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speaker notes ORDER NOW FOR CUSTOMIZED AND ORIGINAL ESSAY PAPERS ON speaker notes I need detailed speaker notes for each slide. Use the references to further elaborate. please keep in mind this is a scientific presentation and not a low grade school presentation. provide details from references.speaker notes attachment_1 DRUG: KYMRIAH (TISAGENLECLEUCEL) MANUFACTURER: NOVARTIS INTERNATIONAL AG LOCATION: BASEL, SWITZERLAND DISEASES/DISORDERS TREATED ? Tisagenlecleucel is the real name of the drug but it is marketed as KYMRIAH (Pharma US, 2017). ? It is used to treat the B-cell acute lymphoblastic leukemia cancer (B-cell all). ? In regard to mechanism of action, KYMRIAH reprograms the T-cells of a patient with transgene encoding of chimeric antigen receptor (CAR). ? The CAR then identifies and destroy any CD19-expressing tumor, malignant or normal cells. The CAR is a single-chain antibody with the ability to recognize CD19. CAR is fused in the intracellular signaling domains – CD3 zeta and 4-1BB (CD137) (Pharma US, 2017). ? The ? The CD3 zeta is responsible for malignant destruction and initiation of T-cell activation. ? The 4-1BB enhances the sensitivity, persistence and expansion of KYMRIAH. ? Once the CD-19 expressing cell is identified, the CAR signals T-cells to expand, activate and work on the destruction of the malignant cell. PRIMARY RESEARCH ? KYMRIAH was once used in the study B2202 with 68 subjects. ? The major adverse effects noted in the study was cytokine release syndrome (CRS). ? Hemophagocytic lymphohistiocytosis (HLH) was also noted, with other side effects occurring due to CRS. ? Grade 3 and 4 CRS was noted among 32 individuals. This was 47% of the sample (Pharma US, 2017). ? CRS resulted in no deaths. ? Other neurological toxicities included delirium, ancephalopathy, seizure, hallucinations, mental status changes, cognitive disorder, dysphagia, and somnolence. ? Another study revealed that KYMRIAH increased in the body with time. ? After 28 days from infusion, KYMRIAH was found to be 44% in the patient’s bone marrow (Pharma US, 2017). ? The product was found to be 67% and 69% respectively for 3 and 6 months after infusion. INTELLECTUAL PROPERTY STATUS ? The product, KYMRIAH, is patented by Novartis and the University of Pennsylvania. ? The patent was effected in 2012. ? The CAR-T technology is patented by Memorial Sloan Kettering Cancer Center whereas the KYMRIAH technology using the CAR-T is patented by Novartis (BioPharm International, 2017). ? The product is thus independently prepared by Novartis and is patient based – based on the patient’s own T-blood cells. DEVELOPMENT GENETICS ? The safety of KYMRIAH is only ascertained among the pediatric patient and those below 25 years of age. is also no evidence whether the drug can be used for geriatric use – those above 65 years of age (Pharma US, 2017). ? There ? There is also no evidence whether KYMRIAH is present in breastfeeding milk or not. ? KYMRIAH was considered specialized for the young from a study involving 107 patients. speaker notes ? The study involved infusing 63 patients with the KYMRIAH, in which 52 of them achieved a CR/CRi which was MRD-negative. PLATFORM TECHNOLOGY ? KYMRIAH ? It is basically utilizes the antigen platform technology. uses the chimeric antigen receptor (CAR) for T cells. ? The dosage is based on the weight of the patient where those below 50kg are receive 0.2 to 5.0 *10^6 CAR positive T cells. ? Those above 50kg are given 0.1-2.5*10^8 (Pharma US, 2017). ? The KYMRIAH also utilizes the anti-CD19 chimeric antigen receptor (CAR) ? The CAR is composed of single chain antibody fragments. ? The technology also uses the anti-CD3/CD28 beads coated with antibodies. ? This is used to activate the KYMRIAH. HOST CELLS AND UPSTREAM PRODUCTION DETAILS ? The patient’s blood is first drawn using a process called “leukapheresis.” ? The main form of drawing blood is using a catheter (Pharma US, 2017). ? The magnocellular cells of the sample is then enriched for T cells. ? The next step is transducing the sample with anti-CD3/CD28 antibodies coated beads. ? The next step is to culture the T-cells and expand them (Pharma US, 2017). ? They ? The ? It are then cleaned and used to formulate a suspension. suspension is then cryopreserved and tested using sterility tests. is then stored in frozen form for easy transportation and to avoid contamination. CELL BANK SYSTEM(S) UTILIZED ? The cell bank system for KYMRIAH utilizes the DMSO solution, which helps in preserving the product until usage. ? The KYMRIAH is typically place in plastic bags, which are doubled to enhance the protection of the product from contamination and bacterial activity. ? The 10% DMSO requires that the product is thawed and diluted to avoid the side effects of DMSO, but this does not occur in KYMRIAH as it can result in negative results. DOWNSTREAM PRODUCT RECOVERY AND PURIFICATION ? After its making, KYMRIAH is frozen and stored in frozen form. ? It is stored in a patient specific bag, labeled and sealed specifically with the patient’s product. ? The product is further put inside another packaging bad and further labeled to reflect patient information (Pharma US, 2017). ? It is then transported in the frozen form to the patient. ? Upon receipt, the physician is expected to confirm whether both bags housing the product read the patient’s name and then thaw the medicine before administration. PRODUCT FORMULATION ? The product contains T cells, monocytes, B cells, and NK cells. ? It also contains Plasma Lyte A at 31.25%v/v, 5% dextrose at 31.25%, sodium chloride (Pharma US, 2017). ? It also has 10% of dextran 40 (LMD)/5% dextrose and 20% of 25% human serum albumin (HSA). ? The product also has Cryoserv dymethylsulfoxide (DMSO) at 7.5% (Pharma US, 2017). ? One single dose of KYMRIAH contains at least 2.5*10^8 CARpositive T cells. ADVANCED STRATEGIES USED (PAT, QBD, CONTINUOUS PROCESSING) ? The fact that the FDA approved KYMRIAH for use in the US healthcare sector and the EU is in the process of approving, it shows that it utilizes the best technologies for production. ? KYMRIAH uses PAT to ensure that the quality of the product is maintained and is high quality. speaker notes ? On the other hand, QBD is used to ensure that the quality of the product is maintained through production as well as during and after delivery. ? Freezing ? Packing ? It of the KYMRIAH suspension is one of the QBD strategies. the product in double patient-addressed bags is also a quality precaution. is not clear whether continuous process is used in KYMRIAH. ACTIVE SUBSTANCE TESTING, PRODUCT STABILITY, BIO-BURDEN ? Active substance testing is usually carried out to determine the specific dosage of the patient. concentration of the T-cells in comparison to the patient’s weight determines the patient’s dosage. ? The ? The product has been considered stable when in frozen form, which necessitates that it is stored in this form. ? The bio-burden associated with the product is limited by freezing the product through out its handling and delivery. ? This ensures that microorganisms including bacteria are not able to grow or be active in the environments surrounding the medicine. CLINICAL TRIALS AND FDA APPROVAL PROCESS ? The clinical trials were conducted under varying environments and conditions. ? The trial utilized 68 patients with refractory or relapsed (R/R) B-cell ALL. ? They received CAR-positive T cells. The dosage for all the patients was weight based (BioPharm International, 2017). were two categories for administering the treatment – those below 50kg and those above 50kg (Pharma US, 2017). ? There ? The major adverse side effect was Cytokine release syndrome that appeared to be 79%. Hypogammaglobulinemia occurred 43%, pyrexia occurred 40% while infections-pathogen unspecified appeared to be 41% (Pharma US, 2017). ? Eleven death were accounted for, seven were disease related and others died due to abdominal compartment syndrome and progressive leukemia. ANNUAL SALES REVENUE, MARKET SHARE ? One dose of KYMRIAH costs $475,000 (BioPharm International, 2017). ? However, Novartis have stated that they will not charge individuals who do not respond on the drug. ? Novartis have gained at least $118,750,000 from the sale of KYMRIAH since it was discovered. ? KYMRIAH has a large market share worldwide (Novartis, 2018). speaker notes ? This is based on the fact that it is the first ever CAR-T therapy and there are many patients that need the medication (Pharma US, 2017). ? The ? The drug was approved by the US FDA on 30, August 2017 (Novartis, 2018). EU is still in the process of verifying the effectiveness of KYRIAH through the European Medicines Agency (EMA). POST-MARKET RESEARCH ? The drug has been used widely and has positive reviews from many studies. ? Novatis has since engaged in the phase II JULIET and the phase II ELIANA study clinical trials (Pharma US, 2017). ? The studies were conducted in 27 sites in 10 countries across Europe and Australia and North America. ? The studies revealed that patients were prone to suffer from hypogammaglobulinemia after using KYMRIAH (Novartis, 2018). ? This is a condition where their bodies immunity weakens, leading to numerous other diseases (Pharma US, 2017). ? To avoid this, patients can be given immunoglobulin to help and boost their immunity levels. ? The outlook is particularly bright in the use of CAR-T cell therapy. ? It is expected that more cancer illnesses can be treated in this manner in future (BioPharm International, 2017). REFERENCES International . (2017, August 30). FDA Approves Novartis’ CAR-T Drug, First Gene Therapy Approval in US. Retrieved from BioPharm : http://www.biopharminternational.com/fda-approves-novartis-car-t-drug-firstgene-therapy-approval-us ? BioPharm ? Novartis . (2018, January 17). Novartis granted US FDA Priority Review for Kymriah(TM) (tisagenlecleucel), formerly CTL019, for adults with r/r DLBCL. Retrieved from Novartis : https://www.novartis.com/news/mediareleases/novartis-granted-us-fda-priority-review-kymriahtm-tisagenlecleucelformerly-ctl019-adults-rr-dlbcl ? Pharma US. (2017). KYMRIAH. Retrieved from Novartis : https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/ky mriah.pdf … Get a 10 % discount on an order above $ 100 Use the following coupon code : NURSING10