New facility boosts UKs cell and gene therapy manufacturing capacity – Pharmaceutical Technology

On 10 March, the National Health Service Blood and Transplant (NHSBT) opened a new Clinical Biotechnology Centre (CBC) with the aim of improving the UKs ability to develop and manufacture cell and gene therapies. A 9.3 million ($11 million) grant is being used to build the facility in Bristol where therapies for currently incurable diseases, such as some forms of cancer, sickle cell disease, and cystic fibrosis can be manufactured. Personalised medicines will also be developed at the centre.

In an email to Pharmaceutical Technology, an NHSBT spokesperson said the centre will support early phase clinical trials and preclinical work, providing a route to eventual commercial scale production. The representative expected the facility to open more treatment opportunities for UK citizens saying, It will help give patients quick access to the latest treatments by increasing the number of UK patients with incurable diseases who are able to take part in clinical trials and bring new treatments into the NHS faster.

This is important due to the UKs currently limited short-scale manufacturing capacity. The NHSBT representative explained that a lack of manufacturing spaces led to delays in production slots for many gene therapy developers. In the past, researchers have often had to seek help from outside the UK, thus delaying clinical trials and patient access. The NHSBT hopes the CBC will increase the UKs competitiveness within the market.

The opening of this new facility plays into the UK governments Life Sciences Industrial Strategy. The strategy, underlines one of the governments goals of increasing the UKs manufacturing capacity for DNA-based therapeutics. Operations at the CBC will focus on building plasmids, viral vectors and recombinant proteins for the production of cell and gene therapies.

This facility will join the NHSBTs five other sites throughout the UK, which provide a combination of stem cell and immunotherapy support services, GMP cell therapy manufacturing services, and advanced therapy medicinal products (ATMP) storage and distribution. The representative said NHSBT plans to continue increasing manufacturing capacity in this way and said, We are actively pursuing collaborations with external partners.

In a statement released along with the centres launch, Steve Barclay, the UKs Health and Social Care Secretary said, The investment in this new centre will continue to develop this area of research and help provide patients the best possible care. Dr Lilian Hook, NHSBTs Director of Cell, Apheresis and Gene Therapies affirmed this sentiment saying, This will enable cutting edge research with the potential to develop cures for some critical diseases which can currently only be treated and often ultimately prove fatal. Well be supporting delivery of these curative treatments into the NHS, so patients can access them more quickly.

Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva.

Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content.

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New facility boosts UKs cell and gene therapy manufacturing capacity - Pharmaceutical Technology

Cyborg technology analyzes the functional maturation of stem-cell … – Harvard School of Engineering and Applied Sciences

Using these techniques in in vitro experiments, the team discovered that the blood vessel lining cells that regulate blood flow between vessels and surrounding tissues (called endothelial cells) play a previously underestimated but crucial role in the rapid and functional maturation of stem-cell derived cardiomyocytes. When cultured together in a 3D cardiac tissue matrix, cardiomyocytes underwent extraordinary electrical maturation in the presence of endothelial cells.

Over the course of seven weeks of monitoring the developing organoids, the team observed that proximity to endothelial cells had a direct impact. Cardiomyocytes cultured next to endothelial cells matured faster compared to cardiomyocytes located farther away from endothelial cells, and they also displayed electrical characteristics typically found in healthy heart tissue.

The new insight is a leap forward for engineering stem-cell derived cardiac tissues. Experimental preclinical research in animals with human-like hearts has proven its difficult to engineer and transplant stem-cell derived cardiomyocytes that can beat in tandem with surrounding heart tissue for extended periods of time. Immature cardiomyocytes transplanted into an animals heart tend to beat to their own drum, and this electrical misfire can cause dangerous irregular heartbeats. Thats why the discovery that co-culturing stem-cell-derived cardiomyocytes with endothelial cells can create more functionally mature cardiomyocytes is so significant.

In their new paper, the team also describes using a novel machine-learning-based analysis to interpret the electrical activity captured by the tissue-embedded nanoelectronic devices, enabling continuous monitoring of the electrical waves generated by maturing cardiomyocytes of interest and enabling a better understanding of how the tissue microenvironment influences electrical stability.

Liu says the nanoelectronic devices and machine-learning-based analysis represent new platform technologies for monitoring and managing stem-cell derived tissue implants enabling scientists to culture cyborgs made from both living tissues and electronics that can be controlled with a high degree of specificity. In cardiac tissues, he envisions that someday these cyborgs could even be used in a sophisticated, real-time feedback system to detect abnormal electrical activity in cardiomyocytes and provide highly targeted voltage, acting like a nanoscale pacemaker, to help correct implanted cells and ensure they continue to beat in rhythm with the rest of the heart.

If we have both nanoelectronic sensors and stimulators, we can monitor electrical activity and use feedback to pace implanted tissues into the same frequency as surrounding tissues, Liu says. This approach could be adapted to so many other types of stem-cell-derived tissues, such as neuronal tissues and pancreatic organoids.

He also says this nanoelectronics platform approach could be used in drug screening, providing single-cell-level, continuous analysis of how tissues respond to different compounds and therapies.

Harvards Office of Technology Developmenthas protected the intellectual property arising from this study and is exploring commercialization opportunities.

Additional authors include Zuwan Lin, Jessica C. Garbern, Ren Liu, Qiang Li, Estela M. Juncosa, Hannah L.T. Elwell, Morgan Sokol, Junya Aoyama, Undine-Sophie Deumer, Emma Hsiao, and Hao Sheng.

This work was supported by the National Institutes of Health (K08 HL150335, HL151684, HL137710, and 1DP1DK130673), National Science Foundation (NSF ECCS-2038603), the William Milton Fund, a Harvard Stem Cell Collaborative Seed Grant, a Blavatnik Biomedical Accelerator Pilot Grant, an American Heart Association Career Development Award, a Boston Childrens Hospital Office of Faculty Development Career Development Award, and an Aramont Fellowship for Emerging Science Research.

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Cyborg technology analyzes the functional maturation of stem-cell ... - Harvard School of Engineering and Applied Sciences

Erythema Extent Predicts Death in Patients With ccGVHD – Medscape

Researchers are calling for the extent of skin erythema to be considered as an outcome measure in patients who develop chronic cutaneous graft-vs-host disease (ccGVHD) after allogeneic stem cell transplants for various blood cancers.

"There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%" to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.

They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.

Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.

With additional research, erythema body surface area (BSA) should be "introduced as an outcome measure in clinical practice and trials," they conclude.

At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.

The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.

Overall, the composite score waters down the weight given to erythema BSA because the score is "driven by stable sclerotic features, and erythema changes are missed," they explain.

The study was published online on March 8 in JAMA Dermatology.

The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.

All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.

They were enrolled from 2007 through 2012 at nine US medical centers all members of the Chronic Graft Versus Host Disease Consortium and followed until 2018.

Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.

The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio [HR], 1.33 per 10% BSA increase; P < .001) and overall survival (HR 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.

Participants in the study were predominantly White. The investigators note that "BSA assessments of erythema may be less reliable in patients with darker skin."

The work was funded by the US Department of Veterans Affairs and the National Institutes of Health. Baumrin had no disclosures; one co-author is an employee of CorEvitas, and two others reported grants/advisor fees from several companies, including Janssen, Mallinckrodt, and Pfizer.

JAMA Dermatol. Published online March 8, 2023. Abstract

M. Alexander Otto is a physician assistant with a master's degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com

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Erythema Extent Predicts Death in Patients With ccGVHD - Medscape

Astellas and Seagen Announce China’s National Medical Products … – PR Newswire

Clinical data submitted are consistent with global data and support enfortumab vedotin as a platinum-free option in patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1/L1 inhibitor and platinum-based chemotherapy

TOKYO and BOTHELL, Wash., March 9, 2023 /PRNewswire/ --Astellas Pharma Inc. (TSE:4503, President and CEO:Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq: SGEN) today announced that the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has accepted the Biologics License Application (BLA) for enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial cancer (la/mUC) who received prior treatment with a PD-1/L1 inhibitor andplatinum-based chemotherapy.

"In China, there were nearly 86,000 new cases of bladder cancer in 2020, and weare working with the NMPA to seek approval for enfortumab vedotin for patients with advanced stage disease," said Ahsan Arozullah, M.D., M.P.H., Senior Vice President and Head of Development Therapeutic Areas, Astellas. "Enfortumab vedotin has become a second- and third-line treatment option for many patients around the world with previously treated locally advanced or metastatic urothelial cancer, and an approval in China may bring this therapy to those patients."

The BLA submission for enfortumab vedotin is based on data from the EV-203 study (NCT04995419), a single-arm, open-label, multicenter Phase 2 study of enfortumab vedotin in Chinese patients with la/mUC who previously received a PD-1/L1 inhibitor and platinum-based chemotherapy. Results showed that EV-203 met its primary endpoint, showing statistical significance in objective response rate (ORR) by independent review committee (IRC) for patients treated with enfortumab vedotin alone compared to historical controls. Efficacy and pharmacokinetic data from the study are in line with global data, and EV-203 is a bridging study to EV-301, a Phase 3 randomized study that has supported global registrations of enfortumab vedotin, and EV-201 Cohort 1.

Please see Important Safety Information, including BOXED WARNING, at the end of this press release for further safety information regarding enfortumab vedotin including serious skin reactions.

Enfortumab vedotin alone and in combination with other therapies is the subject of a robust clinical development program aimed at addressing unmet medical needs across the continuum of urothelial cancer and in other solid tumors.

About Bladder and Urothelial CancerGlobally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.1 Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.2Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.3

In China, the incidence rate of bladder cancer in 2020 ranked 12th among all cancers, with an estimated 85,649 new cases that year. The five-year prevalence of bladder cancer in China is estimated to be 16.26/100,000 cases, or 235,393 cases.4

About the EV-203 TrialThe EV-203 trial (NCT04995419) is a Phase 2, multicenter, single-arm bridging study in China designed to evaluate the efficacy, safety and pharmacokinetic performance of enfortumab vedotin as treatment for patients in China. A total of 40 patients were enrolled in the study.

About the EV-301 TrialThe EV-301 trial(NCT03474107) is a global, multicenter, open-label, randomized Phase 3 trial designed to evaluate enfortumab vedotin versus physician's choice of chemotherapy (docetaxel, paclitaxel or vinflunine) in 608 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapies. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, overall response rate, duration of response and disease control rate, as well as assessment of safety/tolerability and quality-of-life parameters.

About the EV-201 TrialThe EV-201 trial (NCT03219333) is a single-arm, multi-cohort, multicenter, pivotal phase 2 clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (Cohort 1) and those who have not received a platinum-containing chemotherapy in this setting and who are ineligible for cisplatin (Cohort 2). The trial enrolled 125 patients in Cohort 1 and 89 patients in Cohort 2 at multiple centers internationally. The primary endpoint is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety and tolerability.

Results of EV-301 and EV-201 Cohort 2 clinical trials supported the full and supplemental approval of PADCEV (enfortumab vedotin-ejfv) by the U.S. Food and Drug Administration in July 2021. Additionally, results from EV-301 and EV-201 Cohort 1 serve as core data to support the Marketing Authorization Applications for enfortumab vedotin in the global market, including the European Union, Japan and Singapore.

About PADCEVPADCEV (enfortumab vedotin-ejfv) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.5Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4-expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).6

PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information

BOXED WARNING: SERIOUS SKIN REACTIONS

IndicationPADCEV is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who:

Important Safety Information

Warnings and Precautions

Skin reactionsSevere cutaneous adverse reactions, including fatal cases of SJS or TEN, occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatmentbut may occur later. Skin reactions occurred in 55% of the 680 patients treated with PADCEV in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 33% had pruritus. Grade 3-4skin reactions occurred in 13% of patients, including maculo-papular rash, rash erythematous, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmar-plantarerythrodysesthesia. In clinical trials, the median timeto onset of severe skin reactions was 0.6 months (range: 0.1 to 6.4 months). Among patients experiencing a skinreaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade 1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN, or for Grade 4 or recurrent Grade 3 skin reactions.

Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with andwithout pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C8% were excluded from clinical trials. In clinical trials, 14% of the 680 patients treated with PADCEVdeveloped hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. The incidence of Grade3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients withhigher baseline A1C. Five percent (5%) of patients required initiation of insulin therapy for treatment ofhyperglycemia. The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20.3 months). Hyperglycemia led to discontinuation of PADCEV in 0.6% of patients. Closely monitor blood glucoselevels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated(>250 mg/dL), withhold PADCEV.

PneumonitisSevere, life-threatening or fatal pneumonitis occurred in patients treated with PADCEV. Inclinical trials, 3.1% of the 680 patients treated with PADCEV had pneumonitis of any grade and 0.7% hadGrade 3-4. In clinical trials, the median time to onset of pneumonitis was 2.9 months (range: 0.6 to 6 months).Monitor patients for signs and symptoms indicative of pneumonitis, such as hypoxia, cough, dyspnea orinterstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients whodevelop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis.

Peripheral neuropathy (PN)occurred in 52% of the 680 patients treated with PADCEV in clinical trials, including 39% with sensory neuropathy, 7% with muscular weakness and 6% with motor neuropathy; 4%experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without pre-existingPN. The median time to onset of Grade 2 PN was 4.6 months (range: 0.1 to 15.8 months).Neuropathy led to treatment discontinuation in 5% of patients. Monitor patients for symptoms of newor worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV whenPN occurs. Permanently discontinue PADCEV in patients who develop Grade 3 PN.

Ocular disorderswere reported in 40% of the 384 patients treated with PADCEV in clinical trials in which ophthalmologic exams were scheduled.The majority ofthese events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 34% of patients, and blurred vision occurred in 13% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6 months (range: 0 to 19.1 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

Infusion site extravasationSkin and soft tissue reactions secondary to extravasation have beenobserved after administration of PADCEV. Of the 680 patients, 1.6% of patients experienced skin andsoft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed.Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation andresolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions withsecondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicityPADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatmentwith PADCEV and for 4 months after the last dose.

Adverse Reactions

Most Common Adverse Reactions, Including Laboratory Abnormalities (20%)Rash, aspartate aminotransferase (AST) increased, glucose increased, creatinine increased, fatigue, PN, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase (ALT) increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin.

EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-basedchemotherapy.Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each). Adverse reactions leading todiscontinuation occurred in 17% of patients; the most common (2%) were PN (5%) and rash (4%).Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (4%)were PN (23%), rash (11%) and fatigue (9%). Adverse reactions leading to dose reduction occurred in34% of patients; the most common (2%) were PN (10%), rash (8%), decreased appetite and fatigue (3%each). Clinically relevant adverse reactions (<15%) include vomiting (14%), AST increased (12%),hyperglycemia (10%), ALT increased (9%), pneumonitis (3%) and infusion site extravasation (0.7%).

EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for platinum-based chemotherapy.Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia andpneumonitis (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; themost common (2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% ofpatients; the most common (3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), AST increasedand hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients;the most common (3%) were PN (19%), rash (11%) and fatigue (7%). Clinically relevant adverse reactions (<15%) include vomiting (13%), AST increased (12%), lipase increased (11%), ALT increased(10%), pneumonitis (4%) and infusion site extravasation (1%).

Drug InteractionsEffects of other drugs on PADCEV(Dual P-gpand Strong CYP3A4 Inhibitors)Concomitant use with dual P-gpand strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatinE exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitorpatients for signs of toxicity when PADCEV is given concomitantly with dual P-gpand strong CYP3A4 inhibitors.

Specific PopulationsLactationAdvise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.

Hepatic impairmentAvoid the use of PADCEV in patients with moderate or severe hepatic impairment.

For more information, please see the full Prescribing Informationincluding BOXED WARNINGfor PADCEVhere.

About AstellasAstellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+ healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUEfor patients. For more information, please visit our website athttps://www.astellas.com/en.

AboutSeagenSeagenInc. is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people's lives.Seagenis headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland and the European Union. For more information on the company's marketed products and robust pipeline, visitwww.seagen.comand follow @SeagenGlobalon Twitter.

About the Astellas and Seagen CollaborationAstellas and Seagen are co-developing enfortumab vedotin under a 50:50 worldwide development and commercialization collaboration. In the United States, Astellas and Seagen co-promote enfortumab vedotin under the brand name PADCEV (enfortumab vedotin-ejfv). In the Americas outside the US, Seagen holds responsibility for commercialization activities and regulatory filings. Outside of the Americas, Astellas holds responsibility for commercialization activities and regulatory filings.

Astellas Cautionary NotesIn this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development), which is included in this press release, is not intended to constitute an advertisement or medical advice.

SeagenForward-Looking StatementsCertain statements made in this press release are forward-looking, such as those, among others, relating to the potential for NMPA approval in the referenced indication; the timing of any potential approval; the therapeutic potential of enfortumab vedotin alone or in combination; its possible efficacy, safety and therapeutic uses; clinical development programs; and planned and ongoing clinical trials. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include, without limitation, the possibility that the referenced application may not be approved in a timely manner or at all or with the requested label; the risk of adverse events and the potential for newly-emerging safety signals; the risk of adverse regulatory actions; and the risk of delays, setbacks or failures in clinical development and regulatory activities, the submission of regulatory applications and the regulatory review process for a variety of reasons, including without limitation the inherent difficulty and uncertainty of pharmaceutical product development, possible required modifications to clinical trials, the inability to provide information and institute safety mitigation measures as may be required by regulatory authorities from time to time, failure to properly conduct or manage clinical trials, and failure of clinical results to support continued development or regulatory approvals. More information about the risks and uncertainties faced by Seagen is contained under the caption "Risk Factors" included in the company's Annual Report on Form 10-K for the year ended December 31, 2022 filed with the Securities and Exchange Commission. Seagen disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

1 International Agency for Research on Cancer. Cancer Tomorrow: Bladder. http://gco.iarc.fr/tomorrow. Accessed March 6, 2023.2 American Society of Clinical Oncology. Bladder Cancer: Introduction (12-21). https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed March 6, 2023.3 National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer stat facts: bladder cancer. 2022. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed March 6, 2023.4 International Agency for Research on Cancer. Cancer Today. https://gco.iarc.fr/today. Accessed March 6, 2023.5 Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res 2016;76(10):3003-13.6 PADCEV [package insert]. Northbrook, IL: Astellas Pharma US, Inc.

SOURCE Astellas Pharma Inc.

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Astellas and Seagen Announce China's National Medical Products ... - PR Newswire

Diagnostic Imaging Impacting DME and Wet AMD Treatment … – AJMC.com Managed Markets Network

Caesar Luo, MD, FASRS, FACS: What might be the biggest disrupter to our clinical flow is treatment for geographic atrophy and stem cell therapy/complement inhibition. Were at the cusp of geographic atrophy. That conversation is going to be big over the next 6 months to a year. Theres going to be a flood of conversations with payers and managed care and utilization. It is going to be a completely new ball of wax. It will be interesting to hear what the other panelists think, but Im expecting a deluge of new conversations and tricky situations to navigate.

Veeral Sheth, MD, MBA, FACS, FASRS: Thats a great point. One other thing Ill bring up that might be a paradigm shifter is home imaging, like Home OCT [optical coherence tomography]. We havent talked about it. Weve been talking about therapeutics, but diagnostics are equally important. If that means patients can be at home and we can monitor them there because we have to open up space for these patients with geographic atrophy who are going to be coming in. Theres a whole bunch of puzzle pieces that are moving around. Where are they going to end up? Were still going to find out.

Caesar Luo, MD, FASRS, FACS: Thats a great point.

Jim Kenney, RPh, MBA: For our audience, could you describe what OCT is, Dr Sheth?

Veeral Sheth, MD, MBA, FACS, FASRS: OCT is how we scan the retina. Its a pretty quick test. Were able to tell a lot of information from thatin particular, what the anatomy of the macula looks like. Is there fluid? Is there macular degeneration? Is there diabetic retinopathy? As a baseline, thats important. But also as we start to treat that patient and take them through their treatment journey, were going to be able to assess: how well are we treating them? How effectively are we treating them? In all this prior discussion, patients still have fluid. How do we know they have fluid? Its not just the examination, but a lot of the time its the imaging that were doing. If were able to do that imaging remotely at this patients home and get reports, were going to be able to tell if a patient is going in the wrong direction, maybe sooner than we would have if were just bringing them in on a certain interval.

Caesar Luo, MD, FASRS, FACS: Thats a great point. Treatment burden should be broken down into treatmentthe number of times Im sticking that patient with the needleand visits, how many times theyre coming in. Dr Coney, most of us do this treatment and extend regimen, and its the best of both worlds. Youre getting fewer shots and theyre coming into the office less. As-needed dosing didnt work that well. For patients who did better on as-needed dosing, they still have to come in every month. For these sustained drug-delivery systems, like port-delivery systems or potentially gene therapy, are we going to feel comfortable seeing them every 3 months? Probably not without something like Home OCT available to say if there might be some early fluid thats building up.

Joseph Coney, MD, FASRS, FACS: With these alternatives and other modalities of testing with artificial intelligence and Home OCT, we may be revisiting as-needed dosing. This is the best of both worlds if we have some type of feedback, and maybe immediate feedback, that patients can give. If they can just use their iPhone with an app, for example, and get feedback, they could say, You know what? This is what I saw yesterday. This is what Im seeing today. This is a smiley face. This is a sad face. I need to go in and be seen. With this new technology, there may be ways where we revisit as-needed dosing to decrease the number of patient visits to maximize their therapy while increasing the durability of these agents.

Jim Kenney, RPh, MBA: The challenge from the health plan side is that theres a phrase they like to use: We dont pay for convenience. We need to be able to drive the message that its not just convenient when you have an extended-dosing interval or something like that. Theres sustained damage to the eye and vision when youre not treating and the patient isnt adherent to therapy. We have to get beyond that initial barrier because there have been a lot of drugs that are brought to market over the years that were strictly for convenience. You didnt get better clinical results, as long as the patient was adherent with therapy. Thats an avenue that were going to have to focus some attention on to convince payers to open up access a little more for these therapies, and not simply view them as a convenience option rather than a true clinical advantage.

Joseph Coney, MD, FASRS, FACS: Jim, if we learned 1 thing during COVID-19, its that decreasing the number of patients in our office was really effective. Going forward, because of the overwhelming number of patients well be seeingparticularly those with geographic atrophywe need to find better ways to limit individuals from coming to the hospital. This isnt just for patients. For the most part, our patients, at least older patients, need caregivers. Individuals are taking off time from work. Thats lost income and lost taxes. These are things that we may not see from a treatment standpoint, but theres also a burden to the family. When these patients are receiving injections, its not just 1 to 2 hours in the office; its half the day. If thats a working population, that individual isnt going back to work. We need to find better ways to limit the burden and to monitor them so they can have the better lifestyles that we all want for ourselves.

Transcript edited for clarity.

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Diagnostic Imaging Impacting DME and Wet AMD Treatment ... - AJMC.com Managed Markets Network

FDA Accepts Mesoblast’s Resubmission of the Biologic License … – InvestorsObserver

FDA Accepts Mesoblasts Resubmission of the Biologic License Application for Remestemcel-L In Children with Steroid-Refractory Acute Graft Versus Host Disease as a Complete Response and Sets Goal Date of August 2, 2023

NEW YORK, March 07, 2023 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in allogeneic cellular medicines for inflammatory diseases, today announced that the United States Food and Drug Administrations (FDA) Office of Therapeutic Products (OTP) has accepted the Companys Biologics License Application (BLA) resubmission for remestemcel-L in the treatment of children with steroid-refractory acute graft versus host disease (SR-aGVHD). FDA considers the resubmission to be a complete response and has set a Prescription Drug User Fee Act (PDUFA) goal date of August 2, 2023.

Over the last two years we have worked tirelessly to address the issues previously raised by FDA. We look forward to working closely with the Agency over the review period with the aim to make remestemcel-L available as a therapy for children suffering from SR-aGVHD, said Mesoblast Chief Executive Silviu Itescu.

Survival outcomes have not improved over the past two decades for the most severe forms of SR-aGVHD, a life-threatening complication of an allogeneic bone marrow transplant following treatment for blood cancers and other conditions. 1- 3 The lack of any approved treatments for children under 12 means that there is an urgent need for a therapy that improves the dismal survival outcomes. If remestemcel-L receives FDA approval, it will be the first allogeneic off-the-shelf cellular medicine to be approved in the United States, and the first therapy for children under 12 years old with SR-aGVHD.

The resubmission contains the following new information:

FDA granted remestemcel-L Fast Track designation, a process to facilitate the development and expedited review of therapies for serious conditions that fill unmet medical needs, and Priority Review designation, which is given to drugs that treat a serious condition and provide a significant improvement in safety or effectiveness over existing treatments.

About Steroid-Refractory Acute Graft Versus Host Disease Survival outcomes have not improved over the past two decades for children or adults with the most severe forms of SR-aGVHD. 1- 3 The lack of any approved treatments for children under 12 means that there is an urgent need for a therapy that improves the dismal survival outcomes in children.

Acute GVHD occurs in approximately 50% of patients who receive an allogeneic bone marrow transplant (BMT). Over 30,000 patients worldwide undergo an allogeneic BMT annually, primarily during treatment for blood cancers, including about 20% in pediatric patients. 4,5 SR-aGVHD is associated with mortality as high as 90% and significant extended hospital stay costs. 6,7 There are currently no FDA-approved treatments in the US for children under 12 with SR-aGVHD.

About Remestemcel-L Mesoblasts lead product candidate, Remestemcel-L, is an investigational therapy comprising culture expanded mesenchymal stromal cells derived from the bone marrow of an unrelated donor. It is administered to patients in a series of intravenous infusions. Remestemcel-L is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in SR-aGVHD by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

The original BLA submission contained clinical outcomes of 309 children with SR-aGVHD treated with remestemcel-L showing consistent treatment responses and survival across three separate trials. The data were reviewed by the agencys panel of the Oncologic Drugs Advisory Committee (ODAC) which voted in favor 9:1 that the available data support the efficacy of remestemcel-L in pediatric patients with SR-aGVHD.

The BLA resubmission now contains additional clinical and biomarker data, including from a propensity-matched study of children with high-risk disease, based on the validated MAP biomarker score, comparing outcomes in 25 children from Mesoblasts Phase 3 trial and 27 control children treated with various biologics, including ruxolitinib, from the Mount Sinai Acute GvHD International Consortium (MAGIC) database. The study showed that 67% of high-risk children treated with remestemcel responded positively to treatment within 28 days and were alive after 180 days compared to just 10% in both categories in the MAGIC group.

The BLA resubmission also contains results of a 4-year survival study performed by the Center for International Blood and Marrow Transplant Research (CIBMTR) on 51 evaluable patients with SR-aGVHD who were enrolled in the Phase 3 trial. The results demonstrated durability of the early day 180 survival benefits, with 63% survival at 1 year and 51% at 2 years in a group of children with predominantly grade C/D disease (89%) and with expected 2 year survival of just 25-38% using best available therapy. 1 ,8-9

About Mesoblast Mesoblast is a world leader in developing allogeneic (off-the-shelf) cellular medicines for the treatment of severe and life-threatening inflammatory conditions. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of late-stage product candidates which respond to severe inflammation by releasing anti-inflammatory factors that counter and modulate multiple effector arms of the immune system, resulting in significant reduction of the damaging inflammatory process.

Mesoblast has a strong and extensive global intellectual property portfolio with protection extending through to at least 2041 in all major markets. The Companys proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblast is developing product candidates for distinct indications based on its remestemcel-L and rexlemestrocel-L allogeneic stromal cell technology platforms. Remestemcel-L is being developed for inflammatory diseases in children and adults including steroid refractory acute graft versus host disease, biologic-resistant inflammatory bowel disease, and acute respiratory distress syndrome. Rexlemestrocel-L is in development for advanced chronic heart failure and chronic low back pain. Two products have been commercialized in Japan and Europe by Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com , LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

References / Footnotes

Forward-Looking Statements This press release includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward-looking statements include, but are not limited to, statements about: the initiation, timing, progress and results of Mesoblasts preclinical and clinical studies, and Mesoblasts research and development programs; Mesoblasts ability to advance product candidates into, enroll and successfully complete, clinical studies, including multi-national clinical trials; Mesoblasts ability to advance its manufacturing capabilities; the timing or likelihood of regulatory filings and approvals, manufacturing activities and product marketing activities, if any; the commercialization of Mesoblasts product candidates, if approved; regulatory or public perceptions and market acceptance surrounding the use of stem-cell based therapies; the potential for Mesoblasts product candidates, if any are approved, to be withdrawn from the market due to patient adverse events or deaths; the potential benefits of strategic collaboration agreements and Mesoblasts ability to enter into and maintain established strategic collaborations; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement; the scope of protection Mesoblast is able to establish and maintain for intellectual property rights covering its product candidates and technology; estimates of Mesoblasts expenses, future revenues, capital requirements and its needs for additional financing; Mesoblasts financial performance; developments relating to Mesoblasts competitors and industry; and the pricing and reimbursement of Mesoblasts product candidates, if approved. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

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FDA Accepts Mesoblast's Resubmission of the Biologic License ... - InvestorsObserver

Researchers discover the role of intestinal fibrosis in inflammatory … – Drug Target Review

The scientists used a new in vitro platform, which allowed intestinal organoids to be cultured on an open lumen, planar system that could be manipulated experimentally.

Intestinal fibrosis is a common feature of inflammatory bowel disease (IBD) and the primary cause of end-stage organ failure. Traditionally considered a bystander of inflammation, with negligible involvement in disease pathogenesis, new research published inGastroenterologynow shows that fibrosis has a direct bearing on disease progression in IBD.

The investigation was spearheaded by researchers from Massachusetts General Hospital (MGH) and Harvard Medical School, both US.

The critical question posed by the investigators was how tissue stiffening influences the growth and differentiation of intestinal stem cells, which fuel the regeneration of intestinal epithelium?

This was addressed by developing a newin vitroplatform, which allowed intestinal organoids to be cultured on an open lumen, planar system that could be manipulated experimentally.

The platform permitted the use of soft yet tunable substrates with biophysical properties mimicking native tissue, facilitating the long-term growth and differentiation of intestinal stem cells, like native epithelium.

The team discovered that upon elevating substrate stiffness to a similar range observed in IBD patients, both the number and capacity of stem cells to maintain homeostasis and cellular composition of the epithelium were potently reduced.

Concomitantly, the stem cells preferentially differentiated into goblet cells, leading to epithelial deterioration. Similar phenotypes were also noted in mouse models of IBD as well as in samples from human patients.

The investigators concluded that interfering with the molecular machinery involved in the cellular sensing of stiffness conferred protection against the detrimental effects of fibrosis and stiffening.

These findings demonstrate that intestinal fibrosis and stiffening are critical components of IBD pathogenesisand that targeting mechanosensing and mechanotransduction pathways may offer an attractive therapeutic strategy for IBD, said lead author Dr Nima Saeidi.

The scientists also observed that despite the significant reduction in a specific population of stem cells, stiffening led to the expansion of another stem cell marker (OLFM4) outside the stem cell zone.

Our observations that stiffening increased the expression of OLFM4 may have significant implications for the development of colitis-associated colorectal cancer, said co-first author Dr Shijie He.

A collaborative work between scientists from the Massachusetts General Hospital, MIT, Boston Childrens Hospital, Harvard T.H. Chan School of Public Health, and Boston University, all US.

This research was supported by the US National Institute of Diabetes and Digestive and Kidney Diseases.

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Researchers discover the role of intestinal fibrosis in inflammatory ... - Drug Target Review