Stem Cell Clinic

Bluebird responds to FDA on sickle cell gene therapy’s production… – Sickle Cell Disease News

Bluebird Bio has provided the U.S. Food and Drug Administration (FDA) with information regarding the commercial manufacturing of its experimental gene therapy for sickle cell disease (SCD) in preparation for requesting its approval.

The company had expected to submit a biologics license application seeking the approval of the therapy, lovotibeglogene autotemcel or lovo-cel, to the FDA earlier this year.

In February, however, the agency asked for more information to ensure production processes for the commercial use of lovo-cel are comparable to those used in clinical testing. Because the treatment uses the patients own stem cells, which are altered and then infused back to the patient, the complex manufacturing process is a key aspect to take into consideration.

Bluebird now has responded to FDA feedback on manufacture comparability referred to as chemistry, manufacturing, and controls (CMC) comparability and is expecting a response within a matter of weeks, according to a company press release.

The company also plans to request priority review of lovo-cel for SCD patients, ages 12 and older, with a history of vaso-occlusive crisis (VOC), a painful SCD complication. Priority review works to quicken an FDA approval decision.

We remain laser focused on our lovo-cel BLA for sickle cell disease, said Andrew Obenshain, Bluebirds CEO. Following feedback from the FDA in February, bluebird submitted additional information related to CMC comparability analyses to the FDA in early March.

Most importantly, we know that patients and their families are waiting, and we will move quickly to expedite our BLA submission, Obenshain said.

SCD is caused by mutations in the HBB gene, leading to the production of a faulty version of hemoglobin the protein in red blood cells that transports oxygen. As a result, red blood cells acquire a sickle-like shape, becoming more fragile and prone to clumping. Misshapen red blood cells also can block blood vessels and trigger VOCs.

Lovo-cel, previously known as bb1111 or LentiGlobin, is a one-time therapy designed to insert functional copies of a modified HBB gene into blood stem cells isolated from a patient. When returned, the modified stem cells are expected to give rise to new red blood cells capable of producing a working version of hemoglobin.

The therapy is being evaluated in HGB-206 (NCT02140554), an ongoing Phase 1/2 study in up to 50 SCD patients, ages 12-50.

The FDA recently lifted a yearlong partial clinical hold on HGB-206 for patients younger than age 18 after an adolescent developed persistent anemia, a condition caused by a lack of healthy red blood cells, following treatment.

Investigation revealed the patient carried specific mutations in a gene that encodes a part of hemoglobin. As such, these mutations were added to the exclusion criteria for ongoing lovo-cel studies.

Trial data, released in December, showed the one-time gene therapy led to the sustained production of HbAT87Q hemoglobin and nearly eliminated severe VOCs in 29 patients at two years after treatment. HbAT87Q is the protein coded by the modified version of the HBB gene.

Bluebird also is recruiting for its open-label Phase 3 HGB-210 trial (NCT04293185) of lovo-cel in up to 35 adults and children, ages 2-50, with SCD. Eligible patients are being enrolled at sites across the U.S.

The Phase 3 studys main goal is to assess the proportion of participants with a complete resolution of vaso-occlusive events at six to 18 months after treatment.

Lovo-cel is the most deeply studied gene therapy in development for sickle cell disease, with more than 50 patients treated and multiple patients followed for more than six years, Obenshain said. We remain extremely confident in the quality of our BLA submission.

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Bluebird responds to FDA on sickle cell gene therapy's production... - Sickle Cell Disease News

Regenxbio earns key FDA designation for DMD gene therapy – Clinical Trials Arena

Regnexbios bid to develop a gene therapy for Duchenne muscular dystrophy (DMD) has received an important regulatory lift.

The US Food and Drug Administration (FDA) granted fast track designation for Regenxbios DMD candidate RGX-202, hastening the gene therapys development timeline. RGX-202 is currently recruiting for the Phase I/II AFFINITY DUCHENNE study (NCT05693142), which will have initial data available in the second half of 2023.

The regulatory designation gives Regnexbio a much-needed push, as RGX-202 lags behind key competitors in the race to bring a DMD gene therapy to market.

Sareptas gene therapy SRP-9001 is in a Phase III trial (NCT05096221) and could receive an FDA accelerated approval by May 29. Meanwhile, Pfizers gene therapy PF-06939926 is recruiting patients in a Phase III trial (NCT04281485) after rebounding from earlier safety concerns.

The crowded field of DMD drug development also features monoclonal antibodies, synthetic steroids, and even an allogenic stem cell therapy.

DMD is characterized by alterations in the protein dystrophin, causing progressive muscle loss primarily in young boys. RGX-202 is a one-time gene therapy using an adeno-associated vector (AAV) to deliver microdystrophin, a shortened form of the dystrophin protein intended to restore partial muscle function.

RGX-202 forms part of Regenxbios self-described 525 strategy to have five AAV therapies in the market or in late-stage development by 2025. Regenxbio also has gene therapies in development for Hunter syndrome, age related macular degeneration, and diabetic retinopathy, among others.

The Phase I/II AFFINITY DUCCHENE study has a target enrollment of 18 boys between the ages of 4 and 11. The primary endpoint focuses on safety, while secondary endpoints include microdystrophin expression and the North Star Ambulatory Assessment (NSAA) which measures DMD function.

Cell & Gene Therapy coverage on Clinical Trials Arena is supported by Cytiva.

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

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Regenxbio earns key FDA designation for DMD gene therapy - Clinical Trials Arena

7 Unusual Symptoms of Parkinson’s: Expert Advice on Diagnosis and Advances in Treatment | TheHealthSi – TheHealthSite

7 Unusual Symptoms of Parkinson's: Expert Advice on Diagnosis and Advances in Treatment Dr (Lt Gen) CS Narayanan Vsm, HOD And Consultant, Department of Neurology, HCMCT Manipal Hospital, Dwarka talks about the unusual and often ignored symptoms of this condition and the various ways in which it can be treated.

Parkinson's disease is a neurodegenerative disorder that progressively affects the ability to move. It manifests through symptoms such as tremors, muscle stiffness, slow movement, and impaired balance. The disease results from the gradual loss of dopamine-producing cells in the brain, leading to insufficient dopamine levels, a neurotransmitter critical for regulating movement. Today, on World Parkinson's Day, we have Dr (Lt Gen) CS Narayanan Vsm, HOD And Consultant, Department of Neurology, HCMCT Manipal Hospital, Dwarka to tell us more about the unusual and often ignored symptoms of this condition and the various ways in which it can be treated.

Symptoms of Parkinson's disease usually develop slowly over time and can be different for each person. Some common signs and symptoms of Parkinson's disease include:

This is the most common symptom of Parkinson's disease. It usually starts in the hands or fingers and can spread to the arms, legs, and face. The tremors are often more noticeable when the person is at rest.

Parkinson's disease can cause stiffness and rigidity in the muscles, making it difficult to move freely.

This is a slowness of movement that can affect daily activities such as walking, getting dressed, or eating.

Parkinson's disease can cause problems with balance and coordination, leading to falls and injuries.

Parkinson's disease can affect speech and cause a soft, mumbled, or monotone voice.

Many people with Parkinson's disease lose their sense of smell.

Parkinson's disease can cause sleep disturbances, including insomnia and excessive daytime sleepiness.

Depression and anxiety are common in people with Parkinson's disease.

It is important to visit a doctor if you experience any of these symptoms, especially if they are persistent or worsen over time. Early diagnosis and treatment of Parkinson's disease can improve the quality of life and slow the progression of the disease.

The exact cause of Parkinson's disease is not known, but researchers believe it is caused by a combination of genetic and environmental factors. One of the main factors in Parkinson's disease is the death of dopamine-producing cells in the brain. Dopamine is a neurotransmitter that helps regulate movement, and when these cells die, the brain doesn't produce enough dopamine, which leads to the symptoms of Parkinson's disease.

While there is no cure for Parkinson's disease, there are treatments available that can help manage the symptoms. One of the most effective treatments is medication, particularly levodopa, which helps replenish dopamine in the brain. Other medications, such as dopamine agonists, can mimic the effects of dopamine in the brain.

"In addition to medication, there are other therapies that can help manage the symptoms of Parkinson's disease. One of these is deep brain stimulation (DBS), which involves implanting electrodes in the brain to stimulate specific areas. DBS has been shown to improve tremors, stiffness, and other symptoms of Parkinson's disease," says Dr (Lt Gen) CS Narayanan Vsm.

Researchers are also exploring other therapies, such as gene therapy and stem cell therapy, as potential treatments for Parkinson's disease. Gene therapy involves introducing new genetic material into cells to treat or prevent disease. Researchers are investigating gene therapy as a potential treatment for Parkinson's disease by introducing genes that produce dopamine into the brain. Stem cell therapy involves using stem cells, which are cells that can develop into different types of cells in the body, to replace the dopamine-producing cells that have died in the brain.

Dr (Lt Gen) CS Narayanan Vsm also highlighted the importance of regular exercises in the management of this condition. He said, "Exercise is another important part of managing Parkinson's disease. Regular exercise can improve balance, flexibility, and strength, and may help slow the progression of Parkinson's disease. Exercise can also improve mood and overall quality of life".

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7 Unusual Symptoms of Parkinson's: Expert Advice on Diagnosis and Advances in Treatment | TheHealthSi - TheHealthSite

Therapeutic effects of polydeoxyribonucleotide in an in vitro … – Nature.com

Cell culture

The Neuro-2a (N2a) cells, derived from mouse neuroblastoma, were purchased from the American Type Culture Collection (Manassas, VA, USA). N2a cells exhibit properties of neuronal stem cells and can differentiate into neuronal cells when treated with 20M retinoic acid (RA)1,15. The cells were incubated in culture dishes into Dulbeccos modified Eagles medium (DMEM; Hyclone, Logan, UT, USA) with 10% fetal bovine serum (FBS; Serum Source International, Charlotte, NC, USA) and 1% penicillin/streptomycin (Gibco, Rockville, MD, USA) in a humidified 5% CO2 atmosphere at 37C. When the cells reached 7080% of confluency, the medium was replaced as a differentiation medium, which contained 2% FBS and 20M RA in DMEM for four days. Differentiated N2a cells were maintained in a humidified atmosphere of 5% CO2 at 37C, and the differentiation medium was changed every two days.

The following procedures were adapted to establish an in vitro I/R injury model from previous studies1,16,17,18. Differentiated N2a cells were washed three times with phosphate-buffered saline (PBS), and the medium was replaced with deoxygenated, glucose-free balanced salt solution (Gibco) in hypoxic condition (O2 tension 1%) for 3h. Following OGD condition, injured cells were replaced onto the growth medium. PBS and 50 or 100g/ml PDRN (Placentex Integro, Mastelli Srl, Italy) was added to the growth medium of injured cells for 24h according to the following experimental groups. Cells treated with OGD and PBS were classified as the OGD group, and cells treated with OGD and PDRN were classified as the OGD+PDRN group. Differentiated N2a cells without OGD were classified as the non-OGD group (Fig.1A).

Effect of PDRN on an in vitro I/R injury model. (A) Experimental design of PDRN treatment on an in vitro I/R injury model. (B) Effect of PDRN on the cell viability of in vitro I/R injury model. (C) Bar graphs show the number of differentially expressed genes in OGD group compared with Non-OGD group and in OGD+PDRN group compared with OGD group. Values are presented as meansstandard error of the mean (SEM). Statistically significant differences are shown as **p<0.01, ***p<0.001.

To analyze the proliferation of the in vitro I/R injury model, the number of cells in the non-OGD, OGD, and OGD+PDRN groups were calculated using an advanced detection and accurate measurement (ADAM) automatic cell counter (NanoEnTek Inc., Seoul, South Korea).

After the cellular experiments, total RNA was isolated from the cells of all the groups with TRIzol reagent (Thermo Fisher Scientific, Waltham, MA, USA) was used for RNA isolation19 according to the manufacturers instructions. A NanoDrop spectrophotometer (Thermo Fisher Scientific) was used to confirm RNA quantity and purity.

RNA-seq transcriptome array of the non-OGD, OGD, and OGD+PDRN groups was performed at Macrogen Inc. (Seoul, Korea) with the HiSequation 2000 platform (Illumina, San Diego, CA, USA) according to methods detailed in our previous study20.

In this study, fold change (FC) criteria (FC|1.7|) were used to identify the differentially expressed genes (DEGs)from the results of RNA-seq transcriptome array. To identify their roles, three different pairs of DEGs were submitted to the Database for Annotation, Visualization and Integrated Discovery (DAVID) v.6.8 annotation tool21.

RT-qPCR was performed to validate the transcriptome analysis results. ReverTra Ace qPCR RT Master Mix with gDNA Remover (Toyobo, Osaka, Japan) was used to prepare the cDNA from total RNA, according to the manufacturers instructions. RT-qPCR was performed to measure the mRNA levels of the genes of interest using qPCRBIO SyGreen Mix Hi-ROX (PCR BIOSYSTEMS, London, UK) on a StepOnePlus Real-Time PCR System (Applied Biosystems, Foster City, CA, USA). The 2CT method was used for data analysis22. Supplementary Table S1 lists the primers used for RT-qPCR.

The proteins were extracted from the cell pellets. Proteins were boiled for 10min and loaded onto 412% bis Tris gels (Invitrogen, Waltham, MA, USA) for separation. The separated proteins were then blotted onto polyvinylidene difluoride (PVDF) membranes (Invitrogen) with 20% (v/v) methanol in NuPage Transfer Buffer (Invitrogen) at 15V for 4h at 4C. Tris-buffered saline containing 0.01% Tween 20 (TBST) in 5% skim milk (Difco, BD Biosciences, Oxford, UK) was used to block the membranes for 1h. The blots were washed three times with TBST for 10min and then incubated overnight at 4C with primary antibodies specific to the following target proteins: phosphorylated JAK1, phosphorylated JAK2, phosphorylated STAT1 (1:1000; Cell Signaling Technology, Cambridge, UK), CSF1, IL-6, PTPN6, RAC2, TNF, IL-1, IL-1, phosphorylated STAT3, STAT3 ADORA2A, JAK1, JAK2, STAT1, SOCS3, Bax, Bcl-2, and -actin (1:1000; Santa Cruz Biotechnology, Santa Cruz, CA, USA). After incubation, the blots were washed thrice with TBST and incubated for 1h with a horse-radish peroxidaseconjugated secondary antibody (1:3000; Santa Cruz) at 25C. Finally, the blots were visualized using an enhanced chemiluminescence detection system (Amersham Pharmacia Biotech, Little Chalfont, UK).

To analyze neuronal cell death, N2a cells were seeded on a 96-well cell culture plate (SPL Life Sciences, Gyeonggi-do, Korea) and OGD and PDRN treatments were performed as previously described above. The death of the in vitro I/R injury model was evaluated using a cytotoxicity lactate dehydrogenase (LDH) assay kit (Dojindo, Kumamoto, Japan) according to the manufacturer's protocol. Briefly, 10l of lysis buffer was added to each well and the cells were cultured at 37C in CO2 for 30min. A total of 100 L of the working solution was then added to each well, and the samples were cultured at room temperature in the dark. Stop solution (50l) was then added to each well, and LDH levels in the culture supernatant were analyzed immediately by measuring the absorbance at 490nm using a microplate reader (VersaMax, Molecular Devices, San Jose, CA, USA).

To analyze apoptosis, N2a cells were seeded on a cell culture slide (SPL Life Sciences, Gyeonggi-do, Korea) and OGD and PDRN treatments were performed as previously described above. The DeadEnd Fluorometric TUNEL System (Promega Madison WI USA) was used to assess apoptosis according to the manufacturers protocol. Briefly, the samples were mounted on glass slides with a fluorescent mounting medium with DAPI for imaging using an LSM 700 fluorescence microscope (Carl Zeiss, Gottingen, Germany). The number of positively stained cells over the total number of cells per specimen field was measured, and the percentage of positive cells was calculated. Four individual specimens were analyzed per group.

All data are expressed as the meanstandard error of the mean (SEM), and all experiments were repeated at least four times with four technical replicates in each group. The Statistical Package for Social Sciences v.25.0 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, v.25.0. Armonk, NY, USA) was used for the statistical analyses. The significance of intergroup differences was estimated using Students paired t-test or one-way analysis of variance (ANOVA). Statistical significance was set at p<0.05.

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Therapeutic effects of polydeoxyribonucleotide in an in vitro ... - Nature.com

Study Recreates Functional Human Thymus From Stem Cells – The Healthcare Technology Report.

The thymus is a rarely discussed and therefore underappreciated organ positioned below the breastbone which plays a critical role in adaptive immune response by producing T cells. Given that it degrades with advancing age, reducing the human bodys ability to stave off infection, it is worth looking into if its breaking down can be mitigatedor if there is another alternative altogether. To this end, researchers from the University of Florida have devised a means to grow entirely functional thymus organoids from what has proved to be the basic building block of replication in biology: the human stem cell.

This work, now only in the proof-of-concept stage, and its resulting mini-organs will be harnessed to develop a series of patient-unique therapies for thymic dysfunction treatment.An experimental model system to interrogate the mechanisms of thymic insufficiency and function is necessary and could serve to further the development of cell-based therapies for thymic defects, said the corresponding studys senior author, Dr. Holger Russ.

Though animal models have for years been utilized to construct thymus organoids, the T cells derived from Russ and his teams research more closely matches the function of a real human thymus. As detailed in the paper published in Stem Cell Reports, the building of these organoids starts with the growing of thymic epithelial progenitor cells (TEPs) from human stem cells, and which are then combined with mesenchymal cells as well as stem cell-derived blood cell precursors.

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Study Recreates Functional Human Thymus From Stem Cells - The Healthcare Technology Report.

Holloway Discusses Later-Line Treatment in Recurrent or Metastatic … – Targeted Oncology

Targeted OncologyTM: What is the recommended next-line systemic therapy for this patient with recurrent/metastatic endometrial cancer?

HOLLOWAY: The NCCN [National Comprehensive Cancer Network] guidelines preferred regimens for recurrent or metastatic endometrial cancer are carboplatin/paclitaxel or carboplatin/paclitaxel/trastuzumab. For patients with uterine serous carcinoma, there is a role for HER2 testing, IHC, [and] next-generation sequencing, and phase 3 data indicate an improved outcome with carboplatin, paclitaxel, and trastuzumab.1

Robert W. Holloway, MD

Medical Director,

Gynecologic Oncology Program

AdventHealth Cancer Institute

Orlando, FL

Other recommended options include carboplatin/ docetaxel, cisplatin/doxorubicin, and cisplatin/doxorubicin/paclitaxel, which [raises] the toxicity. There is carboplatin/paclitaxel/bevacizumab [Avastin]. My nurse practitioner told me they wouldnt approve these combinations. She said only single agent was [available], which surprised me. Now Ill have to circle back with her on that. Albumin-bound paclitaxel and topotecan [are also options]. Temsirolimus has been used with some limited success, and ifosfamide [has been used] for carcinosarcomas, which can be single agent or combined.

For biomarker-directed systemic therapy, there [are] lenvatinib [Lenvima] and pembrolizumab [Keytruda] as category 1 for nonMSI-H, non-MRD tumors and pembrolizumab for tumor mutational burdenhigh, MSI-H tumors as a single agent. Other regimens [such as] nivolumab [Opdivo] and dostarlimab [Jemperli] recently received the pan-tumor indication. For NTRK gene fusions, [you can use larotrectinib (Vitrakvi) or entrectinib (Rozlytrek)]. Avelumab [Bavencio] has been approved as a secondline option [for MRD/MSI-H tumors], and cabozantinib [Cabometyx] [has been approved] as well.

What data support the use of single-agent pembrolizumab as the next-line therapy in patients with recurrent or metastatic endometrial cancer?

The KEYNOTE-158 study [NCT02628067] is an ongoing, international, open-label, phase 2 study of patients with select solid tumors that have progressed on standard-ofcare therapy. Patients with previously [managed] MSI-H, MRD advanced endometrial cancers enrolled in cohorts D and K in the study. They had progression after a standard line of carboplatin plus paclitaxel and werent curable by other means. They received pembrolizumab once every 3 weeks. They were treated for 2 years or until progression of disease [PD] or intolerable toxicity, and then survival follow-up was done. The overall response rate [ORR] was the primary end point per RECIST version 1.1 [criteria]. The secondary end points were duration of response [DOR], progression-free survival [PFS], overall survival [OS], and safety. The median time from the first dose to data cutoff, which was January 2022, was 54.5 months, a good long-term follow-up in the study. The data are rather mature.2

The mean age in this endometrial [cancer] population was not surprising at 64 years. For ECOG PS, about 50% of them had PS of 1. Disease stage was M0 in 4% and M1 in 96%. For number of prior lines of therapy, about half of them had 1 line, but it was greater than 4 lines in about 10%. Prior adjuvant or neoadjuvant therapies were [used in] 27%, so it looks like the majority had not had neoadjuvant or adjuvant therapy. Prior radiation therapy was [noted] in 67% and prior surgery in 86%. So some of these patients did [have previous operations].

How have patients in KEYNOTE-158 responded to treatment so far?

All patients treated in the study had about a 50% response rate. Patients who had prior neoadjuvant and/or adjuvant therapy, only 10 patients, had a 40% response rate, so I dont know [whether] thats different. Patients who had 1 prior line of therapy had a 59% response rate. I think these numbers are relatively small to discriminate. Patients who had [more] than 1 prior line of therapy had a 44% response rate. Its all clustering in the 40% to 50% [range], so [its] an extraordinarily high response rate if a patient has MSI-H disease on checkpoint inhibitors, even though they had carboplatin, paclitaxel, and/or pelvic radiotherapy before in many cases. The complete response [CR] rate was 16%, partial response [PR] rate was 34%, and stable disease [SD] [rate] was 18%.2 Theres no difference in terms of survival between PR and SD. They both are benefiting.

The median DOR was 63.2 months. The DOR at 1 year was 87%, 2 years was 71%, 3 years was 66%, and 4 years was 66%. The duration and recurrence start to flatten out. If you make it to 3 years, youre going to have an ongoing response.

The PFS and OS plots plateau, which weve seen in other solid tumors [during] immunotherapy. A percentage of patients get a long-lasting DOR and benefit tremendously from the therapy. The median OS was 65.4 months [(95% CI, 29.5-not reached) and the median PFS was 13.1 months (95% CI, 4.3-25.7)].

Prior to pembrolizumab coming on the market, patients had a shortened and significantly toxic environment [for] survival. The treatment options were not good, and patients [experienced pain and died from] this disease in a short period once theyd had carboplatin, paclitaxel, and radiation. Doxorubicin was thrown in the mix there, which isnt a pleasant treatment. So this is a tremendous advance in endometrial cancer management.

Have you used dostarlimab as the next-line therapy in patients with recurrent or metastatic endometrial cancer?

I have used [dostarlimab] in a clinical trial with carboplatin and paclitaxel, and I can say anecdotallyno direct comparisonI dont think theres any significant difference in the AEs compared with any other checkpoint inhibitor. Ive treated a large number of patients on the clinical trial, which has been ongoing for over 2 years, and Ive seen some amazing responses in patients who I would have expected to [die] from their disease within a short time. So based on the OS and PFS curves, some patients do get a tremendous response.3,4

The GARNET study [NCT02715284] is the prospective study of dostarlimab, which received its first approval in endometrial cancer. It is a 2-part phase 1 trial. Part 1 is for dose finding, part 2A is for the fixed-dose and safety run-in, and part 2B is for expansion cohorts. Its another example of an early-phase study that presented data to the FDA, leading to a quick approval because of the significant response rates and benefits. The FDA did not require a large prospective phase 3 randomized trial. Pembrolizumab was already labeled in this setting, and the data points looked like the outcomes with other checkpoint inhibitors. So it probably helped lead to its approval, with no unusual signals of toxicity.

In this study, dostarlimab was dosed at 500 mg every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until PD. The primary end points were the ORR and DOR per RECIST version 1.1 criteria by blinded independent central review assessment. The key inclusion criteria were progression during or after platinum doublet therapy and 2 or fewer prior lines of treatment for advanced or recurrent disease. The patients could have had hormonal therapy and carboplatin, paclitaxel or carboplatin, paclitaxel, or doxorubicin [and join] this trial. They had to have measurable disease. They had not received prior checkpoint inhibitors and had MRD or MSI-H disease by approved laboratory testing.

They had 2 scans demonstrating PD on their last systemic therapy, so they had [experienced progression]. These were not patients with stable disease. The median time from the first dose to data lock was 27.6 months. The efficacy and safety were assessed in all patients with measurable disease.

For the study characteristics, the median age was 65 to 66 years. Slightly less than half of these patients originally had stage I or stage II disease and then [experienced] relapse, and 56% to 62% had stage III or IV disease and then [experienced] relapse. Low-grade endometrioid carcinoma accounted for 64% of the MSI-H [disease] and only 23% of nonMSI-H [disease]. Serous carcinomas flipped the other way. A small percentage were MRD or MSI-H [disease], whereas a larger percentage were MR-proficient. Grade 3 carcinomas, clear cell, and other histology types had relatively small numbers after endometrioid carcinomas and serous carcinomas. All patients had prior anticancer therapy, and the majority had 1 prior line. About 70% of the patients had prior radiation therapy.

What was the efficacy demonstrated in the GARNET trial?

The ORR was 45.5%, very similar to the [ORR from] KEYNOTE158. The CR was also very similar to [the CR from] KEYNOTE158 at 16.1%. The PR was approximately double the CR at 29.4%, and SD was about 15%. Approximately one-third of patients [experienced progression]. The duration of the CR was 60.1%. Response was ongoing in 83%. The median DOR had not been reached. These data were reported without the longterm follow-up of the KEYNOTE-158 study, but the results were so similar at this point that it got FDA approval in this setting.

The estimated probability of maintaining response at 6 months was 97%, 12 months was 93%, and 24 months was 83%. What I see in these data is that if you see a patient whos getting a response, overwhelming odds are theyre going to continue to get a response. The question is, are they going to get a response? About one-third of patients will [experience progression]. Im not intimately familiar with all the research going on in immunotherapy for solid tumors, but it would be a key clinical question about whats different about these patients [with] MSI-H [disease who experience progression] on therapy. What do you do about it? Hopefully, well see more answers about that in the coming years.

As of November 2021, the data cutoff, the median duration of follow-up was about 28 months. The estimated PFS rate at 12 months was 46% and 40% at 24 months. So about 40% of the patients get a long-lasting benefit from checkpoint inhibition.

How do the KEYNOTE-158 and GARNET studies compare?

The KEYNOTE-158 study with 94 patients and GARNET [study] with 143 patients were phase 2 and phase 1 studies. They were done in patients with previously [managed] MRD recurrent or advanced endometrial cancer. The primary end points were ORR in both along with DOR in the GARNET study. The follow-up was longer with KEYNOTE-158 at 54.5 months vs 27.6 months for GARNET.2-4

The ORR was 50% in KEYNOTE-158 and 46% in GARNET. The median DOR was 63.2 months in KEYNOTE-158 and was not reached in GARNET. The 1-year DOR in GARNET was about 93% vs 87% in KEYNOTE-158 and 84% at 2 years vs 71%, respectively. So they were relatively similar, perhaps numerically slightly better in GARNET. But comparisons cannot be looked at in that manner because they are slightly different populations. The median PFS was 13.1 months in KEYNOTE-158 and 6 months in GARNET. Im not sure why there was the big difference in PFS between them because the DOR was similar. The median OS was over 65 months in KEYNOTE-158 and not reached in GARNET. The 1-year OS look[s] rather identical.2-4

I think therell be more follow-up reporting on GARNET as we get more data. My anticipation would be outcomes on these studies are going to be rather identical, and these checkpoints are probably interchangeable with the expected outcomes and AEs.

What is the safety profile of pembrolizumab and dostarlimab based on data from both studies?

For treatment-related AEs [TRAEs] in KEYNOTE-158, grade 3 and grade 4 AEs were a relatively small percentage at 12%, and treatment discontinuations were only 7%. Some AEs that were familiar with were pruritis, fatigue, diarrhea, arthralgia, nausea, hypothyroidism (which is not uncommon), rashes, decreased appetite, and myalgia. ASCO [American Society of Clinical Oncology] has covered it with detailed advice about managing AEs with checkpoint inhibitors.

When these drugs came out, we were all concerned about the AEs, but weve all seen in practice that theyre easily managed. Rarely do we get life-threatening AEs because we are monitoring these patients. So most of these things are manageable. But you do need to pay attention. The percentage of immune-related colitis was very small at 3%. For diabetes, hepatitis, [and] pneumonitis, you get down to 1%.

The GARNET safety data, compared with KEYNOTE-158 data, for AEs grade 3 or [above] had a [slightly] higher percentage. TRAEs of any grade [occurred in] 70% and grade 3 [occurred in] 17%. Treatment-related serious AEs were 11.8% in the population with MSI-H [disease] and 8.7% in the population with nonMSI-H [disease]. TRAEs leading to discontinuation were very similar at about 8%, and those leading to death were 0%. They were all managed appropriately, without toxicity or death.4 I didnt see anything unique in the safety summary of both studiesjust a small percentage of laboratory abnormalities with liver function tests, mild anemia, and low percentage of diarrhea overall.

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Holloway Discusses Later-Line Treatment in Recurrent or Metastatic ... - Targeted Oncology

Mucopolysaccharidosis Treatment Market is projected to reach US … – Future Market Insights

The globalMucopolysaccharidosis Treatment Marketis estimated to be worth aroundUS$ 2.38 Bnin 2022. With increasing prevalence of mucopolysaccharidosis (MSP) worldwide, the overall market is projected to grow at a robust CAGR of5.9%between 2022 and 2029, reaching a valuation ofUS$ 3.37 Bnby 2029.

A market study presented by FMIMucopolysaccharidosis Treatment Market Global Industry Analysis 2014-2018 and Opportunity Assessment 2022-2029, explains the significant factors influencing the current market structure.

According to research, the mucopolysaccharidosis treatment is still emerging, and different geographies have implemented standard treatment options for the condition. However, there is no universally accepted treatment pattern for mucopolysaccharidosis. Mucopolysaccharidosis falls under rare diseases, which is a complex, diverse, constantly evolving field, and there is a significant shortage of medical and scientific data related to it. Mucopolysaccharidosis treatment and diagnosis involves complex managing requirements, which include long-term care, rehabilitation support, and a continuous treatment plan.

To remain ahead of your competitors, request for a sample @

https://www.futuremarketinsights.com/reports/sample/rep-gb-5880

Research Activities Uplift Stem Cell Therapy Application in MPS Treatment

In the present scenario, the drugs that are considered for mucopolysaccharidosis treatment, such as aldurazyme, naglazyme, vimizim, elaprase, mepsevii and hunterase, are the only regulated and recommended drugs present in the market. These drugs fall under enzyme replacement therapies, however, with present research initiatives for stem cell therapies, the latter is considered a prominent mucopolysaccharidosis treatment. Clinical research shows that stem cell transplantation covers a large area that is not covered with the more frequently recommended practice of enzyme replacement therapies, which changes the current market structure for mucopolysaccharidosis treatment, prioritising the latter.

Stem cell therapy is a therapeutic option for mucopolysaccharidosis patients suffering from a severe phenotype, as research shows the method can preserve neurocognition or can even help break the progressive neurodegeneration. The method is provided with strict selection criteria, which is followed by maintained regulations. Research shows that stem cell therapy as a treatment option is gaining popularity among healthcare professionals for mucopolysaccharidosis treatment, which can be attributed to the relation of its better reach towards a normal health condition for the patient.

Enzyme Replacement Therapy Remains Lucrative for Market Investors

As per further assessments of the mucopolysaccharidosis treatment market, it has been difficult to collect epidemiological data pertaining to rare diseases, especially mucopolysaccharidosis treatment, which is likely to impede the actual estimation of the economic burden associated with the condition. The cost estimation for each mucopolysaccharidosis treatment type is affecting and, in turn, creating a more vulnerable situation for the businesses and disrupting research & development activities for each company.

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Enzyme replacement therapy is the most attractive segment for investors, however, the unavailability of reimbursement plans and precise treatment plans is encouraging most patient in developing regions to opt for symptomatic treatments instead of enzyme replacement therapy, which is still considered to be the standard mucopolysaccharidosis treatment.

Key Players Focus on Clinical Research of Treatment Models

The report segments the mucopolysaccharidosis treatment market into seven regions to elaborate on the regional trends pertaining to the treatment plan. Major players are focusing on increasing their market share in the Asia Pacific market through strategic collaborations with regional research institutes. There is a lack of awareness about rare diseases among the general public as well as in medical healthcare facilities in several emerging economies. According to a survey and industry report, it takes patients in the US an average of 7.6 years and patients in the UK an average of 5.6 years to actually receive a proper diagnosis. Moreover, it involves a team of healthcare professionals to actually get the right mucopolysaccharidosis treatment and diagnosis pattern for reported cases.

Manufacturers are in the process of introducing a considerable number of mucopolysaccharidosis treatment options, which are currently under clinical trials. An estimated 160 and above clinical trials are being performed for mucopolysaccharidosis treatment. Thus, ensuring that the manufacturers take this mucopolysaccharidosis treatment market to be lucrative and potential rich in terms of revenue. Medical research institutes play an important role in this particular market. They are expected to be the bridge between treatment plans and economical solutions for manufacturers, thus leaving an explicable and lucrative model for mucopolysaccharidosis treatment.

The mucopolysaccharidosis treatment market includes companies such as BioMarin Takeda Pharmaceutical Company Limited, Sanofi S.A., and Ultragenyx Pharmaceutical Inc. BioMarin accounts for a significant value share in the present mucopolysaccharidosis treatment market. The currently existing promising drug types are expected to face competition from emerging candidates. In addition the mucopolysaccharidosis treatment products of other companies, such as Sangamo Therapeutics, Inc., REGENXBIO Inc., Sarepta Therapeutics, Abeona Therapeutics, Inc., and others, are also in the pipeline.

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