5 (3.39), 276	-2.98 (4.94), 135	18.5 (6.55. 29.93)	=0.0024
Day 28	28.0 (4.05), 206	4.2 (6.07), 98	23.8 (9.16. 37.96)	=0.0014

Baseline shown as mean (SD). LS mean change shown for each evaluation for serum urate in Study 3101 (Schizophrenia). ANCOVA = Analysis of Covariance. CI = Confidence Interval. LS = Least Squares. SE=Standard Error. SD=Standard Deviation. Baseline is defined as the latest non-missing observation across all the visits in the Screening Phase before the first dose of study medication. LS means, CIs, and p-values are based on ANCOVA model with main effects of treatment group and pooled site, and baseline as a covariate. All p values represent the difference between iloperidone and placebo.

Table 3: Study 3201 Change from Baseline for Serum Urate by SLC2A9 Variant rs7442295 Genotype Subgroups (μmol/L)

Visit	Genotype	Iloperidone LS Mean Change (SE), n	Placebo LS Mean Change (SE), n	LS Mean Difference (95% CI)	p-value
Day 28	AA	25.74 (6.53), 73	-6.17 (6.47), 74	31.91 (14.82, 49)	0.0003
Day 28	AG	24.62 (7.61), 51	9.78 (6.67), 68	14.84 (-4.18, 33.86)	0.1256
Day 28	GG	40.09 (12.36), 18	-16.86 (15.37), 12	56.95 (18.91, 94.99)	0.0035

LS mean change from Baseline to Day 28 shown for each genotype, with standard error (SE) and n for observed cases. LS means difference shown with 95% CI. Abbreviations: ANCOVA = Analysis of Covariance. CI = Confidence Interval. LS = Least Squares. Baseline is defined as the latest non-missing observation across all the visits in the Screening Phase before the first dose of study medication. LS means, CIs, and p-values are based on ANCOVA model with main effects of treatment group, pooled site, genetic group and baseline, interaction effects of treatment group and genetic group as a covariate. P-value represents the difference between iloperidone and placebo groups.

Table 4: Study 3201 Change from Baseline for Serum Urate by Sex and SLC2A9 Variant rs7442295 Genotype Subgroups (μmol/L)

Visit	Genotype	Sex	Iloperidone LS Mean Change (SE), n	Placebo LS Mean Change (SE), n	LS Mean Difference (95% CI)	p-value
Day 28	AA	F	25.48 (9.16), 34	-2.37 (9.06), 34	27.85 (2.93, 52.76)	0.0286
Day 28	AA	M	28.89 (8.7), 39	-6.62 (8.58), 40	35.52 (12.82, 58.22)	0.0023
Day 28	AG	F	0.06 (10.14), 27	7.96 (9.87), 29	-7.9 (-34.82, 19.03)	0.5641
Day 28	AG	M	53.41 (10.84), 24	12.62 (8.7), 39	40.79 (14.61, 66.96)	0.0024
Day 28	GG	F	-0.19 (19.49), 7	-3.27 (20.1), 7	3.08 (-50.97, 57.13)	0.9107
Day 28	GG	M	65.61 (15.42), 11	-37.35 (23.02), 5	102.96 (48.93, 156.99)	0.0002

Results of ANCOVA model of change from Baseline to either Day 28 or EOS evaluations for serum urate in Study 3201 (Bipolar Mania). LS mean change from Baseline to Day 28 shown for each genotype, with standard error (SE) and n observed cases. LS means difference shown with 95% CI. Abbreviations: ANCOVA = Analysis of Covariance. CI = Confidence Interval. LS = Least Squares. Baseline is defined as the latest non-missing observation across all the visits in the Screening Phase before the first dose of study medication. LS means, CIs, and p-values are based on ANCOVA model with main effects of treatment group, pooled site, sex, genetic group and baseline, interaction effects of treatment group, genetic group, and sex as a covariate. P-value represents the difference between iloperidone and placebo groups.

Table 5 Study 3201: Proportion of Patients with Serum Urate Concentrations Above the Upper Limit of Normal by Sex and SLC2A9 Variant rs7442295 Genotype Subgroups

Male

Female

rs7442295 genotype

Iloperidone

Placebo

Iloperidone

Placebo

Baseline, percentage of patients above ULN

GG

8.3 %

(1/12)

14.3 %

(1/7)

0.0 %

(0/7)

0.0 %

(0/8)

AG

2.4 %

(1/41)

14.9 %

(7/47)

7.7 %

(3/39)

0.0 %

(0/36)

AA

10.0 %

(6/60)

13.5 %

(7/52)

9.5 %

(4/42)

20.1 %

(10/48)

EOS, percentage of patients above ULN

GG

33.3 %

(4/12)

0.0 %

(0/6)

0.0 %

(0/7)

0.0 %

(0/7)

AG

13.5 %

(5/37)

15.5 %

(7/45)

8.1 %

(3/37)

9.7% (3/31)

AA

12.3 %

(7/57)

4.3 %

(2/46)

15.0 %

(6/40)

14.3 %

(6/42)

Lab-specified ranges of the upper limit of normal (ULN) values of serum urate evaluations in Study 3201 were 453 μmol/L for males and 394 μmol/L for female patients.

Competing interest reported. All authors are employees of Vanda Pharmaceuticals Inc.

Presentation1.pdf

An Association of SLC2A9 variant rs7442295 with Uric Acid at Baseline and in Interaction with Iloperidone

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Abstract

Figures

Introduction

Results

Discussion

Materials and Methods

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

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