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Association of the NPAS3 Gene and Five Other Loci with Response to The Molecular Psychiatry (2009) 14, 804–819 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp ORIGINAL ARTICLE Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study C Lavedan, L Licamele, S Volpi, J Hamilton, C Heaton, K Mack, R Lannan, A Thompson, CD Wolfgang and MH Polymeropoulos Vanda Pharmaceuticals Inc., Rockville, MD, USA A whole genome association study was performed in a phase 3 clinical trial conducted to evaluate a novel antipsychotic, iloperidone, administered to treat patients with schizophrenia. Genotypes of 407 patients were analyzed for 334 563 single nucleotide polymorphisms (SNPs). SNPs associated with iloperidone efficacy were identified within the neuronal PAS domain protein 3 gene (NPAS3), close to a translocation breakpoint site previously observed in a family with schizophrenia. Five other loci were identified that include the XK, Kell blood group complex subunit-related family, member 4 gene (XKR4), the tenascin-R gene (TNR), the glutamate receptor, inotropic, AMPA 4 gene (GRIA4), the glial cell line-derived neurotrophic factor receptor-alpha2 gene (GFRA2), and the NUDT9P1 pseudogene located in the chromosomal region of the serotonin receptor 7 gene (HTR7). The study of these polymorphisms and genes may lead to a better understanding of the etiology of schizophrenia and of its treatment. These results provide new insight into response to iloperidone, developed with the ultimate goal of directing therapy to patients with the highest benefit-to-risk ratio. Molecular Psychiatry (2009) 14, 804–819; doi:10.1038/mp.2008.56; published online 3 June 2008 Keywords: iloperidone; antipsychotic; NPAS3; pharmacogenomics; schizophrenia Introduction the most optimal drug and dosage with less trial and error. Schizophrenia is a psychotic disorder affecting Iloperidone is an investigational drug that has some approximately 1% of the population.1 It is character- of the receptor-binding characteristics of current ized by the presence of positive symptoms (unusual atypical antipsychotics, such as a high 5-HT2A/D2 thoughts or perceptions, including hallucinations and binding ratio, which predicts a tolerability profile delusions), negative symptoms (social withdrawal, better than that of typical antipsychotic agents.6–9 It lack of pleasure in everyday life) and impaired also has receptor-binding characteristics that distin- cognitive functions (verbal memory, information guish it from other atypical antipsychotics, including processing). A number of drugs have been approved high affinity for a2C-adrenergic receptors, which may to treat this chronic illness. However, patient re- result in antidepressant and anxiolytic activity and in sponse to treatment remains highly variable,2,3 and improved cognitive function.6,7 Additionally, it has a the discontinuation rate with antipsychotic treatment low affinity for histamine receptors, which may is high.4 No single antipsychotic agent offers optimal reduce the risk for sedation and weight gain.6,8 effect for every patient with schizophrenia. Few data Iloperidone treatment is associated with a low are available to guide clinicians and patients in the incidence of clinically notable weight gain, low rate selection of the most appropriate medication, and in of extrapyramidal symptoms and akathisia, and improving the treatment specificity for an individual minimal prolactin elevations.10–12 patient.5 Pharmacogenomics provides the opportu- Iloperidone is rapidly absorbed in humans and nity to discover genetic markers predictive of re- extensively metabolized in the liver via multiple sponse. Knowing how a patient with schizophrenia pathways, including pathways mediated by the might respond to a particular therapy based on his or cytochrome P450 enzymes CYP2D6 and CYP3A4. her genetic makeup may enable clinicians to select Furthermore, a pharmacokinetic–pharmacodynamic relationship for the efficacy of iloperidone has been established: statistically significantly greater propor- Correspondence: Dr C Lavedan, Vanda Pharmaceuticals Inc., 9605 tions of responders (X20% improvement from base- Medical Center Drive, Suite 300, Rockville, MD 20850, USA. line) in iloperidone-treated patients had average E-mail: [email protected] À1 Received 3 September 2007; revised 18 February 2008; accepted plasma concentrations X5ngml compared with 25 April 2008; published online 3 June 2008 those with < 5 ng mlÀ1.13 Genetic markers of iloperidone efficacy C Lavedan et al 805 A particular challenge in searching for genetic placebo. The primary efficacy variable was change markers of response to antipsychotic treatment, from baseline to the last scheduled observation especially in double-blind, placebo-controlled stu- in Positive and Negative Syndrome Scale total dies, is that patients are prone to drop out early if they (PANSS-T) score. Comparison of iloperidone re- experience unsatisfactory results before reaching sponse to placebo response was performed to ensure therapeutic steady state concentrations of the active the interpretation of the results and to comply with drug. Two methods have been used to deal with requirements of regulatory agencies. missing values from patient dropout. The first method, known as last observation carried forward PANSS measurements (LOCF), replaces a patient’s missing measurements at During the course of the clinical trial, the PANSS the end of the study with the last recorded measure- score was assessed at baseline and on days 7, 10, 14, ment. LOCF has been used extensively in regulatory 21 and 28 or at the last visit when early termination settings despite recognized biases. In particular, occurred ( < 36% of patients). The PANSS ratings LOCF, which assumes that response of a dropped- were only completed by a qualified MD, DO, PhD, out patient remains constant from the last observed PharmD, BA, BS or trained health care professional. value to the end of the trial, tends to bias efficacy Only those raters who had been qualified by United estimates. It also ignores trends over time and fails to BioSource Corporation (Bethesda, MD, USA) were account for missing-data uncertainty.14–17 The second allowed to rate in this study. Raters were to have a method, called mixed-effects model repeated mea- minimum of 1 year of experience using these scales or sures (MMRM) analysis, which facilitates unbiased comparable rating instruments in rating patients with estimates of postdropout behavior, was recently psychiatric disorders. Each site had to have at least developed to estimate efficacy parameters directly two certified raters for PANSS. Furthermore, inter- from incomplete data.18 rater reliability tests were undertaken. For prequali- We report here on the results of a whole-genome fication, raters were asked to view video recordings of association study (WGAS) of the efficacy response of patient interviews and complete rating of all items. At the novel atypical antipsychotic iloperidone in a an investigators’ meeting, all potential raters were phase 3 trial using both the LOCF and the MMRM further trained until acceptable results were achieved. methods. This clinical trial was a randomized, Interview skills were also assessed for all raters. double-blind, placebo-controlled and ziprasidone- Furthermore, while the study was in progress, controlled multicenter study conducted to evaluate refresher training was conducted, and new training the efficacy, safety, and tolerability of a 24 mg per day tapes were sent out to each site for rater reevaluation dose of iloperidone administered as 12 mg twice a day at appropriate intervals. All the new raters were for 28 days to patients with schizophrenia in acute required to be trained. exacerbation. We identified several single nucleotide polymorphisms (SNPs) associated with iloperidone Pharmacogenomics population efficacy. Further study of these polymorphisms and of Participation in the WGAS was optional, and written associated genes may lead to better understanding of informed consent was required. Blood samples were the etiology of schizophrenia and of patient responses collected, and quality genotype obtained (Quest to antipsychotic treatments. Diagnostics Laboratories, Van Nuys, CA, USA) from 426 of 457 patients who consented to the optional WGAS, including 218 patients administered iloper- Materials and methods idone, 103 treated with the active comparator and 105 Ethical conduct of the study who received placebo. The modified intent-to-treat The clinical study was conducted in accordance with (ITT) population contained all randomized patients the Declaration of Helsinki; with the US Code of who received at least one dose of double-blind study Federal Regulations governing the protection of hu- medication and from whom a baseline PANSS score man subjects (21 CFR 50), Institutional Review measurement was obtained and at least one postbase- Boards (21 CFR 56), and the obligations of clinical line PANSS efficacy measurement was obtained while investigators (21 CFR 312); and with the International on study medication. The ITT population used for the Conference on Harmonisation Guidance for Good analysis consisted of 407 patients, including 210, 98 Clinical Practice (Topic E6). and 99 patients who received iloperidone, ziprasi- done or placebo, respectively. More than 64% of Patients and study design patients completed the 28-day period. Patients 18–65 years of age with diagnosis of schizo- phrenia
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