Data from the ANDROMEDA Study Show Hematologic Response for DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) in Newly Diagnosed Light Chain (AL)…

RARITAN, N.J., Dec. 7, 2020 /PRNewswire/ --The Janssen Pharmaceutical Companies of Johnson & Johnson announced today new data from the Phase 3 ANDROMEDA study, which evaluated DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) as a treatment for patients withlight chain (AL) amyloidosis, a rare disease associated with deterioration of vital organs, most notably the heart, kidneys and liver, for which there are no currently approved therapies.1,2The data, which were featured in an oral presentation at the American Society of Hematology (ASH) 2020 Annual Meeting, showed a significantly higher complete hematologic response rate with DARZALEX FASPRO treatment in patients with this potentially fatal blood disorder compared to the standard regimen and consistent decreases in markers of disease, indicative of deep hematologic responses(Abstract #552).3

These data supported the recent submissionto theU.S. Food and Drug Administration (FDA) seeking approval for DARZALEX FASPRO in combination with bortezomib (VELCADE), cyclophosphamide and dexamethasone (D-VCd) for the treatment of patients with AL amyloidosis. The submission is being reviewed under the Real-Time Oncology Review Programto seek the first approval for any drug to treat this disease.4

"AL amyloidosis is a rare blood disorder in which abnormal proteins build up in the tissues and organs and eventually cause major organ deterioration," said study investigator, Raymond L. Comenzo, M.D., Director, John C. Davis Myeloma and Amyloid Program, Tufts Medical Center. "The data being presented at ASH show the potential of this new treatment regimen. Compared to VCd alone, the D-VCd regimen increased hematologicresponse rates and prolonged major organ deterioration-progression-free survival (MOD-PFS) in patients with AL amyloidosis."

Key Findings from the ANDROMEDA Oral Presentation (Abstract #552):

Additionally, D-VCd had an acceptable safety profile, consistent with that previously observed for each of the agents alone.

"AL amyloidosis is a challenging disease to diagnose and treat, with symptoms that mimic other conditions. During that delay, major organ deterioration can occur," said Jessica Vermeulen, M.D., Ph.D., Global Medical Head/Clinical Leader, Hematology & Oncology, Janssen Research & Development, LLC. "It is our hope that the ANDROMEDA study contributes to raising awareness of AL amyloidosis among patients and providers, and that approval of DARZALEX FASPRO, pending health authority reviews, will bring a much-needed and effective treatment option to patients."

Extent of cardiac involvement at baseline has a major impact on clinical outcomes for patients with AL amyloidosis.5A separate poster presentation of the ANDROMEDA data focused on the impact of cardiac involvement in newly diagnosed AL amyloidosis patients (Abstract #1392).6Results found that rates of hematologic, cardiac and renal response at six months were higher in the D-VCd group than the VCd group regardless of baseline cardiac stage (I, II or III), with more than 76 percent of these patients having a baseline cardiac stage of II or higher.6Additionally, both MOD-PFS and major organ deterioration-event-free survival(MOD-EFS) favored D-VCd across baseline cardiac stages.6

About the ANDROMEDA Study7ANDROMEDA (NCT03201965) is an ongoing Phase 3, randomized, open-label study investigating the safety and efficacy of daratumumab and hyaluronidase-fihj in combination with bortezomib, cyclophosphamide and dexamethasone (D-VCd), compared to VCd alone, for the treatment of patients with newly diagnosed light chain (AL) amyloidosis. The study includes 388 patients with newly diagnosed AL amyloidosis with measurable hematologic disease and one or more organs affected.

The primary endpoint is overall complete hematologic response rate by intent-to-treat (ITT). Secondary endpoints include MOD-PFS,MOD-EFS, organ response rate, overall survival and time to hematologic response, among others.

About DARZALEXFASPROIn August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize daratumumab. Since launch, it is estimated that more than 150,000 patients have been treated with daratumumab worldwide.8 DARZALEX FASPROis the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma.

CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.Daratumumabbinds to CD38 and inhibits tumor cell growth, causing myeloma cell death.9 Daratumumabmay also have an effect on normal cells.10 Data across nine Phase 3 clinical trials in multiple myeloma and AL amyloidosis, in both the frontline and relapsed settings, have shown that daratumumab-based regimens resulted in significant improvement in progression-free survival and/or overall survival.11,12,13,14,15,16,17,18 Additional studies are underway to assess the efficacy and safety of DARZALEX FASPROin the treatment of other malignant and pre-malignant hematologic diseases in which CD38 is expressed, including smoldering myeloma and light chain (AL) amyloidosis.19,20

For the full U.S. Prescribing Information, please visitwww.DARZALEX.com.

About AL AmyloidosisLight chain (AL) amyloidosis is a rare and potentially fatal hematologic disorder that can affect the function of multiple organs. The disease occurs when bone marrow produces abnormal pieces of antibodies called light chains, which clump together to form a substance called amyloid. These clumps of amyloid are deposited in tissues and vital organs and interfere with normal organ function, eventually causing organ deterioration.21,22 It is the most common type of amyloidosis. AL amyloidosis frequently affects the heart, kidneys, digestive tract, liver and nervous system, and is potentially fatal if left untreated.23 Diagnosis is often delayed and prognosis is poor due to advanced, multi-organ, particularly cardiac, involvement.24,25 Each year, an estimated 4,500 people develop AL amyloidosis in the U.S. alone.26

DARZALEX FASPRO is indicated for the treatment of adult patients with multiple myeloma:

DARZALEX FASPROTMIMPORTANT SAFETY INFORMATIONCONTRAINDICATIONSDARZALEX FASPROTMis contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Hypersensitivity and Other Administration Reactions

Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPROTM.

Systemic Reactions

In a pooled safety population of 490patients who received DARZALEX FASPROTMas monotherapy or in combination, 11% of patients experienced a systemic administration-related reaction (Grade 2: 3.9%, Grade 3: 1.4%). Systemic administration-related reactions occurred in 10% of patients with the first injection, 0.2% with the second injection, and cumulatively 0.8% with subsequent injections. The median time to onset was 3.7hours (range: 9minutes to 3.5days). Of the 84systemic administration-related reactions that occurred in 52patients, 73(87%) occurred on the day of DARZALEX FASPROTM administration. Delayed systemic administration-related reactions have occurred in less than 1% of the patients.

Severe reactions included hypoxia, dyspnea, hypertension and tachycardia. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritis, chills, vomiting, nausea, and hypotension.

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPROTM. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPROTMdepending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.

Local Reactions

In this pooled safety population, injection-site reactions occurred in 8% of patients, including Grade2 reactions in 0.6%. The most frequent (>1%) injection-site reaction was injection site erythema. These local reactions occurred a median of 7minutes (range: 0minutes to 4.7days) after starting administration of DARZALEX FASPROTM. Monitor for local reactions and consider symptomatic management.

NeutropeniaDaratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPROTMuntil recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPROTM, higher rates of Grade 3-4 neutropenia were observed.

ThrombocytopeniaDaratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer's prescribing information for background therapies. Consider withholding DARZALEX FASPROTM until recovery of platelets.

Embryo-Fetal ToxicityBased on the mechanism of action, DARZALEX FASPROTMcan cause fetal harm when administered to a pregnant woman. DARZALEX FASPROTMmay cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPROTMand for 3months after the last dose.

The combination of DARZALEX FASPROTMwith lenalidomide is contraindicated in pregnant women, because lenalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide prescribing information on use during pregnancy.

Interference with Serological TestingDaratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient's serum. The determination of a patient's ABO and Rh blood type are not impacted.

Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPROTM. Type and screen patients prior to starting DARZALEX FASPROTM.

Interference with Determination of Complete ResponseDaratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPROTM-treated patients with IgG kappa myeloma protein.

ADVERSE REACTIONSThe most common adverse reaction (20%) with DARZALEX FASPROTM monotherapy is: upper respiratory tract infection. The most common adverse reactions with combination therapy (20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, pyrexia, cough, muscle spasms, back pain, vomiting, upper respiratory tract infection, peripheral sensory neuropathy, constipation, and pneumonia.

The most common hematology laboratory abnormalities (40%) with DARZALEX FASPROTM are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.

Please see full Prescribing Information atwww.DARZALEX.com.

About the Janssen Pharmaceutical Companies of Johnson & Johnson At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.

Learn more at http://www.janssen.com. Follow us at http://www.twitter.com/JanssenGlobal and http://www.twitter.com/JanssenUS.Janssen Research & Development, LLC and Janssen Biotech, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Cautions Concerning Forward-Looking StatementsThis press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding DARZALEX FASPROTM. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, or any of the other Janssen Pharmaceutical Companies,and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 29, 2019, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in the company's most recently filed Quarterly Report on Form 10-Q, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at http://www.sec.gov, http://www.jnj.comor on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

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1National Organization for Rare Disorders. Amyloidosis. Accessed September 2020. https://rarediseases.org/rare-diseases/amyloidosis/. 2Lousada I, Comenzo RL, Landau H, et al. Light chain amyloidosis: patient experience survey from the Amyloidosis Research Consortium. Advances in Therapy. 2015;32(10):920-928. 3 Comenzo, RL et al. Reduction in Absolute Involved Free Light Chain and Difference Between Involved and Uninvolved Free Light Chain Is Associated with Prolonged Major Organ Deterioration Progression-Free Survival in Patients with Newly Diagnosed AL Amyloidosis Receiving Bortezomib, Cyclophosphamide, and Dexamethasone With or Without Daratumumab: Results From ANDROMEDA. Abstract #552. To be presented at 2020 American Society of Hematology Annual Meeting. 4 "Janssen Submits Application Seeking U.S. FDA Approval of DARZALEX FASPRO (Daratumumab and Hyaluronidase-Fihj) for the Treatment of Patients with Light Chain (AL) Amyloidosis." Janssen, 10 Sept. 2020, http://www.janssen.com/janssen-submits-application-seeking-us-fda-approval-darzalex-faspro-daratumumab-and-hyaluronidase. 5 Chaulagain CP, et al. Curr Hematol Malig Rep 2013;8:291-8. 6Minnema, MC et al. Outcomes by Cardiac Stage in Newly Diagnosed AL Amyloidosis: Results from ANDROMEDA. Abstract #1392. To be presented at 2020 American Society of Hematology Annual Meeting. 7Janssen Research & Development, LLC. A Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic Amyloid Light-chain (AL) Amyloidosis. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24]. Available at: https://clinicaltrials.gov/ct2/show/NCT03201965 Identifier: NCT03201965. 8Janssen World wide patients as of October 2020. 9European Medicines Agency. DARZALEX summary of product characteristics. Available at: https://www.ema.europa.eu/documents/product-information/darzalex-epar-productinformation_en.pdfLast accessed May 2020. 102020 Fedele G et al. CD38 Ligation in Peripheral Blood Mononuclear Cells of Myeloma Patients Induces Release of Protumorigenic IL-6 and Impaired Secretion of IFN Cytokines and Proliferation. Mediators Inflamm. 2013;564687. 11Janssen Research & Development, LLC. A Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24]. Available at: https://clinicaltrials.gov/ct2/show/NCT02076009?term=mmy3003&rank=1 Identifier: NCT02136134. Last accessed: October 2020. 12Janssen Research & Development, LLC. Addition of Daratumumab to Combination of Bortezomib and Dexamethasone in Participants With Relapsed or Refractory Multiple Myeloma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24]. Available at: https://clinicaltrials.gov/ct2/show/NCT02136134?term=mmy3004&rank=1 Identifier: NCT02076009. Last accessed: October 2020. 13 Janssen Research & Development, LLC. A Study to Evaluate Daratumumab in Transplant Eligible Participants With Previously Untreated Multiple Myeloma (Cassiopeia). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24]. Available at: https://clinicaltrials.gov/ct2/show/NCT02541383?term=mmy3006 Identifier: NCT02541383.Last accessed: October 2020. 14Janssen Research & Development, LLC. A Study of Combination of Daratumumab and Velcade (Bortezomib) Melphalan-Prednisone (DVMP) Compared to Velcade Melphalan-Prednisone (VMP) in Participants With Previously Untreated Multiple Myeloma In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24]. Available at: https://clinicaltrials.gov/ct2/show/NCT02195479?term=mmy3007&rank=1 Identifier: NCT02195479. Last accessed: October 2020. 15Janssen Research & Development, LLC. Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Participants With Previously Untreated Multiple Myeloma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24]. Available at: https://clinicaltrials.gov/ct2/show/NCT02252172?term=mmy3008&rank=1 Identifier: NCT02252172. Last accessed: October 2020. 16Janssen Research & Development, LLC. A Study of VELCADE (Bortezomib) Melphalan-Prednisone (VMP) Compared to Daratumumab in Combination With VMP (D-VMP), in Participants With Previously Untreated Multiple Myeloma Who Are Ineligible for High-Dose Therapy (Asia Pacific Region). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24]. Available at: https://clinicaltrials.gov/ct2/show/NCT03217812?term=MMY3011&rank=1 Identifier: NCT03217812. Last accessed: October 2020. 17 European Myeloma Network. Compare Progression Free Survival Btw Daratumumab/Pomalidomide/Dexamethasone vs Pomalidomide/Dexamethasone (EMN14). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24] Available at: https://clinicaltrials.gov/ct2/show/NCT03180736?term=MMY3013&rank=2 Identifier: NCT03180736. Last accessed: October 2020. 18Amgen. Study of Carfilzomib, Daratumumab and Dexamethasone for Patients With Relapsed and/or Refractory Multiple Myeloma. (CANDOR). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 July 24] Available at: https://clinicaltrials.gov/ct2/show/NCT03158688?term=NCT03158688&rank=1Identifier: NCT03158688. Last accessed: October 2020. 19Janssen Research & Development, LLC. A Study to Evaluate 3 Dose Schedules of Daratumumab in Participants With Smoldering Multiple Myeloma In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 March 19]. Available at: https://clinicaltrials.gov/ct2/show/NCT03158688?term=NCT03158688&rank=1Identifier: NCT02316106. Last accessed: October 2020. 20Janssen Research & Development, LLC. An Efficacy and Safety Proof of Concept Study of Daratumumab in Relapsed/Refractory Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000-[cited 2018 March 19]. Available at: https://clinicaltrials.gov/ct2/show/NCT02413489?term=lym2001&rank=1 Identifier: NCT02413489. Last accessed: October 2020. 21National Organization for Rare Disorders. Amyloidosis. Accessed October 2020. https://rarediseases.org/rare-diseases/amyloidosis/. 22Lousada I, Comenzo RL, Landau H, et al. Light chain amyloidosis: patient experience survey from the Amyloidosis Research Consortium. Advances in Therapy. 2015;32(10):920-928. 23"AL Amyloidosis (Amyloid Light Chain)." Cleveland Clinic, my.clevelandclinic.org/health/diseases/15718- amyloidosis-al-amyloid-light-chain. 24Weiss BM, et al. J Clin Oncol. 2014;32(25):2699-2704. 25Palladini G, et al. J Clin Oncol. 2012;30:4541-49. 6. Muchtar E, et al. Blood. 2017;129(15):2111-2119. 26 Quock TP, Yan T, Chang E, Guthrie S, Broder MS. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood Adv. 2018;2(10):10461053. doi:10.1182/bloodadvances.2018016402 7 Kastritis, E. et al. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexam.

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Data from the ANDROMEDA Study Show Hematologic Response for DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) in Newly Diagnosed Light Chain (AL)...

US FDA Approves Naxitamab for the Treatment of Neuroblastoma – OncoZine

The U.S. Food and Drug Administration (FDA) has approved naxitamab* (naxitamab-gqgk; Danyelza; Y-mAbs Therapeutics), a humanized form of the mouse antibody 3F8, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response (PR), minor response (mR), or stable disease (SD) to prior therapy.[1]

A rare disease Neuroblastoma is a heterogeneous pediatric neoplasm that arises in the sympathetic nervous system. The disease is the most common extra-cranial solid tumor in infants and children, representing between 8%-10% of all childhood tumors. Overall, neuroblastoma accounts for approximately 15% of all cancer-related deaths in children. [1]

The clinical behavior of neuroblastoma is highly variable, with some tumors being easily treatable, resulting in near-uniform survival. The majority of tumors are, however, very aggressive, with a high risk of death. [2] Age, stage, and amplification of the MYCN oncogene are the most validated prognostic markers.[2]

The incidence of neuroblastoma is 10.2 cases per million children under 15 years of age. [3] In the United States, nearly 700 new cases are reported each year. While 90% of cases are diagnosed before the age of 5, approximately 30% of patients are diagnosed within the first year. The median age of diagnosis is 22 months. [4]

Neuroblastoma develops in very early forms of nerve cells that are usually found in a developing baby, which explains why children as young as newborns can develop this cancer.

The disease rarely presents in adolescence and adulthood, but outcomes are much poorer in this age group. There does not appear to be an increased prevalence among races, but there is a slight predilection for males (1.2:1).[4]

Neuroblastoma develops in a part of the peripheral nervous system called the sympathetic nervous system. Since some of the sympathetic nervous system cells are concentrated in the adrenal glands, which sit above the kidneys, neuroblastoma often starts growing there. Tumors typically begin in the belly, neck, chest, pelvis, or adrenal glands and can spread to other parts of the body, including the bones.

All patients are staged based on the International Neuroblastoma Staging System Committee (INSS) system, ranging from stage 1 through stage 4S. Based on this staging system, patients with stage 4 disease diagnosed after one year of age are classified in the high-risk category, where the neuroblastoma tumor cells have already metastasized to other sites in the body, such as the bone or bone marrow.

Essentially all patients who have tumors with many copies, or amplification, of the MYCN oncogene also have high-risk disease, even if they do not have evidence of the tumor having spread.

Although children with a family history of neuroblastoma may have a higher risk for developing this disease, this factor accounts for only 1-2 % of all cases of neuroblastoma. The vast majority of children who develop the tumor, do not have a family history of the same.

Mechanism of action In simple terms, naxitamab, conceived and developed by physician-scientist Nai-Kong Cheung, M.D., Ph.D., a medical oncologist at Memorial Sloan Kettering ** who heads the organizations neuroblastoma program, detects neuroblastoma cells that have survived chemo- or radiation therapy by attaching to GD2, a ganglioside that is ubiquitously expressed in the plasma membrane of neuroblastoma and is shed into the circulation, after which the patients own immune system, especially white blood cells, can destroy the malignant neuroblastoma cells. [5]

In the late 1980s, investigators at Memorial Sloan Kettering started using 3F8 in combination with surgery and chemotherapy to treat patients diagnosed with neuroblastoma. The investigational treatment significantly improved cure rates for pediatric patients with high-risk disease.

Later, in 2007, Cheung and colleagues began developing a humanized form of 3F8 called Hu3F8. In August 2011 the researchers started a phase I study of Hu3F8 (NCT01419834). The study was designed to investigate the best and safest dose to give to patients.

Accelerated approval The new indication of naxitamab + GM-CSF is approved under accelerated approval regulation based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefits in a confirmatory trial.

Naxitamab is a humanized, monoclonal antibody that targets the ganglioside GD2, which is highly expressed in various neuroectoderm-derived tumors and sarcomas. The drug is administered to patients three times per week in an outpatient setting and the treatment is repeated every four weeks. The product has received Priority Review, Orphan Drug, Breakthrough Therapy, and Rare Pediatric Disease designations from the FDA.

Much needed treatment Over the last decades, the development of novel treatments for pediatric cancers has been successful. For example, the five-year survival rates for children diagnosed with cancer in the late 1980s approaches 70%. For some types of localized embryonal tumors, including retinoblastoma and Wilms tumor, the cure rates approach or exceed 90%.

However, for every two children who survive today, one child still succumbs to their disease. And for some childhood cancers, such as neuroblastoma and certain types of brain cancer, the prognosis remains poor. Hence, despite the observed successes, there remained a major unmet medical need remains patients diagnosed with neuroblastoma. The development and subsequent approval of naxitamab may be one much-needed treatment options for these patients. [6]

[The approval represents a major milestone] for children living with refractory/relapsed high-risk neuroblastoma, noted Thomas Gad, founder, Chairman, and President of Y-mAbs Therapeutics, whose own daughters neuroblastoma was successfully treated with 3F8 at Memorial Sloan Kettering more than a decade ago.

In 2015, Memorial Sloan Kettering licensed Hu3F8 to Y-mAbs Therapeutics tpo expand the clinical trial and development program and manufacturing of naxitamab.

Its very exciting to see this treatment go from being an experimental therapy used at my daughters bedside to now being FDA approved, Gad added.

We believe that naxitamab in combination with GM-CSF is a much-needed treatment for patients with relapsed/refractory high-risk neuroblastoma in the bone or bone marrow who have historically not had approved treatments available. This approval of Y-mAbs first BLA represents a key step in working towards our mission of becoming a world leader in developing better and safer antibody-based oncology products addressing unmet pediatric and adult medical needs, said Claus Moller, Y-mAbs Therapeutics Chief Executive Officer.

Clinical trials The FDA approval of naxitamab is supported by clinical evidence from two pivotal studies in patients with high-risk neuroblastoma with refractory or relapsed disease.

In these clinical studies, naxitamab appears to be well tolerated with few discontinuations of treatment. The observed treatment-related adverse events were clinically manageable.

The efficacy of naxitamab in combination with GM-CSF was evaluated in two open-label, single-arm trials in patients with high-risk neuroblastoma with refractory or relapsed disease in the bone or bone marrow.

Both trials included patients with relapsed or refractory neuroblastoma in the bone marrow or bone. Participating patients received a 3 mg/kg of naxitamab intravenously on days one, three, and five of each four-week cycle, in addition to GM-CSF subcutaneously, or under the skin, at varying doses throughout the cycle. Patients were allowed to receive preplanned radiation in specific areas based on which trial they were enrolled in.

Efficacy outcomes included overall response rate (ORR) according to the revised International Neuroblastoma Response Criteria (INRC), as determined by independent pathology and imaging review and confirmed by at least one subsequent assessment. An additional efficacy outcome measure was the duration of response (DOR).

Study 201 In the first study (Study 201; NCT03363373), a multicenter open-label, single-arm trial. researchers evaluated the combination of naxitamab in combination with GM-CSF in a subpopulation of patients who had refractory or relapsed high-risk neuroblastoma in the bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded.

Of the 22 patients included in the efficacy analysis, 64% had refractory disease and 36% had relapsed disease. The median age was 5 years (range 3 to 10 years), 59% were male; 45% were White, 50% were Asian and 5% were Black.

MYCN amplification was present in 14% of patients and 86% of patients were International Neuroblastoma Staging System (INSS) stage 4 at the time of diagnosis. Disease sites included 59% in the bone only, 9% in bone marrow only, and 32% in both. Prior therapies included surgery (91%), chemotherapy (95%), radiation (36%), autologous stem cell transplant (ASCT) (18%), and anti-GD2 antibody treatment (18%).

Study 12-230 The second study (Study 12-230; NCT01757626), a single-center, open-label, single-arm clinical trial, included a subpopulation of patients who had relapsed or refractory high-risk neuroblastoma in bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. In this study patients with progressive disease were excluded.

Participating patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. They were required to have received at least one dose of naxitamab at a dose of 3 mg/kg or greater per infusion and have evaluable disease at baseline according to independent review per the revised INRC. Radiation to non-target bony lesions and soft tissue lesions was permitted at the investigators discretion (assessment of response excluded sites that received radiation).

Of the 38 patients included in the efficacy analysis, 55% had relapsed neuroblastoma and 45% had refractory disease; 50% were male, the median age was 5 years (range 2 to 23 years), 74% were White, 8% Asian and 5% were Black, 5% Native American/American Indian/Alaska Native, 3% other races and 5% was not available. MYCN-amplification was present in 16% of patients and most patients were International Neuroblastoma Staging System (INSS) stage 4 (95%).

Fifty percent (50%) of patients had disease involvement in the bone only, 11% only in bone marrow, and 39% in both. Prior therapies included surgery (100%), chemotherapy (100%), radiation (47%), autologous stem cell transplant (ASCT) (42%), and anti-GD2 antibody treatment (58%)

Adverse events The most common adverse reactions (incidence 25% in either trial) in patients receiving naxitamab were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability.

The most common Grade 3 or 4 laboratory abnormalities (5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium, and decreased phosphate.

Boxed warning The prescribing information for naxitamab contains a Boxed Warning which states that the drug can cause serious infusion-related reactions and neurotoxicity, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome (RPLS). Hence, to mitigate these risks, patients should receive premedication prior to each naxitamab infusion and be closely monitored during and for at least two hours following completion of each infusion.

Note * Also known as humanized 3F8 or Hu3F8, ** Researchers at Memorial Sloan Kettering Cancer Center (MSK) developed naxitamab, which is exclusively licensed by MSK to Y-mAbs. As a result of this licensing arrangement, MSK has institutional financial interests related to the compound and Y-mAbs.

Clinical trials Humanized 3F8 Monoclonal Antibody (Hu3F8) in Patients With High-Risk Neuroblastoma and GD2-Positive Tumors NCT01419834 Humanized 3F8 Monoclonal Antibody (Hu3F8) When Combined With Interleukin-2 in Patients With High-Risk Neuroblastoma and GD2-positive Solid Tumors NCT01662804 Humanized Anti-GD2 Antibody Hu3F8 and Allogeneic Natural Killer Cells for High-Risk Neuroblastoma NCT02650648 Study of the Safety and Efficacy of Humanized 3F8 Bispecific Antibody (Hu3F8-BsAb) in Patients With Relapsed/Refractory Neuroblastoma, Osteosarcoma and Other Solid Tumor Cancers NCT03860207 Combination Therapy of Antibody Hu3F8 With Granulocyte- Macrophage Colony Stimulating Factor (GM-CSF) in Patients With Relapsed/Refractory High-Risk Neuroblastoma NCT01757626 Naxitamab for High-Risk Neuroblastoma Patients With Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow NCT03363373

Highlights of prescription information Naxitamab (naxitamab-gqgk; Danyelza; Y-mAbs Therapeutics) [Prescribing Information]

Reference [1] Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am. 2010 Feb;24(1):65-86. doi: 10.1016/j.hoc.2009.11.011. PMID: 20113896. [2] Modak S, Cheung NK. Neuroblastoma: Therapeutic strategies for a clinical enigma. Cancer Treat Rev. 2010 Jun;36(4):307-17. doi: 10.1016/j.ctrv.2010.02.006. Epub 2010 Mar 12. PMID: 20227189. [3] Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010 Jun 10;362(23):2202-11. doi: 10.1056/NEJMra0804577. PMID: 20558371; PMCID: PMC3306838. [4] Esiashvili N, Anderson C, Katzenstein HM. Neuroblastoma. Curr Probl Cancer. 2009 Nov-Dec;33(6):333-60. doi: 10.1016/j.currproblcancer.2009.12.001. PMID: 20172369. [5] Balis FM, Busch CM, Desai AV, Hibbitts E, Naranjo A, Bagatell R, Irwin M, Fox E. The ganglioside GD2 as a circulating tumor biomarker for neuroblastoma. Pediatr Blood Cancer. 2020 Jan;67(1):e28031. doi: 10.1002/pbc.28031. Epub 2019 Oct 14. PMID: 31612589. [6] Balis FM. The Challenge of Developing New Therapies for Childhood Cancers. Oncologist. 1997;2(1):I-II. PMID: 10388032.

Featured image: A close up of a newborn babys foot in the neonatal unit in a hospital. Photo courtesy: 2016 2020 Fotolia/Adobe. Used with permission

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US FDA Approves Naxitamab for the Treatment of Neuroblastoma - OncoZine

Coronavirus treatments and vaccines. Here are the latest developments – San Francisco Chronicle

Scientists at Bay Area universities, laboratories, biotechnology companies and drug manufacturers are fashioning drug concoctions out of blood plasma, chimpanzee viruses and cells taken from bone marrow in the race to rid the world of COVID-19.

The microbial treasure hunt is not just to find a cure which may not be possible but to control the debilitating health problems caused by the coronavirus.

Major progress has been made this year. The antiviral drug remdesivir, produced in Foster City, has improved recovery times, and the steroid dexamethasone has cut the number of deaths in severely ill patients.

What follows is a list of some of the most promising medications and vaccines with ties to the Bay Area:

Antibodies

and Immunity

Mesenchymal stem cells / UCSF and UC Davis Medical Center:

UCSF Dr. Michael Matthay is leading a study of whether a kind of stem cell found in bone marrow can help critically ill patients with severe respiratory failure, known as ARDS. Matthay hopes the stem cells can help reduce the inflammation associated with some of ARDS most dire respiratory symptoms, and help patients lungs recover.

In all, 120 patients are being enrolled at UCSF Medical Center, Zuckerberg San Francisco General Hospital, the UC Davis Medical Center in Sacramento and hospitals in Oregon and Texas. He said the trial, which includes a small number of ARDS patients who dont have COVID-19, should have results by summer or fall 2021. So far, 28 patients are enrolled in San Francisco.

Lambda-interferon / Stanford University:

Lambda-interferon is a manufactured version of a naturally occurring protein that had been used to treat hepatitis, and researchers hoped it would help patients in the early stages of COVID-19.

Stanford researchers completed their trial of lambda-interferon and found that it did not boost the immune system response to coronavirus infections.

That trial did not find any difference in outcomes between the treatment and placebo, said Yvonne Maldonado, chief of pediatric infectious diseases at Lucile Packard Childrens Hospital at Stanford, where 120 patients were enrolled in the trial. It didnt work.

Antiviral drugs

Remdesivir / Gilead Sciences (Foster City):

Remdesivir, once conceived as a potential treatment for Ebola, was approved by the Food and Drug Administration in October for use on hospitalized COVID-19 patients.

Trademarked under the name Veklury, the drug interferes with the process through which the virus replicates itself. It was one of the drugs given to President Trump and has been used regularly in hospitals under what is known as an emergency use authorization.

It was approved after three clinical trials showed hospitalized coronavirus patients who received remdesivir recovered five days faster on average than those who received a placebo. Patients who required oxygen recovered seven days faster, according to the studies.

Gilead now plans to conduct clinical trials to see how remdesivir works on pediatric patients, from newborns to teenagers, with moderate to severe COVID-19 symptoms. Remdesivir is also being studied with steroids and other drugs to see if it works better as part of a medicinal cocktail. An inhalable form of the drug is also being developed.

Favipiravir / Fujifilm Toyama Chemical (Stanford University):

This antiviral drug, developed in 2014 by a subsidiary of the Japanese film company to treat influenza, is undergoing numerous clinical studies worldwide, including a trial involving 180 patients at Stanford University.

Stanford epidemiologists are testing favipiravir to see if it prevents the coronavirus from replicating in human cells, halts the shedding of the virus and reduces the severity of infection. Unlike remdesivir, it can be administered orally, so it can be used to treat patients early in the disease, before hospitalization is necessary.

The Stanford study has so far enrolled about 90 patients, who are given the drug within 72 hours of when they were first diagnosed with COVID-19. Half of them get a placebo. People can enroll by emailing treatcovid@stanford.edu.

Monoclonal antibodies

REGN-COV2 / Regeneron Pharmaceuticals / Stanford School of Medicine:

The REGN-COV2 cocktail is the same one Trump received, and Stanford is one of dozens of locations nationwide where clinical trials are being held. Two separate trials are under way at Stanford one for hospitalized patients, the other for outpatients. A third trial is about to begin for people who arent sick but are in contact with carriers of the virus.

Regeneron halted testing on severely ill patients requiring high-flow oxygen or mechanical ventilation after the independent Data and Safety Monitoring Board determined that the drug was unlikely to help them.

The drug is a combination of two monoclonal antibodies lab-made clones of the antibodies produced naturally in people who have recovered from COVID-19. The antibodies bind to the virus spike protein and block the virus ability to enter cells.

Dr. Aruna Subramanian, professor of infectious diseases at Stanford and lead investigator for the inpatient trial, said the 21 hospitalized patients in the study receive a high dose like Trump, a lower dose or a placebo. Subramanian plans to expand the inpatient trial to 45 patients. The outpatient study has enrolled a little more than 40 of the 60 patients researchers intend to sign up.

Theres enough promising evidence that it helps people early in the infection, Subramanian said. What we dont know is whether it helps people who are pretty sick but not critically ill.

Bamlanivimab / Eli Lilly / Stanford and UCSF:

Stanford and UCSF are testing the Eli Lilly monoclonal antibodies on outpatients after the pharmaceutical company halted trials on hospitalized COVID-19 patients because of adverse results.

Dr. Andra Blomkalns, chair of emergency medicine at Stanford and the lead in the Eli Lilly outpatient trial, said she is now enrolling older people with comorbidities like heart disease, chronic lung disease, a history of strokes and severe obesity shortly after they test positive.

The hypothesis is that the bamlanivimab monotherapy, which is very similar to the Regeneron monoclonals, might work best early in the infection. Although about 400 patients have been enrolled in the Lilly phase 3 trials nationwide, to date fewer than 10 have been enrolled at Stanford and UCSF.

Matthay, who headed up the Lilly monoclonal study with LY-CoV555 at UCSF, said the cancellation of this inpatient trial was disappointing, but just because this one did not work, doesnt mean another one wont work for hospitalized patients.

Blomkalns said the testing criteria has been changing. She expects the outpatient trial to open soon to adolescents ages 12 and up to determine whether the drug can be used as a preventive.

Designer monoclonal antibodies / Vir Biotechnology, San Francisco:

Scientists at Vir are studying several types of monoclonal antibodies, including a type engineered to activate T cells, which can search out and destroy cells infected with the coronavirus. A study published in the journal Nature in October found that monoclonals, modified to bind with certain receptors, stimulated T cells and improved the human immune response.

By observing and learning from our bodys powerful natural defenses, we have discovered how to maximize the capacity of antibodies through the amplification of key characteristics that may enable more effective treatments for viral diseases, said Herbert Virgin, the chief scientific officer at Vir and co-author of the study.

A similarly modified monoclonal antibody, leronlimab, is being studied in coronavirus clinical trials by its Washington state drugmaker, CytoDyn, which has developed drugs to treat HIV. The companys chief medical officer is in San Francisco, and the company that does laboratory tests of leronlimab is in San Carlos.

Anti-inflammatory drugs

Colchicine / UCSF (San Francisco and New York):

The anti-inflammatory drug commonly used to treat gout flare-ups is being studied by scientists at UCSF and New York University. The drug short-circuits inflammation by decreasing the bodys production of certain proteins, and researchers hope that it will reduce lung complications and prevent deaths from COVID-19.

Preliminary results from a clinical trial found that Colchicine can be effective in reducing systemic symptoms of COVID-19 by inhibiting inflammatory biomarkers.

Selinexor / Kaiser Permanente:

Kaiser hospitals in San Francisco, Oakland and Sacramento are studying selinexor, an anticancer drug that blocks a key protein in the cellular machinery for DNA processing. Preliminary findings during the trials indicated that low doses of selinexor helped hospitalized patients with severe COVID-19. The drug has both antiviral and anti-inflammatory properties, and its administered orally, according to Kaisers Dr. Jacek Skarbinski.

Vaccines

VXA-COV2-1 / Vaxart, South San Francisco:

The biotechnology company Vaxart is testing VXA-COV2-1, the only potential vaccine in pill form. It uses the genetic code of the coronavirus to trigger a defensive response in mucous membranes. The hope is that the newly fortified membranes will prevent the virus from entering the body.

Its the only vaccine (candidate) that activates the first line of defense, which is the mucosa, said Andrei Floroiu, Vaxarts chief executive. He said intravenous vaccines kill the virus after it is inside the body, but this one stops it beforehand.

The drug, which is effective against influenza and norovirus, induced both neutralizing antibodies and T cells during coronavirus drug trials, according to preliminary trial results published in September.

VaxiPatch / Verndari (Napa and UC Davis Medical Center):

A Napa company, Verndari, is studying vaccines for COVID-19 that can be delivered using an adhesive patch. Researchers at UC Davis Medical Center in Sacramento said the patch caused an immune response in preclinical tests.

An October report in the online journal ScienceDirect touted the system, saying it could serve as a shelter in place vaccination strategy, in which vulnerable populations receive delivery at home without needing to engage an already-overtaxed health care infrastructure.

If the vaccine is proven effective and safe, patients could receive it through the mail, according to Dr. Daniel Henderson, Verndaris chief executive officer.

ChAdOx1 / AstraZeneca (UCSF, San Francisco General Hospital, Bridge HIV):

Enrollment is under way at 80 sites in the United States, including three in the Bay Area, for the phase 3 trial of AstraZenecas vaccine, developed by Oxford University from an adenovirus, which typically causes colds in chimpanzees.

At least 1,000 of the 40,000 participants in the phase 3 AstraZeneca trial will be from the Bay Area, including 500 at Sutter Healths East Bay AIDS Center in Oakland, 250 at Zuckerberg San Francisco General Hospital and another 250 at Bridge HIV San Francisco.

An interim analysis of trials in Britain and Brazil showed the vaccine was 90% effective in preventing COVID-19 in 131 patients who got a half-dose of the vaccine by mistake. The vaccine was only 62% effective in people who got a full dose, leading to major questions about the results and how the trial was conducted.

Bay Area trial leaders Dr. Annie Luetkemeyer of UCSF and Dr. Susan Buchbinder, director of Bridge HIV and a UCSF professor of medicine and epidemiology, are hoping future trial results are more clear. Thats because AstraZenecas vaccine is cheaper than those made by its rivals Pfizer and Moderna, whose vaccines were 95% and 94.5% effective in preliminary tests.

The AstraZeneca candidate can also be stored at temperatures between 36 and 46 degrees Fahrenheit, which is orders of magnitude higher than the Pfizer and Moderna vaccines. The Pfizer and Moderna vaccines must be kept at 94 degrees below zero Fahrenheit, colder than many storage facilities can manage.

Johnson & Johnson (Stanford University)

The Johnson & Johnson clinical trials have enrolled 20,000 of the 60,000 volunteers worldwide that officials expect to have signed up by Christmas. That includes 70 people at Stanford.

The vaccine is, like the AstraZeneca version, a chimpanzee adenovirus that was genetically altered so that it carries the RNA of the coronavirus spike protein. The technique inspires the body to produce antibodies that block the protein without causing people to get sick.

Phase 2 studies show that it produces a good immune response and the early results of phase 3 show that its safe, said Dr. Philip Grant, assistant professor of infectious disease at Stanford and leader of the trial.

Grant, who is enrolling about 15 people a day for the trial, said he doesnt expect results on the vaccines effectiveness until sometime in March.

Peter Fimrite is a San Francisco Chronicle staff writer. Email: pfimrite@sfchronicle.com Twitter: @pfimrite

Peter Fimrite is The Chronicles lead science reporter, covering environmental, atmospheric and ecosystem science. His beat includes earthquake research, marine biology, wildfire science, nuclear testing, archaeology, wildlife and scientific exploration of land and sea. He also writes about the cannabis industry, outdoor adventure, Native American issues and the culture of the West. A former U.S. Forest Service firefighter, he has traveled extensively and covered a wide variety of issues during his career, including the Beijing Olympics, Hurricane Katrina, illegal American tourism in Cuba and a 40-day cross country car trip commemorating the history of automobile travel in America.

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Coronavirus treatments and vaccines. Here are the latest developments - San Francisco Chronicle

Dr Apar Kishor Ganti Outlines the Effectiveness of Lurbinectedin and Benefits Over Competition – AJMC.com Managed Markets Network

So, lurbinectedin is being studied in other diseases like breast cancer, mesothelioma, chronic lymphocytic leukemia, among others. But the difference in these other conditions compared to small cell [lung cancer] is there are other treatment options that are reasonably effective in these other cancers, unlike in small cell, so that's where it becomes much more important in in this particular setting.

One other reason why lurbinectedin may be effective is, like I told you earlier, there is a group of cells that seem to be shielded from chemotherapy. We call them cancer stem cells. And there are some lab data that suggests that lurbinectedin may inhibit cancer stem cells, as well. Again, this is all preliminary data. And we don't necessarily know if that occurs in humans or not, but those are some of the hypothesized mechanisms of action.

What other advantages are there of lurbinectedin over topotecan?

One of the other advantages of lurbinectedin over topotecan is that topotecan has to be given 5 days in a row, whereas lurbinectedin is given just once every 3 weeks. And the side effect profile of lurbinectedin seems to be favorable. The main side effect of lurbinectedin is bone marrow suppression, anemia, leukopenia, neutropenia, [and] thrombocytopenia, but they seem to occur in about 5% to 10% of patients. And so, that's another possible advantage of lurbinectedin over for some of the other drugs that are available.

As far as small cell lung cancer itself is concerned, even though there is a lot of research going on in small cell, multiple different drugs have been triedtargeted therapies, immunotherapythere is some evidence to suggest that immunotherapy helps with chemotherapy in the frontline setting. But immunotherapy by itself in patients who have failed chemotherapy does not seem to be much more effective. People have tried targeted therapies, again, not one of them has shown to have any meaningful benefit for these patients. So that has been very disappointing.

There have been multiple drugs that have been studied. Unfortunately, none of them have had a significant benefit so far. So, it's a fairly difficult to treat disease. And like I mentioned earlier, even though it seems to respond quite well to initial chemotherapymost patients relapse and very few are cured even if they present with very early stage disease. And that's why it's a very challenging disease to treat.

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Dr Apar Kishor Ganti Outlines the Effectiveness of Lurbinectedin and Benefits Over Competition - AJMC.com Managed Markets Network

Commonly used antibiotic shows promise for combating Zika infections – National Institutes of Health

News Release

Tuesday, November 24, 2020

NIH preclinical study suggests FDA-approved tetracycline-based antibiotics may slow infection and reduce neurological problems.

In 2015, hundreds of children were born with brain deformities resulting from a global outbreak of Zika virus infections. Recently, National Institutes of Health researchers used a variety of advanced drug screening techniques to test out more than 10,000 compounds in search of a cure. To their surprise, they found that the widely used antibiotic methacycline was effective at preventing brain infections and reducing neurological problems associated with the virus in mice. In addition, they found that drugs originally designed to combat Alzheimers disease and inflammation may also help fight infections.

Around the world, the Zika outbreak produced devastating, long-term neurological problems for many children and their families. Although the infections are down, the threat remains, said Avindra Nath, M.D., senior investigator at the NIHs National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study published in PNAS. We hope these promising results are a good first step to preparing the world for combating the next potential outbreak.

The study was a collaboration between scientists on Dr. Naths team and researchers in laboratories led by Anton Simeonov, Ph.D., scientific director at the NIHs National Center for Advancing Translational Sciences (NCATS) and Radhakrishnan Padmanabhan, Ph.D., Professor of Microbiology & Immunology, Georgetown University Medical Center, Washington, D.C.

The Zika virus is primarily spread by the Aedes aegypti mosquito. In 2015 and 2016, at least 60 countries reported infections. Some of these countries also reported a high incidence of infected mothers giving birth to babies born with abnormally small heads resulting from a developmental brain disorder called fetal microcephaly. In some adults, infections were the cause of several neurological disorders including Guillain-Barr syndrome, encephalitis, and myelitis. Although many scientists have tried, they have yet to discover an effective treatment or vaccination against the virus.

In this study, the researchers looked for drugs that prevent the virus from reproducing by blocking the activity of a protein called NS2B-NS3 Zika virus protease. The Zika virus is a protein capsule that carries long strings of RNA-encoded instructions for manufacturing more viral proteins. During an infection, the virus injects the RNA into a cell, resulting in the production of these proteins, which are strung together, side-by-side, like the parts in a plastic model airplane kit. The NS2B-NS3 protease then snaps off each protein, all of which are critical for assembling new viral particles.

Proteases act like scissors. Blocking protease activity is an effective strategy for counteracting many viruses, said Rachel Abrams, Ph.D., an organic chemist in Dr. Naths lab and the study leader. We wanted to look as far and wide as possible for drugs that could prevent the protease from snipping the Zika virus polyprotein into its active pieces.

To find candidates, Dr. Abrams worked with scientists on Dr. Simeonovs and Dr. Padmanabhans teams to create assays, or tests, for assessing the ability of drugs to block NS2B-NS3 Zika virus protease activity in plates containing hundreds of tiny test tubes. Each assay was tailored to a different screening, or sifting, technique. They then used these assays to simultaneously try out thousands of candidates stored in three separate libraries.

One preliminary screen of 2,000 compounds suggested that commonly used, tetracycline-based antibiotic drugs, like methacycline, may be effective at blocking the protease.

Meanwhile, a large-scale screen of more than 10,000 compounds helped identify an investigational anti-inflammatory medicine, called MK-591, and a failed anti-Alzheimers disease drug, called JNJ-404 as potential candidates. A virtual screen of over 130,000 compounds was also used to help spot candidates. For this, the researchers fed the other screening results into a computer and then used artificial intelligence-based programs to learn what makes a compound good at blocking NS2B-NS3 Zika virus protease activity.

These results show that taking advantage of the latest technological advances can help researchers find treatments that can be repurposed to fight other diseases, said Dr. Simeonov.

The Zika virus is known to preferentially infect stem cells in the brain. Scientists suspect this is the reason why infections cause more harm to newborn babies than to adults. Experiments on neural stem cells grown in petri dishes indicated that all three drugs identified in this study may counteract these problems. Treating the cells with methacycline, MK-591, or JNJ-404 reduced Zika virus infections.

Because tetracyclines are U.S. Food and Drug Administration-approved drugs that are known to cross the placenta of pregnant women, the researchers focused on methacycline and found that it may reduce some neurodevelopmental problems caused by the Zika virus. For instance, Zika-infected newborn mice that were treated with methacycline had better balance and could turn over more easily than ones that were given a placebo. Brain examinations suggested this was because the antibiotic reduced infections and neural damage. Nevertheless, the antibiotics did not completely counteract harm caused by the Zika virus. The weight of mice infected with the virus was lower than control mice regardless of whether the mice were treated with methacycline.

These results suggest that tetracycline-based antibiotics may at least be effective at preventing the neurological problems associated with Zika virus infections, said Dr. Abrams. Given that they are widely used, we hope that we can rapidly test their potential in clinical trials.

Article:

Abrams, R.P.M., Yasgar, A. et al., Therapeutic Candidates for the Zika Virus Identified by a High Throughput Screen for Zika Protease Inhibitors. PNAS, November 23, 2020 DOI: 10.1073/pnas.2005463117.

These studies were supported by NIH Intramural Research Programs at NINDS and NCATS (TR000291) and an NIH grant (AI109185).

For more information:

NINDS (https://www.ninds.nih.gov) is the nations leading funder of research on the brain and nervous system.The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation the process by which interventions to improve health are developed and implemented to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit ncats.nih.gov.

About the National Institute of Allergy and Infectious Diseases: NIAID conducts and supports research at NIH, throughout the United States, and worldwide to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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Commonly used antibiotic shows promise for combating Zika infections - National Institutes of Health

A real life Superman celebrates 5 years of survival from one of the deadliest cancers – Newswise

Newswise CLEVELAND Three college graduations. Three family weddings. The births of two grandchildren.

Andy Superman Simon has cherished each of these milestones since he was diagnosed five years ago with a glioblastoma multiforme (GBM grade 4), one of the deadliest and most challenging cancers to treat. GBM patients typically survive an average of 12-15 months. Only 6.8 percent of GBM patients survive five years, according to the National Brain Tumor Society.

But the Superman of University Hospitals Seidman Cancer Center who memorably donned a full costume for his final treatment in September 2016 and is free of cancer today with no recurrence is anything but typical.

I feel incredible, says Simon, now 56. I flew through treatment with ease, because I had the best team and the best surgeon. The way I see it, I had cancer, I dont have it.

The crushing headache, similar to a migraine yet inexplicably and mysteriously different, struck early one morning in November 2015. Pulling out of his driveway to head to the ER, Simon was equidistant from two different hospital systems. He and his wife believe that fateful turn to come to UH Ahuja Medical Center, and then UH Seidman Cancer Center, has made all the difference.

If we hadnt gone to UH, I honestly believe in my heart that Andy wouldnt be here today, said Amy, Simons wife.

Neurosurgeon Andrew Sloan, MD, Director of UHs Brain Tumor & Neuro-Oncology Center and the UH Seidman Center for Translational Neuro-Oncology, diagnosed the large mass in Simons brain as a GBM. He performed a craniotomy on Simon using 5-Aminolevulinic Acid (5-ALA), an experimental agent that improves the surgeons ability to identify the tumor. Dr. Sloans own surgical trial assessing this agent was one of only a handful of studies in the United States at the time, though it is now approved for use throughout the US by the FDA. Simon took the 5-ALA prior to surgery, which causes the cancer cells to glow hot pink, for more complete removal of these aggressive, invasive tumors.

Radiation and chemotherapy are the standard of care following a craniotomy for GBM.

Simon also took advantage of a novel phase I clinical trial that involved genetically engineering his own blood cells to express a mutant protein that made them more resistant to chemotherapy enabling him to safely withstand steadily higher doses of toxic chemotherapy through six rounds. While this phase I trial was designed only to show safety and feasibility, the median survival of the participants was 3.3-fold higher than anticipated based on case-matched historical controls with GBM undergoing standard treatment.

A new clinical trial, funded by a $2.3 million grant from the National Cancer Institute and based on the gene therapy Simon participated in, will open at UH Seidman Cancer Center in the next few months.

Andy has been a champion, Dr. Sloan says of the poster-boy for this trial, noting that five-year GBM survivors commonly experience recurrence. Hes a real fighter.

This treatment is really a game-changer. This could be the new standard of care. Its really exciting and very promising.

For the last several years, Simon has celebrated with a big party complete with a photo display of his milestones. He was planning a blowout celebration this year until the pandemic struck.

There is hope, says Simon. I have too many things to fight for, and to live for. Ive gotten too far. Im going to be a statistic for the other side. Every day is a milestone really.

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About University Hospitals / Cleveland, Ohio

Founded in 1866, University Hospitals serves the needs of patients through an integrated network of 19 hospitals, more than 50 health centers and outpatient facilities, and 200 physician offices in 16 counties throughout northern Ohio.The systems flagship academic medical center, University Hospitals Cleveland Medical Center, located in Clevelands University Circle, is affiliated with Case Western Reserve University School of Medicine. The main campus also includes University Hospitals Rainbow Babies & Children's Hospital, ranked among the top childrens hospitals in the nation; University Hospitals MacDonald Women's Hospital, Ohio's only hospital for women; University Hospitals Harrington Heart & Vascular Institute, a high-volume national referral center for complex cardiovascular procedures; and University Hospitals Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, including cancer, pediatrics, women's health, orthopedics, radiology, neuroscience, cardiology and cardiovascular surgery, digestive health, transplantation and urology. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including Americas Best Hospitals from U.S. News & World Report. UH is also home to Harrington Discovery Institute at University Hospitals part of The Harrington Project for Discovery & Development. UH isone of the largest employers in Northeast Ohio with 28,000 physicians and employees.Advancing the Science of Health and the Art of Compassion is UHs vision for benefitting its patients into the future and To Heal. To Teach. To Discover.is the organizations unwavering mission. Follow UH on Facebook @UniversityHospitalsand Twitter @UHhospitals. For more information, visitUHhospitals.org.

About University Hospitals Seidman Cancer Center

UH Seidman Cancer Center is the only freestanding cancer hospital in Northeast Ohio, where all clinicians and staff are dedicated to the prevention, diagnosis and treatment of cancer while researching new and innovative treatment options through clinical trials. Nationally ranked cancer care is also available to patients through the 11-country region at 18 community-based locations. Our UH Seidman specialists make up 14 cancer-specific teams focused on determining integrated care plans tailored to patients needs. UH Seidman Cancer Center is part of the National Cancer Institute (NCI)-designated Case Comprehensive Cancer Center at Case Western Reserve University, one of 50 comprehensive cancer centers in the country. Patients have access to advanced treatment options, ranging from a pioneering stem cell transplant program founded more than 40 years ago and a wide range of immunotherapy to the first and only proton therapy center in northern Ohio for adults and children. Go to UHhospitals.org/Seidman for more information.

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A real life Superman celebrates 5 years of survival from one of the deadliest cancers - Newswise

Global Cell Harvesting Market to Reach US$381,4 Million by the Year 2027 – Salamanca Press

NEW YORK, Nov. 25, 2020 /PRNewswire/ --Amid the COVID-19 crisis, the global market for Cell Harvesting estimated at US$233.2 Million in the year 2020, is projected to reach a revised size of US$381.4 Million by 2027, growing at a CAGR of 7.3% over the period 2020-2027.Manual, one of the segments analyzed in the report, is projected to grow at a 7.9% CAGR to reach US$284.4 Million by the end of the analysis period. After an early analysis of the business implications of the pandemic and its induced economic crisis, growth in the Automated segment is readjusted to a revised 5.6% CAGR for the next 7-year period. This segment currently accounts for a 28.3% share of the global Cell Harvesting market.

Read the full report: https://www.reportlinker.com/p05798117/?utm_source=PRN

The U.S. Accounts for Over 30.9% of Global Market Size in 2020, While China is Forecast to Grow at a 10.4% CAGR for the Period of 2020-2027

The Cell Harvesting market in the U.S. is estimated at US$72 Million in the year 2020. The country currently accounts for a 30.86% share in the global market. China, the world second largest economy, is forecast to reach an estimated market size of US$34.9 Million in the year 2027 trailing a CAGR of 10.4% through 2027. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 6.1% and 7% respectively over the 2020-2027 period. Within Europe, Germany is forecast to grow at approximately 6.6% CAGR while Rest of European market (as defined in the study) will reach US$34.9 Million by the year 2027.We bring years of research experience to this 5th edition of our report. The 226-page report presents concise insights into how the pandemic has impacted production and the buy side for 2020 and 2021. A short-term phased recovery by key geography is also addressed.

Competitors identified in this market include, among others,

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I. INTRODUCTION, METHODOLOGY & REPORT SCOPE I-1

II. EXECUTIVE SUMMARY II-1

1. MARKET OVERVIEW II-1 Cell Harvesting - A Prelude II-1 Impact of Covid-19 and a Looming Global Recession II-1 With Stem Cells Holding Potential to Emerge as Savior for Healthcare System Struggling with COVID-19 Crisis, Demand for Cell Harvesting to Grow II-1 Select Clinical Trials in Progress for MSCs in the Treatment of COVID-19 II-2 Lack of Antiviral Therapy Brings Spotlight on MSCs as Potential Option to Treat Severe Cases of COVID-19 II-3 Stem Cells Garner Significant Attention amid COVID-19 Crisis II-3 Growing R&D Investments & Rising Incidence of Chronic Diseases to Drive the Global Cell Harvesting Market over the Long-term II-3 US Dominates the Global Market, Asia-Pacific to Experience Lucrative Growth Rate II-4 Biopharmaceutical & Biotechnology Firms to Remain Key End-User II-4 Remarkable Progress in Stem Cell Research Unleashes Unlimited Avenues for Regenerative Medicine and Drug Development II-4 Drug Development II-5 Therapeutic Potential II-5

2. FOCUS ON SELECT PLAYERS II-6 Recent Market Activity II-7 Innovations and Advancements II-7

3. MARKET TRENDS & DRIVERS II-8 Development of Regenerative Medicine Accelerates Demand for Cell Harvesting II-8 The Use of Mesenchymal Stem Cells in Regenerative Medicine to Drive the Cell Harvesting Market II-8 Rise in Volume of Orthopedic Procedures Boosts Prospects for Stem Cell, Driving the Cell Harvesting II-9 Exhibit 1: Global Orthopedic Surgical Procedure Volume (2010- 2020) (in Million) II-11 Increasing Demand for Stem Cell Based Bone Grafts: Promising Growth Ahead for Cell Harvesting II-11 Spectacular Advances in Stem Cell R&D Open New Horizons for Regenerative Medicine II-12 Exhibit 2: Global Regenerative Medicines Market by Category (2019): Percentage Breakdown for Biomaterials, Stem Cell Therapies and Tissue Engineering II-13 Stem Cell Transplants Drive the Demand for Cell Harvesting II-13 Rise in Number of Hematopoietic Stem Cell Transplantation Procedures Propels Market Expansion II-15 Growing Incidence of Chronic Diseases to Boost the Demand for Cell Harvesting II-16 Exhibit 3: Global Cancer Incidence: Number of New Cancer Cases in Million for the Years 2018, 2020, 2025, 2030, 2035 and 2040 II-17 Exhibit 4: Global Number of New Cancer Cases and Cancer-related Deaths by Cancer Site for 2018 II-18 Exhibit 5: Number of New Cancer Cases and Deaths (in Million) by Region for 2018 II-19 Exhibit 6: Fatalities by Heart Conditions: Estimated Percentage Breakdown for Cardiovascular Disease, Ischemic Heart Disease, Stroke, and Others II-19 Exhibit 7: Rising Diabetes Prevalence Presents Opportunity for Cell Harvesting: Number of Adults (20-79) with Diabetes (in Millions) by Region for 2017 and 2045 II-20 Ageing Demographics to Drive Demand for Stem Cell Banking II-20 Global Aging Population Statistics - Opportunity Indicators II-21 Exhibit 8: Expanding Elderly Population Worldwide: Breakdown of Number of People Aged 65+ Years in Million by Geographic Region for the Years 2019 and 2030 II-21 Exhibit 9: Life Expectancy for Select Countries in Number of Years: 2019 II-22 High Cell Density as Major Bottleneck Leads to Innovative Cell Harvesting Methods II-22 Advanced Harvesting Systems to Overcome Centrifugation Issues II-23 Sophisticated Filters for Filtration Challenges II-23 Innovations in Closed Systems Boost Efficiency & Productivity of Cell Harvesting II-23 Enhanced Harvesting and Separation of Micro-Carrier Beads II-24

4. GLOBAL MARKET PERSPECTIVE II-25 Table 1: World Current & Future Analysis for Cell Harvesting by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-25

Table 2: World Historic Review for Cell Harvesting by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-26

Table 3: World 15-Year Perspective for Cell Harvesting by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets for Years 2012, 2020 & 2027 II-27

Table 4: World Current & Future Analysis for Manual by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-28

Table 5: World Historic Review for Manual by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-29

Table 6: World 15-Year Perspective for Manual by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-30

Table 7: World Current & Future Analysis for Automated by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-31

Table 8: World Historic Review for Automated by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-32

Table 9: World 15-Year Perspective for Automated by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-33

Table 10: World Current & Future Analysis for Peripheral Blood by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-34

Table 11: World Historic Review for Peripheral Blood by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-35

Table 12: World 15-Year Perspective for Peripheral Blood by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-36

Table 13: World Current & Future Analysis for Bone Marrow by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-37

Table 14: World Historic Review for Bone Marrow by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-38

Table 15: World 15-Year Perspective for Bone Marrow by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-39

Table 16: World Current & Future Analysis for Umbilical Cord by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-40

Table 17: World Historic Review for Umbilical Cord by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-41

Table 18: World 15-Year Perspective for Umbilical Cord by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-42

Table 19: World Current & Future Analysis for Adipose Tissue by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-43

Table 20: World Historic Review for Adipose Tissue by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-44

Table 21: World 15-Year Perspective for Adipose Tissue by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-45

Table 22: World Current & Future Analysis for Other Applications by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-46

Table 23: World Historic Review for Other Applications by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-47

Table 24: World 15-Year Perspective for Other Applications by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-48

Table 25: World Current & Future Analysis for Biotech & Biopharma Companies by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-49

Table 26: World Historic Review for Biotech & Biopharma Companies by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-50

Table 27: World 15-Year Perspective for Biotech & Biopharma Companies by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-51

Table 28: World Current & Future Analysis for Research Institutes by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-52

Table 29: World Historic Review for Research Institutes by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-53

Table 30: World 15-Year Perspective for Research Institutes by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-54

Table 31: World Current & Future Analysis for Other End-Uses by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 II-55

Table 32: World Historic Review for Other End-Uses by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 II-56

Table 33: World 15-Year Perspective for Other End-Uses by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2012, 2020 & 2027 II-57

III. MARKET ANALYSIS III-1

GEOGRAPHIC MARKET ANALYSIS III-1

UNITED STATES III-1 Increasing Research on Stem Cells for Treating COVID-19 to drive the Cell Harvesting Market III-1 Rising Investments in Stem Cell-based Research Favors Cell Harvesting Market III-1 Exhibit 10: Stem Cell Research Funding in the US (in US$ Million) for the Years 2011 through 2017 III-2 A Strong Regenerative Medicine Market Drives Cell Harvesting Demand III-2 Arthritis III-3 Exhibit 11: Percentage of Population Diagnosed with Arthritis by Age Group III-3 Rapidly Ageing Population: A Major Driving Demand for Cell Harvesting Market III-4 Exhibit 12: North American Elderly Population by Age Group (1975-2050) III-4 Increasing Incidence of Chronic Diseases Drives Focus onto Cell Harvesting III-5 Exhibit 13: CVD in the US: Cardiovascular Disease* Prevalence in Adults by Gender & Age Group III-5 Rising Cancer Cases Spur Growth in Cell Harvesting Market III-5 Exhibit 14: Estimated Number of New Cancer Cases and Deaths in the US (2019) III-6 Exhibit 15: Estimated New Cases of Blood Cancers in the US (2020) - Lymphoma, Leukemia, Myeloma III-7 Exhibit 16: Estimated New Cases of Leukemia in the US: 2020 III-7 Market Analytics III-8 Table 34: USA Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-8

Table 35: USA Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-9

Table 36: USA 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-10

Table 37: USA Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-11

Table 38: USA Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-12

Table 39: USA 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-13

Table 40: USA Current & Future Analysis for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-14

Table 41: USA Historic Review for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-15

Table 42: USA 15-Year Perspective for Cell Harvesting by End-Use - Percentage Breakdown of Value Sales for Biotech & Biopharma Companies, Research Institutes and Other End-Uses for the Years 2012, 2020 & 2027 III-16

CANADA III-17 Market Overview III-17 Exhibit 17: Number of New Cancer Cases in Canada: 2019 III-17 Market Analytics III-18 Table 43: Canada Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-18

Table 44: Canada Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-19

Table 45: Canada 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-20

Table 46: Canada Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-21

Table 47: Canada Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-22

Table 48: Canada 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-23

Table 49: Canada Current & Future Analysis for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-24

Table 50: Canada Historic Review for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-25

Table 51: Canada 15-Year Perspective for Cell Harvesting by End-Use - Percentage Breakdown of Value Sales for Biotech & Biopharma Companies, Research Institutes and Other End-Uses for the Years 2012, 2020 & 2027 III-26

JAPAN III-27 Increasing Demand for Regenerative Medicine in Geriatric Healthcare and Cancer Care to Drive Demand for Cell Harvesting III-27 Exhibit 18: Japanese Population by Age Group (2015 & 2040): Percentage Share Breakdown of Population for 0-14, 15-64 and 65 & Above Age Groups III-27 Exhibit 19: Cancer Related Incidence and Deaths by Site in Japan: 2018 III-28 Market Analytics III-29 Table 52: Japan Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-29

Table 53: Japan Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-30

Table 54: Japan 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-31

Table 55: Japan Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-32

Table 56: Japan Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-33

Table 57: Japan 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-34

Table 58: Japan Current & Future Analysis for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-35

Table 59: Japan Historic Review for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-36

Table 60: Japan 15-Year Perspective for Cell Harvesting by End-Use - Percentage Breakdown of Value Sales for Biotech & Biopharma Companies, Research Institutes and Other End-Uses for the Years 2012, 2020 & 2027 III-37

CHINA III-38 Rising Incidence of Cancer Drives Cell Harvesting Market III-38 Exhibit 20: Number of New Cancer Cases Diagnosed (in Thousands) in China: 2018 III-38 Market Analytics III-39 Table 61: China Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-39

Table 62: China Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-40

Table 63: China 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-41

Table 64: China Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-42

Table 65: China Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-43

Table 66: China 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-44

Table 67: China Current & Future Analysis for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-45

Table 68: China Historic Review for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-46

Table 69: China 15-Year Perspective for Cell Harvesting by End-Use - Percentage Breakdown of Value Sales for Biotech & Biopharma Companies, Research Institutes and Other End-Uses for the Years 2012, 2020 & 2027 III-47

EUROPE III-48 Cancer in Europe: Key Statistics III-48 Exhibit 21: Cancer Incidence in Europe: Number of New Cancer Cases (in Thousands) by Site for 2018 III-48 Ageing Population to Drive Demand for Cell Harvesting Market III-49 Exhibit 22: European Population by Age Group (2016, 2030 & 2050): Percentage Share Breakdown by Age Group for 0-14, 15- 64, and 65 & Above III-49 Market Analytics III-50 Table 70: Europe Current & Future Analysis for Cell Harvesting by Geographic Region - France, Germany, Italy, UK and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 III-50

Table 71: Europe Historic Review for Cell Harvesting by Geographic Region - France, Germany, Italy, UK and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-51

Table 72: Europe 15-Year Perspective for Cell Harvesting by Geographic Region - Percentage Breakdown of Value Sales for France, Germany, Italy, UK and Rest of Europe Markets for Years 2012, 2020 & 2027 III-52

Table 73: Europe Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-53

Table 74: Europe Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-54

Table 75: Europe 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-55

Table 76: Europe Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-56

Table 77: Europe Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-57

Table 78: Europe 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-58

Table 79: Europe Current & Future Analysis for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-59

Table 80: Europe Historic Review for Cell Harvesting by End-Use - Biotech & Biopharma Companies, Research Institutes and Other End-Uses Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-60

Table 81: Europe 15-Year Perspective for Cell Harvesting by End-Use - Percentage Breakdown of Value Sales for Biotech & Biopharma Companies, Research Institutes and Other End-Uses for the Years 2012, 2020 & 2027 III-61

FRANCE III-62 Table 82: France Current & Future Analysis for Cell Harvesting by Type - Manual and Automated - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-62

Table 83: France Historic Review for Cell Harvesting by Type - Manual and Automated Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-63

Table 84: France 15-Year Perspective for Cell Harvesting by Type - Percentage Breakdown of Value Sales for Manual and Automated for the Years 2012, 2020 & 2027 III-64

Table 85: France Current & Future Analysis for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 III-65

Table 86: France Historic Review for Cell Harvesting by Application - Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 III-66

Table 87: France 15-Year Perspective for Cell Harvesting by Application - Percentage Breakdown of Value Sales for Peripheral Blood, Bone Marrow, Umbilical Cord, Adipose Tissue and Other Applications for the Years 2012, 2020 & 2027 III-67

Excerpt from:
Global Cell Harvesting Market to Reach US$381,4 Million by the Year 2027 - Salamanca Press

Tanya Siddiqi, MD, Discusses the Promise of Reduced Toxicity With Liso-Cel – AJMC.com Managed Markets Network

In addition, liso-cels distinct manufacturing process creates a defined composition of CD8+ and CD4+ T-cells, which may reduce product variability; however, the manufacturer states, the clinical significance of defined composition is unknown.

For insights on what the arrival of liso-cel could mean in the treatment landscape, The American Journal of Managed Care (AJMC) turned to Tanya Siddiqi, MD, director of the Chronic Lymphocytic Leukemia Program at Toni Stephenson Lymphoma Center and associate clinical professor, Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, Duarte, California.

Siddiqi was an investigator for ZUMA-1, which led to the approval of axicabtagene ciloleucel(axi-cel), sold as Yescarta, and the TRANSCEND NHL trial for liso-cel.She has addressed major scientific meetings on the challenge of managing the toxicities associated with CAR T-cell therapyand discussed how liso-cel represents a step forward over its predecessors.

This interview, conducted before the BMS announcement, has been edited for clarity and length.

AJMC: We're anticipating an FDA decision on liso-cel before the end of the year. Can you discuss the need of the patients who would take this new CAR T-cell therapy?

Siddiqi: So, for CAR T-cell therapy targeting CD19-positive B-cell lymphomasspecifically aggressive B-cell lymphomaswe already have a couple of FDA-approved options. The question is: what is liso-cel? How is it different? Why would people pick this over other things? In the trials that we've conducted, we found that liso-cel seems to have lesser toxicity in terms of the specific CAR T-cell side effects of cytokine release syndrome or hyper-inflammation, as well as neurotoxicity. We've just seen fewer severe adverse events so much so that at some [cancer] centers across the country, weve been able to give liso-cel CAR T-cells to patients in the clinic or outpatient setting rather than having to admit them to the hospital , depending on the patient's situation.

Those are the strengths of liso-celless toxicity and thus, a better chance of giving it in the outpatient setting with hospital admission available to anyone who develops a fever or other side effects. This means fewer days of inpatient hospitalization for these patients, so it may be less costly overall. I dont think the efficacy is necessarily differentmeaning that it seems to work as well as the other FDA-approved products already commercially available. But for the reasons that I've listed, I think it might be a very good option for older patients, maybe patients who are bit more frail, or younger patients who just don't want to be admitted to the hospitalthey just want to try to do it in the outpatient setting.

AJMC:You touched on this already, but can you discuss how Iiso-cel differs from earlier CAR T-cell therapiesboth in the way it's manufactured and how it works, and what that reduced variability means for patients?

Siddiqi: Liso-celis manufactured in a way that it gives very precise, equal numbers of CAR cells that are labeled CD4 and CD8, in a 1:1 ratio. All of us have T cells to fight infections with, and these T cells are what we take from patients. Then, we modify them in the lab by genetic engineering in order to produce CAR T-cells so that now instead of looking for infections, these CAR T cells are going to look for B-cell lymphoma cells and fight lymphoma.

The other products are given back to patients as a bag of CAR T cells mixed with potentially varying ratios of different types of T cellsCD4+, CD8+, etc. With liso-cel the manufacturing process actually separates out the CD4+ and CD8+ types of T cells first, and then manufactures CAR-T cells out of them separately. So, when we give the cells back to patients, we give it in a 1:1 ratio of CD4+ and CD8+ cells. We know exactly how many CD4+ and how many CD8+ T-cells these patients receive. And the thought is, the researchers and the drug manufacturer feel that this helps to have an expectation of what expansion you will have of these cells in the body.

Therefore, we potentially have an idea of what type of side effects or how severe the side effects might be. It may limit some of those side effects, or at least make them a little bit more predictable or controlled.

AJMC:Thats a great way to shift to your own work on length of stay due to CRS. What do we know about the key variables in determining whether a patient will experience a side effect that requires an extended stay in the hospital, and can more be done to avoid lengthy hospital stays?

Siddiqi: That's a very important question. Because lengthy hospital stays, especially in the [intensive care unit], really adds to the bill and the financial burden of these treatments. We know that people who have a big burden of disease going into CAR T-cell therapy, meaning they have a lot of lymphoma in their bodies, they tend to be at higher risk for more side effects like cytokine release syndrome and neurotoxicity. Probably because there's so much inflammation thats generated while these CAR T-cells are trying to fight the lymphoma. What we know is that people who come to us for CAR T-cells with lesser disease might have fewer side effects potentially and a better overall outcome.

So, we always try to advise our referring physicians, and educate patients, at conferences, to try to send these patients to us before they are at the end of the linebefore theyve tried and failed everything, and now theres just rampant disease. [At that point,] you're dealing with a situation where the patient is going to have more side effects and will not be able to tolerate the CAR T cells as well. Instead, if they fail two lines of therapy and the disease is still small in volume, but it's starting to progress, we can treat them more effectively with CAR T cells and with fewer side effects potentially.

AJMC:That brings up the next topicthere have been discussions that CAR T-cell therapy should be given earlier during treatment. As you said, if its not given as the last resort, patients might respond better. Where do you see those patterns heading in the future? And would that be truer for some patients than others?

Siddiqi: With aggressive diffuse large B-cell lymphoma, there's about a 60% to 70% chance of curing that in the frontline setting. With the line of chemo-immunotherapy, you can cure 60% to 70% of patients so that it never comes back. But the rest of themwhen it just relentlessly keeps coming back and it's hard to cureonce those patients relapse they tend to keep relapsing. So, our mainstay in the relapse setting is to give them salvage chemo-immunotherapy, collect stem cells, and take them to autologous stem cell transplantation if they've achieved a remission with the salvage chemotherapy. If they haven't achieved remission with that salvage chemotherapy, then they should go on to CAR T cells directly instead of waiting and trying more and more chemotherapies. After failing second line therapy, the FDA approval allows us to try CAR T cells. There are studies that are now ongoing that are comparing CAR T cells to autologous stem cell transplantation after failing first line therapy. So, once patients relapse the first time, these studies are comparing giving them salvage chemotherapy and transplant, versus taking them straight to CAR T cells. Once we have that data, we'll know better whether we can do CAR T cells even earlier in the lines of therapy.

AJMC:Weve been hearing for some time more about allogeneic or off-the-shelf therapies. What progress has been made on in that technology?

Siddiqi: I'm not too involved with these trials myself, but I know we have trials at City of Hope that are ongoing with off-the-shelf therapy. What I can tell you is that it's very attractive in that you don't have to collect T cells from patients, keeping their lymphoma under control while these T cells then go to the lab and CAR T cells are manufactured in 2-4 weeks depending on which product it is, and then they come back and get infused. With off-the-shelf products, you can just grab it and go as soon as you know the patient needs it.

The initial concerns were because the cells are not from the patient themselvesthe cells are from donors. Across the board there might be concerns of rejection and what's called graft-versus-host disease and things like that. So far, I don't think in the trial they've come up with such side effects to any significant extent. What I don't know is whether they've come up with a good result yet. Is it looking like the benefits of taking off-the-shelf CAR T cells are as good as autologous CAR T cells, meaning patients own CAR T cells? I think that remains to be seen. If they are, then it's much easier to use off-the-shelf CAR T cells. Maybe at the American Society of Hematology annual meeting in December we will see more data.

AJMC: How is COVID-19 affecting the clinical trial process for CAR T cell therapy?

Siddiqi: When the pandemic kind of started surging early in the year, and when we went into lockdown mode from March onward, we and other centers across the country took a lot of steps to slow down our clinical trial enrollment. Our staff started staggering who would come into work which day of the week and who could work from home. For those in the clinical trials office, there was a lot of need for safety and logistical reasons for us to slow down enrollment onto clinical trials. And there were other questions, such as, who would take care of patients at home once we discharged them after they received CAR T cells? What if their caregivers were exposed and got sick? Logistically, it was difficult to safely do many trials, especially CAR T cell trials and transplants earlier in the year.

Since the end of summer, we ramped up again, and we're now doing as many transplants and CAR T cells as we were probably doing last year. So, we're pretty much all the way up again, but I don't know how this winter will go because COVID is surging again.

As far as just CAR T cells themselves, we had to also think about travel for the cells because Juno Therapeutics is in Seattle, and Kite Pharma is here in Los Angeles, but Novartis is elsewhere. Just the movement of these cells was a concern because of travel restrictions during COVID-19. But as far as I know, the companies did not lose that commitmentthey told us, well get the cells to you, we will find a way to do it. I don't think any patients went without cells who should have received cells.

AJMC: What advice do you have for community oncologists interested in CAR T cell therapy for their patients?

Siddiqi: Theres good news for community physicians. We may soon have a therapeutic option of liso-cel CAR T cell therapy which seems to have lesser side effects. So, this might make things cheaper due to less need for hospitalization potentially without compromising the chance of cure. We want these patients to try CAR T cell therapy sooner rather than later in their relapses. You can always try multiple cycles of chemotherapy at some other time if you relapse again, but if you can be cured with CAR T cells such that you never need treatment again, why not try that first? For the patients who respond well to CAR T cells, the treatment works extremely well. And that's the Holy Grail to find the cure for all patients.

Maybe only half the patients will currently have a very good and durable responsebut those patients may never relapse again. So why not try it sooner rather than later? And of course, we're always looking for trial patients, because now we need to improve these results even further. So, community oncologists should also refer for trials, because I think that its very important to have trials with different combinationsCAR T cells plus another immunotherapy agentto see if we can improve upon the response rates even more.

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Tanya Siddiqi, MD, Discusses the Promise of Reduced Toxicity With Liso-Cel - AJMC.com Managed Markets Network

Tetracycline-based Antibiotics Show Promise for Combating Zika Infections – Global Biodefense

A widely used antibiotic methacycline was shown effective at preventing brain infections and reducing neurological problems associated with Zika virus in mice models.

National Institutes of Health (NIH) researchers used advanced drug screening techniques to test out more than 10,000 compounds in search of Zika virus therapeutics. The scientists discovered that the widely used antibiotic methacycline was effective at preventing brain infections and reducing neurological problems associated with the virus in mice. Additionally, they found that drugs originally designed to combat Alzheimers disease and inflammation may also help fight infections.

In this study, the researchers looked for drugs that prevent the virus from reproducing by blocking the activity of a protein called NS2B-NS3 Zika virus protease. The Zika virus is a protein capsule that carries long strings of RNA-encoded instructions for manufacturing more viral proteins. During an infection, the virus injects the RNA into a cell, resulting in the production of these proteins, which are strung together, side-by-side, like the parts in a plastic model airplane kit. The NS2B-NS3 protease then snaps off each protein, all of which are critical for assembling new viral particles.

The study was a collaboration between scientists on Dr. Naths team and researchers in laboratories led by Anton Simeonov, Ph.D., scientific director at the NIHs National Center for Advancing Translational Sciences (NCATS) and Radhakrishnan Padmanabhan, Ph.D., Professor of Microbiology & Immunology, Georgetown University Medical Center, Washington, D.C.

The Zika virus is primarily spread by the Aedes aegypti mosquito. In 2015 and 2016, at least 60 countries reported infections. Some of these countries also reported a high incidence of infected mothers giving birth to babies born with abnormally small heads resulting from a developmental brain disorder called fetal microcephaly. In some adults, infections were the cause of several neurological disorders including Guillain-Barr syndrome, encephalitis, and myelitis. Although many scientists have tried, they have yet to discover an effective treatment or vaccination against the virus.

Proteases act like scissors. Blocking protease activity is an effective strategy for counteracting many viruses, said Rachel Abrams, Ph.D., an organic chemist in Dr. Naths lab and the study leader. We wanted to look as far and wide as possible for drugs that could prevent the protease from snipping the Zika virus polyprotein into its active pieces.

To find candidates, Dr. Abrams worked with scientists on Dr. Simeonovs and Dr. Padmanabhans teams to create assays, or tests, for assessing the ability of drugs to block NS2B-NS3 Zika virus protease activity in plates containing hundreds of tiny test tubes. Each assay was tailored to a different screening, or sifting, technique. They then used these assays to simultaneously try out thousands of candidates stored in three separate libraries.

One preliminary screen of 2,000 compounds suggested that commonly used, tetracycline-based antibiotic drugs, like methacycline, may be effective at blocking the protease.

Meanwhile, a large-scale screen of more than 10,000 compounds helped identify an investigational anti-inflammatory medicine, called MK-591, and a failed anti-Alzheimers disease drug, called JNJ-404 as potential candidates. A virtual screen of over 130,000 compounds was also used to help spot candidates. For this, the researchers fed the other screening results into a computer and then used artificial intelligence-based programs to learn what makes a compound good at blocking NS2B-NS3 Zika virus protease activity.

These results show that taking advantage of the latest technological advances can help researchers find treatments that can be repurposed to fight other diseases, said Dr. Simeonov.

The Zika virus is known to preferentially infect stem cells in the brain. Scientists suspect this is the reason why infections cause more harm to newborn babies than to adults. Experiments on neural stem cells grown in petri dishes indicated that all three drugs identified in this study may counteract these problems. Treating the cells with methacycline, MK-591, or JNJ-404 reduced Zika virus infections.

Because tetracyclines are U.S. Food and Drug Administration-approved drugs that are known to cross the placenta of pregnant women, the researchers focused on methacycline and found that it may reduce some neurodevelopmental problems caused by the Zika virus. For instance, Zika-infected newborn mice that were treated with methacycline had better balance and could turn over more easily than ones that were given a placebo. Brain examinations suggested this was because the antibiotic reduced infections and neural damage. Nevertheless, the antibiotics did not completely counteract harm caused by the Zika virus. The weight of mice infected with the virus was lower than control mice regardless of whether the mice were treated with methacycline.

These results suggest that tetracycline-based antibiotics may at least be effective at preventing the neurological problems associated with Zika virus infections, said Dr. Abrams. Given that they are widely used, we hope that we can rapidly test their potential in clinical trials.

Therapeutic Candidates for the Zika Virus Identified by a High Throughput Screen for Zika Protease Inhibitors.PNAS, November 23, 2020

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Study Suggests AYAs Treated for AML Have High Risk of Developing Long-Term Complications – Cancer Network

Study results published in the International Journal of Epidemiology suggested that adolescent and young adult (AYA) patients treated for acute myeloid leukemia (AML) have a high risk of developing long-term health complications.1

The most common complications, or late effects as they are referred to in the study, observed among AYA survivors in this study were cardiovascular, endocrine, and respiratory diseases. Moreover, these complications were found to be more prevalent among non-white AYA patients and those living in more impoverished communities.

Our study shed light on the high burden of late effects among young survivors of AML, lead author Renata Abraho, MD, MSc, PhD, a postdoctoral fellow at theUC Davis Comprehensive Cancer Centerand the Center for Healthcare Policy and Research, said in a press release.2

To estimate the cumulative incidence and investigate the main predictors of late effects among this patient population, researchers identified 1168 eligible AYAs with AML who survived at least 2years after diagnosis from 1996 to 2012 in the California Cancer Registry. Importantly, late effects were reported from State hospital discharge data, and patients were followed through 2014.

Ultimately, the most common late effects reported at 10years after diagnosis were endocrine (26.1%), cardiovascular (18.6%), and respiratory (6.6%), followed by neurologic (4.9%), liver/pancreatic (4.3%), renal (3.1%), avascular necrosis (2.7%), and second primary malignancies (2.4%). Moreover, of the total study cohort, 547 (46.8%) received a hematopoietic stem cell transplant (HSCT).

Following multivariable adjustments, the investigators found that AYAs who underwent HSCT or had non-favorable risk AML experienced an approximately 2-fold or higher increased likelihood of all late effects. Additionally, AYAs of Hispanic, Black, or Asian/Pacific Islander race or ethnicity and those who resided in lower socio-economic neighborhoods were shown to be at higher risk of numerous late effects when compared with non-Hispanic White patients.

This higher risk may relate to the financial hardship that patients with cancer often experience, senior author Theresa Keegan, PhD, MS, associate professor at the UC Davis Comprehensive Cancer Center, said in a press release. As a result of cancer, AYA survivors and their families may miss work, experience income loss, and incur substantial out-of-pocket expenses.

According to the researchers, many factors may have led to the observed disparities in disease burden. These include differences in therapeutic management, patients response to treatment, AML with high-risk mutations, coexisting diseases, and socioeconomic factors.

Further, compared to younger or older cancer survivors, the investigators indicated AYA patients suffer a higher financial burden. They may go without treatment and long-term follow-up visits that could mitigate the impact of late effects. Moreover, their risk of late effects may be exacerbated by unhealthy lifestyle habits such as smoking, excessive alcohol consumption, lack of exercise, non-protected sun exposure, and poor diet.

Our findings underscore the need for long-term surveillance for the prevention, early detection and treatment of late effects, and can inform the development of AYA-focused consensus-based guidelines that will ultimately improve the quality of life and survival of these young vulnerable patients, the study authors wrote.

References:

1. Abraho R, Huynh JC, Benjamin DJ, et al. Chronic medical conditions and late effects after acute myeloid leukaemia in adolescents and young adults: a population-based study. International Journal of Epidemiology. doi: 10.1093/ije/dyaa184

2. Young survivors of acute myeloid leukemia have long-term complications from treatment [news release]. Published November 9, 2020. Accessed November 17, 2020. https://www.newswise.com/articles/young-survivors-of-acute-myeloid-leukemia-have-long-term-complications-from-treatment?sc=sphr&xy=10019792

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Study Suggests AYAs Treated for AML Have High Risk of Developing Long-Term Complications - Cancer Network