Real-world effectiveness of dupilumab versus benralizumab and mepolizumab.

INTRODUCTION: In the United States, this real-world study compared the effectiveness of dupilumab, benralizumab, andmepolizumab in reducing exacerbations and systemic corticosteroid (SCS) prescriptions among patients with asthma. METHODS: Patients (12 years old) who initiated dupilumab, benralizumab, or mepolizumab (index) between November 2018 and September 2020 were identified by using electronic medical record data. Subjects were included if they had greater than or equal to 12 months of data before and after the index date and two or more severe asthma-related exacerbations before the index date. Differences in baseline characteristics were addressed by using inverse probability treatment weighting (IPTW). Pairwisecomparisons between dupilumab and benralizumab, or mepolizumab were conducted by using negative binomial regression, adjusting for baseline rates and unbalance characteristics (greater than or equal to 10% standardized differences) after IPTW. RESULTS: Overall, a total of 1737 subjects met all criteria: 825 dupilumab, 461 benralizumab, and 451 mepolizumab initiators.In the postindex period, dupilumab was associated with a 24% and 28% significant reduction in the risk of severe asthmaexacerbations versus benralizumab (incidence rate ratio [IRR] 0.76 [95% confidence interval {CI}, 0.67-0.86)] and mepolizumab(IRR 0.72 [95% CI, 0.63-0.82]), respectively. In addition, dupilumab treatment significantly reduced SCS prescriptionsby 16% and 25% versus benralizumab and mepolizumab, respectively (p < 0.05). CONCLUSION: This study represents one of the largest real-world comparisons of biologics (dupilumab, benralizumab, and mepolizumab) for asthma in the United States to date. This analysis shows that the use of dupilumab was associated with a significantly greater reduction in both severe asthma exacerbations and SCS prescriptions compared with benralizumab and mepolizumab.

The long-term effect of dupilumab on dyspnea, sleep, and activity in oral corticosteroid-dependent severe asthma.

BACKGROUND: Severe asthma impacts quality of life (QoL), including dyspnea, sleep, and activity limitation. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4 and -13, which are key and central drivers of type 2 inflammation. Phase 3 LIBERTY ASTHMA VENTURE (NCT02528214) and LIBERTY ASTHMA TRAVERSE open-label extension (NCT02134028) evaluated dupilumab 300 mg vs placebo every 2 weeks for 24 weeks (VENTURE) and dupilumab only for an additional 48 to 96 weeks (TRAVERSE) in patients with oral corticosteroid (OCS)-dependent severe asthma. OBJECTIVE: To assess dupilumab's impact on Asthma QoL Questionnaire (AQLQ) items related to breathing symptoms, sleep, and activity limitation, and on OCS reduction. METHODS: The proportion of patients with AQLQ scores of 6 or 7 for breathing symptoms-, sleeping-, and activity-related items in VENTURE and TRAVERSE, together with OCS dose reductions in VENTURE. RESULTS: In VENTURE, significantly greater proportions of dupilumab- vs placebo-treated patients achieved scores of 6 or 7 by week 24 in breathing symptoms-related (42.7%-60.2% vs 22.4%-39.3%), sleeping-related (45.6%-65.0% vs 27.1%-47.7%), and activity-related (44.7%-51.5% vs 22.4%-34.6%) AQLQ items. Improvements were maintained through TRAVERSE in the dupilumab/dupilumab group and increased to dupilumab treatment levels in the placebo/dupilumab group. Significant OCS dose reductions were observed in VENTURE; up to 90% and 60% of dupilumab-treated vs 65% and 41% of placebo-treated patients with AQLQ scores of 6 or 7 in breathing symptoms-, sleeping-, and activity-related items achieved greater than or equal to 50% dose reduction and eliminated OCS at week 24, respectively. CONCLUSION: In patients with severe OCS-dependent asthma, dupilumab improved QoL related to breathing symptoms, sleep, and activity limitation, and reduced OCS use. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02528214 and NCT02134028.

Development and content validation of patient-reported outcomes tools for ulcerative colitis and Crohn's disease in adults with moderate-to-severe disease.

BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are associated with a range of symptoms that adversely affect health-related quality of life. This research aimed to develop and validate two patient-reported outcome (PRO) tools to assess signs and symptoms in patients with moderate-to-severe UC or CD. METHODS: PRO-UC and PRO-CD Diaries were developed in accordance with US Food and Drug Administration (FDA) recommendations. Data were collected from concept elicitation interviews (in which patients described their symptoms and experience of the disease) and further refined through cognitive interviews (in which patients assessed the relevance and clarity of questions in the tools). RESULTS: Interviews were conducted with 12 patients for each indication. Five symptoms (urgent bowel movements, abdominal pain, frequent bowel movements, bloody stools, diarrhea/watery stools) were reported by 83-100% of participants with UC and were included in the final 6-item PRO-UC Diary: stool frequency, rectal bleeding (2 items), diarrhea, rectal urgency, and abdominal pain. For CD, seven symptoms (abdominal pain, diarrhea/loose stools, urgent bowel movements, fatigue/tiredness/weakness, frequent bowel movements, bloody stools, nausea) were reported by 50-100% of participants. These, together with vomiting and incontinence (reported by 42% and 33% of participants, respectively), were included in the final 10-item PRO-CD Diary, covering abdominal pain (2 items), stool frequency, liquid/very soft stool frequency, rectal bleeding, rectal urgency, nausea, vomiting, bowel incontinence, and general well-being. Symptoms were consistently cited across both indications to have an impact on quality of life, with frequent complaints being the need to always be near a toilet and inability to leave home, as well as general pain, discomfort, and nausea. For both tools, questions were accurately interpreted, with at least 67% of participants in both indications stating that items were easy to answer/relevant to their condition and symptoms were easy to recall over the last 24 h. CONCLUSIONS: Both the PRO-UC and PRO-CD Diaries were developed and validated in accordance with FDA recommendations, providing two new tools for use in clinical trials to assess response to treatment in patients with UC or CD. Psychometric analyses are warranted to fully evaluate their properties and value for use in clinical trials.

Improving Asthma Management: Patient-Pharmacist Partnership Program in Enhancing Therapy Adherence.

Community pharmacist interventions can assist in improving adherence in patients with asthma. The objective of the study was to assess the feasibility of patient-centered counseling using the developed asthma-specific tools to identify barriers to adherence and identify their preliminary effect on adherence barrier score and asthma control. Adult patients with persistent asthma were invited to participate in a 3-month pre-post intervention study involving community pharmacist-provided patient-centered counseling. Bivariate analyses were conducted to determine whether there were changes in outcomes from the pre to post period. Of 36 recruited patients, 17 completed both pre and post surveys. At baseline, patients had a mean ACT score of 15.1 ± 3.5, with 94% having uncontrolled asthma, and an average of 4.2 ± 2.5 reported barriers. The following barriers were most common: not having an Asthma Action Plan (52.9%), use of inhaler more or less often than prescribed (47.1%) and forgetfulness (41.2%). The ACT score increased by 2.7 ± 5.4, which was not statistically significant; however, it might be clinically significant. Two barrier scores improved as a result of the intervention. Preliminary evidence on the feasibility of identifying and addressing patient-specific barriers to adherence delivered by pharmacists showed that it has the potential to resolve barriers and improve asthma outcomes.

Real-World Treatment Patterns and Physician Preferences for Biologics in Moderate-to-Severe Inflammatory Bowel Disease: Retrospective Chart Review in Europe.

Background: With many options available for treating inflammatory bowel disease (IBD) in Europe, this study sought to characterize physician treatment preferences and real-world treatment patterns in patients with moderate-to-severe ulcerative colitis (UC) and Crohn's disease (CD). Methods: This was a retrospective, noninterventional, physician-administered study. Gastroenterologists and general practitioners (n = 348) in France, Germany, and the United Kingdom provided information on treatment preferences and extracted information from records of patients with moderate-to-severe UC (n = 587) or CD (n = 417) who had received biologic, biosimilar or Janus kinase inhibitor therapies (2014-2019) and had IBD-related medical history available 6 months before and after treatment initiation. Results: Physicians largely preferred infliximab and adalimumab or their biosimilars as first-line therapy for UC (originators, 65.8%; biosimilars, 26.1%) and CD (originators, 61.8%; biosimilars, 30.5%). Effectiveness was the most cited reason for treatment preference (92%-93% of physicians). Three-quarters of patients (UC, 75.8%; CD, 73.6%) received infliximab or adalimumab originators in the first line, with more patients receiving infliximab biosimilars than adalimumab biosimilars (12.4%-12.5% and 0.5%-4.1%, respectively, across UC and CD). Persistence was longer for first-line infliximab than adalimumab (UC, 26.6 vs 21.2 months; CD, 31.2 vs 26.7 months) and was generally shorter for their respective biosimilars. Nonbiologic treatments were used in combination with biologics in 14.1% (UC) and 11.5% (CD) of patients. Most patients received 1 biologic therapy (UC, 90.6%; CD, 83.2%); only 9.4% (UC) and 16.8% (CD) received a second biologic. Conclusions: Infliximab and adalimumab originators dominated first-line biologic therapy for moderate-to-severe UC and CD. Understanding real-world treatment patterns can help assess new treatment uptake and suggest opportunities for improving treatment.

The impact of clinical symptoms and endoscopic and histologic disease activity on health-related quality of life in patients with ulcerative colitis following treatment with multimatrix mesalazine.

PURPOSE: Studies of patients with ulcerative colitis (UC) report that reduced clinical symptoms and endoscopic activity predict better health-related quality of life (HRQoL). However, no study has examined the joint and unique associations of clinical and endoscopic activity with HRQoL, nor of histologic inflammation and HRQoL. These post hoc analyses evaluated whether reduced clinical, endoscopic, and histologic disease activity were uniquely associated with improved HRQoL for adults with active mild-to-moderate UC receiving once-daily 4.8 g/day multimatrix mesalazine for 8 weeks. METHODS: Assessments at baseline and week 8 (i.e., treatment completion) included clinical and endoscopic activity (modified UC-Disease Activity Index), histology (Geboes scoring), and HRQoL (Short Inflammatory Bowel Disease Questionnaire [SIBDQ]; SF-12v2® Health Survey [SF-12v2]). Associations among each type of disease activity and HRQoL were examined by correlations and by mean changes in SIBDQ and SF-12v2 scores between disease activity subgroups (e.g., achievement of clinical remission; mucosal healing). Regression models estimated unique variance in HRQoL accounted by each type of disease activity. RESULTS: Within the analysis sample (n = 717), patients with reduced clinical and endoscopic activity had significantly larger improvements in all HRQoL domains (p < 0.001), as did patients in both endoscopic and clinical remission compared to patients in endoscopic remission only (p < 0.05). Patients with histologic activity post-treatment scored significantly worse on all HRQoL domains than patients with no activity (p < 0.05). Correlations and regression models found that decreases in clinical and endoscopic activity were associated with improvements in HRQoL domain scores. CONCLUSIONS: Clinical symptoms and mucosal health have separable, distinct impacts on UC patients' HRQoL.

Examination of Barriers to Medication Adherence, Asthma Management, and Control Among Community Pharmacy Patients With Asthma.

OBJECTIVE: To describe the prevalence of common barriers to asthma medication adherence and examine associations between patient-reported asthma controller adherence and asthma control, therapy adherence barriers, and asthma management characteristics. METHODS: Previously developed asthma-specific tool was pilot tested on a convenience sample of adult patients with persistent asthma. The following data were collected via patient survey: demographic characteristics and comorbidities, adherence, asthma control, and asthma management characteristics. Descriptive and inferential statistics were used to address the study objective. RESULTS: The patients (N = 93) were 45.4 (17.2) years of age, and 66.7% were female. The majority had poor (68.8%) adherence, with 61.3% of patients having controlled asthma. There was no significant association between adherence and asthma control. The mean number of barriers for good and poor adherence groups differed significantly: 2.0 ± 1.1 and 5.4 ± 2.4, respectively (P < .0001). Having an asthma action plan (AAP) was the only asthma management characteristic significantly related to adherence. The majority of patients with poor adherence did not have an AAP (76.6%), whereas 81.5% of patients with good adherence did have an AAP (P < 0.0001). CONCLUSIONS: The use of this survey tool confirmed presence of asthma-specific barriers, thus using this specialized approach may lead to more effective, targeted counseling in community pharmacy settings.

Pharmacotherapy patterns in patients with chronic idiopathic constipation beginning treatment with linaclotide or lubiprostone in the United States.

BACKGROUND: Chronic idiopathic constipation (CIC) is a common gastrointestinal disorder in community settings. Limited information exists on its treatment with the prosecretory agents linaclotide and lubiprostone. This retrospective cohort study investigated real-world pharmacotherapy patterns of linaclotide and lubiprostone. METHODS: Patients (≥18 years) with CIC who received linaclotide or lubiprostone between January 2013 and December 2015 were identified in a United States health insurance claims database. Follow-up was from the date of the earliest claim for either drug to the end of continuous enrolment or switch to the alternative agent. Patterns of pharmacotherapy, evidence of irritable bowel syndrome (IBS), and concomitant use of selective serotonin reuptake inhibitors were examined using the International Classification of Diseases, Ninth or Tenth Revision, Clinical Modification codes and National Drug Codes. RESULTS: In total, 43,164 and 17,743 patients with CIC received linaclotide and lubiprostone, respectively (~80% women, mean age ~47 years). Approximately 40% of subjects (linaclotide: 40.1%; lubiprostone: 37.6%) had evidence of IBS. Over a mean follow-up of 17 months, mean (standard deviation) treatment duration in patients without IBS was 6.6 (7.9) months for linaclotide and 4.5 (6.5) months for lubiprostone. Treatment episodes >180 days were more common with linaclotide (36.1%) than with lubiprostone (23.2%). At 12 months, Kaplan-Meier estimates of switching from lubiprostone to linaclotide and from linaclotide to lubiprostone were 13.4 and 5.6%, respectively. The number of patients receiving serotonin reuptake inhibitors was unchanged with treatment (~22%). CONCLUSIONS: Most patients with CIC receive linaclotide or lubiprostone for <6 months; few remain on therapy for >1 year. Additional research is warranted to understand the potential reason(s) for early discontinuation.

The Humanistic and Economic Burden of Chronic Idiopathic Constipation in the USA: A Systematic Literature Review.

BACKGROUND: Chronic idiopathic constipation (CIC) is a functional gastrointestinal disorder with an estimated prevalence of 16% in the USA; however, the humanistic and economic burden of CIC is poorly characterized. AIM: This systematic literature review aimed to assess the humanistic and economic burden of CIC in adults in the USA. METHODS: Two systematic literature searches of English-language publications on the humanistic and economic burden of CIC in adults in the USA were conducted using electronic databases and other resources. Both searches included the terms "chronic idiopathic constipation" and "functional constipation". Specific terms used in the search on humanistic burden included "quality of life", "SF-36", "SF-12", and "PAC-QOL"; search terms for economic burden included "cost", "resource use", "absenteeism", and "productivity". RESULTS: Overall, 16 relevant articles were identified. Health-related quality of life (HRQoL) appeared to be reduced in patients with CIC compared with controls and the general US population. Abdominal (r=0.33-0.49), stool (r=0.23-0.33), and rectal symptoms (r=0.53) appeared to be associated with reduced HRQoL. Younger age and female sex were associated with reduced overall HRQoL and greater symptom severity. Direct outpatient costs were higher in patients with CIC than those without CIC (US$6284 vs US$5254). Patients with CIC and abdominal symptoms reported more days of disrupted productivity per month than those without abdominal symptoms (3.2 days vs 1.2 days). The overall prevalence of complementary and alternative medicine use by patients with CIC was similar to that in the general US population. CONCLUSION: The reduced HRQoL and increased costs associated with CIC indicate unmet therapeutic need in this disorder. Further research is required to better understand the humanistic and economic burden of CIC in the USA.

Chronic Constipation in the United States: Results From a Population-Based Survey Assessing Healthcare Seeking and Use of Pharmacotherapy.

OBJECTIVES: Chronic idiopathic constipation (CIC) is characterized by unsatisfactory defecation and difficult or infrequent stools. CIC affects 9%-20% of adults in the United States, and although prevalent, gaps in knowledge remain regarding CIC healthcare seeking and medication use in the community. We recruited a population-based sample to determine the prevalence and predictors of (i) individuals having discussed their constipation symptoms with a healthcare provider and (ii) the use of constipation therapies. METHODS: We recruited a representative sample of Americans aged 18 years or older who had experienced constipation. Those who met the Rome IV criteria for irritable bowel syndrome and opioid-induced constipation were excluded. The survey included questions on constipation severity, healthcare seeking, and the use of constipation medications. We used multivariable regression methods to adjust for confounders. RESULTS: Overall, 4,702 participants had experienced constipation (24.0% met the Rome IV CIC criteria). Among all respondents with previous constipation, 37.6% discussed their symptoms with a clinician (primary care provider 87.6%, gastroenterologist 26.0%, and urgent care/emergency room physician 7.7%). Age, sex, race/ethnicity, marital status, employment status, having a source of usual care, insurance status, comorbidities, locus of control, and constipation severity were associated with seeking care (P < 0.05). Overall, 47.8% of respondents were taking medication to manage their constipation: over-the-counter medication(s) only, 93.5%; prescription medication(s) only, 1.3%; and both over-the-counter medication(s) and prescription medication(s), 5.2%. DISCUSSION: We found that 3 of 5 Americans with constipation have never discussed their symptoms with a healthcare provider. Furthermore, the use of prescription medications for managing constipation symptoms is low because individuals mainly rely on over-the-counter therapies.

Cross-sectional survey study to examine underuse of twice daily inhaled maintenance therapy among patients with asthma.

Objective: Anecdotal evidence suggests that some patients with asthma intentionally use their twice-daily (BID) inhaled controller therapy once daily (QD), thus not achieving optimal dosing levels. This study identified the prevalence of and factors associated with intentional QD use of BID-indicated controllers among adult patients with asthma. Methods: This was a cross-sectional survey study of adults using inhaled controllers intended for BID dosing for treatment of asthma and/or COPD. Survey responses were linked to administrative claims data for the prior 12 months (baseline). Results of patients indicating both an asthma diagnosis and current intentional QD or BID use of controllers are presented. Results: Of 1401 patients with asthma, 30.9% reported intentional QD use of their controller and 69.1% reported BID use. Intentional QD use was mostly a function of patients' lack of perceived need for BID treatment (44.1%) or physician orders to take their controller QD (34.0%). Patients reporting intentional QD use tended to be healthier (higher health status scores, and lower Charlson comorbidity scores, ambulatory and ER visits, and healthcare costs) with better asthma control (lower asthma-related ER and ambulatory visits and rescue medication use, and higher Asthma Control Test scores) compared with patients reporting BID use. Conclusions: Perceptions regarding health and the necessity of controller use to control or treat asthma were the main drivers of medication-taking behavior. Patients with less severe asthma were more likely to report once daily use of their inhaled controller, but still maintained asthma control.

Claims-based risk model for first severe COPD exacerbation.

OBJECTIVES: To develop and validate a predictive model for first severe chronic obstructive pulmonary disease (COPD) exacerbation using health insurance claims data and to validate the risk measure of controller medication to total COPD treatment (controller and rescue) ratio (CTR). STUDY DESIGN: A predictive model was developed and validated in 2 managed care databases: Truven Health MarketScan database and Reliant Medical Group database. This secondary analysis assessed risk factors, including CTR, during the baseline period (Year 1) to predict risk of severe exacerbation in the at-risk period (Year 2). METHODS: Patients with COPD who were 40 years or older and who had at least 1 COPD medication dispensed during the year following COPD diagnosis were included. Subjects with severe exacerbations in the baseline year were excluded. Risk factors in the baseline period were included as potential predictors in multivariate analysis. Performance was evaluated using C-statistics. RESULTS: The analysis included 223,824 patients. The greatest risk factors for first severe exacerbation were advanced age, chronic oxygen therapy usage, COPD diagnosis type, dispensing of 4 or more canisters of rescue medication, and having 2 or more moderate exacerbations. A CTR of 0.3 or greater was associated with a 14% lower risk of severe exacerbation. The model performed well with C-statistics, ranging from 0.711 to 0.714. CONCLUSIONS: This claims-based risk model can predict the likelihood of first severe COPD exacerbation. The CTR could also potentially be used to target populations at greatest risk for severe exacerbations. This could be relevant for providers and payers in approaches to prevent severe exacerbations and reduce costs.

Validation of a New Risk Measure for Chronic Obstructive Pulmonary Disease Exacerbation Using Health Insurance Claims Data.

RATIONALE: Current chronic obstructive pulmonary disease (COPD) exacerbation risk prediction models are based on clinical data not easily accessible to national quality-of-care organizations and payers. Models developed from data sources available to these organizations are needed. OBJECTIVES: This study aimed to validate a risk measure constructed using pharmacy claims in patients with COPD. Administrative claims data were used to construct a risk model to test and validate the ratio of controller (maintenance) medications to total COPD medications (CTR) as an independent risk measure for COPD exacerbations. The ability of the CTR to predict the risk of COPD exacerbations was also assessed. METHODS: This was a retrospective study using health insurance claims data from the Truven MarketScan database (2006-2011), whereby exacerbation risk factors of patients with COPD were observed over a 12-month period and exacerbations monitored in the following year. Exacerbations were defined as moderate (emergency department or outpatient treatment with oral corticosteroid dispensings within 7 d) or severe (hospital admission) on the basis of diagnosis codes. Models were developed and validated using split-sample data from the MarketScan database and further validated using the Reliant Medical Group database. The performance of prediction models was evaluated using C-statistics. MEASUREMENTS AND MAIN RESULTS: A total of 258,668 patients with COPD from the MarketScan database were included. A CTR of greater than or equal to 0.3 was significantly associated with a reduced risk for any (adjusted odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.97); moderate (OR, 0.93; 95% CI, 0.87-1.00), or severe (OR, 0.87; 95% CI, 0.80-0.95) exacerbation. The CTR, at a ratio of greater than or equal to 0.3, was predictive in various subpopulations, including those without a history of asthma and those with or without a history of moderate/severe exacerbations. The C-statistics ranged from 0.750 to 0.761 for the development set and 0.714 to 0.761 in the validation sets, indicating the CTR performed well in predicting exacerbation risk. CONCLUSIONS: The ratio of controller to total medications dispensed for COPD is a measure that can easily be calculated using only pharmacy claims data. A CTR of greater than or equal to 0.3 can potentially be used as a quality-of-care measurement for prevention of exacerbations.

Health-related quality-of-life evaluation of crohn disease patients after receiving natalizumab therapy.

Crohn disease (CD) is a chronic inflammatory condition without a permanent medical cure and commonly requiring a lifetime of care. This article discusses the impact of natalizumab induction and maintenance therapy on the health-related quality of life (HRQoL) of CD patients. Two natalizumab phase III studies were evaluated: the Efficacy of Natalizumab in Crohn's Disease Response and Remission (ENCORE) study evaluated the HRQoL of CD patients during 12 weeks of natalizumab induction therapy, and the Evaluation of Natalizumab As Continuous Therapy (ENACT-2) trial evaluated the effect of natalizumab maintenance therapy on HRQoL for a period of 48 weeks past a 12-week induction period (ENACT-1). HRQoL assessments were made with the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Short Form-36 (SF-36). In the ENCORE study, induction therapy with natalizumab was demonstrated to significantly increase HRQoL scores at 12 weeks when compared with patients on placebo. During the ENACT-2 trial, IBDQ and SF-36 scale scores of patients who responded to natalizumab induction remained stable whereas those on placebo worsened. At week 60, the mean change from baseline on all scales of the IBDQ and the SF-36 were significantly higher for those who continued to receive natalizumab as compared to those who received placebo (p

Sphingosine kinase 1 expression is regulated by signaling through PI3K, AKT2, and mTOR in human coronary artery smooth muscle cells.

Sphingosine kinase 1 (SphK1) is a lipid kinase implicated in mitogenic signaling pathways in vascular smooth muscle cells. We demonstrate that human coronary artery smooth muscle (HCASM) cells require SphK1 for growth and that SphK1 mRNA and protein levels are elevated in PDGF stimulated HCASM cells. To determine the mechanism of PDGF-induced SphK1 expression, we used pharmacological inhibitors of the PI3K/AKT/mTOR signaling pathway. Wortmannin, SH-5, and rapamycin significantly blocked PDGF-stimulated induction of SphK1 mRNA and protein expression, indicating a regulatory role of the PI3K/AKT/mTOR pathway in SphK1 expression. To determine which isoform of AKT regulates SphK1 mRNA and protein levels, siRNAs specific for AKT1, AKT2, and AKT3 were used. We show that AKT2 siRNA significantly blocked PDGF-stimulated increases in SphK1 mRNA and protein expression levels as well as SphK1 enzymatic activity levels. In contrast, AKT1 or AKT3 siRNA did not have an effect. Together, these results demonstrate that the PI3K/AKT/mTOR signaling pathway is involved in regulation of SphK1, with AKT2 playing a key role in PDGF-induced SphK1 expression in HCASM cells.