Novartis Pharmaceuticals Corporation Research Articles

Association of Sacubitril/Valsartan vs Valsartan With Blood Pressure Changes and Symptomatic Hypotension: the PARAGLIDE-HF Trial

In PARAGLIDE-HF, among patients with ejection fraction (EF) >40%, stabilized after worsening heart failure (WHF), sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared to valsartan alone, despite more symptomatic hypotension (SH). Concern over SH may be limiting use of sacubitril/valsartan in appropriate patients. We characterized patients by the occurrence of SH (investigator-reported) after randomization to either sacubitril/valsartan or valsartan. A key trial inclusion criterion was systolic blood pressure (SBP) ≥100 mmHg for the preceding 6 hours and no SH. We also compared outcomes based on baseline SBP stratified by the median blood pressure. The primary endpoint was time-averaged proportional change in NT-proBNP from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: a) cardiovascular death, b) HF hospitalizations, c) urgent HF visits, and d) change in NT-proBNP. Among 466 randomized patients, 92 (19.7%) experienced SH (sacubitril/valsartan, N=56 [24.0%]; valsartan, N=36 [15.5%], p=0.020). The median time to the first SH event was similar between treatment arms (18 days vs. 15 days, respectively, p=0.42) as was the proportion of first SH events classified as "serious" by investigators. Patients who experienced SH with sacubitril/valsartan were more likely to be White (OR 1.87 [95%CI: 0.31, 11.15]), to have a lower baseline SBP (per 10mmHg increase OR 0.68 [95%CI: 0.55, 0.85]), or to have a left ventricular ejection fraction (LVEF) of >60% (OR 2.21 [95%CI: 1.05, 4.65]). Time-averaged change in NT-proBNP did not differ between patients with baseline SBP ≥128 mmHg vs. SBP<128mmHg (interaction p=0.43). The composite hierarchical outcome for sacubitril/valsartan in patients with baseline SBP≥128mmHg had a win ratio of 1.34 ([95%CI: 0.91, 1.99], p=0.096) vs SBP<128mmHg with a win ratio of 1.09 ([95%CI: 0.73, 1.66], p=0.62; interaction p value=0.42). Among patients with LVEF>40% stabilized after WHF, incident SH was more common with sacubitril/valsartan compared with valsartan. SH was associated with lower baseline SBP, White race, and higher LVEF. Treatment benefits with sacubitril/valsartan may be more pronounced in patients with higher baseline SBP and lower LVEF (≤ 60%). (Funded by Novartis Pharmaceutical Corporation; ClinicalTrials.gov number, NCT03988634.) ABBREVIATIONS: : HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NT-proBNP, amino terminal-pro b-type natriuretic peptide; SBP, systolic blood pressure; WHF, worsening heart failure.

Methodology for Good Machine Learning with Multi-Omics Data.

In 2020, Novartis Pharmaceuticals Corporation and the U.S. Food and Drug Administration (FDA) started a 4-year scientific collaboration to approach complex new data modalities and advanced analytics. The scientific question was to find novel radio-genomics-based prognostic and predictive factors for HR+/HER- metastatic breast cancer under a Research Collaboration Agreement. This collaboration has been providing valuable insights to help successfully implement future scientific projects, particularly using artificial intelligence and machine learning. This tutorial aims to provide tangible guidelines for a multi-omics project that includes multidisciplinary expert teams, spanning across different institutions. We cover key ideas, such as "maintaining effective communication" and "following good data science practices," followed by the four steps of exploratory projects, namely (1) plan, (2) design, (3) develop, and (4) disseminate. We break each step into smaller concepts with strategies for implementation and provide illustrations from our collaboration to further give the readers actionable guidance.

Risk Stratified Treatment for Patients with Newly Diagnosed Juvenile Myelomonocytic Leukemia: A Phase 1/2 Non-Randomized Study of Trametinib and Azacitidine with or without Chemotherapy

Background: Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of childhood. The biochemical hallmark of JMML is aberrant signaling through the Ras pathway caused by initiating mutations in NF1, NRAS, KRAS, RRAS, RRAS2, SH2B3, PTPN11,or CBL. While hematopoietic stem cell transplantation (HSCT) can be curative, 5-year event-free survival of children with JMML after HSCT is only ~50%. Recently, several studies have identified mutational burden and DNA methylation as predictive of clinical outcomes in patients with JMML. In the T2020-004 phase 1/2 clinical trial, we will define lower-risk patients as those with one somatic alteration and low DNA methylation and high-risk patients as those with more than one somatic alteration or intermediate/high DNA methylation. Trametinib is an orally bioavailable, reversible, highly selective allosteric inhibitor of MEK1/2 in the Ras/MAPK signaling pathway. Trametinib is FDA-approved for the treatment of adults with advanced melanoma with BRAF V600E or V600K mutations and in children with Ras-mutant solid tumors in combination with dabrafenib. Clinical investigation of trametinib monotherapy via the Children's Oncology Group ADVL1521 phase 2 trial (NCT03190915) showed efficacy in children with relapsed/refractory JMML. Phase 2 clinical trial evaluation of azacitidine in children with newly-diagnosed JMML was also efficacious and led to its FDA approval. In this trial, trametinib will be tested in combination with azacitidine in lower-risk patients and in combination with azacitidine and chemotherapy for high-risk patients. Study Design and Methods: This is a non-randomized, risk stratified, Phase 1/2 study for patients with newly-diagnosed JMML (NCT05849662) conducted via the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium with safety and efficacy phases for both lower-risk and high-risk cohorts. Lower-risk patients will receive trametinib once-daily for 28 days in combination with azacitidine administered daily for five days per cycle. Lower-risk patients can receive up to 12 cycles and will proceed to HSCT only if they experience progressive disease or relapse. High-risk patients will receive trametinib administered once-daily for 28 days in combination with azacitidine, fludarabine, and cytarabine (aza/FLA) administered daily for five days per cycle. High-risk patients will receive up to two cycles of therapy before proceeding to HSCT off protocol. Key Eligibility: Patients aged 1 month to 21 years who meet World Health Organization criteria for JMML will be eligible. Objectives: The primary safety objectives are to determine the safety of combining trametinib with azacitidine for lower-risk patients and combining trametinib with aza/FLA for high-risk patients. The secondary efficacy objectives are to determine the event-free survival for lower-risk patients in the absence of HSCT and the molecular response rates pre-HSCT for high-risk patients. Sample Size and Statistical Design: A rolling 6 trial design will be used during Phase 1 of the study to determine the recommended phase II dose (RP2D) of trametinib for lower-risk and high-risk patients in combination with their respective therapies. Starting trametinib dose is 0.032mg/kg daily if less than 6 years of age, or 0.025mg/kg daily if 6 years or older, with one dose level de-escalation if indicated. Phase II of the study involves lower-risk and high-risk cohort expansions at the RP2D of trametinib. Target accrual is 22 patients in the lower-risk arm and 42 patients in the high-risk arm. The study is open to accrual at all TACL consortium sites. We acknowledge the TACL Consortium's scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center. Novartis Pharmaceuticals Corporation provided the investigative drug in support of this trial. This study is supported by the National Institute of Health, National Cancer Institute (R37CA266550), the Pediatric Cancer Research Foundation, and the Cannonball Kids Cancer Foundation.

Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial

Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.

1275-P: Incident Diabetes Before and During the COVID-19 Pandemic among Youth in Kaiser Permanente Southern California

Background: Prior research found increases in type 1 and type 2 diabetes (T1D/T2D) among youth during the COVID-19 pandemic but did not focus on age, sex, or race/ethnicity variation. We examined incidence rates from 2016-2021 in Kaiser Permanente Southern California (KPSC), a large, integrated healthcare delivery system. Methods: KPSC members &amp;lt;20 years old, with no diabetes prior to their incidence year were followed using electronic health records for diabetes defined using diagnoses, labs, and diabetes medications. We calculated age- and sex-standardized incidence rates per 100,000 person-years (PY) for T1D and T2D between 2016-2021 overall and by age, sex, and race/ethnicity. We used Poisson regression to calculate incidence rate ratios (IRR) comparing 2020-2021 to 2016-2019. Results: Incidence of T1D increased from 18.5/100,000 PY in 2016-2019 to 22.4/100,000 PY in 2020-2021 with increased IRR among 10-19-year-olds, both sexes, and Hispanic individuals. (Table) Incidence of T2D increased from 14.8/100,000 PY in 2016-2019 to 24.7/100,000 PY in 2020-2021 with increased IRR among 10-19-year-olds, both sexes, and those with non-Hispanic Black, Hispanic, and other/unknown race/ethnicity. Conclusion: Incidence of both T1D and T2D increased following the start of the pandemic. Future research to understand potential underlying physiologic and behavioral risk factors is warranted. Disclosure M.T.Mefford: None. R.Wei: None. E.Lustigova: None. J.P.Martin: None. K.Reynolds: Research Support; Novartis Pharmaceuticals Corporation.

1003-P: Cost of Care for Patients with Diabetic Kidney Disease in Veterans Health Administration

Introduction: Diabetic kidney disease (DKD) represents a substantial burden on the Veterans Health Administration (VHA). We calculated the cost of DKD care for US Veterans from the healthcare system perspective. Methods: Veterans with type 2 diabetes (T2D) in 2015-2021 were identified using diagnosis codes, prescription records, and problem lists. We identified prevalent and incident DKD stages based on urine albumin, urine protein, and eGFR, and following the Kidney Disease Improving Global Outcome definitions. Aggregate all-cause monthly healthcare costs per patient for managing each DKD stage (ie, stages 1 through 5) were estimated by summing patient-level VHA costs in incident DKD stages from January 2018 until December 2021. Summary statistics include descriptive median and interquartile ranges of per-patient per-month [PPPM] cost. All costs were inflated to 2022 US dollars (USD) based on the Consumer Price Index of all items for urban consumers. Results and Conclusion: Out of two million US Veterans with T2D, we identified 401,214 DKD patients with 1+ incident stage progression in the follow-up period. Median PPPM all-cause healthcare cost increased exponentially from $748 at Stage 1 to $2,661 at Stage 5 (Figure). Interventions targeting patients with rapid DKD progression could markedly decrease the burden of DKD in US Veterans. Disclosure K.Kim: Research Support; Renalytix, GRAIL (acquired by Illumina in 2021), AstraZeneca. J.L.Crook: None. C.S.Lu: None. R.E.Nelson: None. H.Nyman: None. J.Lafleur: Research Support; Renalytix, Genentech, Inc., Novartis Pharmaceuticals Corporation.

1375-P: Child-Reported Food Security in Children with Type 1 Diabetes—Association with Glycemic Control and Mental Health Symptoms Independent of Household Food Security

Introduction: Typically, caregivers report on household food security (FS), but children’s experiences may differ from caregiver reports. We assessed if child-reported food insecurity (FI) was associated with glycemic control, acute complications of diabetes, depressive symptoms, and disordered eating in children with type 1 diabetes (T1D), independently from household FS. Methods: In a cross-sectional analysis of the multicenter SEARCH for Diabetes in Youth Study (Phase 4, 2016-2019), including 601 children age 10-17 years with T1D, household FS and child-reported FS were assessed using the 18-item Household Food Security Survey Module and the six-item Child Food Security Assessment questionnaire. Age-stratified (10-13, 14-17) regression models were performed to estimate independent associations, adjusting for sociodemographic and clinical factors and household FS. Results: FI was reported by 13.1% (n=79) of children and 15.6% (n=94) of caregivers. Among child-caregiver dyads, 82.5% (n=496) of reports were concordant and 17.5% (n=105) discordant, Cohen’s kappa = 0.3. Child-reported FI was not independently associated with hemoglobin A1c, diabetic ketoacidosis, and hypoglycemia, including in age-stratified analyses. Child-reported FI was independently associated with elevated odds of depressive symptoms (OR 3.6, 95% CI 1.3-10.3) and disordered eating (OR 2.5, 95% CI 1.4-4.6) compared to FS; these associations remained in both age groups for disordered eating and in the older group for depressive symptoms. Conclusion: Children with T1D may experience FI differently than caregivers. Child-reported FI was independently associated with depressive symptoms and disordered eating and thus may be an important attribute to assess in addition to household FS in children with T1D. Disclosure E.F.Julceus: None. B.A.Reboussin: None. K.Reynolds: Research Support; Novartis Pharmaceuticals Corporation. C.Pihoker: None. A.D.Liese: None. E.A.Frongillo: None. J.A.Mendoza: None. K.A.Sauder: None. F.Malik: None. E.T.Jensen: Consultant; Regeneron. L.M.Dolan: None. A.Bellatorre: None. D.Dabelea: None. Funding National Institutes of Health (R01DK117461, 1R01DK127208, 1UC4DK108173, T32GM081740)

505-P: Real-World Use of Inclisiran in Outpatient Physician Clinics

Objective: In clinical trials, inclisiran, a novel siRNA therapy, reduced LDL-C equally among diabetic and nondiabetic patients. This study aimed to characterize a cohort of obese, prediabetic, and diabetic patients prior to initiating inclisiran in outpatient clinics. Methods: This was a retrospective, longitudinal cohort study of patients referred for treatment with inclisiran between February and November 2022 in 23 clinics in 11 states. Patients with obesity (BMI&amp;gt;30 kg/m2), prediabetes (5.7≤ HbA1c≤ 6.5%), or diagnosed diabetes at the time of referral were assessed. The log rank test was used to identify differences in time from referral to first administration between above groups. Results: Of 81 identified patients, 48.2% were diabetic, 27.2% obese, and 24.7% prediabetic. Median age was 71 (IQR: 68-75) years, 60.5% were male, and 60.5% were Medicare beneficiaries. At referral, 81.4% had a primary diagnosis of atherosclerotic cardiovascular disease (ASCVD), 30.9% were on concurrent statins, 30.9% on ezetimibe, 66.7% had documented statin intolerance, 50.6% had prior PCSK9 monoclonal antibody use, and the median Elixhauser comorbidity score was 6.0 (IQR: 2-15). Elixhauser score was notably higher among the diabetic group (Median: 9, IQR: 3-18) compared to the prediabetic (Median: 4, IQR: 0-13) and obese (Median: 3, IQR: -3-12) patient groups. Median baseline LDL-C was 135 (IQR: 99-166) mg/dL with no differences between groups. Median time to initiation was 27 (IQR: 16-49) days with no notable difference between obese, prediabetic, and diabetic patients. Conclusion: Inclisiran can be promptly initiated in the clinic setting for the management of LDL-C in obese, prediabetic, and diabetic patients. Future work will focus on measuring real-world effectiveness and adherence to inclisiran in each of these groups. Disclosure T.E. Graham: None. T.J. Varisco: Consultant; HEALIX. C.M. Ballantyne: Research Support; Abbott Diagnostics, Akcea, Amgen Inc., Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc., Ionis Pharmaceuticals, Merck &amp; Co., Inc., Novartis, Novo Nordisk, Regeneron, Roche Diagnostics. Consultant; Alnylam Pharmaceuticals, Inc., Althera Pharmaceuticals, Amarin Corporation, Amgen Inc., Arrowhead Pharmaceuticals, Inc., AstraZeneca, ESPERION Therapeutics, Inc., 89bio, Inc., Abbott Diagnostics, Denka Seiken, Genentech, Inc., Gilead Sciences, Inc., Illumina, Matinas BioPharma Inc, Merck &amp; Co., Inc., New Amsterdam Pharma, Novartis, Novo Nordisk, Pfizer Inc., Regeneron, Roche Diagnostics. B.J. Iteld: Speaker's Bureau; Amgen Inc. Research Support; Amgen Inc., Novartis AG, Bayer Inc. Speaker's Bureau; ESPERION Therapeutics, Inc. Research Support; BMS. Speaker's Bureau; Boehringer-Ingelheim. H. Serota: Speaker's Bureau; Amarin Corporation. Advisory Panel; Bayer Inc. Speaker's Bureau; Janssen Pharmaceuticals, Inc., Boehringer Ingelheim and Eli Lilly Alliance. S. McElligott: Employee; Novartis. Stock/Shareholder; Janssen Pharmaceuticals, Inc. Employee; Sanofi. Stock/Shareholder; Merck &amp; Co., Inc. X. Niu: Employee; Novartis, Sunovion Pharmaceuticals Inc. L.J. Van Anglen: Research Support; Novartis Pharmaceuticals Corporation, Merck &amp; Co., Inc., ADMA Biologics, Inc., Octapharma USA, Paratek Pharmaceuticals. Funding Novartis Pharmaceuticals Corporation

259-OR: Arterial Stiffness and Diabetes-Associated Complications in the SEARCH for Diabetes in Youth Study

Arterial stiffness and vascular complications contribute to the burden of disease in diabetes, and it is unclear how they relate to each other. The relationship between arterial stiffness, an early marker of cardiovascular disease, and microvascular complications has not been comprehensively assessed in youth-onset diabetes. This study included 1226 individuals (mean age 22.8 years, 58% female, 53% Non-Hispanic White, 22% Non-Hispanic Black, 20% Hispanic) with type 1 (n=999) and type 2 (n=227) diabetes. Arterial stiffness measures included pulse wave velocity for carotid-femoral (PWVcf), carotid-radial (PWVcr), and femoral-foot (PWVff) and augmentation index (AIx). Microvascular complications included diabetic kidney disease, peripheral neuropathy, and retinopathy. Logistic regression was used to analyze associations between arterial stiffness and microvascular complications. PWVcf and AIx were associated with higher odds of having any microvascular complication, p&amp;lt;0.05 (Table). PWVcf, PWVff, and AIx were each associated with diabetic kidney disease. PWVcf was associated with peripheral neuropathy and PWVcr and AIx were associated with retinopathy. Arterial stiffness is related to diabetes microvascular complications in youth-onset diabetes. Future work will determine whether arterial stiffness is a marker for early onset and progression of microvascular complications. Disclosure R.Brady: None. L.Sancrainte: None. A.S.Shah: None. E.M.Urbina: Advisory Panel; Astellas Pharma Inc., Other Relationship; Targus Medical, Inc. Z.Gao: None. L.M.Dolan: None. D.Dabelea: None. E.Lustigova: None. A.K.Mottl: Advisory Panel; Bayer Inc., Chinook Therapeutics Inc., Consultant; Bayer Inc., Research Support; Bayer Inc., Alexion Pharmaceuticals, Inc., Pfizer Inc., Boehringer Ingelheim Inc., Calliditas. C.Pihoker: None. K.Reynolds: Research Support; Novartis Pharmaceuticals Corporation. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK127208-01); Centers for Disease Control and Prevention (00097, DP-05-069, DP-10-001)

992-P: Coronary Artery Calcium Scoring to Improve Statin Use in Adults with Type 2 Diabetes Not on Statin Therapy—Anticipated Cost Utility

Background: Statin use in adults with diabetes is sub-optimal. Coronary artery calcium (CAC) scoring can provide a visual quantification of CV risk and may improve statin initiation and long-term use. Objective: Estimate the cost-utility of CAC scoring compared to traditional CV risk counselling only, for improving statin use in adults with diabetes who have not previously had a CV event, and are not on statin therapy. Methods: Probabilistic Markov model from a health system perspective, over a 10-year time horizon. The effectiveness of CAC scoring was obtained from the EISNER trial. Outcomes included acute coronary syndrome (ACS), stroke, heart failure, mortality, and radiation-induced cancer. Outcome rates and costs were obtained from an analysis of Alberta administrative data, and from publicly available sources. The base population modeled was men age 60, with additional analyses for other age, sex-groups and scenarios. Results: CAC scoring increased statin use to 44% vs 25% with traditional CV risk counselling only. There were 8.4 fewer ACS, 5.5 fewer strokes, and 1.6 fewer deaths / 1000 individuals. Costs were slightly lower (-$14, 95% CI [-$402-(+$208)]) (CAD), for a small benefit in quality-adjusted life years (+0.01, [0.00-0.02]), with mean ICER of $7,132 (-$27,828-(+$65,513)) / QALY. At a willingness-to-pay of $50,000 / QALY, CAC was cost-effective in 95% of trials. CAC scoring was not cost-effective in younger men or in women, but could be cost-effective or cost savings in men (age ≥ 40) and older women (age ≥ 60) who refuse statin therapy, but would be persuaded by personalized evidence of coronary artery disease (CAC score &amp;gt; 10). Conclusion: CAC scoring may be cost-effective in older men not receiving statins, and in men or older women who agree to use statins if shown personalized evidence of coronary artery disease. Disclosure D.Lau: None. G.J.Pearson: Advisory Panel; HLS Therapeutics Inc., Novartis Pharmaceuticals Corporation, Pharmacience, Consultant; Trimedic Therapeutics. P.Raggi: None. S.Klarenbach: Research Support; Bayer Inc., Allergan, GlaxoSmithKline plc., CSL Behring, Lundbeck, University Hospital Foundation (University of Alberta), Purdue Canada.

858-P: Recruitment Strategies for a Cellular Therapy Study for Type 1 Diabetes

Mesenchymal stem cells may be a novel T1D treatment based on immunoregulatory and tissue-protective properties. Therefore, an NIDDK sponsored prospective, single center, double blind study of MSCs for new onset T1D (NCT04061746) has generated significant social media interest. This trial is hard to enroll because of a narrow age range (18-30 years) and requirement of a new onset diagnosis (6 months). We evaluated the impact of social media tools, clinicaltrials.gov advertisement, and medical record review (EPIC) to define the optimal screening process for this and future trials. Through clinicaltrials.gov the study piqued the interest of 173 participants. Additionally, the study team has pre-screened 346 patients from an EPIC generated report. Among the 22 patients consented, referrals were received from physicians (N=5), clinicaltrials.gov (N=13), and EPIC reports (N=4). Among those discovered via EPIC list, we depicted the main reasons for study ineligibility (Fig. 1). The study recently launched a social media campaign in December 2022, initially reaching a total of 16,593 viewers. 4,475 viewers (26.97%) interacted with the campaign, and 2 (0.012%) were potentially interested in follow up from the research team. We conclude that clinicaltrials.gov, medical record review, and physician referrals are all critical to screening for new-onset diabetes studies. Other T1D studies might benefit from utilizing these strategies. Disclosure L.Benn: None. W.Gou: None. P.J.Nietert: None. M.Cornier: Consultant; Novo Nordisk, Alnylum, Letsgetchecked, Research Support; Novartis Pharmaceuticals Corporation, Amgen Inc., Kaneka. S.Norton: None. C.Strange: None. H.Wang: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK118529, DK120394, DK105183, DK125454); U.S. Department of Veterans Affairs (I01BX004536)

Quality care of patients with HR+/HER2- breast cancer: Insights from an implementation science program.

e18756 Background: Oral oncolytics have transformed the treatment landscape of HR+/HER2- breast cancer, shifting the responsibility for medication adherence and side effect management to patients. To optimize patient outcomes, collaborative patient-provider education on treatment expectations, adverse event management, and shared decision-making is imperative. Methods: From 11/2021 to 2/2022, HR+/HER2- breast cancer patients (N = 55) and health care professionals (HCPs) (N = 69) who treat breast cancer from 5 community practices were surveyed on attitudes, values, and challenges related to treatment, adherence, and adverse event management on oral therapies. HCPs (N = 59) participated in audit-feedback (AF) sessions to reflect on their own practice and develop action plans to improve care, which were implemented in subsequent collaborative patient-provider learning sessions. Informed by survey findings and insights from patient focus groups a, a point-of-care oral oncolytic toolkit was disseminated to support patients and providers in effective communication, treatment adherence, and side effect management. Results: In surveys, HCPs and patients reported side effects of medication as the top challenge impacting treatment adherence, with fatigue (33%), nausea/vomiting (28%), and hair loss (28%) the most challenging side effects. Notably, 46% of HCPs reported inadequate time to discuss patient goals, preferences and concerns as the biggest barrier for shared decision-making, and 15% of patients reported their doctor does not always ask about goals, preferences, and concerns. Reflection on survey and focus group insights in AF sessions enabled providers to develop and implement action plans including the provision of patient education resources on medication adherence and side effect recognition and management, scheduling adequate follow-up appointments to ensure side effect management and medication compliance, and engaging in shared decision-making. In patient-provider collaborative sessions, patients demonstrated substantial knowledge gains in how to communicate, recognize, and manage side effects associated with treatment, and providers committed to continuing patient education. Conclusions: Through a combination of a patient and provider survey study, patient focus groups, HCP AF sessions, and collaborative patient-provider learning sessions, action plans and education resources were developed and implemented to support the provision of effective treatment management for HR+/HER2- breast cancer. The methods and findings of this study represent key opportunities for improvement in caring for patients with HR+/HER2- breast cancer. Study Sponsor Statement: This activity is supported by educational grants from Lilly and Novartis Pharmaceuticals Corporation, who had no role in the study design, execution, analysis, or reporting.

Protecting Mothers and Babies Through Research

CBR is employed by and is a stockholder of Novartis Pharmaceuticals Corporation. No.

Alpelisib: a novel PI3K inhibitor for the treatment of breast cancer

Breast cancer is a common malignancy that causes people to die easily, especially for women. HR-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers occur in more than 70% of patients, who have a driver mutant kinase catalytic subunit alpha (PIK3CA) in the phosphatidylinositol 4, 5-diphosphate 3-kinase gene, resulting in impaired phosphatidylinositol 3-kinase (PI3K) and in 40% of cases, loss of cell growth. However, drug resistance remains a problem in the early stages of endocrine therapy in these patients. And a promising new approach to overcome resistance to autologous treatment in breast cancer is the inhibition of PI3K. Alpelisib is a selection PI3K inhibitor for HR-positive, HER2-negative, PIK3CA patients - with mutant breast cancer that has advanced on autologous treatment. FDA approved alpelisib in 2019 which was produced by Novartis Pharmaceuticals Corporation. It is recommended to take this drug with fulvestrant which is also an estrogen receptor antago-nist that slows the growth of breast cancer. Although alpelisib is an effective drug for the treatment of breast cancer, some adverse reactions may happen, such as stomatitis, nausea, diarrhe, dermatitis, and so on. Sometimes it also causes skin reactions, such as SIS, TEN, EM. Thus, when these serious adverse reactions happen, dosage should be reduced. As a result, some recommendations are provided for patients, and they must follow the instructions in or-der to live a more pleasant life. In this article, the working mechanism, structure, characteris-tics, clinical studies of alpelisib were reviewed and its comparison with other drugs was also provided for reference.

Wearing-Off Effect Toward the End of Treatment Cycles in Patients With MS Receiving High-Efficacy Disease-Modifying Therapies: Data From Social Media Listening (P3-3.009)

<h3>Objective:</h3> To explore how various stakeholders (patients living with multiple sclerosis [PlwMS], caregivers [CGs], health care practitioners [HCPs], advocacy groups) describe symptoms, timing, coping strategies, and impact on quality of life (QoL) of the wearing-off effect (WOE) while receiving disease-modifying therapies (DMTs; natalizumab, ocrelizumab, ofatumumab, rituximab). <h3>Background:</h3> Symptoms such as fatigue, mobility issues, and physical pain toward the end of treatment cycles (WOE) have been reported in PlwMS receiving DMTs. Patients on social media report a QoL impact associated with WOE. <h3>Design/Methods:</h3> Publicly available posts related to WOE on social media, blogs, and forums were reviewed. WOE-specific posts authored in English by key stakeholders and posted between February 1, 2020 and February 16, 2022 were analyzed. Posts were identified through a specific search term–based funneling methodology. <h3>Results:</h3> We identified 43,834 posts related to broader MS and WOE; 730 conversations were WOE specific, with 725 authored by PlwMS or CGs. Of these 725 posts, 535 were related to experiencing WOE and 277/535 posts mentioned WOE-associated symptoms. The most commonly reported WOE durations were 2–4 weeks; fatigue was the most mentioned symptom, followed by mobility issues and physical pain. Treatment was specified in 374/535 posts; 9% of these mentioned a QoL impact, such as need for more downtime, interference with work, and difficulty walking. WOE coping strategies mentioned by patients included switching to other DMTs, reducing intervals between cycles, and taking steroids/other medications. WOE-related conversations by HCPs and advocacy groups were scarce (4 and 1 posts, respectively). <h3>Conclusions:</h3> Mentions of WOE by patients receiving DMTs and reports of WOE-related symptoms impacting QoL were common. Factors like differing DMT durations and numbers of patients receiving different DMTs make observations of social media conversations prone to an inherent bias. Further research regarding WOE and potential gaps between HCP and patient perceptions/awareness of WOE is needed. <b>Disclosure:</b> Mr. Clement has received personal compensation for serving as an employee of Novartis. Mr. Clement has stock in Roche. Joanne Fielding, 24833 has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis . The institution of Joanne Fielding, 24833 has received research support from BioEye. The institution of Joanne Fielding, 24833 has received research support from Equity Trustees. The institution of Joanne Fielding, 24833 has received research support from Macquarie Group Foundation. The institution of Joanne Fielding, 24833 has received research support from Genzyme. The institution of Joanne Fielding, 24833 has received research support from Biogen. The institution of Joanne Fielding, 24833 has received research support from Open Medicines Australia. The institution of Joanne Fielding, 24833 has received research support from EyeOnVision. Ms. Serceau has nothing to disclose. Ms. Robinson has nothing to disclose. Chinmay Deshpande has received personal compensation for serving as an employee of Novartis Pharmaceutical Corporation . Chinmay Deshpande has stock in Novartis Pharmaceutical Corporation .

Intravenous and Intrathecal Onasemnogene Abeparvovec Gene Therapy in Symptomatic and Presymptomatic Spinal Muscular Atrophy: Long-Term Follow-Up Study (S34.002)

Intravenous and Intrathecal Onasemnogene Abeparvovec Gene Therapy in Symptomatic and Presymptomatic Spinal Muscular Atrophy: Long-Term Follow-Up Study (S34.002)

An online survey among US patients with immune-mediated conditions: Attitudes about biosimilars.

BACKGROUND: Few surveys about biosimilars have been conducted among US patients. OBJECTIVE: To evaluate attitudes about biosimilars among patients with rheumatoid arthritis (RA), psoriasis and/or psoriatic arthritis (PsO/A), and/or inflammatory bowel disease (IBD). METHODS: WebMD, LLC fielded a 16-item online survey to members of the US Dynata consumer panel meeting these criteria: aged 18 years or older; self-reported specialist diagnosis of RA, PsO/A, or IBD of at least 1 year; and not currently receiving an infliximab biosimilar. A quota of 500 was set, stratified by region and condition. The survey was exempt by the institutional review board, exploratory, and not registered. RESULTS: Overall, 44% (n = 221) of patients were on a biologic; 56% (n = 279) were not on a biologic (40% [n = 199] were biologic naive and 16% [n = 80] used biologics in the past). Among all patients, 66% were unaware of biosimilars and 24% were aware (10% unsure). After being shown the US Food and Drug Administration definition of a biosimilar, main concerns were side effects (59%), long-term safety (50%), and not knowing a lot (46%). Among current users, 43% would switch to a biosimilar and 26% would not (32% unsure). Of those unwilling to switch, 51% were concerned about side effects, 42% about financial support, and 40% about efficacy. When those not on a biologic were asked if their doctor prescribed an original anti-tumor necrosis factor α but their insurance required its biosimilar, 49% would switch and 8% would not (43% unsure). 51% of patients surveyed thought pharmacist-level substitution of an interchangeable biosimilar was acceptable with notification. Survey findings were consistent among the RA, PsO/A, and IBD subgroups. CONCLUSIONS: Although two-thirds of patients surveyed were unaware of biosimilars, the majority were potentially receptive to biosimilar treatment after being provided with the definition of a biosimilar. Patients expressed a desire to know more about biosimilars in general, how they compare with original biologics, their benefits, and cost. DISCLOSURES: This study was funded by Boehringer Ingelheim Pharmaceuticals Inc. (BIPI). WebMD, LLC, fielded the survey. BIPI was given the opportunity to review the article for medical and scientific accuracy and intellectual property considerations. Dr Gibofsky is a consultant/advisor for AbbVie Inc., Biosplice Therapeutics, Lilly, Novartis Pharmaceuticals Corporation, and Pfizer Inc., and he is on the speakers' bureau for AbbVie Inc., Amgen, Lilly, and Pfizer Inc., and has stock ownership in AbbVie Inc., Amgen, Bristol-Myers Squibb Company, Horizon Pharma plc, and Pfizer Inc. Dr Peyrin-Biroulet reports that he has received personal consulting fees from Merck Sharp & Dohme, AbbVie, Janssen, Takeda, Celltrion, Pfizer, Bristol-Myers Squibb Company, Pharmacosmos, Shire, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, UCB-Pharma, Hospira, BIPI, and Lilly. Dr McCabe is an employee of BIPI. Dr McGrath was an employee of BIPI at the time the survey was conducted. Mr Jacobson, Mr Franklin, and Ms O'Hara-Levi report no disclosures.

MDS-476 Sabatolimab (MBG453) Combination Treatment Regimens for Patients With Higher-Risk Myelodysplastic Syndromes (HR-MDS): The Myelodysplastic Syndromes Studies in the STIMULUS Immuno-Myeloid Clinical Trial Program

Patients with HR-MDS unfit for hematopoietic stem cell transplant (HSCT) have poor outcomes with hypomethylating agents (HMAs). Novel treatments with durable responses and survival benefit are needed. Sabatolimab is a novel immuno-myeloid therapy that binds to TIM-3 on immune cells, facilitating immune activation and phagocytosis of leukemic cells. Sabatolimab also binds to TIM-3 on leukemic cells, potentially impeding self-renewal of leukemic stem cells (LSCs). Early phase trials of sabatolimab+HMAs show promising efficacy and response durability, with few significant immunologic AEs. To summarize the designs of 4 ongoing STIMULUS trials evaluating the safety and efficacy of sabatolimab-based combination therapies in untreated adults with HR-MDS ineligible for intensive chemotherapy or HSCT. Study Summaries:STIMULUS-MDS1 (NCT03946670): an international, randomized, double-blind, placebo-controlled, Phase II trial evaluating sabatolimab+HMA in very-high, high-, or intermediate-risk (vH/H/IR)-MDS patients; enrollment complete (N=127). CR and PFS. STIMULUS-MDS2 (NCT04266301): an international, randomized, double-blind, placebo-controlled, Phase III trial of sabatolimab+azacitidine in vH/H/IR-MDS or chronic myelomonocytic leukemia-2 patients. Recruitment completed (N=530). OS. Key secondary endpoints: time to definitive deterioration of fatigue; RBC transfusion-free interval; improvement of fatigue, physical, and emotional functioning. STIMULUS MDS-US (NCT04878432): a US-based, open-label, single-arm, Phase II trial of sabatolimab+HMA of investigator's choice (azacitidine IV or subcutaneous, decitabine IV, or oral decitabine/cedazuridine) in vH/H/IR-MDS patients. Target enrollment (N=90). safety. Key secondary endpoints: CR, PFS, leukemia-free survival (LFS), and OS. STIMULUS-MDS3 (NCT04812548): an international, open-label, single-arm, Phase II trial of sabatolimab+azacitidine+venetoclax in vH/HR-MDS patients. Part 1: two safety run-in cohorts (~6 patients receiving sabatolimab 400mg +azacitidine+venetoclax; and ~12 receiving sabatolimab 800mg +azacitidine+venetoclax). Primary endpoint (Part 1): safety. If both regimens are safe, ~58 patients in expansion cohort will receive sabatolimab 800mg Q4W +azacitidine+venetoclax. CR. Key secondary endpoints: CR+mCR rate, overall response rate (CR+mCR+PR+hematologic improvement), OS, PFS, LFS, and event-free survival. The STIMULUS immuno-myeloid clinical trial program is investigating the efficacy and safety of sabatolimab-based combination therapies in patients with myeloid malignancies. The STIMULUS-MDS trials aim to elucidate the durable benefit of sabatolimab combination therapies in HR-MDS patients. Study sponsored by Novartis Pharmaceuticals Corporation.

HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE BRAZILIAN SUPPLEMENTARY HEALTH SYSTEM: A RETROSPECTIVE COHORT ANALYSIS

To analyze resource usage and costs of patients who underwent Hematopoietic Stem Cell Transplantation (HSCT) in the Brazilian Supplementary Health System (SHS). Data from a longitudinal retrospective dynamic cohort study (from January/2014 to December/2019) were analyzed. The population consisted of SHS patients who underwent HSCT (regardless of being autologous, allogeneic related or unrelated), and were beneficiaries of one of the 15 main health maintenance organizations that use Orizon billing system (25% of total Brazilian private market). The follow-up period ranged from six months prior to HSCT, to identify the total costs of hospitalization and preparatory exams for the procedure, up to one year after HSCT, or until censored/death. 1,265 HSCT procedures were analyzed (1,132 patients). Sex and age were missing data in 40% of the patients’ records, however from the data that were possible to collect, 33.0% were males, and 42.75% were between 30 and 70 years old. The most common causes for transplant were Multiple Myeloma (ICD-10 C90.0) and Acute Myeloid Leukemia (C92.0). During the six months that precede transplant, each patient cost an average of BRL 303,500 (total cohort cost of BRL 383.6 million, 55% of this total consisting of hospitalization expenses). During hospitalization for HSCT procedure, 41.2% of patients were admitted to the ICU, with a median length of stay of 21 days. Total hospitalization costs for transplant in this cohort was BRL 503.4 million (average of BRL 398,000 per patient). Additionally, 4.24% of patients presented an immediate adverse event after HSCT. Graft-Failure (T86.0) was the most common event (26,19%). Of the 1,132 patients followed, 26% had new admissions within one month after transplant; Acute Myeloid Leukemia and Multiple Myeloma relapse were the most common causes for re-hospitalization, followed by other transplanted organs and tissues (Z94.8), Acute Lymphoblastic Leukemia (C91.0), unspecified medical care (Z51.9), Cytomegalovirus unspecified disease (B25.9) and unspecified fever (R50.9). The highest costs after discharge from transplant were associated to hospitalizations (BRL 231 million in total, average of BRL 67,300 per hospitalization). HSCT is a growing procedure in the SHS in Brazil, and is associated with high costs, especially those with repeated hospitalizations, either caused by diseases that were the primary cause for HSCT indication or by infections after the procedure. The comprehension on HSCT-related costs in Brazilian SHS setting can help to define actions oriented to a improve patients’ quality of life and treatment strategies, thus achieving better patients’ outcomes. This study was sponsored by Novartis Pharmaceuticals Corporation. Dr. Funke and Dr. Schmidt-Filho have participated on this study for the sole purpose of scientific exchange and report no conflicts of interest.

Patient perspectives on diagnosis and management of hidradenitis suppurativa: A web-based survey

Patient perspectives on diagnosis and management of hidradenitis suppurativa: A web-based survey