Novartis Pharma AG Research Articles

Study design: Development of an advanced machine learning algorithm for the early diagnosis of Gaucher disease using real-world data

Background: Gaucher disease (GD) is a rare, autosomal recessive condition, characterized by deficiency of the lysosomal enzyme β-glucocerebrosidase. The main disease features are anemia, thrombocytopenia, hepato-splenomegaly and bone infarction, osteonecrosis, and pathological fractures. However, diagnosis of GD can be challenging, especially for non-specialists, owing to wide variability in age at presentation, non-specific features, severity and type of clinical manifestations, and lack of awareness of the early signs and symptoms of the disease. Delayed and misdiagnosis of GD may lead to irreversible bone disease, severe growth retardation, and high risk of bleeding; in rare cases, misdiagnosis may be life-threatening. Developing a system for early and accurate diagnosis of GD is thus an essential unmet need. The development of an algorithm for early diagnosis of patients with rare diseases such as GD may help reduce delays in diagnosis and enable prompt, appropriate initiation of therapy, earlier decision-making, prevent potentially irreversible morbidities and unnecessary tests (some invasive), reduce anxiety, and facilitate genetic counseling. This study aims to develop a predictive model for the accurate diagnosis of GD using machine learning based on real-world clinical data. Methods: This study will be comprised of three parts. Part 1, a retrospective observational database analysis, will use data from the electronic patient database of the Maccabi Healthcare Service (MHS), the second largest Health Maintenance Organization in Israel. The MHS includes 2.2 million health records from 25% of the Israeli population. Clinical records have been fully computerized for >20 years and are fully integrated with automated central laboratory, digitized imaging and pharmacy purchase data. Patients with confirmed GD who have been enrolled in the MHS health plan for ≥1 year will be eligible for inclusion, with approximately 250 patients with GD expected to be enrolled. Using MHS data from patients with GD, the Gaucher Earlier Diagnosis Consensus (GED-C) scoring system, developed by a consensus panel using Delphi methodology on the signs and co-variables that may be important for the diagnosis of GD, will be evaluated and compared with alternative scores developed directly from clinical data based on supervised machine learning. In Part 2, a clinical study, the best performing modeled scores from Part 1 will be applied to the MHS database to identify individuals who may have undiagnosed GD (‘GD suspects‘). Samples for diagnostic testing (using a specific and sensitive biomarker (glucosylsphingosine, lyso-Gb1) followed by beta-glucocerebrosidase (GBA) genotyping for positive samples) will be collected from MHS biobank (for individuals who have consented). Individuals not participating in the biobank will be asked to provide a sample. This part of the study will evaluate the predictive value of the modeled scores, and assess the sensitivity and specificity of the model for the diagnosis of new patients with GD. In Part 3, analysis of data from newly diagnosed patients identified in Part 2 will be used to develop machine learning models for the diagnosis of GD (Figure 1). Signs and co-variables included in the GED-C score will be used, eliminating features that are non-informative. Features will be quantitative where possible, and interaction terms will be added for age of onset and trend for key features. A number of methods will be developed, with the best performing, based on its precision at a given sensitivity level, being selected as the final model. External validation of the best identified model is planned, to ensure unbiased estimate of the model's accuracy. Discussion: The main goal of the study is to develop an algorithm to help detect patients with GD, independent of physicians' ability to recognize signs and symptoms, using the application of machine learning to data from a large health database. The study is expected to result in a practical tool that will alert physicians to the possibility of GD. The resulting model will also improve our understanding of GD based on the relative importance of features for GD prediction. Such tools will have a positive impact on patient care and quality of life and on healthcare costs and may lead to a change in approach for diagnosing rare diseases. Download : Download high-res image (323KB) Download : Download full-size image Disclosures Revel-Vilk: Takeda: Honoraria; sanofi-Genzyme: Honoraria; Pfizer: Honoraria. Chodick: Novartis Pharma AG: Other: Institutional grant. Gadir: Takeda: Current Employment.

Factors Impacting Managed Access/Compassionate Use of Therapeutic Products in Countries

Background: Managed Access/Expanded Access/Compassionate Use offers a mechanism of access to a locally unapproved or unavailable product outside of a clinical trial, subject to specific access criteria and local regulations. There is significant variation in the regulations and requirements for Managed Access across countries, with varying levels of awareness and usage by patients and HCPs. Methods: We analyzed Novartis Managed Access request activity between January 01, 2018 and December 31, 2020. For countries with request activity during this three-year period, we investigated, aggregated, and compared select country factors to identify potential causal links, which might explain the trends observed. The factors evaluated included public availability of local regulations, robustness of local regulations (using an eight-factor regulatory framework), clinical trial activity, and select macroeconomic factors. Findings: During the 36-month observation period, a total of 31,712 Managed Access requests were received from 111 countries. About 73% (23,194) of these requests came from 10 countries. Approximately 94% of the requests (29,871) came from countries that had publicly available Managed Access regulations on the internet. In addition, the presence of the eight-factor regulatory framework we posited was a useful indicator of the robustness of a country’s Managed Access regulations, as observed in countries with the highest request rates. Overall, countries conducting more clinical trials on average had higher request rates, with a correlation observed between a country’s economic development and its Managed Access activity. Interpretation: Regulatory robustness, public availability of regulations, as well as local clinical trial activity, correlated positively with higher levels of Managed Access requests activity. This analysis was limited to a single company’s Managed Access dataset and should be supplemented by access to and analysis of other comparable experience across the industry to confirm our initial observations reported here. Funding: Novartis Pharma AG Declaration of Interest: PA, SS, RR, ES, MS, SPK, and SNR are employees of Novartis and PA, SS, RR, ES, and SNR own company shares. PF is an employee of the GE2P2 Global Foundation and GE2P2 Global Advisory Services pbc, which provides bioethics advisory services to Novartis Pharma AG.

Increasing Use of Compassionate Use/Managed Access Channels to Obtain Medicines for Use in COVID-19.

The COVID-19 pandemic has triggered an extensive need for new therapeutics and there has been widespread use of unapproved/repurposed medicines. Several countries have regulations for access to unapproved medicines, known as compassionate use, managed/expanded access or emergency use. The Novartis Managed Access activity for COVID-19 delivered unapproved/repurposed medicines to nearly 6,000 patients over a 6-month period. With the rapid growth of such access mechanisms to address COVID-19, a better understanding of these channels is required.

Comparative Study cf Biosimilar Genolar® Clinical Efficacy оп the Randomized Phase III Study Results

There are results of a comparative phase III clinical study on the efficiency and safety of the biosimilar drug Genolar® (Generium JSC, Russia) and the reference drug Xolair® (Novartis Pharma AG, Switzerland) ((NCT04607629). The study is aimed to establish the clinical equivalence of the compared drugs for additional therapy of patients with moderate and severe bronchial asthma (BA) are considered in the article. Methods. The study enrolled 191 patients aged 18 to 75 years with a moderate to severe atopic asthma for ≥ 1 year, the symptoms of which were insufficiently controlled by therapy corresponding to the 4 th stage of treatment (GINA, 2017) for ≥ 2 months before the screening. Patients were divided into the two groups in a ratio of 2 : 1 with the block randomization. 127 patients of the Group 1 were administered Genolar® for 52 weeks ± 3 days; 64 patients of the Group 2 were administered Xolair® for 26 weeks ± 3 days. The dose and frequency of the compared drugs administration were determined based both the initial IgE concentration (IU/mL) measured before treatment and the current body weight (kg) of the patient. The recommended omal-izumab dose was 75 to 600 mg once every 2 or 4 weeks. The primary efficacy endpoint was the patients’ percentage with a physician evaluation of “excellent” or “good” on the Global Evaluation of Treatment Effectiveness (GETE) scale after 26 weeks of comparative treatment. Results. According to the data analysis results, the patients’ proportion with a GETE score of “excellent” or “good” after 26 weeks of therapy were no statistically significant differences between the groups in both investigated populations (PP-population (per protocol) and FAS-population (full analyses set)) (p > 0.05). Primary efficacy endpoint data analysis showed that the patients’ proportion of the PP population with a GETE score of “excellent” or “good” was 57.4% of the Group 1 and 45.2% of the Group 2 (p = 0.132). The calculated one-sided 95% CI in order to test the study statistical hypothesis showed that the investigated drug Genolar® (Generium JSC, Russia) is “non-inferior” than the reference drug. The PP population onesided 95% CI was from -0.5 to 25.0% (p = 0.116), the FAS population one was from -1.1 to 24.2% (p = 0.134). According to the safety analysis results, the comparability of the investigated and reference drugs in terms of the frequency of the adverse events was demonstrated. The analysis results of the anti-drug antibodies to omalizumab detection revealed the antibody production absence in response to the administration of the studied drugs. Conclusion. The clinical study results have proved the equivalence of the biological analogue Genolar® (Generium JSC, Russia) and the reference drug Xolair® (Novartis Pharma AG, Switzerland).

Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs

Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs

Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion–Related Events with Brolucizumab: Post Hoc Review of HAWK and HARRIER

An independent Safety Review Committee (SRC), supported by Novartis Pharma AG, analyzed investigator-reported cases of intraocular inflammation (IOI), endophthalmitis, and retinal arterial occlusion in the phase 3 HAWK and HARRIER trials of brolucizumab versus aflibercept in neovascular age-related macular degeneration (nAMD). A post hoc analysis of a subset of data from two 2-year, double-masked, multicenter, active-controlled randomized phase 3 trials (NCT02307682, NCT02434328). Patients (N= 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye were randomized and treated in HAWK/HARRIER. The SRC reviewed data from cases of investigator-reported IOI (60/1088 brolucizumab-treated eyes; 8/729 aflibercept-treated eyes). The SRC received details and images (color fundus photography, fluorescein angiography, and OCT) for all investigator-determined cases of IOI, retinal arterial occlusion, and endophthalmitis. Cases were reviewed in detail by ≥2 readers, then adjudicated by the SRC as a group. Within this patient subset: incidence of IOI, signs and incidence of retinal vasculitis and/or retinal vascular occlusion, and visual acuity loss; time since first brolucizumab injection to IOI event onset; and frequency of visual acuity loss after brolucizumab injection by time of first IOI event onset. Fifty brolucizumab-treated eyes were considered to have definite/probable drug-related events within the spectrum of IOI, retinal vasculitis, and/or vascular occlusion. On the basis of these cases, incidence of definite/probable IOI was 4.6% (IOI+ vasculitis, 3.3%; IOI+ vasculitis+ occlusion, 2.1%). There were 8 cases (incidence 0.74%) of at least moderate visual acuity loss (≥15 ETDRS letters) in eyes with IOI (7 in eyes with IOI+ vasculitis+ occlusion). Of the 8 cases, 5 experienced their first IOI-related event within 3 months of the first brolucizumab injection (increasing to 7/8 within 6 months). Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual acuity loss in 0.14%. This analysis of IOI cases after brolucizumab injection identified signs of retinal vasculitis with or without retinal vascular occlusion and an associated risk of visual acuity loss. The findings will help physicians to evaluate the risks and benefits of brolucizumab treatment for nAMD.

Clinical & Economic Implications of Hydroxyurea Intolerance in Polycythemia Vera in Routine Clinical Practice in Israel

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<0.001). Progression to MF occurred in 28% versus 5% (p<0.001), and progression to AML occurred in 6% compared with 1% (p<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<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<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.

Structural and Biochemical Studies Confirming the Mechanism of Action of Asciminib, an Agent Specifically Targeting the ABL Myristoyl Pocket (STAMP)

Tyrosine kinase inhibitors (TKIs) that inhibit the transphosphorylation activity of the BCR-ABL1 oncoprotein by binding the ATP-binding site of the catalytic domain of protein kinases are well established as being effective drugs for the treatments of chronic myeloid leukemia (CML). However, the off-target kinase activities of these non-specific TKIs are associated with adverse events that can limit their suitability for the treatment of patients and can negatively impact quality of life. Therefore, a new drug combining high efficacy with minimal side-effects could provide substantial therapeutic advantages. Asciminib is a new investigational agent that at concentrations <10 micromolar has very little effect (residual activities ≥66%) on the transphosphorylation activity of a large panel comprising of 335wild-typeprotein kinases (including ABL1 and ABL2). In this study (33PanQinase® Activity Assay, ProQinase GmbH, Freiburg, Germany) the radiometric kinase assay employed recombinant kinase constructs of the catalytic domains including the ATP-binding site. However, in isothermal calorimetry studies asciminib showed strong binding affinity (KD 0.5 nM) to a much larger construct ofwild-typeABL1 that contains the catalytic, SH2 and SH3 domains (residues 46-534, ABL46-534), with thermodynamic parameters (ΔH = -72.8 kJ/mol, ΔS = -65.3 J/mol/K, resulting in ΔG = -53.2 kJ/mol) indicating strong enthalpy-driven, entropically unfavorable binding. This binding translates to inhibition of tyrosine phosphorylation catalysed by the ABL64-515 construct with a mean IC50 value of 2.6 ± 0.8 nM (radiometric filter binding assay) and 0.5 ± 0.1 nM (fluorescence resonance energy transfer assay). This data shows that asciminib inhibits the kinase activity of ABL1 by an allosteric mechanism which does not involve direct interaction with the ATP-binding pocket. X-ray crystallographic studies of a ternary complex between asciminib, nilotinib and the ABL146-534 protein possessing Thr315Ile and Asp382Asn substitutions show that asciminib binds to ABL1 in a deep-pocket on the C-lobe of the kinase domain, referred to as the myristate (or myristoyl) pocket. Nuclear magnetic resonance studies confirm that asciminib can also form asciminib-ABL1-TKI ternary complexes with thewild-typeABL83-534 protein in solution. Native ABL1 kinase is post-translationally myristoylated at the N-terminal glycine residue and this myristate group plays an important role in autoregulating the kinase by binding to a pocket (myristate pocket) on the catalytic domain of the protein to induce the formation of an inactive conformation of the enzyme. This regulatory mechanism is lost in BCR-ABL1 since the N-terminal region is replaced in the fusion protein with a fragment of the BCR protein, thus rendering the ABL1 kinase constitutively active. The binding of asciminib in this pocket therefore mimics that of myristate, thus stabilizing the inactive state of the ABL1 kinase. Consistent with this binding mode to the ABL1 kinase, asciminib potently inhibits BCR-ABL1 driven proliferation of leukemia-derived cell lines, while having little effect on cells that do not express BCR-ABL1 (Figure 1). Thein vitrodata translates into anti-tumor activity in mouse models of CML where asciminib dose-dependently inhibited the growth of subcutaneous KCL22 cell xenografts, with 30 mg/kg administered twice-daily by oral gavage affording 92% tumor regression (Figure 2). Asciminib, the first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, has several important features as a potential treatment of CML. At physiologically achievable concentrations asciminib can overcome mutations on the ATP-binding site of BCR-ABL1 that impede the binding of TKIs which lead to drug resistance in patients with CML. Secondly, by not inhibiting kinases such as EGFR, KIT, CSF1R, PDGFR or the sSRC-family kinases that are associated with off-target activities of TKIs such as bosutinib, dasatinib, imatinib, nilotinib and ponatinib, asciminib is not expected to be associated with cross-intolerance. Thirdly, asciminib can bind to the ABL1 kinase domain together with ATP-competitive TKIs to form ternary complexes, such that appropriate drug combinations should greatly impede the emergence of drug resistant kinase mutations. Disclosures Schuld: Novartis Pharma AG:Current Employment, Current equity holder in publicly-traded company.Grzesiek:Novartis Pharma:Research Funding.Jahnke:Novartis:Current Employment, Current equity holder in publicly-traded company, Patents & Royalties, Research Funding.Barys:Novartis Pharma AG:Current Employment.Cowan-Jacob:Novartis Pharma AG:Current Employment.Loo:Novartis Pharma AG:Current Employment.Wiget:Novartis Pharma AG:Current Employment.Manley:Novartis Pharma AG:Current Employment.

Adore: A Randomized, Open-Label, Phase 1/2 Open-Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Patients with Myelofibrosis

Adore: A Randomized, Open-Label, Phase 1/2 Open-Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Patients with Myelofibrosis

A Patient-Centric Approach to Improve the Understanding of Sickle Cell Disease Using Real-World Data

Background: Sickle cell disease (SCD) comprises a group of inherited blood disorders, and is a complex, multi-system, disease. SCD is associated with a variety of clinical complications that affect multiple organ systems. These complications are driven primarily by vaso-occlusion and hemolytic anemia, and can result in end-organ damage and early death. Painful vaso-occlusive crises (VOCs) are a characteristic feature of SCD and can require healthcare intervention. Despite recent advances in the screening, management and treatment of SCD, gaps remain in our understanding of the disease in the real-world setting. These include how best to transition from pediatric to adult care and how to manage specific complications. Currently, most real-world evidence (RWE) is generated from information captured in payer databases, which is not as comprehensive as the information recorded in electronic medical records (EMRs). Despite being potentially valuable sources of real-world, clinical information, EMRs for individual patients in the USA are not centralized, often being held by multiple healthcare providers using different EMRs. This fragmented system prevents generation of clear, comprehensive RWE, both in general and for SCD specifically. Furthermore, there is a lack of harmonization between EMR companies/systems in the types of information included and how it's recorded. A separate approach that collates all available data from EMRs into a single, comprehensive record prior to RWE analysis would therefore greatly improve the accessibility of the available information and the quality of subsequent data analysis. Aims: In contrast to existing RWE, this study explores the value of collating EMRs for each patient into a single, consistently structured format, with the aim of developing richer RWE to complement existing data on SCD. It is hypothesized that the resulting longitudinal overview of each patient's care will contribute to an improved understanding of SCD in the real-world setting: firstly, by better capturing how many VOCs patients with SCD experience, with an indication of the proportion of VOCs that are being home-managed; secondly, by gaining deeper insights into the prevalence and progression of end-organ damage and any association with VOCs; and finally, by highlighting the type and site of care of SCD in the real world (eg medications, treating healthcare professional [HCP] specialties and the type of clinic visited). Study design: The study population will comprise 400 patients with SCD from the USA. Patient recruitment occurs directly via social media and indirectly through a variety of partnerships including HCPs and patient advocacy groups. To enroll, patients sign an informed consent form allowing their de-identified medical information to be shared with third-party organizations to advance SCD research. Enrolled patients gain access to their medical records via a dashboard. The key inclusion criteria are: a confirmed SCD diagnosis (irrespective of phenotype); aged ≥16 years at enrollment; and ≥1 inpatient admission for a VOC in the 12 months prior to enrollment. The key exclusion criterion is the absence of medical records. Components of EMRs collected include doctors' notes, laboratory and test results, clinical imaging and treatment records. Human-curated natural language processing and machine learning is used to extract, structure and code data from the structured sections and unstructured narrative text of the EMR. All medical records, from all visits, will be collected where possible and are expected to comprise ≥7 years of retrospective data for each patient. Results: Between 1 December 2019 and 24 June 2020, a total of 46 patients with a mean age of 36 years (SD 9.7) were enrolled. For each patient, a median of 6.8 years of data from a median of 32.5 providers were obtained. Conclusions: The evidence derived from this study aims to advance the understanding of real-world practices in the management of SCD. It may also provide further learnings regarding the prevalence of complications and any association between VOCs and end-organ damage. Generating a single, structured overview of all EMRs for each patient allows for richer insight generation and a more comprehensive analysis of RWE, compared with existing approaches. The insights gained from this RWE may inform future studies and clinical trials in SCD, with the ultimate aim of improving the quality of life of patients. Disclosures Clay: Novartis: Consultancy; GBT: Consultancy. Bailey:Novartis Pharmaceuticals Corporation: Current Employment. Drozd:F. Hoffmann-La Roche Ltd: Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; PicnicHealth: Current Employment, Current equity holder in private company. Paulose:Novartis Pharma AG: Current Employment. Ramscar:Novartis Pharma AG: Current Employment. Mace:Roche/Genentech: Ended employment in the past 24 months; PicnicHealth: Current Employment. Wormser:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company.

Experiences and Support Needs of Caregivers of Patients with Higher-Risk MDS: Qualitative Insights Via Online Bulletin Board in the US, UK, and Canada

Higher-risk MDS patients and caregivers can face many challenges in the course of the disease and disease management. Patients with advanced cancer and their caregivers can both experience physical, emotional, social, spiritual, and functional issues. Research on the burden of caring for advanced cancer patients suggest that there is insufficient support for caregivers, which might be due to the lack of knowledge about their needs and burdens (Friðriksdóttir et al. 2011; Chambers et al. 2012; Sklenarova et al. 2015). The overall experience of caregivers for MDS patients has not been evaluated to date. Our key research questions are related to: Caregiver role before, during, and after diagnosis; and along the disease journeyImpact on the caregiver's life and well-being; consequently their areas of need for supportImpact of decisions made, including treatments We used the online bulletin board (OBB) as the qualitative research methodology for this research. OBB enables data collection via a web-based platform. This innovative type of online focus group, can generate more meaningful and impactful insights compared to traditional focus groups (Reid et al. 2005). A mix of moderator-led Q&A and participant discussion will provide the caregiver insights as online dialogue. OBB is especially advantageous when participants are located in various geographic locations, time zones, and with differing availabilities (Rolland et al. 2013; Nyumba et al. 2018). This methodology will guide the caregiver discussions, optimize the gathering of caregiver insights, and facilitate interactive activities, including appropriate probes and follow up questions. Since it would be challenging to identify caregivers of higher-risk MDS patients, the research uses convenience sampling with the support of patient organizations. Fifteen participants were targeted for recruitment by patient organizations in their respective countries - Myelodysplastic Syndromes (MDS) Foundation in the US, Aplastic Anemia & Myelodysplasia Association of Canada, and MDS UK Support Group - through outreach to their membership. Participants were to be selected based on the inclusion and exclusion criteria, with additional screening by the researchers. Inclusion criteria Caregiver of patient diagnosed with high or very high risk MDS as diagnosed per IPSS-R category or high-risk MDS as per IPSS (intermediate-risk patients on hypomethylating agents (HMAs) will be considered only if it is challenging to recruit caregivers of high and higher-risk patients) Aged 18+ Able to communicate in written English Caregiver is able to provide consent to participate in research Exclusion criteria Caregiver of patient diagnosed with low or very low risk MDS as diagnosed per IPSS-R category or low-risk as per IPSS Caregiver of patients currently active in a clinical trial Paid caregiver who is a nurse or aide We present in this abstract an interim report of the research, which is still ongoing. A total of 16 caregivers participated in the OBB with additional recruitment to cover any potential drop outs or withdrawals - 5 from the US, 6 from the UK, and 5 from Canada. There are 14 female and 2 male caregivers whereby 13 are spouses of the patient, 2 are children of the patient, and 1 is a friend of the patient. Full content analysis will be conducted at the completion of the research. However the interim findings already indicate there are unmet patient and caregiver needs in higher-risk MDS. For example, although the caregiver role for more recently diagnosed patients (≤ 1 year) is perceived as minimal effort, their role increases significantly if a stem cell or bone marrow transplant occurs, and/or if there are changes in the patient's health status (e.g. infection, medication change, managing side effects like nausea). The implications of this vary depending on the personal situation of the caregiver - the ability to continue in any employment and financial consequences if not; the demand on their time if they are balancing family and other commitments; and the impact on their own health particularly if they have their own health issues to manage. Most caregivers can manage the physical and functional aspects of care, however, many state that the bigger unmet need for both patient and caregiver is emotional support, which has not typically been part of the standard of care provided to MDS patients. Disclosures Frank: Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Sasse:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company.

Pharmacokinetics/Pharmacodynamics, Safety and Efficacy of Crizanlizumab in Patients with Sickle Cell Disease and a History of Vaso-Occlusive Crises: Results from the Phase II, Multicenter, Open-Label Solace-Adults Study

Pharmacokinetics/Pharmacodynamics, Safety and Efficacy of Crizanlizumab in Patients with Sickle Cell Disease and a History of Vaso-Occlusive Crises: Results from the Phase II, Multicenter, Open-Label Solace-Adults Study

A Novel Therapy-Resistance Transcriptional Signature Based on Single Cell Analysis in Kydar Clinical Trial

Substantial progress in the treatment of Multiple Myeloma (MM) extends survival for many patients (Pts), though most Pts eventually relapse and become therapy refractory. Patients with induction resistant multiple myeloma (IRMM), either primary refractory or early (≤18 months) relapse, have a particularly compromised survival. New treatment strategies and molecular biomarkers for patient stratification and effective clinical care are needed. We previously reported outcomes of KYDAR (NCT04065789) single-arm prospective clinical trial, in which pts primary resistant to a bortezomib-based induction achieved high rates of durable responses when treated with carfilzomib/daratumumab/lenalidomide/dexamethasone (Cohen YC et al. Blood (2019) 134 (Suppl 1): 982). We applied comprehensive single cell RNA-seq analysis of plasma cells (PCs) obtained from longitudinal bone marrow aspirate samples, taken from KYDAR participants (n=34), compared to newly diagnosed MM Pts (n=15) and to healthy controls (n=11). We discovered a novel MM resistance signature differentially expressed between IRMM and newly diagnosed MM groups. This "gene module is enriched for several pathways that were perturbed in the IRMM Pts, including mitochondrial stress genes, the ER and UPR pathway, and the proteasome machinery. Furthermore, differential gene expression analysis between KYDAR responders and non-responders unveil potentially druggable escape mechanisms. These include upregulation of genes associated with immune regulation, proteasome, apoptotic and ER-stress pathways, e.g. Cyclophilin A (PPIA) creating an elaborated signature and potential target list of pathways and escape mechanisms from a highly potent quadruple therapy. This signature includes many novel genes which were not previously described in the context of MM (Fig 1A). Here we report external validation of this novel resistance signature among 908 MM Pts in the MMRF CoMMpass dataset. We found that our genes signature expression follows a normal distribution with no apparent sub-populations in naïve patients, but when examining Pts after multiple relapses, we detected gradient increase in our signature with a clear bi-model distribution (Fig. 1B). The prevalence of high module-1 expression was 5% in newly diagnosed Pts vs 14% in Pts in 3rd or subsequent relapse (p<0.001). Survival analysis on MMRF "module 1 high" (module 1 score > 200) Pts (n = 68) compared with the rest of the population (n = 711) revealed a striking hazard-ratio of 3.9 (2.22 - 6.87) with p-value = 4.57x10-17 (Fig 1C). Module-1 was highly predictive of treatment outcome in KYDAR trials, beyond FISH cytogenetics (Fig 1D). We hypothesized that PPIA may function as a protective resistance gene in MM malignant cells, by accelerating protein folding pathways and reducing stress associated to proteasome inhibitors. In order to test whether PPIA is merely a marker for highly resistant patients or has a causal role in MM resistance to proteasome inhibitors, we used Cyclosporine A (CsA), a known inhibitor of PPIA, in a series of in vitro experiments, to explore it's potential synergy with carfilzomib, a proteasome inhibitor, on RPMI-8226 and U266B MM cell lines, expressing high levels of PPIA. Using MTS proliferation assay, we found that the combined CsA and carfilzomib therapy was significantly more effective than carfilzomib alone. Apoptosis as measured by Propidium Iodide, DAPI and Annexin V FITC staining, was dramatically increased in the combination therapy setting compared to carfilzomib or CsA monotherapy (Fig 1E). In summary, our study defines a roadmap for combining single cell RNA-seq profiling with clinical trials. We reveal and externally-validate a novel transcriptional signature for therapy resistance. We show inhibition of PPIA, a potential target identified, by CsA, overcomes relative resistance of MM cell lines to carfilzomib. We anticipate that such studies will significantly improve the ability to define mechanism of action of treatment, molecularly characterize the Pts that may benefit from the treatment, and reveal potential novel targets. Disclosures 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.

Study Design: Development of an Advanced Machine Learning Algorithm for the Early Diagnosis of Gaucher Disease Using Real-World Data

Background: Gaucher disease (GD) is a rare, autosomal recessive condition, characterized by deficiency of the lysosomal enzyme β-glucocerebrosidase. The main disease features are anemia, thrombocytopenia, hepato-splenomegaly and bone infarction, osteonecrosis, and pathological fractures. However, diagnosis of GD can be challenging, especially for non-specialists, owing to wide variability in age at presentation, non-specific features, severity and type of clinical manifestations, and lack of awareness of the early signs and symptoms of the disease. Delayed and misdiagnosis of GD may lead to irreversible bone disease, severe growth retardation, and high risk of bleeding; in rare cases, misdiagnosis may be life-threatening. Developing a system for early and accurate diagnosis of GD is thus an essential unmet need. The development of an algorithm for early diagnosis of patients with rare diseases such as GD may help reduce delays in diagnosis and enable prompt, appropriate initiation of therapy, earlier decision-making, prevent potentially irreversible morbidities and unnecessary tests (some invasive), reduce anxiety, and facilitate genetic counseling. This study aims to develop a predictive model for the accurate diagnosis of GD using machine learning based on real-world clinical data. Methods: This study will be comprised of three parts. Part 1, a retrospective observational database analysis, will use data from the electronic patient database of the Maccabi Healthcare Service (MHS), the second largest Health Maintenance Organization in Israel. The MHS includes 2.2 million health records from 25% of the Israeli population. Clinical records have been fully computerized for >20 years and are fully integrated with automated central laboratory, digitized imaging and pharmacy purchase data. Patients with confirmed GD who have been enrolled in the MHS health plan for ≥1 year will be eligible for inclusion, with approximately 250 patients with GD expected to be enrolled. Using MHS data from patients with GD, the Gaucher Earlier Diagnosis Consensus (GED-C) scoring system, developed by a consensus panel using Delphi methodology on the signs and co-variables that may be important for the diagnosis of GD, will be evaluated and compared with alternative scores developed directly from clinical data based on supervised machine learning. In Part 2, a clinical study, the best performing modeled scores from Part 1 will be applied to the MHS database to identify individuals who may have undiagnosed GD ('GD suspects'). Samples for diagnostic testing (using a specific and sensitive biomarker (glucosylsphingosine, lyso-Gb1) followed by beta-glucocerebrosidase (GBA) genotyping for positive samples) will be collected from MHS biobank (for individuals who have consented). Individuals not participating in the biobank will be asked to provide a sample. This part of the study will evaluate the predictive value of the modeled scores, and assess the sensitivity and specificity of the model for the diagnosis of new patients with GD. In Part 3, analysis of data from newly diagnosed patients identified in Part 2 will be used to develop machine learning models for the diagnosis of GD (Figure 1). Signs and co-variables included in the GED-C score will be used, eliminating features that are non-informative. Features will be quantitative where possible, and interaction terms will be added for age of onset and trend for key features. A number of methods will be developed, with the best performing, based on its precision at a given sensitivity level, being selected as the final model. External validation of the best identified model is planned, to ensure unbiased estimate of the model's accuracy. Discussion: The main goal of the study is to develop an algorithm to help detect patients with GD, independent of physicians' ability to recognize signs and symptoms, using the application of machine learning to data from a large health database. The study is expected to result in a practical tool that will alert physicians to the possibility of GD. The resulting model will also improve our understanding of GD based on the relative importance of features for GD prediction. Such tools will have a positive impact on patient care and quality of life and on healthcare costs and may lead to a change in approach for diagnosing rare diseases. Disclosures Revel-Vilk: Takeda: Honoraria; sanofi-Genzyme: Honoraria; Pfizer: Honoraria. Chodick:Novartis Pharma AG: Other: Institutional grant. Gadir:Takeda: Current Employment.

Outcome By Mutation Status and Line of Treatment in Optic, a Dose-Ranging Study of 3 Starting Doses of Ponatinib in Patients with CP-CML

Outcome By Mutation Status and Line of Treatment in Optic, a Dose-Ranging Study of 3 Starting Doses of Ponatinib in Patients with CP-CML

The Final Analysis of Expand: A Phase 1b, Open-Label, Dose-Finding Study of Ruxolitinib (RUX) in Patients (pts) with Myelofibrosis (MF) and Low Platelet (PLT) Count (50 × 109/L to < 100 × 109/L) at Baseline

The Final Analysis of Expand: A Phase 1b, Open-Label, Dose-Finding Study of Ruxolitinib (RUX) in Patients (pts) with Myelofibrosis (MF) and Low Platelet (PLT) Count (50 × 109/L to < 100 × 109/L) at Baseline

Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients with Steroid-Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study

Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients with Steroid-Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study

Efficacy and Safety of Front-Line Nilotinib Treatment and Discontinuation in Older Patients (≥65 years) with Chronic Myeloid Leukemia in Chronic Phase Who Have Achieved MR4.5: Results from ENESTfreedom

Efficacy and Safety of Front-Line Nilotinib Treatment and Discontinuation in Older Patients (≥65 years) with Chronic Myeloid Leukemia in Chronic Phase Who Have Achieved MR4.5: Results from ENESTfreedom

The Effect of Crizanlizumab on the Number of Days Requiring Opioid Use for Management of Pain Associated with Vaso-Occlusive Crises in Patients with Sickle Cell Disease: Results from the Sustain Trial

The Effect of Crizanlizumab on the Number of Days Requiring Opioid Use for Management of Pain Associated with Vaso-Occlusive Crises in Patients with Sickle Cell Disease: Results from the Sustain Trial

A Systematic Literature Review of the Burden of Central Nervous System Complications for Patients with Sickle Cell Disease

INTRODUCTION: Sickle cell disease (SCD), a complex genetic blood disorder involving multicellular interactions between blood and endothelial cells, is often accompanied by central nervous system (CNS) complications. Effects range from silent cerebral infarct (SCI) to abnormal blood flow, and consequent overt stroke. This study assessed the humanistic and economic burden associated with CNS complications in patients with SCD and identified patient-reported outcome (PRO) instruments for future research. METHODS: MEDLINE, Embase, Cochrane CENTRAL/CDSR and 11 congresses were searched to identify English language studies published from January 2000 to May 2020 and screened with predefined criteria by two independent researchers. Clinical trials (CT) or observational studies assessing humanistic burden, economic burden, or instruments used to measure burden in patients with SCD and CNS complications (N≥15) were included. Humanistic burden was broadly defined to include quality of life (QoL), symptoms and function. RESULTS: Of the 3194 articles identified, 34 were included. Study designs were 29% retrospective observational (10/34), 29% cross-sectional (10), 26% prospective (9), 9% randomized CT (3), and 6% systematic reviews (2). Study size varied widely (16-4,485 patients with SCD and CNS complications). 77% (26) focused on pediatric patients. Separately, 77% (26) were in a US setting. Overt stroke (12), stroke and SCI (11), or SCI only (7) were the most frequently described CNS complications. Twenty-five studies reported on humanistic burden, 18 of which measured cognitive function using the Wechsler Intelligence Scales. A significant decrease was reported in full scale (FS) (stroke vs. no stroke: 73.5 vs. 84.7; P=.04), verbal (abnormal vs. normal MRI: 74.1 vs. 84.6; P=.02), and performance IQ (stroke vs. no stroke: 69.5 vs. 81.5; P=.02) for patients with overt strokes or SCI compared to non-stroke SCD controls. Greater impairment was reported for overt stroke compared with SCI (multivariate meta-analysis of mean IQ difference: -10.3; P=.0013). In addition to stroke/SCI, socio-environmental factors (i.e., family income level, lack of college education) were significantly associated with a decrease in IQ (P=.005 and P=.023, respectively). Five studies assessed motor function, reporting significantly impaired function for patients with stroke compared to non-stroke SCD controls (Purdue Pegboard both hands: 7.5 vs. 10.1; P=.0001). Among children with SCD who had experienced their first stroke, those receiving hydroxyurea (HU) for prevention of recurrent stroke had significantly less moderate to severe motor disability (physician assessed) than children not receiving HU (23.1 vs. 88.9%; P&amp;lt;.001). Nine studies reported economic outcomes related to healthcare resource use (HCRU) (8) and direct costs (5). HCRU and cost to manage CNS complications are high, with a median LOS of 5 days (IQR 3-9) and median hospitalization charges of $18,956 (2012 USD) for patients with SCD and stroke. Treatment costs were also substantial in patients with SCI, with annual transfusion plus chelation costs ranging between $18,149 and $67,361/year (2016 USD). No studies reported indirect costs. While many studies used clinician-administered performance outcome (PerfO) measures such as the Wechsler Scales, only 1 study employed a PRO instrument: the Children's Depression Index. In addition to the Wechsler Scales, PerfO measures of cognitive function included the Woodcock-Johnson Psychoeducational Battery (6 studies), Children's Memory Scale (4), and California Verbal Learning Test for Children (4). CONCLUSIONS: This systematic review found that SCD patients with CNS complications often experience diminished cognitive/motor function and incur substantial costs. In particular, the mean FSIQ for SCD patients with stroke and SCI was reported to be 'extremely low' to 'low' (65.9 to 83.6) and 'low' to 'average' (77.2 to 95.9), respectively across studies. The Wechsler Scales were the most commonly used PerfO measure of cognitive function, while use of disease-specific PRO instruments was extremely limited. Given that the majority of published data focuses on children, future research is needed to evaluate the burden of disease for SCD adults with CNS complications, and to assess patient perspectives and QoL to better quantify aspects of burden beyond cognitive performance. Disclosures Lee: Novartis Pharmaceuticals Corporation: Current Employment. Nellesen:Analysis Group, Inc.: Consultancy. Lucas:Analysis Group, Inc.: Consultancy. Paulose:Novartis Pharma AG: Current Employment.