Category Archives: Cell Medicine

Feb. 8, 2021 13:00 UTC

CARLSBAD, Calif.--(BUSINESS WIRE)-- Lineage Cell Therapeutics, Inc.(NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, today announced that it has entered into an exclusive option and license agreement with Neurgain Technologies, Inc. (Neurgain), a medical device company that is commercializing technology developed by neurosurgeons at the University of California San Diego (UC San Diego). Under the terms of the agreement, Lineage and Neurgain will collaborate on the clinical testing of Neurgains novel Parenchymal Delivery Injection (PDI) system, which is designed to allow for the administration of cells to the spinal cord without stopping the patients respiration. Elimination of the need to stop respiration during surgery is expected to reduce the complexity, risk, and variability of administering cells to the area of injury. Lineage also will be hosting an OPC1 Investor and Analyst Day on February 22, 2021 to provide details on recent OPC1 milestones and plans for 2021.

Lineage will evaluate the Neurgain PDI systems ability to safely and effectively deliver OPC1, Lineages allogeneic oligodendrocyte progenitor cell (OPC) transplant, to the spinal cord in both preclinical and clinical studies beginning this year. If results from the PDI system are positive, then Lineage may exercise its option to enter into a pre-negotiated license and commercialization agreement with Neurgain. Pursuant to that agreement, Lineage may integrate the PDI system into a later-stage clinical trial and if approved, commercial use of OPC1 for the treatment of patients with a cervical spinal cord injury. There currently are no U.S. Food and Drug Administration (FDA) approved treatments for spinal cord injury.

Brian M. Culley, Lineage CEO stated, Several months ago, we announced we had significantly improved the process for manufacturing OPC1, leading to large increases in purity and scale. More recently, we successfully developed a new 'thaw-and-inject' formulation, eliminating the commercially undesirable steps of handling and preparing cells one day prior to their use. Today, we are announcing another valuable improvement to the OPC1 program: access to a novel and convenient delivery system, which reduces a significant technical hurdle of conducting a larger-scale clinical trial. The Neurgain PDI offers an easier, potentially safer, and commercially more attractive option to treat SCI patients and is preferable to the complicated gantry utilized in an earlier study. It also will allow us to incorporate our new 'thaw-and-inject' formulation of OPC1, thereby enabling faster patient enrollment via access to a larger number of clinical trial sites. Most importantly, the PDI can eliminate the need for a patients respirator to be turned off during the procedure, facilitating a measured and targeted transplantation of cells to the affected area.

We look forward to collaborating with Lineage on their novel OPC1 program and demonstrating the value that Neurgains PDI system can provide for the effective delivery of cell therapies in general and for the treatment of spinal cord injury in particular, stated Michael Krupp, Neurgain CEO.

Brian Culley added, Similar to our alliance with Gyroscope Therapeutics for the Orbit Subretinal Delivery System, this new partnership with Neurgain delivers on our stated commitment to identifying and deploying optimal combinations of allogeneic cell therapies, modern manufacturing techniques, and superior delivery solutions in pursuit of our goal of becoming the pre-eminent allogeneic cell transplant company.

The Neurgain PDI System has been designed to provide specific, on-target delivery of cells with accurate dosing. The PDI system is more compact than existing devices and it is attached directly to the patient during the procedure. It is comprised of a platform and manipulator with a disposable magnetic needle assembly. This novel delivery system is expected to provide a significant improvement in usability and precision when compared to the methods and tools utilized to deliver OPC1 cells in the completed phase 1/2a SCiStar study of OPC1 for the treatment of acute cervical SCI.

About Spinal Cord Injuries

A spinal cord injury (SCI) occurs when the spinal cord is subjected to a severe crush or contusion and frequently results in severe functional impairment, including limb paralysis, aberrant pain signaling, and loss of bladder control and other body functions. There are approximately 18,000 new spinal cord injuries annually in the U.S. There are no FDA-approved drugs specifically for the treatment of SCI. The cost of a lifetime of care for a severe spinal cord injury can be as high as $5 million.

About OPC1

OPC1 is an oligodendrocyte progenitor cell (OPC) transplant therapy designed to provide clinically meaningful improvements in motor recovery in individuals with acute spinal cord injuries (SCI). OPCs are naturally occurring precursors to the cells which provide electrical insulation for nerve axons in the form of a myelin sheath. The OPC1 program has been partially funded by a $14.3 million grant from the California Institute for Regenerative Medicine (CIRM). OPC1 has received Regenerative Medicine Advanced Therapy (RMAT) designation and Orphan Drug designation from the FDA.

About the OPC1 Clinical Study

The SCiStar Study of OPC1 is an open-label, 25-patient, single-arm trial testing three sequential escalating doses of OPC1 administered 21 to 42 days post-injury in patients with subacute motor complete (AIS-A or AIS-B) cervical (C-4 to C-7) acute spinal cord injuries (SCI). Patient enrollment in this study is complete; 96% of patients reported one level of improved motor function and 33% of patients reported two levels of improved motor function. Patients continue to be evaluated on a long-term basis. Patients enrolled in the study had experienced severe paralysis of the upper and lower limbs. The primary endpoint in the study was safety. Secondary outcome measures included neurological function measured by upper extremity motor scores (UEMS) and motor level on International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) examinations through 365 days post-treatment.

About Neurgain Technologies, Inc.

Neurgain Technologies (NGT) was founded in 2013 to develop technologies focused on the treatment of neurodegenerative diseases and neuropathic pain. Neurgain is developing a novel gene therapy technology and delivery devices to treat chronic neuropathic pain and spinal spasticity. 7-8% of the population suffers from Neuropathic Pain. Current therapeutic management is not working: Drugs in use have poor efficacy, and cause undesirable side effects such as resistance, addiction, and other disorders. NGTs mission is to positively impact this problem by means of our patented innovation to provide a therapy that works and improves the patients quality of life. The Company is developing two assets: 1. Spinal subpial gene delivery platform (device), 2. Pre-clinical gene therapy for severe neuropathic pain. NGT plans to license the platform delivery technologies to multiple pharma/biotech which are developing gene or cell therapies in CNS. Neurgains business strategy involves the out-licensing of spinal cord delivery technology and clinical development of a gene therapy for neuropathic pain and chronic spasticity. For more information, please visit https://neurgaintech.com/.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include three allogeneic (off-the-shelf) product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, a leading cause of blindness in the developed world; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; and (iii) VAC, an allogeneic dendritic cell therapy platform for immuno-oncology and infectious disease, currently in clinical development for the treatment of non-small cell lung cancer. For more information, please visit http://www.lineagecell.com or follow the Company on Twitter @LineageCell.

Forward-Looking Statements

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as believe, may, will, estimate, continue, anticipate, design, intend, expect, could, plan, potential, predict, seek, should, would, contemplate, project, target, tend to, or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the potential benefits of using the Neurgain PDI device. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineages actual results, performance, or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including risks and uncertainties inherent in Lineages business and other risks in Lineages filings with the Securities and Exchange Commission (the SEC). Lineages forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading Risk Factors in Lineages periodic reports with the SEC, including Lineages Annual Report on Form 10-K filed with the SEC on March 12, 2020 and its other reports, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

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Lineage Enters Into Exclusive Agreement with Neurgain Technologies to Evaluate Novel Delivery System for OPC1 to Treat Spinal Cord Injury - BioSpace

ALAMEDA, Calif.--(BUSINESS WIRE)--Exelixis, Inc. (NASDAQ: EXEL) today announced results from a retrospective analysis evaluating CABOMETYX (cabozantinib) activity in brain metastases in patients with renal cell carcinoma (RCC). The findings will be presented as part of the Poster Session: Renal Cell Cancer at the 2021 American Society of Clinical Oncologys Genitourinary Cancers Symposium (ASCO GU), which is being held virtually, February 11-13, 2021. All posters will be available on demand beginning at 5:00 a.m. PT on Thursday, February 11.

In this retrospective analysis of medical records from patients with metastatic RCC with brain metastases, an intracranial response rate of 61% (95% CI: 39%-80%), including a complete response rate of 13%, was seen for patients with progressing intracranial metastases at baseline (Cohort 1; n=25) who were treated with CABOMETYX. Patients without progressing intracranial metastases (Cohort 2; n=44) had an intracranial response rate of 57% (95% CI: 41%-72%). The rate of brain disease progression at six months was 16% for patients with progressive brain disease at baseline and 9% for those without. Median overall survival was 14.7 months for Cohort 1 and 14.1. months for Cohort 2. The reported safety data are consistent with the known safety profile for CABOMETYX.

With these exciting results, oral systemic cabozantinib is showing intriguing activity on brain metastases in renal cell carcinoma, said Dr. Toni Choueiri, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. The high intracranial response rates seen in this retrospective analysis suggest cabozantinib has the potential for helping patients with difficult-to-treat brain lesions from kidney cancer. We look forward to building on these encouraging findings through the ongoing phase 2 CABRAMET trial (NCT03967522) led by our French colleagues, which is prospectively evaluating cabozantinib in patients with brain metastases from renal cell carcinoma.

Brain metastases resulting from renal cell carcinoma are especially difficult to treat, as the blood-brain barrier poses a challenge for therapies to reach their targets, said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. These encouraging results including a high intracranial response rate, suggest CABOMETYX may reduce the size of brain metastases, without neurological toxicity, and thereby may be of interest to physicians treating kidney cancer patients with brain metastases.

About the Study

For this retrospective study, sponsored by the Dana-Farber Cancer Institute, consecutive medical records from patients with metastatic RCC with brain metastases who had been treated with cabozantinib monotherapy across 15 institutions in the United States (ten centers), Belgium (three centers), Spain (one center) and France (one center) were reviewed.

Patients were divided into two cohorts based on the presence (n=25) or absence (n=44) of progressing intracranial metastases at start of CABOMETYX therapy. Most patients (87%) were International Metastatic RCC Database Consortium (IMDC) intermediate/poor risk, and 75% had been previously treated. Prior brain-directed therapy was received by 65% of patients with progressing brain metatstases and by 93% of those without. All patients were treated with CABOMETYX. Four patients were not included in the intracranial analysis due to brain lesion size under 5 mm.

About RCC

The American Cancer Societys 2021 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common form of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 13%.1 Approximately 32,000 patients in the U.S. and 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2021.3

About 70% of RCC cases are known as clear cell carcinomas, based on histology.4 The majority of clear cell RCC tumors have below-normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.5,6 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.7,8,9,10 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.6,7

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with nivolumab. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States.

Important Safety Information

Warnings and Precautions

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade 2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade 2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade 2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. Johns wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.FDA.gov/medwatch or call 1-800-FDA-1088.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX (cabozantinib), COMETRIQ (cabozantinib), COTELLIC (cobimetinib) and MINNEBRO (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of the Standard & Poors (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. In November 2020, the company was named to Fortunes 100 Fastest-Growing Companies list for the first time, ranking 17th overall and the third-highest biopharmaceutical company. For more information about Exelixis, please visit http://www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

Forward-Looking Statements

This press release contains forward-looking statements, including, without limitation, statements related to: the presentation of data from a retrospective analysis evaluating CABOMETYX activity in brain metastases in patients with RCC at ASCO GU; the therapeutic potential of CABOMETYX for patients with difficult-to-treat brain lesions from kidney cancer; and Exelixis plans to reinvest in its business to maximize the potential of the companys pipeline, including through targeted business development activities and internal drug discovery. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the availability of data at the referenced times; the potential failure of cabozantinib to demonstrate safety and/or efficacy in future trials; unexpected concerns that may arise as a result of the occurrence of adverse safety events or additional data analyses of clinical trials evaluating CABOMETYX; Exelixis continuing compliance with applicable legal and regulatory requirements; Exelixis dependence on third-party vendors for the development, manufacture and supply of cabozantinib; Exelixis ability to protect its intellectual property rights; market competition, including the potential for competitors to obtain approval for generic versions of CABOMETYX; changes in economic and business conditions, including as a result of the COVID-19 pandemic; and other factors affecting Exelixis and its development programs discussed under the caption Risk Factors in Exelixis Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 5, 2020, and in Exelixis future filings with the SEC. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law.

Exelixis, the Exelixis logo, CABOMETYX, COMETRIQ and COTELLIC are registered U.S. trademarks. MINNEBRO is a Japanese trademark.

1 American Cancer Society: Cancer Facts & Figures 2021. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf. Accessed February 2021.2 Jonasch, E., Gao, J., Rathmell, W., Renal cell carcinoma. BMJ. 2014; 349:g4797.3 Decision Resources Report: Renal Cell Carcinoma. October 2014 (internal data on file).4 American Cancer Society: What is Kidney Cancer? Available at: https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.html. Accessed February 2021.5 Harshman, L., and Choueiri, T. Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J. 2013; 19:316-323.6 Rankin, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci USA. 2014; 111:13373-13378.7 Zhou, L., Liu, X-D., Sun, M., et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016; 35:2687-2697.8 Koochekpour, et al. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999; 19:59025912.9 Takahashi, A., Sasaki, H., Kim, S., et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994; 54:4233-4237.10 Nakagawa, M., Emoto, A., Hanada, T., Nasu, N., Nomura, Y. Tubulogenesis by microvascular endothelial cells is mediated by vascular endothelial growth factor (VEGF) in renal cell carcinoma. Br J Urol. 1997; 79:681-687.

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Exelixis Announces Positive Findings at ASCO GU for CABOMETYX (cabozantinib) in Patients with Brain Metastases from Renal Cell Carcinoma - Business...

PRINCETON, N.J., & ALAMEDA, Calif.--(BUSINESS WIRE)--Bristol Myers Squibb (NYSE: BMY) and Exelixis, Inc. (NASDAQ: EXEL) today announced results from new analyses from the pivotal Phase 3 CheckMate -9ER trial, demonstrating clinically meaningful, sustained efficacy benefits as well as quality of life improvements with the combination of OPDIVO (nivolumab) and CABOMETYX (cabozantinib) compared to sunitinib in the first-line treatment of advanced renal cell carcinoma (RCC). These data will be presented in two posters at the virtual American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium from February 11 to 13, 2021 and featured in the Poster Highlights Session on February 13, 2021 from 9:00 a.m. 9:45 a.m. EST.

Abstract #308: Nivolumab + cabozantinib (NIVO+CABO) vs. sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate -9ER (Motzer, et. al.)

With a median follow-up of two years (23.5 months), OPDIVO in combination with CABOMETYX continued to show superior progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) versus sunitinib, with a low rate of treatment-related adverse events (TRAEs) leading to discontinuation. No new safety signals were identified with extended follow-up. Across the full study population:

In an exploratory subgroup analysis of 75 patients with sarcomatoid features, the combination of OPDIVO and CABOMETYX showed benefit in this population typically associated with a poor prognosis, reducing the risk of death by 64% vs. sunitinib (HR 0.36; 95% CI: 0.17 to 0.79) and demonstrating both superior PFS (10.3 months vs. 4.2 months) and ORR (55.9% vs. 22.0%).

Abstract #285: Patient-reported outcomes of patients with advanced renal cell carcinoma (aRCC) treated with first-line nivolumab plus cabozantinib versus sunitinib: the CheckMate -9ER trial (Cella, et. al.)

In a separate analysis from the CheckMate -9ER trial conducted with 18.1 months of median follow-up, patients treated with the combination of OPDIVO and CABOMETYX reported statistically significant health-related quality of life benefits. Treatment with OPDIVO in combination with CABOMETYX was associated with a lower treatment burden, decreased risk of deterioration and a reduction of disease-related symptoms compared to sunitinib. These exploratory outcomes were measured using Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), a quality of life tool specific to kidney cancer, and EQ-5D-3L instruments.

There is a continued need for new therapies that show benefit across subgroups of patients with advanced renal cell carcinoma, said Robert Motzer, M.D., Kidney Cancer Section Head, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center. In CheckMate -9ER, nivolumab in combination with cabozantinib doubled progression-free survival, increased overall survival and response rate and, in an exploratory analysis, showed impressive disease control, and these promising efficacy results were sustained with extended follow-up. Also of note, patients in this study reported significant quality of life improvements, which are important for patients undergoing treatment for this challenging disease.

These additional data from CheckMate -9ER provide strong evidence that OPDIVO in combination with CABOMETYX may help patients achieve and maintain control of their disease, said Dana Walker, M.D., M.S.C.E., vice president, development program lead, genitourinary cancers, Bristol Myers Squibb. This regimen brings together two proven agents in advanced renal cell carcinoma, and we believe it will play an important role alongside other first-line treatment options. We look forward to the potential to build on our heritage of transforming patient outcomes with OPDIVO-based combinations across a wide range of tumor types.

The overall survival benefit and quality-of-life measures reported in these findings continue to show improvement with the combination of CABOMETYX and OPDIVO after an extended follow-up of two years, said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. These new findings from CheckMate -9ER and the recent FDA approval of the combination regimen are extremely encouraging as we further explore the potential of CABOMETYX in combination with immunotherapies to help more patients with difficult-to-treat tumor types.

OPDIVO in combination with CABOMETYX was approved for the first-line treatment of advanced RCC by the U.S. Food and Drug Administration (FDA) in January 2021, and further applications are under review with health authorities globally.

Bristol Myers Squibb and Exelixis thank the patients and investigators involved in the CheckMate -9ER clinical trial.

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized, multi-national Phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma (RCC). A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L11%) were randomized to receive OPDIVO plus CABOMETYX (n=323) vs. sunitinib (n=328). The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS) and objective response rate (ORR). The primary efficacy analysis is comparing the doublet combination vs. sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 179,000 deaths worldwide each year. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. The five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 13%.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision transforming patients lives through science. The goal of the companys cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patients life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About OPDIVO

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the bodys own immune system to help restore anti-tumor immune response. By harnessing the bodys own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivos leading global development program is based on Bristol Myers Squibbs scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Companys Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with nivolumab. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States.

OPDIVO INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 10% (5/49) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%) and Grade 2 (5%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO monotherapy in Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients. In patients receiving OPDIVO 1 mg/ kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%) and Grade 2 (2.5%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushings syndrome.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated rash occurred in 15% (76/511) of patients, including Grade 3-5 (2.5%) and Grade 2 (12%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients.

In separate Phase 3 trials of YERVOY 3 mg/kg and 10 mg/kg monotherapy, infusion-related reactions occurred in 2.9% (28/982) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in 2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=154). The most frequent serious adverse reactions reported in 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, pneumonia, and anemia. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in 4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in 2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 227, the most common (20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigators choice. In Checkmate 275, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Checkmate 238, the most common adverse reactions (20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Attraction-3, the most common adverse reactions (20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%).

In a separate Phase 3 trial of YERVOY 3 mg/kg, the most common adverse reactions (5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

Clinical Trials and Patient Populations

Checkmate 037previously treated metastatic melanoma; Checkmate 066previously untreated metastatic melanoma; Checkmate 067previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 227previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LApreviously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 017second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 743previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 214previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ERpreviously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 025previously treated renal cell carcinoma; Checkmate 205/039classical Hodgkin lymphoma; Checkmate 141recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275urothelial carcinoma; Checkmate 142MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040hepatocellular carcinoma, as a single agent or in combination with YERVOY; Checkmate 238adjuvant treatment of melanoma; Attraction-3esophageal squamous cell carcinoma

CABOMETYX INDICATIONS

CABOMETYX(cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

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OPDIVO (nivolumab) in Combination with CABOMETYX (cabozantinib) Shows Sustained Survival and Response Rate Benefits as First-Line Treatment for...

A surface view of the organ of hearing (cochlea) from a mouse, using confocal microscopy. The sensory cells are named hair cells because of their apical projections (stereocilia) which move from stimulation by sound. Credit: University of Maryland School of Medicine

Researchers at the University of Maryland School of Medicine (UMSOM) have conducted a study that has determined the role that a critical protein plays in the development of hair cells. These hair cells are vital for hearing. Some of these cells amplify sounds that come into the ear, and others transform sound waves into electrical signals that travel to the brain. Ronna Hertzano, MD, PhD, Associate Professor in the Department of Otorhinolaryngology Head and Neck Surgery at UMSOM and Maggie Matern, PhD, a postdoctoral fellow at Stanford University, demonstrated that the protein, called GFI1, may be critical for determining whether an embryonic hair cell matures into a functional adult hair cell or becomes a different cell that functions more like a nerve cell or neuron.

The study was published in the journal Development, and was conducted by physician-scientists and researchers at theUMSOM Department of Otorhinolaryngology Head and Neck Surgery and the UMSOM Institute for Genome Sciences (IGS), in collaboration with researchers at the Sackler School of Medicine at Tel Aviv University in Israel.

Hearing relies on the proper functioning of specialized cells within the inner ear called hair cells. When the hair cells do not develop properly or are damaged by environmental stresses like loud noise, it results in a loss of hearing function.

In the United States, the prevalence of hearing loss doubles with every 10-year increase in age, affecting about half of all adults in their 70s and about 80 percent of those who are over age 85. Researchers have been focusing on describing the developmental steps that lead to a functional hair cell, in order to potentially generate new hair cells when old ones are damaged.

To conduct her latest study, Dr. Hertzano and her team utilized cutting-edge methods to study gene expression in the hair cells of genetically modified newborn mice that did not produce GFI1. They demonstrated that, in the absence of this vital protein, embryonic hair cells failed to progress in their development to become fully functional adult cells. In fact, the genes expressed by these cells indicated that they were likely to develop into neuron-like cells.

Our findings explain why GFI1 is critical to enable embryonic cells to progress into functioning adult hair cells, said Dr. Hertzano. These data also explain the importance of GFI1 in experimental protocols to regenerate hair cells from stem cells. These regenerative methods have the potential of being used for patients who have experienced hearing loss due to age or environmental factors like exposure to loud noise.

Dr. Hertzano first became interested in GFI1 while completing her M.D., Ph.D. at Tel Aviv University. As part of her dissertation, she discovered that the hearing loss resulting from mutations in another protein called POU4F3 appeared to largely result from a loss of GFI1 in the hair cells. Since then, she has been conducting studies to discover the role of GFI1 and other proteins in hearing. Other research groups in the field are now testing these proteins to determine whether they can be used as a cocktail to regenerate lost hair cells and restore hearing.

Hearing research has been going through a Renaissance period, not only from advances in genomics and methodology, but also thanks to its uniquely collaborative nature among researchers, said Dr. Herzano.

The new study was funded by the National Institute on Deafness and Other Communication Disorders (NIDCD) which is part of the National Institutes of Health (NIH). It was also funded by the Binational Scientific Foundation (BSF).

This is an exciting new finding that underscores the importance of basic research to lay the foundation for future clinical innovations, said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. Identifying the complex pathways that lead to normal hearing could prove to be the key for reversing hearing loss in millions of Americans.

Reference: GFI1 functions to repress neuronal gene expression in the developing inner ear hair cells by Maggie S. Matern, Beatrice Milon, Erika L. Lipford, Mark McMurray, Yoko Ogawa, Andrew Tkaczuk, Yang Song, Ran Elkon and Ronna Hertzano, 11 September 2020, Development.DOI: 10.1242/dev.186015

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Protein Discovery in the Development of New Hearing Hair Cells Could Lead to Treatments for Hearing Loss - SciTechDaily

Study shows that senescent cells accumulate in the eye of patients with diabetic retinopathy, and elimination of these cells in preclinical models ameliorates disease

Researchers at UNITY Biotechnology and University of Montreal provide mechanistic evidence supporting potential for vascular regeneration in retinal diseases

SOUTH SAN FRANCISCO, Calif., Feb. 08, 2021 (GLOBE NEWSWIRE) -- UNITY Biotechnology, Inc. (UNITY) [NASDAQ: UBX], a biotechnology company developing therapeutics to slow, halt or reverse diseases of aging, today announced new preclinical research that reveals a novel mechanism for treating age-related eye diseases such as diabetic retinopathy and diabetic macular edema by restoring vascular health in the retina. One of the limitations of current standards of care for vascular diseases of the retina is that they target both sick and healthy parts of the eye and hence can lead to significant side-effects. By selectively eliminating the senescent cells accumulating in diseased blood vessels of the eye, researchers identified a way to target diseased vasculature while leaving healthy blood vessels intact, thus enabling the retina to repair itself. The study is featured in the April issue of the peer-reviewed journal Cell Metabolism and is currently available online.

A team of scientists from UNITY and University of Montreal demonstrated that diseased blood vessels in the retina trigger molecular pathways associated with aging, collectively termed cellular senescence. The authors used a combination of animal models and human samples to identify a molecular target, called Bcl-xL, that is highly expressed in diseased retinal blood vessels. Targeting these senescent cells with a single dose of UNITYs Bcl-xL small molecule inhibitor led to selective elimination of diseased vasculature, while enabling functional, healthy blood vessels to reorganize and regenerate.

In this study, we showed that diseased blood vessels in retinopathy are characterized by senescent cells and that vasculature can be restored through senolytic therapeutics, in this case a novel Bcl-xL inhibitor, said Przemyslaw (Mike) Sapieha, Ph.D., a lead author of the paper. These findings suggest that Bcl-xL inhibition has the potential to selectively target diseased retinal blood vessels, while sparing healthy ones and promoting more functional vasculature in the eye.

According to the National Eye Institute, diabetic retinopathy is the most prominent complication of diabetes and the leading cause of blindness in working age individuals. They estimate that ~8 million Americans are afflicted by the eye disease and predicts the incidence will double over the next 15 years. In diabetic retinopathy, small calibre blood vessels feed the back of the eye (retina), degenerate and re-grow in an abnormal manner. These new vessels obstruct light and can leave scars in the retina.

UNITY is currently conducting a Phase 1 clinical trial of UBX1325, a small molecule inhibitor of Bcl-xL, for the treatment of diabetic macular edema, a common complication of diabetic retinopathy. Initial results from the study are expected in the first half of 2021.

Bcl-xL inhibition may be the key to a new class of neovascular retinal medicine, in which a targeted treatment allows the retina to repair itself while eliminating diseased vasculature, said Anirvan Ghosh, chief executive officer of UNITY. These findings support the role cellular senescence plays in age-related eye diseases and that senolytic medicines may provide not only a viable strategy for promoting vasculature health, but an important new treatment option for these debilitating diseases.

The paper, titled Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition, is co-authored by a team of scientists from the University of Montreal and UNITY Biotechnology. The senior authors are Dr. Sapieha who recently joined UNITY as chief scientific advisor, and Pam Tsuruda, Ph.D., of UNITY.

About UNITYUNITY is developing a new class of therapeutics to slow, halt or reverse diseases of aging. UNITYs current focus is on creating medicines to selectively eliminate or modulate senescent cells and thereby provide transformative benefit inage-relatedophthalmologic and neurologic diseases. More information is available atwww.unitybiotechnology.comor follow us onTwitter and LinkedIn.

Forward-Looking StatementsThis press release contains forward-looking statements including statements related to UNITYs understanding of cellular senescence and the role it plays in diseases of aging, the potential for UNITY to develop therapeutics to slow, halt or reverse diseases of aging, including for ophthalmologic and neurologic diseases, the potential for UNITY to successfully commence and complete clinical studies of UBX1325 for diabetic macular edema and other ophthalmologic diseases, the expected timing of initial results of the Phase 1 study of UBX1325 in diabetic macular edema, and UNITYs expectations regarding the sufficiency of its cash runway. These statements involve substantial known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements, including the risk that theCOVID-19worldwide pandemic may continue to negatively impact the development of preclinical and clinical drug candidates, including delaying or disrupting the enrollment of patients in clinical trials. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. The forward-looking statements in this press release represent our views as of the date of this release. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements at some point in the future, we have no current intention of doing so except to the extent required by applicable law. You should, therefore, not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this release.For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of the Company in general, see UNITYs most recent Quarterly Report on Form 10-Q for the quarter endedSeptember 30, 2020, filed with theSecurities and Exchange CommissiononNovember 4, 2020, as well as other documents that may be filed by UNITY from time to time with theSecurities and Exchange Commission.

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Study published in Cell Metabolism Reveals New Therapeutic Approach Aimed at Restoring Vascular Health and Reversing Age-Related Eye Disease -...

MIAMI, Feb. 8, 2021 /PRNewswire/ -- Ponce Therapeutics, Inc. ("Ponce"), a company leveraging the growing scientific knowledge surrounding the aging process to develop anti-aging technologies, has now become operational with the launching of its first R & D program, targeting aging-associated skin disorders. The Company has secured laboratory space in Houston, TX, and has hired its first scientists for executing their R & D plan targeting the elimination of p16-expressing cells in the skin. The cell proliferation inhibitor, p16, is highly expressed in both senescent cells and in in situ carcinoma (Bowen's Disease), which will be the focus of Ponce's efforts for first product approval.

Rapha Capital Management, LLC (https://www.raphacap.com), an investment management firm located in Miami, Florida, through Rapha Capital Investment XIII, LLC ("RCI XIII") (an entity managed by Rapha Capital), led Ponce's recently closed Convertible Note financing. The $1,500,000 financing will be used to transition Ponce into an operational company and begin execution of Ponce's R & D plan. With the close of the Convertible Note financing, Kevin Slawin, founder and President of Rapha Capital Management, added the title of Executive Chairman, to his CEO role at Ponce.

Rapha Capital is an investment management firm focused on making strategic investments in early stage, non-public biotechnology companies, through special purpose joint venture entities which it manages. Rapha Capital was founded by its President, Kevin Slawin, M.D., a successful and experienced oncologic and robotic surgeon. After leaving practice, Dr. Slawin has been serving as a biotech consultant, investor, and founder, focusing on disruptive technologies in oncology, T cells and immunotherapy, and other breakthrough healthcare technologies. He is the founder of Bellicum Pharmaceuticals, Inc.("Bellicum"), a publicly traded company listed on NASDAQ, leading Bellicum to a successful $161 million IPO in December, 2014. He also plays a guiding role in several of the investments managed by Rapha Capital in certain companies, serving as a board member at 3DBio Therapeutics, Inc. (https://3dbiocorp.com/), FIZE Medical, Inc. (www.fizemedical.com), and Demeetra AgBio, Inc. (www.demeetra.com).

Kevin Slawin, MD is the founder of Ponce, and will serve as the Chairman and CEO. David Spencer, PhD. is the founding Chief Technology Officer. Ponce Therapeutics, Inc. reunites the team that founded Bellicum Pharmaceuticals and took it public in 2014 with a $55 million crossover Series C and a $161 million IPO. The team is retooling their original cell control technology with state-of-the-art advances towards their new goal of creating anti-aging products with a solid underlying scientific basis that actually work.

"The science of aging has continued to mature and can now provide a scientific basis for technologies to reverse the aging process in humans. Proof of concept data in animal models demonstrates that removal of senescent cells from organs improves their function and imbues them with a more youthful profile. Targeting p16-expressing cells for apoptotic elimination is one approach to removing senescent cells from the body and is also a valid approach to targeting Bowen's disease of the skin, which also expresses high levels of p16, profile," said Dr. Slawin. "I'm excited to begin work in the anti-aging space, which I believe will quickly rival oncology in both value and interest" he added. "Given our greater than two-decade animal model and clinical experience with regulated cell signaling and cell survival, along with recent advances in non-viral gene delivery platforms, we are now poised to leverage an increasingly detailed, mechanistic understanding of aging to arrest or even reverse it," added Dr. Spencer.

About Rapha Capital Management, LLC Rapha Capital Management, LLC is an investment management firm located in Miami, Florida, focusing on strategic investments in early stage, non-public biotechnology companies. Rapha Capital was founded by its President, Kevin Slawin, MD, a successful and experienced oncologic and robotic surgeon, biotech consultant, investor, and founder focusing on technologies in oncology, T cells and immunotherapy, as well as other breakthrough healthcare technologies. He is the founder of Bellicum Pharmaceuticals, Inc. (NASDAQ: BLCM). He is co-Inventor of the FDA,-approved "prostate health index (phi)" test licensed and marketed by Beckman Coulter and utilized around the world. He has published extensively in top medical and scientific journals including theJournal of the American Medical Association (JAMA), Journal of the National Cancer Institute (JNCI), and the New England Journal of Medicine (NEJM). He has also been routinely listed in America's Top Doctors for Cancer (Castle Connolly Medical) and The Best Doctors in America (Woodward/White). In 2003, he was awarded the F. Brantley Scott, Jr., Award for Innovation and Creativity in Urology.

About Ponce Therapeutics, Inc.Ponce Therapeutics "Anti-aging Technologies Based on Real Science and Developed by Real Scientists" - Ponce Therapeutics is leveraging the growing scientific knowledge surrounding the process of aging to develop its first state-of-the-art biotechnology platform to restore the youthful balance of aged or "senescent" and young cells in the skin, targeting the p16-expressing senescent cells for elimination. This provides a "reboot" of one's genetic program to turn the clock on one's skin back to its youthful exuberance. Targeting p16 will also potentially allow targeting of Bowen's disease as the regulatory pathway for approval. While initially focused on skin, Ponce is planning to develop a wide-ranging portfolio of anti-aging products based on the best science in the nascent anti-aging field. Ponceis headquartered in Miami, Florida with research facilities located in Houston, TX. For more information, visitwww.poncethera.comor email info@poncethera.com.

For more information about Ponce Therapeutics, Inc., email info@poncethera.com or visit https://www.poncethera.com

For more information about Rapha Capital Management, email info@raphacapital.comor visit https://www.raphacap.com

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SOURCE Rapha Capital Management, LLC and Ponce Therapeutics, Inc.

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Ponce Therapeutics Inc. Commences First R & D Program in Anti-Aging Products for Skin - BioSpace

Patients with head and neck squamous cell carcinoma (HNSCC), the sixth most common epithelial cancer worldwide, are treated with surgery, chemotherapy and radiotherapy. In addition, targeted agents, including an EGFR monoclonal antibody (mAb) inhibitor and two programmed cell death protein 1 (PD-1) inhibitors, have been approved by the U.S. Food and Drug Administration for HNSCC treatment, but response rates are moderate.

In this study, researchers led by Baylor College of Medicine, Johns Hopkins University and the National Cancer Institutes Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigated what new insight proteogenomic analysis might offer into understanding why certain patients respond to certain treatments while other patients do not. They propose that their findings may help better match patients to an appropriate course of treatment in the future.

The team profiled proteins, phosphosites (a site on a protein associated with phosphorylation) and signaling pathways in 108 human papillomavirus-negative HNSCC tumors in order to understand how genetic aberrations drive tumor behavior and response to therapies.

We found three subtypes of head and neck squamous cell carcinoma, and each subtype may be a good candidate for a different type of therapy EGFR inhibitors, CDK inhibitors or immunotherapy, saidDr. Bing Zhang, lead contact of the study and professor in theLester and Sue Smith Breast Centerand theDepartment of Molecular and Human Geneticsat Baylor. We also identified candidate biomarkers that could be used to match patients to effective therapies or clinical trials.

One important finding involved matching HNSCC patients to EGFR mAb inhibitors. Cetuximab, an EGFR mAb medication, was approved by the FDA in 2006 as the first targeted therapy for HNSCC, however the success rate for this treatment is low. Moreover, EGFR amplification or overexpression cannot predict response to EGFR mAbs. In this study, researchers found that EGFR ligands, instead of EGFR itself, act as the limiting factor for EGFR pathway activation. When ligand is low, the downstream pathway will not be triggered, even if EGFR protein is highly overexpressed.

We proposed that the EGFR ligand should be used as a biomarker, rather than EGFR amplification or overexpression, to help select patients for the EGFR monoclonal antibody treatment, said Zhang, a member of the Dan L Duncan Comprehensive Cancer Center, a Cancer Prevention & Research Institute of Texas (CPRIT) Scholar and aMcNair Scholarat Baylor.

Tumors with high EGFR amplification do not necessarily have high levels of EGFR ligands, which may underlie their lack of response to EGFR mAb therapy. The team confirmed this hypothesis by analyzing previously published data from patient-derived xenograft models and a clinical trial.

Additionally, tracking a key tumor suppressor known as Rb (retinoblastoma), the research team identified a striking finding that suggests that Rb phosphorylation status could potentially be a better indicator of a patients response to CDK4/6 inhibitor therapy. The study showed that the many mutations in the genes regulating CDK4/6 activity were neither necessary nor sufficient for activation of CDK4/6.

The team found that the CDK4 activity was best measured through Rb phosphorylation measurements, thus identifying a potential measure for patient selection in CDK inhibitor clinical trials.

The research team also found important insights into the effectiveness of immunotherapy. PD-1 inhibitors target the interaction between immune checkpoints PD-1 and PD-L1, but success rates of immunotherapy are low, even when PD-L1 expression is used for patient selection. The researchers examined tumors with high expression of PD-L1 and found that when a tumor overexpresses PD-L1, it also upregulates other immune checkpoints, thus allowing the tumor growth despite the use of PD-1 inhibitors.

This observation suggests that PD-1- and PD-L1-activated tumors with hot immune environments may require multiple types of immunotherapy, which target different immune checkpoint proteins, to be effective.Conversely, tumors with cold immune environments are not good targets for immunotherapy.

Immune-cold tumors are tumors that contain few if any infiltrating immune T cells. Examination of how a tumor becomes immune-cold showed that the problem stems from a flaw in its antigen presentation pathway, a first step toward triggering an immune response against tumor antigens. In immune-cold tumors multiple key gene components of the antigen presentation pathway were deleted. As a result, although tumor antigens are being expressed, the immune system is not able to recognize them on the surface of cancer cells and therefore fails to activate the bodys defense system against the tumor. These deletions have the potential to be effective targets for future therapies.

This study extends our biological understanding of HPV-negative HNSCCs and generates therapeutic hypotheses that may serve as the basis for future studies and clinical trials toward molecularly-guided precision medicine treatment of this aggressive cancer type, saidDr. Daniel W. Chan, co-corresponding author of the study, professor of pathology and oncology, and director of theCenter for Biomarker Discovery and Translationat theJohns Hopkins University School of Medicine.

Find all the details of this study and a full list of contributing authors in the journalCancer Cell.

This work was supported by grants U24 CA210954, U24 CA210985, U24 CA210972, U24 CA210979, U24 CA210986, U24 CA214125, U24 CA210967, and U24 CA210993 from the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC), by a Cancer Prevention Institute of Texas (CPRIT) award RR160027, by grant T32 CA203690 from the Translational Breast Cancer Research Training Program, and by funding from the McNair Medical Institute at the Robert and Janice McNair Foundation.

By Molly Chiu

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Using proteogenomics to improve the treatment of squamous cell carcinoma - Baylor College of Medicine News

Leukemia is a type of cancer that affects the blood. The two most common types in children are acute lymphoblastic leukemia and acute myelogenous leukemia.

In a person with leukemia, blood cells are released into the bloodstream before they are fully formed, so there are fewer healthy blood cells in the body.

Below, we describe the types of childhood leukemia, the symptoms, and the treatments. We then look at when to contact a doctor, what questions to ask, and where to find support.

Childhood leukemia is the most common form of cancer in children. It affects up to 3,800 children under the age of 15 in the United States each year.

Leukemia occurs when bone marrow releases new blood cells into the bloodstream before they are fully mature.

These immature blood cells do not function as they should, and eventually, the number of immature cells overtakes the number of healthy ones.

Leukemia can affect red and white blood cells and platelets.

The bone marrow produces stem cells. A blood stem cell can become a myeloid stem cell or a lymphoid stem cell.

Lymphoid stem cells become white blood cells. Myeloid stem cells can become:

Leukemia is typically acute or chronic, and chronic types are rare in children. They can include chronic myeloid leukemia or chronic lymphocytic leukemia.

Most childhood leukemias are acute, meaning that they progress quickly and need treatment as soon as possible.

Acute lymphoblastic leukemia (ALL) is the most common type in children, accounting for 75% of childhood leukemia cases.

It affects cells called lymphocytes, a type of white blood cell.

In a person with ALL, the bone marrow releases a large number of underdeveloped white blood cells called blast cells. As the number of these increases, the number of red blood cells and platelets decreases.

There are two subtypes of ALL: B-cell and T-cell.

In most childhood cases of ALL, the cancer develops in the early forms of B-cells. The other type, T-cell ALL, typically affects older children.

Research from 2020 reports that the majority of people diagnosed with ALL are under 18 and typically between 2 and 10 years old.

The American Cancer Society report that children under 5 years old have the highest risk of developing ALL and that this risk slowly declines until a person reaches their mid-20s.

The outlook for ALL depends on the subtype, the persons age, and factors specific to each person.

Myeloid leukemias account for approximately 20% of childhood leukemia cases, and most myeloid leukemias are acute.

Acute myelogenous leukemia (AML) affects white blood cells other than the lymphocytes. It may also affect red blood cells and platelets.

AML can begin in:

Juvenile myelomonocytic leukemia (JMML) accounts for approximately 12% of leukemia cases in children.

This rare type is neither acute nor chronic. JMML begins in the myeloid cells, and it typically affects children younger than 2 years.

Symptoms can include:

The symptoms of leukemia may be nonspecific similar to those of other common childhood illnesses.

A doctor will ask how long the child has been experiencing the symptoms, which can include:

Children may experience specific symptoms depending on the type of blood cell that the leukemia is affecting.

A low number of red blood cells can cause:

A low number of healthy white blood cells can cause infections or a fever with no other sign of an infection.

A low platelet count can cause:

Various factors can increase a childs risk of leukemia, and most are not preventable.

The following genetic conditions can increase the risk of leukemia:

Also, having a sibling with leukemia may increase the risk of developing it.

These can include exposure to:

If a child has symptoms that might indicate leukemia, a doctor may perform or request:

A bone marrow aspiration involves using a syringe to take a liquid sample of bone marrow cells. The doctor may give the child a drug that allows them to sleep through this test.

During the diagnostic process, a person might ask:

The doctor may recommend a variety of treatments for childhood leukemia, and the best option depends on a range of factors specific to each person.

The treatment usually consists of two phases. The first aims to kill the leukemia cells in the childs bone marrow, and the second aims to prevent the cancer from coming back.

The child may need:

Before or during treatment, a person might ask the doctor:

Questions to ask after the treatment might include:

Children who have undergone leukemia treatments require follow-up care, as the treatments often cause late effects.

These can develop in anyone who has received treatment for cancer, and they may not arise for months or years after the treatment has ended.

Treatments that can cause late effects include:

These complications may affect:

The late effects that may come can also depend on the type of treatment and the form of leukemia.

Because many leukemia symptoms can also indicate other issues, it can be hard to know when to contact a doctor.

Overall, it is best to seek medical advice if a child shows symptoms or behaviors that are not normal for them.

If a child has received a leukemia diagnosis, the effects can extend to parents, other family members, caregivers, and friends.

A person can find support and additional resources from:

The following organizations based in the United Kingdom also provide support and guidance:

Childhood leukemia can affect mental health, as well as physical health.

Learn more about mental health resources here.

According to the American Cancer Society, most children with leukemia have no known risk factors. There is no way to prevent leukemia from developing.

Because there are very few lifestyle-related or environmental causes of childhood leukemia, it is very unlikely that a caregiver can do anything to help prevent the disease.

A childs outlook depends on the type of leukemia. It is important to keep in mind that current estimates do not take into account recent advances in technology and medicine.

For example, the most recent 5-year survival rate estimates reflect the experiences of children who received their diagnoses and treatments more than 5 years ago.

The American Cancer Society report that the 5-year survival rate for children with ALL is 90%. The same rate for children with AML is 6570%.

Childhood leukemia is typically acute, which means that it develops quickly. As a result, a person should contact a doctor if they notice any of the symptoms.

The most common type of childhood leukemia is ALL, representing 3 out of 4 leukemia cases in children.

Treatment may include a combination of chemotherapy, targeted drugs, immunotherapy, stem cell transplants, surgery, and radiation.

The prognosis depends on the type of leukemia and the childs age.

This diagnosis can affect mental as well as physical health, and the effects can extend to caregivers, family members, and friends. Many different resources are available for support.

Originally posted here:
Leukemia in children: Symptoms, causes, treatment, outlook, and more - Medical News Today

New York, Feb. 05, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Cell Line Development and Characterization Services by Sources of Cell Lines / Expression Systems, Applications of Cell Lines, and Geography : Industry Trends and Global Forecasts, 2020-2030" - https://www.reportlinker.com/p06020735/?utm_source=GNW As a result, the pipeline of biologics and biosimilars is growing at a commendable pace. Given that the development and manufacturing of such therapies require living biological systems, there has been a surge in demand for different types of cell lines. In fact, around 84% of the therapeutic proteins marketed in the last five years, were produced using various mammalian and microbial cells. A recent study revealed that over 30,000 research articles published in 33,000 journals featured data generated from experiments that used misidentified or contaminated cell lines. This is a genuine concern in the field of medical research, which is becoming increasingly dependent on cell-based assays and experimentation. Therefore, in modern medical research, proper cell line characterization is a necessity in order to preserve the authenticity and accuracy of experimental research.

Given the cost intensive nature of pharmacological R&D, medical researchers / drug developers are consistently on the lookout for ways to optimize operational efficiencies, as well as reduce affiliated costs; in this context, outsourcing has emerged as a preferred business model. Presently, there are several contact service providers that claim to have the necessary expertise to develop and characterize cell lines. The technical aspect of this field is also witnessing a lot of innovation, especially with regard to automating various steps of the cell line development process. New genome editing technologies, such as the CRISPR/Cas-9, are also being extensively used to improve the quality of recombinant cell lines. Unlike drug developers, the capabilities of service providers are usually more focused to their respective service portfolios. Moreover, such companies ensure that they have the latest upgrades in equipment and infrastructure, in order to improve the quality of services offered. In fact, in the recent past, a number of service providers offering cell lines-related services, have forged strategic alliances with and / or acquired other players, in order to further enhance their respective portfolios. Considering the growing trend of outsourcing and the ongoing efforts of service providers to improve / expand their offerings, we believe the contract services market for cell line development and characterization is likely to evolve at a steady pace, till 2030.

SCOPE OF THE REPORT The Cell Line Development and Characterization Services Market (2nd Edition), 2020-2030 report features an extensive study on the current market landscape, offering an informed opinion on the likely evolution in this industry, over the next ten years. The study underlines an in-depth analysis of the services offered for the development and characterization of cell lines, which are intended for use in various R&D and / or therapeutic purposes. In addition to other elements, it includes: - A detailed review of the overall landscape of the cell line development services market, highlighting the contributions of contract service providers, along with the information on year of establishment, company size, location of headquarters, sources of cell lines and expression systems offered (mammalian, microbial, insect and avian), integrated cell line characterization, biosimilar cell line development and gene editing cell line development services offered, gene delivery method used (physical, chemical, biological and non-biological), type of gene expression (stable and transient), usage of serum-free / animal component free cell culture media, types of cell cultures (suspension and mixed growth properties), types of cells offered (recombinant, hybridoma and primary), applications of cell lines (R&D, biomanufacturing, diagnostics and cell therapy / regenerative medicine / tissue culture). In addition, the chapter includes information on additional cell line related services (bio-analytical / protein purification, cell banking, cell bank characterization, process development, GMP manufacturing and fill-finish), types of cell banks developed (master cell banks, working cell banks, research cell banks and end-of-production cell banks) and protein yield from cell lines. - A company competitiveness analysis, highlighting prominent cell line development service providers based in different regions, taking into consideration their supplier strength (experience of the service provider), and portfolio specifications (sources of cell lines and expression systems handled, availability of proprietary / licensed technology platform, type of gene expression and availability of additional cell line related services). - Elaborate profiles of cell line development service providers. Each company profile features a brief overview of the company, its financial information (if available), cell line development and complementary services portfolio and an informed future outlook. - A detailed review of the overall landscape of the cell line characterization services market, highlighting the contributions of industry and non-industry players along with the information on year of establishment, company size, location of headquarters, types of cells handled (mammalian, microbial, insect and others), types of cell line characterization services offered (identity / stability testing, sterility / biosafety testing, expression testing and oncogenicity / tumorigenicity testing), types of cell line identity / stability testing services offered (analysis of cell morphology, cytochrome c oxidase 1 barcoding assay, DNA fingerprinting / profiling, gene copy number analysis, isozyme analysis, karyotype analysis, nucleic acid sequencing, southern blotting and viability testing) types of sterility / biosafety testing services offered (mycoplasma contamination testing, microbial contamination testing, viral / adventitious agents contamination testing, retroviral contamination testing and rodent virus testing / in-vivo biosafety testing), availability of other cell line related services (cell line development, cell banking and mycoplasma clearance service), information on regulatory accreditations / certifications and overall turnaround time. In addition, it lists the non-industry players and provides information on number of STR loci amplified, type of genotyping kit used and service fee charged. - A company competitiveness analysis, highlighting prominent cell line characterization service providers based in different regions, taking into consideration their supplier strength (experience of the service provider), and portfolio specifications (sources of cell lines and expression systems handled and size of the service portfolio.) - Elaborate profiles of cell line characterization service providers. Each company profile features a brief overview of the company, its financial information (if available), cell line characterization services portfolio and an informed future outlook. - A detailed analysis of the partnerships that have been established in the cell line development and characterization domain since 2015, covering technology platform utilization agreements, R&D collaborations, licensing agreements, mergers and acquisitions, product development and / or commercialization agreements, process development agreements, clinical trial agreements, and other relevant deals. - Detailed profiles of the biorepositories across the globe that play an important role in developing cell lines and have also undertaken initiatives to limit the use of contaminated and / or misidentified cell lines. Each profile features a brief overview of the repository and its cell line characterization service portfolio. - An elaborate discussion on the requirements established by various regulatory authorities, across different regions, related to characterization of cell lines. In addition, it provides insights from the various guideline documents that have been issued by these bodies on protocols that need to be followed and general tips for the testing of cell lines. It also features a brief historical overview and discussion on the contributions of key institutes / organizations involved in this domain. - A survey analysis featuring inputs solicited from various experts who are directly / indirectly involved in providing cell line development and / or cell line characterization services.

One of the key objectives of the report was to estimate the existing market size and future growth opportunities for cell line development and characterization service providers. Based on multiple parameters, such as the number of projects completed annually, price of the projects, the overall R&D expenditure available to CROs and the overall growth of the biologics market, we have developed informed estimates on the financial evolution of the market over the period 2020-2030.

For cell line development services market, our year-wise projections of the current and future opportunity have further been segmented on the basis of [A] sources of cell lines and expression systems (mammalian, microbial, insect and avian), [B] applications of cell lines (R&D operations and drug development), [C] company size (small, mid-sized and large) and key geographies (North America, Europe, Asia, Oceania and Rest of the World).

For cell line characterization services market, our year-wise projections of the current and future opportunity have further been segmented on the basis of [A] sources of cell lines and expression systems (mammalian, microbial and others), [B] applications of cell lines (R&D operations and drug development), [C] type of service provider (industry players and non-industry players) and [D] key geographies (North America, Europe, Asia, Middle East & North Africa (MENA), Latin America (LATAM) and Rest of the World (RoW)). To account for the uncertainties associated with this industry and to add robustness to our model, we have provided three forecast scenarios, portraying the conservative, base and optimistic tracks of the markets evolution.

The opinions and insights presented in this study were influenced by inputs solicited via a comprehensive survey and discussions conducted with several key players in this domain. The report features detailed transcripts of interviews held with the following industry stakeholders (in reverse chronological order): - Fai Poon (Founder and President, Quacell Biotechnology) - Louis Boon (Chief Scientific Officer, Polpharma Biologics) - Fan Chen (Former Vice President BioProcessing, LakePharma) - Michael Pointek (Founder and Managing Director, ARTES Biotechnology) - Nienke Smits (Client Relations Manager, Immunoprecise Antibodies) - Oscar Hoogteijling (Former Global Business Development Manager, Polpharma Biologics)

All actual figures have been sourced and analyzed from publicly available information forums and primary research discussions. Financial figures mentioned in this report are in USD, unless otherwise specified.

RESEARCH METHODOLOGY The data presented in this report has been gathered via secondary and primary research. For all our projects, we conduct interviews with experts in the area (academia, industry, medical practice and other associations) to solicit their opinions on emerging trends in the market. This is primarily useful for us to draw out our own opinion on how the market will evolve across different regions and segments. Where possible, the available data has been checked for accuracy from multiple sources of information.

The secondary sources of information include - Annual reports - Investor presentations - SEC filings - Industry databases - News releases from company websites - Government policy documents - Industry analysts views

While the focus has been on forecasting the market till 2030, the report also provides our independent view on various non-commercial trends emerging in the industry. This opinion is solely based on our knowledge, research and understanding of the relevant market gathered from various secondary and primary sources of information.

KEY QUESTIONS ANSWERED - Who are the leading players offering cell line development services? - What kind of CDMO support is available for cell line development, across different regions? - What are the common sources, gene delivery methods, protein yield and affiliated services offered by the cell line development service providers? - Who are the leading industry and non-industry players offering cell line characterization services? - What are the most popular services offered for characterization of cell lines? - Which partnership models are commonly adopted by stakeholders in this industry? - How is the current and future opportunity likely to be distributed across key market segments? - What are the anticipated future trends related to cell line development and characterization market?

CHAPTER OUTLINES Chapter 2 is an executive summary of the insights captured in our research. The summary offers a high-level view on the likely evolution of the cell line development and characterization services market in the mid to long term.

Chapter 3 provides a general introduction to cell cultures and cell lines, including details related to various types of cell lines, based on their sources of origin, and key characteristics, applications and concerns associated with their use in drug development and research. The chapter also elaborates the recombinant and hybridoma cell line development process workflow. Further, it outlines the general concepts of cell line characterization along with a detailed description of different types of testing methods used for such purposes. In addition, it also presents the advantages and associated risks related to outsourcing of cell line development and characterization operations. In this chapter, we have briefly discussed the most common services offered by the service providers, along with cell line development and characterization services.

Chapter 4 provides an overview of the overall cell line development services landscape. It includes information related to over 220 contract service providers that are currently active in this domain. It features an in-depth analyses of the market, information on year of establishment, company size, location of headquarters, sources of cell lines and expression systems offered (mammalian, microbial, insect and avian), integrated cell line characterization, biosimilar cell line development and gene editing cell line development services offered, gene delivery method used (physical, chemical, biological and non-biological), type of gene expression (stable and transient), usage of serum-free / animal component free cell culture media, types of cell cultures (suspension and mixed growth properties), types of cells offered (recombinant, hybridoma and primary), applications of cell lines (R&D, biomanufacturing, diagnostics and cell therapy / regenerative medicine / tissue culture). In addition, the chapter includes information on additional cell line related services (bio-analytical / protein purification, cell banking, cell bank characterization, process development, GMP manufacturing and fill-finish), types of cell banks developed (master cell banks, working cell banks, research cell banks and end-of-production cell banks) and protein yield from cell lines.

Chapter 5 provides an insightful competitiveness analysis of the cell line development service providers that we came across during our research. The analysis compares the companies on the basis of supplier strength (experience of the service provider) and service portfolio strength (considering sources of cell lines and expression systems offered, availability of proprietary / licensed technology platform, type of gene expression and availability of additional cell line related services).

Chapter 6 features detailed profiles of some of the key players that are active in the cell line development domain. Each profile presents a brief overview of the company, its cell line development and complementary services portfolio, financial information (if available), recent developments and an informed future outlook.

Chapter 7 provides an overview of the overall cell line characterization services landscape. It includes information related to over 140 industry and non-industry contract service providers that are currently active in this domain. It features in-depth analyses of the market, based on a number of relevant parameters, such as year of establishment, company size, location of headquarters, types of cells handled (mammalian, microbial, insect and others), types of cell line characterization services offered (identity / stability testing, sterility / biosafety testing, expression testing and oncogenicity / tumorigenicity testing), types of cell line identity / stability testing services offered (analysis of cell morphology, cytochrome c oxidase 1 barcoding assay, DNA fingerprinting / profiling, gene copy number analysis, isozyme analysis, karyotype analysis, nucleic acid sequencing, southern blotting and viability testing) types of sterility / biosafety testing services offered (mycoplasma contamination testing, microbial contamination testing, viral / adventitious agents contamination testing, retroviral contamination testing and rodent virus testing / in-vivo biosafety testing), availability of other cell line related services (cell line development, cell banking and mycoplasma clearance service), information on regulatory accreditations / certifications and overall turnaround time. For non-industry players, the report features additional information on number of STR loci amplified, type of genotyping kit used and service fee charged.

Chapter 8 provides an insightful competitiveness analysis of the cell line characterization service providers that we came across during our research. The analysis compares the companies on the basis of supplier strength (in terms of experience of the service provider) and service portfolio strength (considering sources of cell lines and expression systems handled and size of the service portfolio).

Chapter 9 features detailed profiles of some of the key players that are active in the cell line characterization domain. Each profile presents a brief overview of the company, its cell line characterization services portfolio, financial information (if available), recent developments and an informed future outlook.

Chapter 10 features an in-depth analysis and discussion on the various partnerships that have been inked between the players in the cell line development and characterization market in the time period between 2015 and 2020 (till September). It includes a brief description of partnership models (such as technology platform utilization agreements, R&D collaborations, licensing agreements, mergers and acquisitions, product development and / or commercialization agreements, process development agreements, clinical trial agreements and other relevant deals) adopted by the stakeholders.

Chapter 11 features detailed profiles of the biorepositories across the globe that play an important role in developing cell lines and have also undertaken initiatives to limit the use of contaminated and / or misidentified cell lines. Each profile features a brief overview of the repository and its cell line characterization service portfolio.

Chapter 12 presents an elaborate discussion on the requirements defined by various regulatory authorities, across different regions, related to the characterization of cell lines. In addition, it provides insights from the various guideline documents that have been issued by these bodies on protocols that need to be followed and general tips for the testing of cell lines. It also features a brief historical overview and discussion on the contributions of key institutes / organizations involved in this domain.

Chapter 13 presents a comprehensive market forecast analysis, highlighting the likely growth of cell line development services market till the year 2030. In order to provide a detailed future outlook, our projections have been segmented on the basis of sources of cell lines / expression systems (mammalian, microbial, insect and avian), applications of cell lines (R&D operations and drug development), company size (small, mid-sized and large) and key geographical regions (North America, Europe, Asia, Oceania and Rest of the World).

Chapter 14 presents a comprehensive market forecast analysis, highlighting the likely growth of cell line characterization services market till the year 2030. In order to provide a detailed future outlook, our projections have been segmented on the basis of sources of cell lines (mammalian, microbial and others), applications of cell lines (R&D operations and drug development), type of player (industry and non-industry) and key geographies (North America, Europe, Asia, Middle East & North Africa (MENA), Latin America (LATAM), Rest of the World (RoW)).

Chapter 15 is a collection of interview transcripts of the discussions held with key stakeholders in the industry. We have presented details of interviews held with Fai Poon (Founder and President, Quacell Biotechnology), Louis Boon (Chief Scientific Officer, Polpharma Biologics), Fan Chen (Former Vice President BioProcessing, LakePharma), Michael Pointek (Founder and Managing Director, ARTES Biotechnology), Nienke Smits (Client Relations Manager, Immunoprecise Antibodies) and Oscar Hoogteijling (Former Global Business Development Manager, Polpharma Biologics).

Chapter 16 presents insights from the survey conducted for this study. The participants, who were primarily Directors / CXO level representatives, helped us develop a deeper understanding on the nature of their services and their associated commercial potential.

Chapter 17 summarizes the entire report. It presents a list of key takeaways and offers our independent opinion on the current market scenario.

Chapter 18 is an appendix, which provides tabulated data and numbers for all the figures in the report.

Chapter 19 is an appendix, which provides the list of companies and organizations mentioned in the report.Read the full report: https://www.reportlinker.com/p06020735/?utm_source=GNW

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Cell Line Development and Characterization Services by Sources of Cell Lines / Expression Systems, Applications of Cell Lines, and Geography :...

LEXINGTON, Mass., Feb. 3, 2021 /PRNewswire/ -- iSpecimen today announced it has expanded its cellular biospecimen offeringsby introducing new cryopreserved stem and immune cell products for life science research and preclinical drug development. The new products are intended to support the growth of regenerative medicine by giving researchers broader access to the materials they need to develop new therapies.

Peripheral blood mononuclear cells (PBMCs), also provided as "leukopacks," are critical for the research and development of stem cell and immunotherapies, vaccines, diagnostics, and new treatments for cancer, infectious, and autoimmune diseases. PBMCs are an important source of CD34+Hematopoietic Stem Cells (HSCs), CD3+ Pan T cells, CD4+Helper T cells, CD8+Cytotoxic T cells, CD56+ Natural Killer (NK) cells, CD14+Monocytes, antibody-secreting CD19+ B cells, and other primary cell types that are commonly used in cell-based assays to help advance drug discovery and development.

iSpecimen provides centralized access to a repository of banked cell types available for prompt delivery, plus mononuclear cells that can be collected prospectively and subsequently cryopreserved, depending on project and specific donor phenotype requirements. When compared to fresh cell collections, cryopreserved products provide researchers with increased flexibility in the timing and rollout of their research studies, especially when dealing with unexpected changes to lab schedules or pandemic-related disruptions. Moreover, cryopreserved cells collected from multiple donor phenotypes may helpresearchers execute side-by-side studies within preclinical development workflows.

The new offerings, which supplement iSpecimen's line of fresh immune cells, include:

"We're committed to supplying life science researchers with more of what they need in some of medical research's most promising areas," said Wayne Vaz, iSpecimen's vice president of growth and corporate development. "To provide a broad choice for demanding research, we continue to focus on expanding our extensive network of trusted suppliers, increasing industry access to difficult-to-source specimens, and providing a proprietary Marketplace platform that improves the overall experience of acquiring annotated biomaterials."

Trusted, accredited partners

iSpecimen sources these stem and immune cells from a wide network of supplier donor facilities. Each leukopack has been collected and/or cryopreserved in a US-FDA registered, AABB-accredited cell collection and storage center using a controlled-rate freezer and validated processing protocols.

Streamlined discovery, access, and procurement

Researchers can access the new selection of cells, as well as a range of other human biospecimens, by contacting iSpecimen directly and through the iSpecimen Marketplace, an online platform that increases access to human biospecimens from specific patients and healthy donors who provide them.

For those needing cells, the iSpecimen Marketplace gives researchers centralized, single-source access to a growing population of healthy donors and patients with hematopoietic and immune cell phenotypes that can match particular research study criteria.

Hematopoietic stem and immune cells may be selected based upon a variety of donor phenotype parameters such as HLA type, blood type, body mass index, ethnicity, race, age, and gender. The iSpecimen Marketplace also offers a comprehensive donor screening capability, permitting researchers to select the required scope of infectious disease testing such as CMV, hepatitis (B&C), HIV, West Nile Virus, syphilis, Chagas, and more.

About iSpecimen

Headquartered in Lexington, MA, iSpecimen offers an online marketplace for human biospecimens, providing researchers with the specimens they need from the patients they want. The privately held company has developed theiSpecimen Marketplace, an online platform connecting healthcare organizations that have access to patients and specimens with the scientists who need them. Proprietary, cloud-based technology enables researchers to intuitively search for specimens and patients across a federated partner network of hospitals, labs, biobanks, blood centers, and other healthcare organizations. Researchers easily and compliantly gain access to specimens to drive scientific discovery. Partner sites gain an opportunity to contribute to biomedical discovery as well as their bottom line. Ultimately, healthcare advances for all. For more information about iSpecimen, please visitwww.ispecimen.com.

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