Novartis (Israel)

Initial multiple drug therapy for hypertension achieves greater and quicker reductions and higher blood pressure (BP) control rates than monotherapy. This 8-week, prospective, multicenter, randomized, double-blind study compared the efficacy and safety of the initial combination of aliskiren/amlodipine with amlodipine monotherapy in African Americans with stage 2 hypertension. After a 1- to 4-week washout, patients received aliskiren/amlodipine 150/5 mg or amlodipine 5 mg for 1 week and then were force-titrated to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. At week 8, greater reductions in mean sitting systolic BP were obtained with aliskiren/amlodipine (n = 220) than with amlodipine (n = 223) (least squares mean change [standard error of the mean], -34.1 [1.14] mm Hg vs -28.9 [1.12] mm Hg; P<.001). Ambulatory and central BP measures were consistent with clinic BP findings, although these were conducted in a small subset of patients (n = 94 in ambulatory BP monitoring substudy and n = 136 for central BP). More patients achieved goal BP (<140/90 mm Hg) with aliskiren/amlodipine than with amlodipine at week 8 (57.3% vs 48.0%; P = .051). Both treatment groups had similar adverse event rates (35.0% and 32.7%, respectively). The most common adverse events were peripheral edema (7.7% with aliskiren/amlodipine and 9.0% with amlodipine), headache, fatigue, and nausea. The combination of aliskiren/amlodipine reduced peripheral, ambulatory, and central BP more than amlodipine alone with similar tolerability in African Americans with stage 2 hypertension.

PURPOSE: The purpose of our work was to collate information from studies published to date focusing on switching in anti-VEGF therapy and describe the currently available data on anti-VEGF switching in nAMD. METHODS: A PubMed search of published articles from January 2010 to January 2017 was conducted. Published studies were compared in parameters of sample size, reason for switch, duration of follow-up, and switch outcome (functional and anatomical). RESULTS: Our search revealed 31 relevant publications. Switching from bevacizumab to ranibizumab mostly resulted in improvement in visual acuity (VA) and anatomical outcomes (CMT, CRT; 7/8 and 6/8 studies, respectively), whereas switching from ranibizumab to bevacizumab was less effective (no VA or anatomical improvement in 2/4 studies). Switching from either agent to aflibercept resulted mostly in improvement of anatomical outcomes (19/21 studies), but rarely in VA improvement (6/21 studies). Not all results were statistically significant, likely due to small sample sizes. CONCLUSION: Switching anti-VEGF therapy from bevacizumab to ranibizumab might be of benefit (functionally and anatomically) for patients who failed to improve with intravitreal bevacizumab injections, whereas switching from either agent to aflibercept resulted mostly in reduced macular thickness only.

Background/Purpose: Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory syndrome. FMF is caused by mutations in the MEFV gene which encodes the pyrin protein, that has an important role in the activation of IL‐1β. Evidence from case reports/series and one controlled study supports IL‐1 blockage as a potential treatment for FMF. Canakinumab (CAN) is a selective fully human monoclonal anti‐IL‐1β antibody. This study served as a proof of concept to evaluate the role of CAN in the treatment of pediatric colchicine resistant (CR)‐FMF with a longterm extension. Methods: This was a 2‐center, 2‐part, phase II, open‐label, single‐arm study. Subjects consisted of CRFMF patients (pts) 4–16 years of age, with a history of ≥3 documented FMF attacks in the 3 months prior to enrollment. In part I, pts with an investigator‐confirmed FMF attack during the 30‐day run‐in period (RI) could enter the treatment phase. These subjects received the 1st dose of CAN (2 mg/kg, max 150 mg) via subcutaneous (SC) injection during the subsequent attack and then every 4 weeks for three times. The dose was doubled to 4 mg/kg (max 300 mg) if an attack occurred between Day 1 and Day 29 visits. Primary outcome was the proportion of pts with ≥50% reduction in FMF attack rate during the treatment vs. pretreatment period. Following the end of the treatment period, pts were followed until day 144 or until an attack occurred, whichever occurred first. CAN was then renewed and pts entered the long‐term extension study (part II), in which the dose and frequency of CAN administration and colchicine dose could be adjusted by investigators based on pt response. Results: Seven pts (5 males, 2 females; median age 9.5 yrs, range 6.8–14.9) received treatment. In part I, 6/7 (86%) pts attained the primary outcome. The median attack rate was reduced by 89% from 2.7 to 0.3 per 28 days; 2 pts had their CAN dose uptitrated. Elevated median baseline CRP normalized by Day 8 with ESR and SAA by Day 28. Following the end of the treatment period 5 pts developed attacks within a median of 25 days. In part II, all 7 pts (no drop‐outs) were followed for a median of 17 (range 13–25) months. During this period, 3 pts experienced 6 attacks (0.05 attacks per pt month) and in 2 pts the CAN doses were increased. Two additional pts experienced 3 mild increases in the ESR and CRP (not associated with an attack) that resolved after CAN dose increase. At the end of part II, the global physician assessment was rated as very good for all pts; median CAN dose was 3 (range 1.8–4.8) mg/kg with administration interval lengthened in 3 pts to every 7 wks. Colchicine dose was decreased to 1 mg/d in 3 pts and discontinued (by self) in 1 pt. 22 AEs were recorded in 5 pts, with 11 in each study part. All were mild except for 3 moderate AEs (Strep throat infection, laceration, tinea capitis) assessed as unrelated to study treatment by the study investigators. No AEs led to medication discontinuation. Conclusion: This study demonstrated the longterm therapeutic effect of canakinumab in pediatric pts with CR‐FMF. AEs were manageable. Occasional increases in dose were needed while the dosing interval could be lengthened in some patients. A larger study is needed to better evaluate the benefit and optimal dosing of canakinumab for CR‐FMF.

599 Background: Adjuvant treatment with aromatase inhibitors (AIs) in postmenopausal women (PMW) with early breast cancer (EBC) can be associated with decreased bone mineral density (BMD) and increased risk of osteoporosis and fractures. Tamoxifen (TAM) has bone protective effect. BIG 1–98 recent, 71 months update suggests that sequential therapy of TAM and letrozole (LET) in either order, have similar efficacy to 5 years of LET. This study is designed to evaluate the efficacy and safety of zoledronic acid (ZA) in preventing AIs bone loss after 2.5 years of TAM. Methods: This is an open-label, randomized phase II study of PMW with hormone receptor positive EBC previously treated with TAM for the last 2.5 years (with BMD T score ≥ -2.5). Patients are randomly assigned to receive LET (2.5mg/ daily) ± ZA. Patients on treatment arm receive 4 mg IV ZA every 6 months for 2 years. All patients are being evaluated every 6 (0–36) months with blood chemistry and BMD test. All patients receive vitamin D and calcium supplement. A comparison between groups and between time points is performed by one-way ANOVA with repeated measures using the Mixed model. Results: Seventy four patients were screened. Median age was 58.9 years (46.5–83.6). All patients are alive, one had an ipsilateral recurrence. Seventy two patients were evaluable (2 were screening failure), 33 randomized to receive ZA and 39 to the control group. Median follow-up (FU) was 18.2 months (1–47). At this point in time a significant interaction between groups and time trend was found, in favor of ZA treated group in lumbar T score (p = 0.0055). While in the control group a significant decline in lumbar BMD was noticed (p = 0.008), in the treatment group BMD did not change over time (p = 0.2971). Adverse events with ZA were mild with some flue like syndrome. No serious renal adverse event or ONJ (osteonecrosis of jaw) cases were reported. ZA was safe and well tolerated. Conclusions: Sequential adjuvant treatment with TAM and AIs in PMW with EBC can be associated with decreased BMD and increased risk of osteoporosis. In our study, LET-induced bone loss increases with time. A significant benefit in BMD was seen when ZA was added to LET. A longer follow up is needed to evaluate the real magnitude of ZA protective effects. [Table: see text]

Background/Objectives: Polycythemia vera (PV) is a chronic hematologic neoplasm commonly treated with hydroxyurea (HU). We utilized the advanced digitalized database of Maccabi Healthcare Services to retrospectively investigate the clinical and economic implications of HU intolerance in the routine clinical care of PV patients in Israel. Methods: We collected data on demographics, physician visits, hospitalizations, laboratory results, medication purchases, cardiovascular and thrombotic events, mental health, economic outcomes, and mortality. Outcomes included cardiovascular and other thrombotic events, disease progression, mental health events, economic outcomes, and overall mortality. Results: Of the 830 patients studied, 3 (0.4%) were resistant to HU treatment, 318 (38.3%) were intolerant to HU treatment, and 509 (61.3%) were stable on HU treatment. The venous thrombosis rate was significantly higher among HU-intolerant compared to HU-stable patients (1.58 vs. 0.47 per 100 person-years [PY], respectively; p &lt; 0.001). The rate of progression to myelofibrosis was 6 vs. 0.9 per 100 PY in HU-intolerant patients vs. HU-stable patients, respectively (p &lt; 0.001), and the rate of progression to acute myeloid leukemia (AML) was 1.16 vs. 0.2 per 100 PY in HU-intolerant patients vs. HU-stable patients, respectively (p &lt; 0.001). The phlebotomy requirement, mortality rate, and total hospitalization days among HU-intolerant patients were significantly higher than in HU-stable patients (p = 0.049, p &lt; 0.001, p &lt; 0.001, respectively). More mental health-related events were noted in HU-intolerant patients vs. HU-stable patients (p = 0.007), and the total healthcare cost ratio was 2.65 for the HU-intolerant patients compared with HU-stable patients. Conclusions: This study suggests that HU-intolerant patients are more likely to have worse outcomes than HU-stable patients, highlighting the need for the close monitoring of these patients for disease-related complications or progression.

C100 Introduction: Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, is a potent inhibitor of the activity of farnesyl-pyrophosphate synthase leading to a blockade of the mevalonate pathway and interfering with protein modifications critical for cell signaling and growth. However, cell permeability to ZOL is poor, and therefore cytotoxic activity is minimal except when internalized by fluid-phase endocytosis into osteoclasts. The purpose of this study was to deliver ZOL to the intracellular compartment of tumor cells via encapsulation in liposomes targeted to the folate receptor (FR), which is over-expressed in a broad spectrum of tumors. Methods: ZOL was entrapped passively in the water phase of liposomes of various compositions.with or without a lipophilic folate ligand inserted in the lipid bilayer. The formulations tested had a ZOL:phospholipid molar ratio of ~0.1, a folate:phospholipid molar ratio of 0.005, and a mean vesicle diameter of ~100 nm. A spike of C14-radiolabeled ZOL was included in some formulations for cell uptake experiments. All formulations tested were highly stable in buffer and plasma with negligible in vitro leakage of ZOL. The in vitro cytotoxic activities of liposomal ZOL (Lip-ZOL) and folate-targeted (FT) Lip-ZOL were examined on various human and mouse cell lines with or without up-regulation of the FR by standard 72-hour colorimetric assays. Results: Free ZOL growth-inhibitory concentrations were in the range of 100 µM, far beyond the pharmacologically feasible range, for all cell lines tested. Non-targeted Lip-ZOL was devoid of any cytotoxic activity at concentrations up to 100 µM, regardless of the type of liposome composition. The cytotoxic activity of FT-Lip-ZOL was composition-dependent, with optimal activity for liposomes containing a small fraction of dipalmitoyl-phosphatidylglycerol (DPPG) and reduced activity for pegylated (PEG) formulations. IC50 values in FR-expressing tumor cells reached the sub-micromolar range, and were 100 to 1000-fold lower than those of free ZOL. The cytotoxicity of DPPG-FT-Lip-ZOL was comparable to that of doxorubicin in sensitive cell lines, and much greater than doxorubicin in resistant cell lines. FT-Lip-ZOL showed reduced cytotoxicity but still superior to that of non-targeted Lip-ZOL when tested on the non-FR upregulated tumor cell line counterparts, on normal fibroblasts and on J774 macrophages. The uptake of ZOL by FR-expressing tumor cells was enhanced ~30-fold with DPPG-FT-Lip-ZOL, but only ~4-fold with PEG-FT-Lip-ZOL. Conclusions: Targeting ZOL to tumor cells via the FR with a ZOL-loaded liposome formulation appears to be an effective means to selectively exploit the cell growth inhibitory properties of ZOL. DPPG-containing liposomes are significantly more efficient at intracellular delivery of ZOL than PEG-based formulations.

Aims: In this retrospective study, we analyzed data from patients with hypercholesterolemia to describe treatment patterns, adherence, low-density lipoprotein cholesterol (LDL-C) control, cardiovascular outcomes, and healthcare resource utilization among treated patients in a real-world setting in Israel. Methods: Deidentified data from the medical records of patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalent (ASCVD-RE), and familial hypercholesterolemia (FH) treated with lipid-lowering therapy (LLT) between 2013 and 2019 were analyzed. LDL-C values were based on routine laboratory reporting in Maccabi Healthcare Services and were calculated using the Friedewald equation during the study period. Controlled LDL-C was defined as LDL-C < 70 mg/dL for ASCVD patients and <100 mg/dL for ASCVD-RE and FH patients. Adherence to LLTs was assessed using the proportion of days covered (PDC), and associations with cardiovascular outcomes and healthcare resource utilization were evaluated. Results: A total of 15,258 patients with hypercholesterolemia (FH [7.0%], ASCVD [33.3%], and ASCVD-RE [59.7%]) were identified. Most of them (>90%) received statin monotherapy, while 2.9% received a combination of a statin and other LLTs. High adherence to LLTs (PDC ≥ 80%) was achieved by 54.1% of ASCVD patients, followed by 35.3% of ASCVD-RE patients and 17.7% of FH patients. Combination therapy with high-intensity statins (HIS) plus ezetimibe was associated with lower first postinitiation LDL-C levels in the ASCVD and ASCVD-RE groups, with 47.6% and 52.0% of patients, respectively, achieving LDL-C < 55 mg/dL; Among FH patients, 30.8% achieved LDL-C levels of 70-100 mg/dL with HIS monotherapy. A PDC ≥ 80% was significantly associated with a longer time to percutaneous coronary intervention and CABG procedures and a longer time to death in both the ASCVD and ASCVD-RE groups. During the study period, LDL-C targets were achieved by 61.1% of ASCVD patients. LDL-C < 100 mg/dL was reached by 79.9% of ASCVD-RE patients and 33.5% of FH patients. Conclusions: In this large, treated real-world cohort, substantial gaps in LDL-C control and treatment adherence were observed across high-risk populations. Higher adherence to lipid-lowering therapy was associated with better LDL-C control and longer time to selected clinical outcomes; however, these findings should be interpreted as associations rather than evidence of causality, given the observational study design. Translational perspective: In this real-world cohort, higher adherence to lipid-lowering therapy (PDC ≥ 80%) was associated with better LDL-C control and more favorable cardiovascular outcome patterns. These findings highlight the potential importance of sustained treatment adherence as a key determinant of lipid control in routine clinical practice and suggest that strategies supporting long-term adherence may contribute to improved cardiovascular risk management in high-risk populations.

Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory syndrome affecting >10,000 people in Israel. FMF is caused by mutations in the MEFV gene, which encodes for the pyrin protein that is part of the inflammation complex that activates IL-1β. Evidence from case reports/series and one controlled study supports IL-1 blockage as a potential treatment for FMF. Canakinumab (CAN) is a selective fully human monoclonal anti-IL-1β antibody.

Abstract Abstract #1153 BACKGROUND: Adjuvant treatment with aromataze inhibitors (AI's) in postmenopausal women (PMW) with early breast cancer (BC) can be associated with decreased bone mineral density (BMD) and increase risk of osteoporosis and fractures. Tamoxifen on the contrary, increases BMD, and has bone protective effect. Previous studies showed that the addition of Zolandronic (ZA) acid to adjuvant treatment with AI's reduce bone loss. This study is designed to evaluate the efficacy and safety of ZA in preventing AI's bone loss in PMW with early BC who are receiving adjuvant Letrozole therapy after Tamoxifen.&amp;#x2028; PATIENTS AND METHODS: This is an open-label, randomized phase II. The study enrolled PMW diagnosed and treated for stage I-III hormone receptor positive BC previously treated with Tamoxifen for the last 2.5 years with BMD T- score &amp;gt; -2.5. Patients were randomly assigned to receive Letrozole +/- ZA. Patients on treatment arm received ZA at base-line and every 6 months for 2 years. All patients are being evaluated every 6 months with blood chemistry and BMD test to detect changes in Lumbar and hips BMD and Alkaline phosphatase as serum bone turnover markers (at 6,12,18,24 and 36 months). Letrozole dose was 2.5mg/ daily and ZA 4 mg IV. All patients received supplemental vitamin D and calcium.&amp;#x2028; RESULTS: Sixty one patients were screened. Median age was 58.9 years (46.5-83.6), all patients were postmenopausal for at least 12 months, median ECOG performance status was 1 (0-2).). All patients are alive and only one patient had an ipsilateral breast cancer recurrence.&amp;#x2028; Fifty eight patients were evaluable (3 pts were screening failure), 26 randomized to receive ZA and 32 to the control group. Four patients withdrew from the protocol.&amp;#x2028; Median follow up (FU) is 15.6 months (0.7-41.9), 13 patients had 4 BMD evaluations, 24 had 3 and 39 had 2 (including base-line evaluations). A comparison between groups and between time points was performed by one-way Analysis of Variance with repeated measures using the Mixed model. At this point in time a significant interaction between groups and time trend was found, in favor of ZA treated group in lumbar T score (p=0.0422). While in the control group a significant decline in lumbar BMD was noticed (p= (0.0009, in the treatment group BMD did not change over time (p= 0.9783).&amp;#x2028; Adverse events with ZA were mild with some musculoskeletal pain within 2 days post infusion as the most common reported toxicity, one patient had fever and severe pain for 5 days. No serious renal adverse event or ONJ cases were reported. ZA was safe and well tolerated.&amp;#x2028; CONCLUSION: Our study reports, a significant benefit in bone mineral density (BMD) when adding Zolandronic Acid to letrozole after switching from Tamoxifen. Letrozole induced bone loss, increases with time and a longer follow up is needed to evaluate the real magnitude of ZA protection effects. Further investigation is warranted. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1153.

Background: Hydroxyurea (HU) is an effective and common therapy for high-risk Polycythemia Vera (PV). Some patients may demonstrate resistance or intolerance to HU, but the consequences of these warrant further studies. Objective: Evaluate the clinical and economic implications of HU resistance/intolerance, in routine clinical practice in Israel. Methods: A retrospective analysis of Maccabi Health Services' (MHS) database was performed. MHS is a Non-for-Profit healthcare insurer and provider in Israel, with over 2.2 million members. Patients were included in the study if they had a recorded PV diagnosis or complete blood count indicative of PV, and had purchased HU for at least 3 months between 2000-2015. Enrolled patients were divided into 3 groups: A) Resistant to HU (patients prescribed 2g/day of HU); B) Intolerant of HU (patients who stopped HU, transitioned to another line of therapy or who developed HU related cytopenias); C) Stable on HU. A mid-time point was added to "Stable" to compensate for the time required for transition in the "Intolerant" group. Only patients who developed Intolerance within 5 years were included. Collected data pertained to demographics, clinical outcomes, resource utilization and expenditure data. Results: A total of 830 patients were identified. Only 3 met criteria for Resistance and were disregarded for further analysis, while 318 (38%) were defined as "Intolerant" and 509 (61%) as "Stable". At baseline, there were no significant differences between "Intolerant" and "Stable" groups, apart from platelet counts (431 vs. 495, respectively) and red cell distribution width (RDW) (18.4 vs. 17.6, respectively). Intolerance was determined based on HU-related cytopenias (n=144, 45% of Intolerant), transition to other treatment line (n=52, 16%) or stopping HU (n=122, 38%). These results indicate some patients continue HU treatment despite lack of disease control. "Intolerant" patients who had transitioned by 5 years from first HU purchase (N=173) and "Stable" patients who met the mid-point of time to transition (N=487) were eligible for comparison. Median follow up time was 4.9 and 5.5 years for "Intolerant" and "Stable" groups, respectively. Thrombotic events occurred in 8% of the "Intolerant" group compared with 3% of "Stable" (p=0.003) and event rate per 100 patient-years was 1.6 versus 0.5 (p&amp;lt;0.001). Progression to MF occurred in 28% versus 5% (p&amp;lt;0.001), and progression to AML occurred in 6% compared with 1% (p&amp;lt;0.001) among "Intolerant" and "Stable", respectively. Interestingly no significant difference was found regarding major arterial thrombotic complications, (myocardial infarction, acute coronary syndrome, cerebrovascular accident or limb ischemia). During study follow up, hospitalization occurred in 84% versus 69% (p&amp;lt;0.001), and hospitalization days were 5.3 vs 1.9 per year (p=0.004) among "Intolerant" and "Stable" groups, respectively. Death occurred in 58% of "Intolerant" compared with 30% of "Stable"(p&amp;lt;0.001). Treatment costs for an Intolerant patient in the first year after intolerance were 2.6-fold higher than those for a Stable patient, driven mainly by hospitalization costs being 3.6-fold higher (data available from 2010). Conclusions: The results of this analysis indicate that intolerance to HU treatment in PV patients is associated with serious clinical and economic implications, indicating a need for improved treatment for these patients. Disclosures Ellis: Novartis Pharma AG: Consultancy, Honoraria, Other: Institutional research grant; BMS: Consultancy, Other: Institutional research grant; Gilead: Other: Institutional research grant. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Chodick:Novartis Pharma AG: Other: Institutional grant. Yekutiel:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Other: Institutional grant. Sharf:Novartis Pharma AG: Consultancy, Other: Institutional Grant; Leukaemia Patient Advocates Foundation: Ended employment in the past 24 months, Membership on an entity's Board of Directors or advisory committees; Israeli CML Patient Organisation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Other: Institutional grant; AbbVie: Consultancy, Other: Institutional Grant; Amgen: Consultancy, Other: Institutional grant; Bristol Mayers Squibb: Consultancy, Other: Institutional Grant; Celgene: Consultancy, Other: Institutional Grant; AOP Orphan: Other: Institutional grant; CTI: Other: Institutional grant; Medison: Other; Roche: Other; Jansseb: Other; Pfizer: Consultancy, Other; Takeda: Other; Gilead: Other. Feine:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment. Leef:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment. Ben Zvi:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment. Shavit:6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment.