StemCell Therapy

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Phase 3 KEYNOTE-604 trial investigating KEYTRUDA, Mercks anti-PD-1 therapy, in combination with chemotherapy met one of its dual primary endpoints of progression-free survival (PFS) in the first-line treatment of patients with extensive stage small cell lung cancer (ES-SCLC). In the study, treatment with KEYTRUDA in combination with chemotherapy (etoposide plus cisplatin or carboplatin) resulted in a statistically significant improvement in PFS compared to chemotherapy alone (HR=0.75 [95% CI, 0.61-0.91]), which was observed at a prior interim analysis. At the final analysis of the study, there was also an improvement in overall survival (OS) for patients treated with KEYTRUDA in combination with chemotherapy compared to chemotherapy alone; however, these OS results did not meet statistical significance per the pre-specified statistical plan (HR=0.80 [95% CI, 0.64-0.98]). The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies. Results will be presented at an upcoming medical meeting and discussed with regulatory authorities.

Results of KEYNOTE-604 demonstrated the potential of KEYTRUDA, in combination with chemotherapy, to improve outcomes for patients newly diagnosed with extensive stage small cell lung cancer, a highly aggressive malignancy, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. We sincerely thank the patients and investigators for their participation in this study and are committed to helping patients who face difficult-to-treat types of lung cancer.

In addition to KEYTRUDAs five current indications in lung cancer, Merck is continuing to study KEYTRUDA across multiple settings and stages of lung cancer through a broad clinical program, which is comprised of more than 10,000 patients enrolled or expected to be enrolled across 20 Merck-sponsored clinical studies.

About KEYNOTE-604

KEYNOTE-604 is a randomized, double-blind, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT03066778) investigating KEYTRUDA in combination with chemotherapy compared to chemotherapy alone in patients with newly diagnosed ES-SCLC. The dual primary endpoints were OS and PFS. Secondary endpoints included objective response rate (ORR), duration of response (DOR), safety and quality of life (QoL). The study enrolled 453 patients who were randomized to receive either:

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon and breast cancers combined. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. Small cell lung cancer (SCLC) accounts for about 10 to 15% of all lung cancers. The five-year survival rate for patients diagnosed in the U.S. with any stage of SCLC is estimated to be 6%.

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,000 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. 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.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA 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 tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

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

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

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

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those 2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those 2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 34) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 34) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 34) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

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Merck's KEYTRUDA (pembrolizumab) in Combination with Chemotherapy Significantly Improved Progression-Free Survival Compared to Chemotherapy Alone as...

DetailsCategory: AntibodiesPublished on Friday, 20 December 2019 13:14Hits: 658

- BLISS-LN achieves primary endpoint and all major secondary endpoints

- On-track for regulatory submission during the first half of 2020

LONDON, UK I December 18, 2019 I GSK today announced positive headline results for intravenous (IV) Benlysta (belimumab) in the largest controlled phase 3 study in active lupus nephritis (LN), an inflammation of the kidneys caused by systemic lupus erythematosus (SLE) which can lead to end-stage kidney disease.

The Efficacy and Safety of Belimumab in Patients with Active Lupus Nephritis (BLISS-LN) study, involving 448 patients, met its primary endpoint demonstrating that a statistically significant greater number of patients achieved Primary Efficacy Renal Response (PERR) over two years when treated with belimumab plus standard therapy compared to placebo plus standard therapy in adults with active LN (43% vs 32%, odds ratio (95% CI) 1.55 (1.04, 2.32), p=0.0311).

Dr Hal Barron, Chief Scientific Officer and President R&D, GSK said: "Lupus nephritis is one of the most common and serious complications of SLE, occurring in up to 60% of adult patients. The results of the BLISS-LN study show that Benlysta could make a clinically meaningful improvement to the lives of these patients who currently have limited treatment options."

Dr Richard Furie,Chief of the Division of Rheumatology and Professor at the Feinstein Institutes atNorthwell Health and Lead Investigator of BLISS-LN said: "My journey with Benlysta began nearly twenty years ago when we performed the very first clinical research trial in lupus patients. To see it culminate in a successful phase 3 lupus nephritis study is a key achievement as the inadequate response of our patients with kidney disease to conventional treatment has long been an area in need of major improvement."

Belimumab also demonstrated statistical significance compared to placebo across all four major secondary endpoints: Complete Renal Response (CRR) after two years (the most stringent measure of renal response), Ordinal Renal Response (ORR) after two years, PERR after one year, and the time to death or renal-related event. In BLISS-LN, safety results for patients treated with belimumab were generally comparable to patients treated with placebo plus standard therapy. The safety results are consistent with the known profile of belimumab.

Benlysta is currently not recommended for use in severe active lupus nephritis anywhere in the world because it has not been previously evaluated in these patients. Based on these positive phase 3 data, GSK plans to progress regulatory submissions in the first half of 2020 to seek an update to the prescribing information.

The full results will be submitted for future presentation at upcoming scientific meetings and in peer-reviewed publications.

About lupus nephritisSystemic lupus erythematosus (SLE), the most common form of lupus, is a chronic, incurable, autoimmune disease associated with a range of symptoms that can fluctuate over time including painful or swollen joints, extreme fatigue, unexplained fever, skin rashes and organ damage. In lupus nephritis (LN), SLE causes kidney inflammation, which can lead to end-stage kidney disease. Despite improvements in both diagnosis and treatment over the last few decades, LN remains an indicator of poor prognosis.1,2 Manifestations of LN include proteinuria, elevations in serum creatinine, and the presence of urinary sediment.

About BLISS-LNBLISS-LN,which enrolled 448 adult patients, was a phase 3, 104-week, randomised, double-blind, placebo-controlled post-approval commitment study to evaluate the efficacy and safety of IV belimumab 10 mg/kg plus standard therapy (mycophenolate mofentil for induction and maintenance, or cyclophosphamide for induction followed by azathioprine for maintenance, plus steroids) compared to placebo plus standard therapy in adult patients with active lupus nephritis. Active lupus nephritis was confirmed by kidney biopsy during screening visit using the 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) criteria, and clinically active kidney disease.

The primary endpoint PERR was defined as estimated Glomerular Filtration Rate (eGFR) 60 mL/min/1.73m2 or no decrease in eGFR from pre-flare of > 20%; and urinary protein:creatinine ratio (uPCR) 0.7; and not a treatment failure. The most stringent secondary endpoint CRR was defined as eGFR is no more than 10% below the pre-flare value or within normal range; and uPCR < 0.5; and not a treatment failure. ORR was defined as complete, partial or no response.

About Benlysta (belimumab)Benlysta, a BLyS-specific inhibitor, is a human monoclonal antibody that binds to soluble BLyS. Benlysta does not bind B cells directly. By binding BLyS, Benlysta inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

The current US and EU indication for Benlysta are summarised below:

In the US, "Benlysta is indicated for the treatment of patients aged 5 years and older with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy. Limitations of Use: The efficacy of Benlysta has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. Benlysta has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of Benlysta is not recommended in these situations."

Full US prescribing information including Medication Guide is available at: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Benlysta/pdf/BENLYSTA-PI-MG.PDF

In the EU, "Benlysta is indicated as "add-on therapy in patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g., positive anti-dsDNA and low complement) despite standard therapy."

The Precaution and Warnings for Benlysta includes information that "Benlysta has not been studied in the following adult and paediatric patient groups, and is not recommended: severe active central nervous system lupus; severe active lupus nephritis; HIV; a history of, or current, hepatitis B or C; hypogammaglobulinaenia (IgG < 400mg/dl) or IgA deficiency (IgA < 10 mg/dl); a history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant."

The EU Summary of Product Characteristics for Benlysta is available on: http://www.ema.europa.eu

Benlysta is available as an intravenous and a subcutaneous formulation. The Benlysta subcutaneous formulation is not approved for use in children.

GSK's commitment to immunologyGSK is focused on the research and development of medicines for immune-mediated diseases, such as lupus and rheumatoid arthritis, that are responsible for a significant health burden to patients and society. Our world-leading scientists are focusing research on the biology of the immune system with the aim to develop immunological-based medicines that have the potential to alter the course of inflammatory disease. As the only company with a biological treatment approved for adult and paediatric lupus, GSK is leading the way to help patients and their families manage this chronic, inflammatory autoimmune disease. Our aim is to develop transformational medicines that can alter the course of inflammatory disease to help people live their best day, every day.

SOURCE: GlaxoSmithKline

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KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that KEYTRUDA, Mercks anti-PD-1 therapy, received new approvals from the Japan Pharmaceuticals and Medical Devices Agency (PMDA) in advanced renal cell carcinoma (RCC) and head and neck cancer for the following additional indications in Japan:

Advanced renal cell carcinoma and head and neck cancer have historically been associated with poor outcomes and new treatment options are needed in Japan, said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories. Todays approval of three new first-line KEYTRUDA regimens represents a significant milestone for patients diagnosed with these aggressive forms of cancer and will provide patients in Japan with important alternatives to standard therapies.

The approval for KEYTRUDA in combination with axitinib for radically unresectable or metastatic RCC is based on results from the KEYNOTE-426 trial, in which KEYTRUDA in combination with axitinib demonstrated statistically significant improvements in the dual primary endpoints of overall survival (OS) (HR=0.53 [95% CI, 0.38-0.74]; p=0.00005) and progression-free survival (PFS) (HR=0.69 [95% CI, 0.56-0.84]; p=0.00012) compared to sunitinib monotherapy.

The approval for KEYTRUDA for the first-line treatment of patients with recurrent or distant metastatic head and neck cancer is based on results from the Phase 3 KEYNOTE-048 trial which evaluated KEYTRUDA in combination with platinum and 5-fluorouracil (5-FU), or KEYTRUDA monotherapy compared with standard treatment (cetuximab in combination with platinum and 5-FU), as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma. In the trial, KEYTRUDA in combination with platinum and 5-FU significantly prolonged OS (HR=0.77 [95% CI, 0.63-0.93]; p=0.00335) compared with standard treatment. As monotherapy, KEYTRUDA demonstrated non-inferiority (HR=0.85 [95% CI, 0.71-1.03]; p=0.00014) compared with standard treatment. Additionally, KEYTRUDA monotherapy demonstrated a statistically significant improvement in OS in patients whose tumors expressed PD-L1 (CPS 1) compared with standard treatment.

Last year, an estimated 850,000 new cancer diagnoses were made in Japan alone, underscoring the critical need for innovative research and development to identify additional treatment options, said Jannie Oosthuizen, managing director of MSD in Japan. The new approvals of KEYTRUDA in advanced renal cell carcinoma and head and neck cancer build on previous approvals in melanoma, advanced non-small cell lung cancer and advanced MSI-H cancers, allowing us to bring KEYTRUDA to even more patients in Japan.

Renal cell carcinoma is by far the most common type of kidney cancer, with approximately 403,000 cases of kidney cancer diagnosed worldwide in 2018 and about 175,000 deaths from the disease. In Japan, it is estimated there were more than 24,000 people diagnosed with kidney cancer, and more than 8,000 deaths occurred in 2018.

Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. It is estimated that there were more than 705,000 new cases of head and neck cancer diagnosed and over 358,000 deaths from the disease worldwide in 2018. In Japan, it is estimated that more than 22,000 new cases of head and neck cancer were diagnosed, and more than 8,000 deaths occurred in 2018.

About KEYTRUDA (pembrolizumab) Injection

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,000 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected Indications for KEYTRUDA (pembrolizumab) in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. 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.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA 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 tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

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

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

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

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those 2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those 2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 34) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 34) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 34) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

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Merck's KEYTRUDA (pembrolizumab) Approved in Japan for Three New First-Line Indications Across Advanced Renal Cell Carcinoma (RCC) and Recurrent or...

"Metastatic urothelial cancer is an aggressive and devastating disease with limited treatment options, and the approval of PADCEV is a significant advance for these patients who previously had limited options after initial therapies failed," said Jonathan E. Rosenberg, M.D., Medical Oncologist, Chief, Genitourinary Medical Oncology Service, Memorial Sloan Kettering Cancer Center in New York. "The PADCEV clinical trial enrolled a range of patients whose cancer was difficult to treat, including those whose disease had spread to the liver."

"The FDA approval of PADCEV is welcome news for patients with bladder cancer," said Andrea Maddox-Smith, Chief Executive Officer, Bladder Cancer Advocacy Network. "Though new medicines for bladder cancer have been approved in recent years, most people living with advanced stages of this disease face a difficult journey with few treatment options."

"This approval underscores our commitment to develop novel medicines that address unmet patient needs, and we're grateful to the patients and physicians whose participation led to this outcome," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas.

"PADCEV is the first antibody-drug conjugate approved for patients facing this aggressive disease, and it is the culmination of years of innovative work on this technology," said Roger Dansey, M.D., Chief Medical Officer, Seattle Genetics.

PADCEV was evaluated in the pivotal trial EV-201, a single-arm phase 2 multi-center trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy.1 In the study, the primary endpoint of confirmed objective response rate (ORR) was 44 percent per blinded independent central review (55/125; 95% Confidence Interval [CI]: 35.1, 53.2). Among patients treated with the single agent PADCEV, 12 percent (15/125) experienced a complete response, meaning no cancer could be detected at the time of assessment, and 32 percent (40/125) experienced a partial response, meaning a decrease in tumor size or extent of cancer in the body. The median duration of response (DoR), a secondary endpoint, was 7.6 months (95% CI: 6.3, not estimable [NE]). The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). The most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

The FDA's Accelerated Approval Program allows approval of a medicine based on a surrogate endpoint if the medicine fills an unmet medical need for a serious condition.A global, randomized phase 3 confirmatory clinical trial (EV-301) is underway and is also intended to support global registrations.

About PADCEV PADCEV 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.1,2 Nonclinical 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). PADCEV is co-developed by Astellas and Seattle Genetics.

PADCEV Support Solutions offers access and reimbursement support to help patients access PADCEV. For more information, go to PADCEV Support Solutions at PADCEVSupportSolutions.com.

About Bladder and Urothelial CancerApproximately 80,000 people in the U.S. will be diagnosed with bladder cancer this year.4 Urothelial cancer accounts for 90 percent of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.5

Important Safety Information

Warnings and Precautions

Adverse Reactions Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab Abnormalities In one clinical trial, Grade 3-4 laboratory abnormalities reported in 5% were: lymphocytes decreased, hemoglobin decreased, phosphate decreased, lipase increased, sodium decreased, glucose increased, urate increased, neutrophils decreased.

Drug Interactions

Specific Populations

For more information, please see the full Prescribing Information for PADCEV here.

About Astellas Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. For more information, please visit our website at https://www.astellas.com/en.

About Seattle Genetics Seattle Genetics, Inc. is an emerging multi-product, global biotechnology company that develops and commercializes transformative therapies targeting cancer to make a meaningful difference in people's lives. The company is headquartered in Bothell, Washington, and has a European office in Switzerland. For more information on our robust pipeline, visit http://www.seattlegenetics.comand follow @SeattleGenetics on Twitter.

About the Astellas and Seattle Genetics CollaborationSeattle Genetics and Astellas are co-developing PADCEV (enfortumab vedotin) under a collaboration that was entered into in 2007 and expanded in 2009. Under the collaboration, the companies are sharing costs and profits on a 50:50 basis worldwide.

Astellas Cautionary Notes In 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.

Seattle Genetics Forward Looking StatementsCertain statements made in this press release are forward looking, such as those, among others, relating to the continued FDA approval of PADCEV (enfortumab vedotin-ejfv) for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/L1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting; the conduct of an ongoing randomized phase 3 confirmatory clinical trial (EV-301) intended to verify the clinical benefit of PADCEV and support global registrations; and the therapeutic potential of PADCEV including its efficacy, safety and therapeutic uses. 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 the possibility that EV-301 and subsequent clinical trials may fail to establish sufficient efficacy; that adverse events or safety signals may occur; that utilization and adoption of PADCEV by prescribing physicians may be limited by the availability and extent of reimbursement or other factors; and that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption "Risk Factors" included in the company's Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 filed with the Securities and Exchange Commission. Seattle Genetics 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 Padcev [package insert]. Northbrook, IL: Astellas, Inc. 2 Rosenberg JE, O'Donnell PH, Balar AV, et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol 2019;37(29):2592600.3 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. 4 American Society of Clinical Oncology. Bladder cancer: introduction (10-2017). https://www.cancer.net/cance rtypes/bladdercancer/introduction. Accessed 05-09-2019. 5National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: bladder cancer. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed 05-01-2019.

SOURCE Astellas Pharma US, Inc.

https://www.astellas.com

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FDA Grants Accelerated Approval to Astellas' and Seattle Genetics' PADCEV (enfortumab vedotin-ejfv) for People with Locally Advanced or Metastatic...

Fibrosis, or scarring, is central to a number of diseases, including cirrhosis of the liver, chronic kidney disease and several lung diseases. Generally, any organ in the body can repair itself after injury. Normally, scarring occurs and then recedes, making room for normal tissue as healing occurs. But sometimes the healing goes awry and the cells that make up scar tissue continue dividing and spreading until the scar tissue itself strangles the organ it was healing. This can cause organ failure.

Researchers at the University of California-Los Angeles Health Sciences have developed a scar-in-a-dish model derived from stem cells that can mimic fibrosis. They then identified a drug that could stop the fibrotic progression and, in further animal models, actually reverse fibrosis. They published their research in the journal Cell Reports.

Millions of people living with fibrosis have very limited treatment options, said Brigitte Gomperts, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. Once scarring gets out of control, we dont have any treatments that can stop it, except for whole-organ transplant.

The scar-in-a-dish model utilized several different types of cells derived from human stem cells. It used induced pluripotent stem cells (iPS).

Fibrosis likely occurs as the result of interactions between multiple different cell types, so we didnt think it made sense to use just one cell type to generate a scarring model, said Preethi Vijayaraj, the reports first author and an assistant adjunct professor of pediatric hematology/oncology at the David Geffen School of Medicine at UCLA and a member of the UCLA Johnsson Comprehensive Cancer Center.

The mixture of cells they grew had many types that are believed to participate in fibrosis, including mesenchymal cells, epithelial cells and immune cells. All of them maintained some plasticity, allowing them to change cells types. This is the first known model to recreate that plasticity, which is associated with progressive fibrosis.

They then placed the cells in a rigid hydrogel that was similar to the stiffness of a scarred organ. The cells behaved the same way they would to injury, producing damage signals and activating transforming growth factor beta (TGF beta), which typically stimulates fibrosis.

The use of the gel, as opposed to tissue, meant it couldnt heal itself. This allowed the researchers to test molecules on the scarring in a way that isolated the drug and scarring tissues. They tested more than 17,000 small molecules. They identified one that stopped progressive scarring and healed the damage. They believe the compound activates the cells innate wound healing processes.

This drug candidate seems to be able to stop and reverse progressive scarring in a dish by actually breaking down the scar tissue, said Gomperts. We tested it in animal models of fibrosis of the lungs and eyes and found that it has promise to treat both of those diseases.

The next steps are to determine how the drug candidate works and also screen more molecules. The drug has not been tested in humans. The therapeutic strategy is covered by a patent application the UCLA Technology Development Group filed on behalf of the Regents of the University of California, with Gomperts and Vijayaraj listed as co-inventors. Gomperts is also a co-founder and stock owner of a biotech company, InSpira, which is focused on developing the molecule and strategy for fibrosis.

Link:
Researchers ID Molecule that Appears to Halt and Reverse Scarring in Fibrotic Diseases - BioSpace

Inadequate prediction of drug metabolism or toxicity is the Achilles heel of the pharmaceutical industry, leading to high drug attrition rates. This can have significant implications for companies, with late-stage failure typically resulting in the loss of substantial financial investments, time and resources. By defining and predicting the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME-Tox) profile of compounds as early as possible, companies can focus their resources on the most relevant candidates to increase the likelihood of successfully bringing new safe and efficient therapies to the market.To implement early ADME-Tox testing, its crucial to have access to valid in vitro models of the key sites of drug metabolism the liver, kidneys and intestines. Preclinical models that reliably replicate the in vivo cellular environment of these organs enable scientists to study and accurately predict drug metabolism, transport and toxicity prior to targets entering the clinical trial phase, ultimately helping to lower attrition rates.

For many years, biologists have relied on in vitro 2-dimensional (2D) cell culture models to perform preclinical ADME-Tox assays. While these models are useful for informing aspects of drug discovery, such as cytotoxicity, they are limited in their translatability to drug metabolism and toxicity in humans. Recently, in vitro 3-dimensional (3D) organoid models that more closely mimic human biological systems show promise in supporting ADME-Tox studies in the early stages of the drug development process, compared to their 2D counterparts.

For modeling kidney cell function in vitro and to evaluate general nephrotoxicity, researchers use various types of human proximal tubule cell lines. These cells demonstrate specific properties of the kidney epithelium, such as the transport of solutes, which plays an important role in drug excretion,. Limitations of these in vitro models are due to the different cell types not expressing all necessary transporters, metabolizing enzymes or biomarkers at physiological levels.3

Given these challenges, there is a clear need for advanced in vitro 3D models that more accurately emulate drug permeability, metabolism, transport and toxicity in humans.

Due to a greater understanding of the cell microenvironment, organoid technology has advanced over the last few years and has the potential to streamline the drug development process. Using organoids to support in vitro ADME-Tox studies can help to predict metabolic mechanisms and ascertain key safety and efficacy measures before commencing human clinical trials. Evidence suggests that kidney and intestine organoid models could be more valuable to investigate the metabolism, transport and toxicity of drugs.3,4 Indeed, a kidney organoid model has recently been cultured using human induced pluripotent stem cells. Composed of both glomerular tissue, as well as proximal and distal tubule cells, this model offers a more accurate representation of the kidney. As such, it has the potential to inform and refine preclinical toxicity screening studies.3

In another recent study, human primary cells from intestinal epithelium was engineered into a 3D intestinal organoid using a scaffold system [4]. This model showed complex tissue properties and characteristics of mature epithelium, including the four main types of differentiated epithelial cells (enterocytes, goblet cells, paneth cells and enteroendocrine cells). The tight junction formation, microvilli polarization, digestive enzyme secretion and low oxygen tension in the lumen were also representative of mature epithelium. In addition to these physical properties, the organoids also exhibited complex behavior, such as innate antibacterial responses to E. coli similar to those observed in patients with inflammatory bowel disease (IBD). This suggests that the model could be used in in vitro studies investigating host-microbe-pathogen interplay and IBD pathogenesis.

These findings highlight the future potential of in vitro 3D kidney and intestine organoids for drug development. Because these systems closer resemble in vivo tissues, they could help predict drug responses early in development and offer vast possibilities for modeling many diseases in the future.

1. Van Breemen R.B and Li Y. Caco-2 cell permeability assays to measure drug absorption. Expert Opin Drug Metab Toxicol. 2005 Aug;1(2):17585

2. Yamaura Y, et al. Functional Comparison of Human Colonic Carcinoma Cell Lines and Primary Small Intestinal Epithelial Cells for Investigations of Intestinal Drug Permeability and First-Pass Metabolism. Drug Metabolism and Disposition. March 2016;44:329335

3. Bajaj P, et al. Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics. Drug Metabolism and Disposition. November 2018;46(11):16921702

4. Chen Y, et al. In vitro enteroid-derived three-dimensional tissue model of human small intestinal epithelium with innate immune responses. PLoS One. 2017;12(11): e0187880

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The Promise of in vitro 3D Organoid Models: Meeting the ADME-Tox Testing Needs of the Pharmaceutical Industry - Technology Networks

After years of trying, researchers finally were able to transform human stem cells into mature cells that produce insulin. In the long term, this can cure people with diabetes. It can change the lives of millions of people worldwide with type 1 diabetes. For the first time, according to a study published in the journal Nature Cell Biology, American researchers have successfully transformed human stem cells into mature cells that produce insulin in the laboratory.

Diabetes Test

This success is the result of many years of work. The cells produced were trapped in an immature stage where they could not respond adequately to blood glucose and secrete insulin according to Matthias Hevrock of the San Francisco Diabetes Center, the author of the study. Then he and his team realized that the key to success is the neglected aspect of beta cell development, the physical process by which cells are separated from the rest of the pancreas and form the so-called Islets of Langerhans.

Then the researchers reproduced this process in the laboratory, artificially separating the stem cells from the pancreas and transforming them into groups of islets. As a result, beta cells and other cells delta and alpha cells began to react to glucose as mature insulin-producing cells.

The researchers then transplanted these islets into healthy mice and found that they worked for several days, producing insulin that reacts to blood sugar levels just like the natural islets in life animals.

According to Matthias Hevrock now they can produce insulin cells that look and act like the pancreatic cells that we have in our body. This is a big step towards our goal of creating cells that can be transplanted into diabetic patients.

Type 1 diabetes accounts for 10% of all diabetes cases worldwide. It is an autoimmune disease that occurs most often in childhood and destroys the insulin-producing cells of the pancreas. Without the insulin that regulates blood glucose levels, sugar peaks can cause severe organ damage and even death. Although the disease can be treated with regular insulin injections, some people still suffer from acute or chronic complications due to poor blood glucose control. These include retinopathy, neuropathy, heart disease, lower limb arteriopathy and renal failure. These complications can be fatal. Therefore, diabetics who are at risk of death may now receive pancreatic transplants which in most cases will be in addition to kidney transplants.

https://pubs.acs.org/doi/10.1021/acssynbio.9b00262

https://www.cdc.gov/diabetes/basics/type1.html

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Diabetes 1 Breakthrough: Researchers Are Now Able to Create Insulin-Producing Cells - Gilmore Health News

The 2019 Nobel Prize in Medicine awarded for research in cellular responses to oxygen By Benjamin Mateus 10 October 2019

In the course of a lifetime, the human heart will beat more than three billion times. We will have taken more than 670 million breaths before we reach the end of our lives. Yet, these critical events remain unconscious and imperceptible in everyday life, unless we exert ourselves, such as running up several flights of stairs. We quickly tire, stop to take deep breaths and become flushed.

With the deepening comprehension by medical science of how our bodies work, we have come to better understand the fundamental importance of oxygen to life. Every living organism relies on it in one form or another. However, how cells and tissues can monitor and respond to oxygen levels remained difficult to elucidate. It has only been late in the 20th century with advances in cellular biology and scientific instrumentation that these processes have finally been explained.

On Monday, the 2019 Nobel Prize in Physiology or Medicine was awarded jointly to three individuals: William G. Kaelin, Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza. Specifically, their discoveries helped elucidate the mechanisms for lifes most basic physiologic processes.

They were able to discover how oxygen levels directly affect cellular metabolism, which ultimately controls physiological functions. More importantly, their findings have significant implications for the treatments of conditions as varied as chronic low blood counts, kidney disease, patients with heart attacks or stroke and cancers. One of the hallmarks of cancer is its ability to generate new blood vessels to help sustain its growth. It also uses these oxygen cellular mechanisms to survive in low oxygen environments.

Dr. William G. Kaelin Jr. is a professor of medicine at Harvard University and the Dana-Farber Cancer Institute. The main focus of his work is on studying how mutations in what are called tumor suppressor genes lead to cancer development. Tumor suppressor genes are special segments of the DNA whose function is to check the integrity of the DNA before allowing a copy of itself to be made and undergo cell division, which prevents cells from propagating errors. Cellular mechanisms are then recruited to fix these errors or drive the cell to destroy itself if the damage is too severe or irreparable.

His interest in a rare genetic disorder called Von Hippel-Lindau disease (VHL) led him to discover that cancer cells that lacked the VHL gene expressed abnormally high levels of hypoxia-regulated genes. The protein called the Hypoxia-Inducible Factor (HIF) complex was first discovered in 1995 by Gregg L. Semenza, a co-recipient of the Nobel Prize. This complex is nearly ubiquitous to all oxygen-breathing species.

The function of the HIF complex in a condition of low oxygen concentration is to keep cells from dividing and growing, placing them in a state of rest. However, it also signals the formation of blood vessels, which is important in wound healing as well as promoting the growth of blood vessels in developing embryos. In cancer cells, the HIF complex helps stimulate a process called angiogenesis, the formation of new blood vessels, which allows the cancer cells to access nutrition and process their metabolic waste, aiding in their growth. When the VHL gene is reintroduced back into the cancer cells, the activity of the hypoxia-regulated genes returns to normal.

Dr. Gregg L. Semenza is the founding director of the vascular program at the Johns Hopkins Institute for Cell Engineering. He completed his residency in pediatrics at Duke University Hospital and followed this with a postdoctoral fellowship at Johns Hopkins. His research in biologic adaptations to low oxygen levels led him to study how the production of erythropoietin (EPO) was controlled by oxygen. EPO is a hormone secreted by our kidneys in response to anemia. The secretion of EPO signals our bone marrow to produce more red blood cells.

His cellular and mouse model studies identified a specific DNA segment located next to the EPO gene that seemed to mediate the production of EPO under conditions of low oxygen concentration. He called this DNA segment HIF.

Sir Peter J. Ratcliffe, a physician and scientist, trained as a nephrologist, was head of the Nuffield Department of Clinical Medicine at the University of Oxford until 2016, when he became Clinical Research Director at the Francis Crick Institute. Through his research on the cellular mechanisms of EPO and its interaction between the kidneys and red cell production, he found that these mechanisms for cellular detection of hypoxia, a state of low oxygen concentration, were also present in several other organs such as the spleen and brain. Virtually all tissues could sense oxygen in their micro-environment, and they could be modified to give them oxygen-sensing capabilities.

Dr. Kaelins findings had shown that the protein made by the VHL gene was somehow involved in controlling the response to low oxygen concentrations. Dr. Ratcliffe and his group made the connection through their discovery that the protein made by the VHL gene physically interacts with HIF complex, marking it for degradation at normal oxygen levels.

In 2001, both groups published similar findings that demonstrated cells under normal oxygen levels will attach a small molecular tag to the HIF complex that allows the VHL protein to recognize and bind HIF, marking it for degradation by enzymes. If the oxygen concentration is low, the HIF complex is protected from destruction. It begins to accumulate in the nucleus where it binds to a specific section of the DNA called hypoxia-regulating genes, which sets into motion the necessary mechanisms to respond to the low oxygen concentration.

The ability to sense oxygen plays a vital role in health and various disease states. Patients who suffer from chronic kidney failure also suffer from severe anemia because their ability to produce EPO is limited. This hormone is necessary for the stem cells in our bone marrow to produce red blood cells. Understanding how cancer cells utilize oxygen-sensing mechanisms has led to a variety of treatments that targets these pathways. The ability to elucidate these mechanisms offers insight into directions scientists and researchers can take to design or create novel treatments.

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The 2019 Nobel Prize in Medicine awarded for research in cellular responses to oxygen - World Socialist Web Site

MUNICH--(BUSINESS WIRE)--An interdisciplinary jury of ten evaluated the applications by medical startups in the categories biotechnology, medical technology and digital health. The products and projects ranked among the top 3 received the Most Innovative Product Award. The discipline-specific awards were presented during the Pharma Trend Image & Innovation Awards, which took place on September 17, 2019, at the German Museum in Munich, this year marking the 20th award ceremony.

The jury assessed the submitted product and project applications based on criteria such as the benefit for the patients, the innovative content, efficiency in application and the transition to standard care. In 2019, the following companies received the Most Innovative Product award:

Digital health: BOCAhealth, the body fluids manager of the future

Body fluids disorders (dehydration or its opposite, chronic fluid retention) are a common and risky issue in many clinical situations, especially in heart failure, chronic kidney disease and elderly patients. It is estimated that every other patient is released from hospital with a hydration problem, and their 1-year mortality is up to 30%. Inside the hospital ward, the patients hydration status is checked through the inaccurate fluid balance (inflow of infusions outflow of urine). At home the patients use weight scales that do not allow an accurate assessment of body water changes either. So far, there is no accurate, easy to use, digital and versatile solution for both hospital and home monitoring.

BOCAhealth is a portable bioimpedance device connected with a smartphone application that easily measures the patients hydration and nutrition status and estimates their cardiac output and systemic vascular resistance. The BOCAhealth software provides doctors with a real-time risk prediction score based on artificial intelligence to guide the infusion and medical therapy.

BOCAhealth is the first body fluid composition analyzer that combines portability, accuracy and a risk predictor score based on artificial intelligence. These benefits convinced the jury to grant BOCAhealth the award for the Most Innovative Product. The award was accepted by the CEO and founder Dr. Allesandro Faragli.

Medical technology: Surge-on Medical, Freedimensional surgical instruments to empower surgeons

Founded in 2015 in the Netherlands, Surge-on Medical has developed the next generation of minimally invasive surgical instruments. Through cable-free technologies, they have created freedimensional instruments that provide better access to surgical areas and replace current pre-bent instrumentation, while complying with current and future FDA and European regulation. Surge-on Medical has been granted four international patents which make minimally invasive instruments steerable, detachable and cleanable. The company is currently active in arthroscopy, laparoscopy and robotic surgery, but it is also preparing to expand to additional surgical fields to keep empowering surgeons. It aims to become the worldwide leader in the development of minimally invasive instruments.

The Most Innovative Product award for the second place was accepted by Dr. Tim Horeman, CTO of Surge-on Medical.

Biotechnology: Letermovir (Prevymis) by AiCuris

AiCuris has developed a new agent against the human cytomegalovirus (HCMV), which occurs around the world. More than half of the global population are chronically infected with the virus, but only patients with a weakened or lacking immune system are at risk of serious illness or even death. The new agent Letermovir inhibits an enzyme within the virus and thus prevents its spread without damaging the host cell. This allows very good tolerability, which for the first time enables prophylactic life-saving therapy.

Letermovir was initially developed, and has already been successfully applied, for HCMV prophylaxis in patients who have undergone stem cell and bone marrow transplantation. Following a successful phase 3, Letermovir was approved in the USA, Canada, Japan and other countries as part of a process of introducing the drug to the global market. In the future, Letermovir will also benefit organ transplant recipients, AIDS patients and new-borns. The drug has been available from German pharmacies since 2018 under the brand MSD brand name Prevymis. It was very well received by the medical community and significantly exceeds revenue expectations in the first months of sales.

AiCuris was founded in 2006 as a spin-off from what was then Bayer research division on infectious diseases. Since then, the company has been researching and developing new drugs to treat virological and bacteriological conditions. In 2012, AiCuris was able to conclude a much-noticed license agreement with MSD concerning HCMV drugs.

Dr. Holger Zimmermann, CEO of AICuris, accepted the third-place award The Most Innovative Product on behalf of his company.

A successful jubilee ceremony

The patron to the jubilee awards ceremony was the Bavarian Permanent Secretary for Health, Melanie Huml. Around 140 invited decision-makers from the pharmaceuticals industry and health care communications agencies attended the event. Keynote speakers were Dr. Peter-Andreas Lschmann, board member of Bio Deutschland (the German biotechnology industry association), and Dr. Thomas Rodenhausen, board member of Harris Interactive AG. The host for the night was Tamara Sedmak, who regularly presents on TV channels including Sat 1, n-tv and N24.

For more information on Pharma Trend, see https://pharma-trend.com/en/pharma-award/ https://youtu.be/ZTnvSoPeZfQ

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Eurecon Verlag GmbH: 20th Pharma Trend Image & Innovation Awards The Winners and Runner-ups - Business Wire

More than 55% of VHL-affected individuals develop only multiple renal cell cysts. The VHL-associated RCCs that occur are characteristically multifocal and bilateral and present as a combined cystic and solid mass.[66] Among individuals with VHL, the cumulative RCC risk has been reported as 24% to 45% overall. RCCs smaller than 3 cm in this disease tend to be low grade (Fuhrman nuclear grade 2) and minimally invasive,[67] and their rate of growth varies widely.[68] An investigation of 228 renal lesions in 28 patients who were followed up for at least 1 year showed that transition from a simple cyst to a solid lesion was infrequent.[66] Complex cystic and solid lesions contained neoplastic tissue that uniformly enlarged. These data may be used to help predict the progression of renal lesions in VHL. Figure 1 depicts bilateral renal tumors in a patient with VHL.

EnlargeFigure 1. von Hippel-Lindau diseaseassociated renal cell cancers are characteristically multifocal and bilateral and present as a combined cystic and solid mass. Red arrow indicates a lesion with a solid and cystic component, and white arrow indicates a predominantly solid lesion.

Tumors larger than 3 cm may increase in grade as they grow, and metastasis may occur.[68,69] RCCs often remain asymptomatic for long intervals.

Patients can also develop pancreatic cysts, cystadenomas, and pancreatic NETs.[2] Pancreatic cysts and cystadenomas are not malignant, but pancreatic NETs possess malignant characteristics and are typically resected if they are 3 cm or larger (2 cm if located in the head of the pancreas).[70] A review of the natural history of pancreatic NETs shows that these tumors may demonstrate nonlinear growth characteristics.[71]

Retinal manifestations, first reported more than a century ago, were one of the first recognized aspects of VHL. Retinal hemangioblastomas (also known as capillary retinal angiomas) are one of the most frequent manifestations of VHL and are present in more than 50% of patients.[72] Retinal involvement is one of the earliest manifestations of VHL, with a mean age at onset of 25 years.[1,2] These tumors are the first manifestation of VHL in nearly 80% of affected individuals and may occur in children as young as 1 year.[2,73,74]

Retinal hemangioblastomas occur most frequently in the periphery of the retina but can occur in other locations such as the optic nerve, a location much more difficult to treat. Retinal hemangioblastomas appear as a bright orange spherical tumor supplied by a tortuous vascular supply. Nearly 50% of patients have bilateral retinal hemangioblastomas.[72] The median number of lesions per affected eye is approximately six.[75] Other retinal lesions in VHL can include retinal vascular hamartomas, flat vascular tumors located in the superficial aspect of the retina.[76]

Longitudinal studies are important for the understanding of the natural history of these tumors. Left untreated, retinal hemangioblastomas can be a major source of morbidity in VHL, with approximately 8% of patients [72] having blindness caused by various mechanisms, including secondary maculopathy, contributing to retinal detachment, or possibly directly causing retinal neurodegeneration.[77] Patients with symptomatic lesions generally have larger and more numerous retinal hemangioblastomas. Long-term follow-up studies demonstrate that most lesions grow slowly and that new lesions do not develop frequently.[75,78]

Hemangioblastomas are the most common disease manifestation in patients with VHL, affecting more than 70% of individuals. A prospective study assessed the natural history of hemangioblastomas.[79] The mean age at onset of CNS hemangioblastomas is 29.1 years (range, 773 y).[80] After a mean follow-up of 7 years, 72% of the 225 patients studied developed new lesions.[81] Fifty-one percent of existing hemangioblastomas remained stable. The remaining lesions exhibited heterogeneous growth rates, with cerebellar and brainstem lesions growing faster than those in the spinal cord or cauda equina. Approximately 12% of hemangioblastomas developed either peritumoral or intratumoral cysts, and 6.4% were symptomatic and required treatment. Increased tumor burden or total tumor number detected was associated with male sex, longer follow-up, and genotype (all P < .01). Partial germline deletions were associated with more tumors per patient than were missense variants (P < .01). Younger patients developed more tumors per year. Hemangioblastoma growth rate was higher in men than in women (P < .01). Figures 2 and 3 depict cerebellar and spinal hemangioblastomas, respectively, in patients with VHL.

EnlargeFigure 2. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau disease. The left panel shows a sagittal view of brainstem and cerebellar lesions. The middle panel shows an axial view of a brainstem lesion. The right panel shows a cerebellar lesion (red arrow) with a dominant cystic component (white arrow).

EnlargeFigure 3. Hemangioblastomas are the most common disease manifestation in patients with von Hippel-Lindau disease. Multiple spinal cord hemangioblastomas are shown.

The rate of pheochromocytoma formation in the VHL patient population is 25% to 30%.[82,83] Of patients with VHL-associated pheochromocytomas, 44% developed disease in both adrenal glands.[84] The rate of malignant transformation is very low. Levels of plasma and urine normetanephrine are typically elevated in patients with VHL,[85] and approximately two-thirds will experience physical manifestations such as hypertension, tachycardia, and palpitations.[82] Patients with a partial loss of VHL function (Type 2 disease) are at higher risk of pheochromocytoma than are VHL patients with a complete loss of VHL function (Type 1 disease); the latter develop pheochromocytoma very rarely.[13,14,82,86] The rate of VHL germline pathogenic variants in nonsyndromic pheochromocytomas and paragangliomas was very low in a cohort of 182 patients, with only 1 of 182 patients ultimately diagnosed with VHL.[87]

Paragangliomas are rare in VHL patients but can occur in the head and neck or abdomen.[88] A review of VHL patients who developed pheochromocytomas and/or paragangliomas revealed that 90% of patients manifested pheochromocytomas and 19% presented with a paraganglioma.[84]

The mean age at diagnosis of VHL-related pheochromocytomas and paragangliomas is approximately 30 years,[83,89] and patients with multiple tumors were diagnosed more than a decade earlier than patients with solitary lesions in one series (19 vs. 34 y; P < .001).[89] Diagnosis of pheochromocytoma was made in patients as young as 5 years in one cohort,[83] providing a rationale for early testing. All 21 pediatric patients with pheochromocytomas in this 273-patient cohort had elevated plasma normetanephrines.[83]

VHL patients may develop multiple serous cystadenomas, pancreatic NETs, and simple pancreatic cysts.[1] VHL patients do not have an increased risk of pancreatic adenocarcinoma. Serous cystadenomas are benign tumors and warrant no intervention. Simple pancreatic cysts can be numerous and rarely cause symptomatic biliary duct obstruction. Endocrine function is nearly always maintained; occasionally, however, patients with extensive cystic disease requiring pancreatic surgery may ultimately require pancreatic exocrine supplementation.

Pancreatic NETs are usually nonfunctional but can metastasize (to lymph nodes and the liver). The risk of pancreatic NET metastasis was analyzed in a large cohort of patients, in which the mean age at diagnosis of a pancreatic NET was 38 years (range, 1668 y).[90] The risk of metastasis was lower in patients with small primary lesions (3 cm), in patients without an exon 3 pathogenic variant, and in patients whose tumor had a slow doubling time (>500 days). Nonfunctional pancreatic NETs can be followed by imaging surveillance with intervention when tumors reach 3 cm. Lesions in the head of the pancreas can be considered for surgery at a smaller size to limit operative complexity.

ELSTs are adenomatous tumors arising from the endolymphatic duct or sac within the posterior part of the petrous bone.[91] ELSTs are rare in the sporadic setting, but are apparent on imaging in 11% to 16% of patients with VHL. Although these tumors do not metastasize, they are locally invasive, eroding through the petrous bone and the inner ear structures.[91,92] Approximately 30% of VHL patients with ELSTs have bilateral lesions.[91,93]

ELSTs are an important cause of morbidity in VHL patients. ELSTs evident on imaging are associated with a variety of symptoms, including hearing loss (95% of patients), tinnitus (92%), vestibular symptoms (such as vertigo or disequilibrium) (62%), aural fullness (29%), and facial paresis (8%).[91,92] In approximately half of patients, symptoms (particularly hearing loss) can occur suddenly, probably as a result of acute intralabyrinthine hemorrhage.[92] Hearing loss or vestibular dysfunction in VHL patients can also present in the absence of radiologically evident ELSTs (approximately 60% of all symptomatic patients) and is believed to be a consequence of microscopic ELSTs.[91]

Hearing loss related to ELSTs is typically irreversible; serial imaging to enable early detection of ELSTs in asymptomatic patients and resection of radiologically evident lesions are important components in the management of VHL patients.[94,95] Surgical resection by retrolabyrinthine posterior petrosectomy is usually curative and can prevent onset or worsening of hearing loss and improve vestibular symptoms.[92,94]

Tumors of the broad ligament can occur in females with VHL and are known as papillary cystadenomas. These tumors are extremely rare, and fewer than 20 have been reported in the literature.[96] Papillary cystadenomas are histologically identical to epididymal cystadenomas commonly observed in males with VHL.[97] One important difference is that papillary cystadenomas are almost exclusively observed in patients with VHL, whereas epididymal cystadenomas in men can occur sporadically.[98] These tumors are frequently cystic, and although they become large, they generally have a fairly indolent behavior.

Fluid-filled epididymal cysts, or spermatoceles, are very common in adult men. In VHL, the epididymis can contain more complex cystic neoplasms known as papillary cystadenomas, which are rare in the general population. More than one-third of all cases of epididymal cystadenomas reported in the literature and most cases of bilateral cystadenomas have been reported in patients with VHL.[99] These well-circumscribed lesions have variable amounts of cystic and papillary components that are lined with epithelial cuboidal or columnar clear cells.[100] Among symptomatic patients, the most common presentation of epididymal cystadenoma is a painless, slow-growing scrotal swelling. The differential diagnoses of epididymal tumors include adenomatoid tumor (which is the most common tumor in this site), metastatic ccRCC, and papillary mesothelioma.[101]

In a small series, histological analysis did not reveal features typically associated with malignancy, such as mitotic figures, nuclear pleomorphism, and necrosis. Lesions were strongly positive for CK7 and negative for RCC. Carbonic anhydrase IX (CAIX) was positive in all tumors. PAX8 was positive in most cases. These features were reminiscent of clear cell papillary RCC, a relatively benign form of RCC without known metastatic potential.[97]

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Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ ...

Kidney disease treatment is no longer limited to conventional medicine, dialysis, or surgery. Alternative treatments are also available to treat some types of kidney disease and to manage its symptoms. Alternative treatments enhance standard kidney disease treatment. They do not replace conventional therapies, rather they complement them. Here are 7 alternative kidney disease treatment options worth looking into:

Note: Make sure to consult with a doctor before taking herbal medicine. Notall herbs may be beneficial for patients with renal disease.

Note: Consult a doctor before taking any supplements to ensure safety.

Learn more about alternative kidney disease treatment with this video by HealthP1:

These are just some of the alternative kidney disease treatments for patients with chronic renal illness. Again, it is important to note that these treatments complement standard or conventional therapies such as dialysis and surgery. Consult with a doctor before starting a particular alternative treatment to ensure safe and effective results.

What are your thoughts on alternative kidney disease treatment? Share with us your ideas in the comments section below!

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7 Alternative Kidney Disease Treatments | Stem Cell Research

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7 Alternative Kidney Disease Treatments | Stem Cell Research

About Kidney Failure

Kidney failure (or renal failure) is a condition in which the kidneys fail to filter waste products from your blood. When your kidneys lose their filtering ability, dangerous levels of wastes may accumulate, and your blood's chemical makeup may get out of balance.

When your kidneys have failed, it typically means they have stopped working well enough for you to survive without dialysis or a kidney transplant.

Acute renal failure (ARF) is a rapidly progressive loss of renal function, characterized by oliguria, water imbalance of body fluids, a decreased urine production, and electrolyte disorders.

Chronic renal failure (CRF) is the condition that is caused by permanent damage to kidney function, secondary to any cause. Common causes of chronic kidney disease include diabetes, hypertension, and obstructive diseases of the urinary tract (such as stones, tumors, etc.). It can arise from the complication of inflammatory diseases of the kidney like chronic pyelonephritis and urinary retention, and the use of toxic drugs to the kidney (particularly some antibiotics).

When the disease is detected early, the speed with which the damage progresses can be slowed, delaying the onset of replacement therapies and giving the patient more time to prepare for such therapy.

Stem cell treatment for Kidney Failure is customized to each patients individual needs. The kidney is a very complex organ consisting of many different types of cells. To make a new kidney in the lab, all these different cells would need to be formed in a different way and in the hope that they would reconstruct a functional kidney. Treatment results may vary from patient to patient. You may notice slow or gradual improvements over time, or you may not see results at all.

Stem cell research enables the scientific community to utilize the bodys own repair mechanisms to find new treatment methods for Kidney Disease. In Acute Renal Failure, the body can often repair kidney damage itself, but it is unable to do this well enough to tackle the damage that occurs in Chronic Renal Failure. We look forward to becoming an active partner in helping you achieve a better quality of life.

To learn more about becoming a patient and receiving Stem Cell Therapy for Kidney Disease, please contact one of our Patient Advocates at +1 855 232 3303.

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Kidney failure is the Rodney Dangerfield of diseases, it really doesnt get the respect it deserves. An estimated 660,000 Americans suffer from kidney failure and around 47,000 people die from it every year. Thats more than die from breast or prostate cancer. But now a new study has identified a promising stem cell candidate that could help in finding a way to help repair damaged kidneys.

Kidneys are the bodys waste disposal system, filtering our blood and cleaning out all the waste products. Our kidneys have a limited ability to help repair themselves but if someone suffers from chronic kidney disease then their kidneys are slowly overwhelmed and that leads to end stage renal disease. At that point the patients options are limited to dialysis or an organ transplant.

Survivors hold out hope

Italian researchers had identified some cells in the kidneys that showed a regenerative ability. These cells, which were characterized by the expression of a molecule called CD133, were able to survive injury and create different types of kidney cells.

Researchers at the University of Torino in Italy decided to take these findings further and explore precisely how CD133 worked and if they could take advantage of that and use it to help repair damaged kidneys.

In their findings, published in the journal Stem Cells Translational Medicine, the researchers began by working with a chemotherapy drug called cisplatin, which is used against a broad range of cancers but is also known to cause damage to kidneys in around one third of all patients. The team found that CD133 was an important factor in helping those damaged kidneys recover. They also found that CD133 prevents aging of kidney progenitor cells, the kind of cell needed to help create new cells to repair the kidneys in future.

Hope for further research

The finding opens up a number of possible lines of research, including exploring whether infusions of CD133 could help patients whose kidneys are no longer able to produce enough of the molecule to help repair damage.

In an interview in DD News, Dr. Anthony Atala, Director of the Wake Forest Institute for Regenerative Medicine praised the research:

This is an interesting and novel finding. Because the work identifies mechanisms potentially involved in the repair of tissue after injury, it suggests the possibility of new therapies for tissue repair and regeneration.

CIRM is funding several projects targeting kidney disease including four clinical trials for kidney failure. These are all late-stage kidney failure problems so if the CD133 research lives up to its promise it might be able to help people at an earlier stage of disease.

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Regeneration is, of course, the Holy Grail of medicine. Many diseases are chronic because they are a consequence of damage to organs or tissues beyond any natural repair mechanism. When kidneys are damaged beyond repair, the only answer may be transplantation (severely restricted due to the scarcity of donors) or dialysis a terrible burden on patients (over 350,000 in the U.S.) who are forever tethered to their condition by weekly and sometimes daily visits to a machine. Harnessing the power of the kidneys innate ability to regenerate could enable patients to regain their health.

The kidney actually ranks very highly in its ability to repair itself, said Joseph Bonventre, MD, PhD Professor of Medicine at Harvard Medical School, Chief of the Renal Division at Brigham and Womens Hospital, and head of the HSCI Kidney Disease Program.

Bonventre and his team study the mechanisms by which the kidney repairs tissue after disease, particularly the repair of nephrons, which are the key functional units of the kidney. The nephron consists of a filtering unit for the blood, the glomerulus, and a complex tubule responsible for filtering the blood. The small tubules collect the filtrate and process it before passing it on to ducts leading to the bladder. If tubules are damaged they can be repaired but if the damage is severe enough the nephron may be destroyed. Unfortunately the kidney can regenerate and recover, but the kidney cannot make new nephrons, and in that context, its regeneration is limited.

What happens to the tubules is a clinically relevant question. In kidney disease, whether the disease starts in the filters or the tubules, the tubules ultimately become involved as they are highly susceptible to injury. A reduction in blood flow can lead to a restriction in the supply of oxygen, which can be lethal to the epithelial cells that form the lining of the tubules. For acute kidney injury, the tubules are often (but not always) capable of recovering completely. In chronic kidney failure, the injuries are progressive and nephrons are lost.

Many theories exist on kidney repair. Some suggest that the kidney may recruit circulating stem cells to migrate into and regenerate the damaged area, others that local tissue specific stem cells may be triggered to differentiate and rebuild, and still others that the kidney may forego a direct role for stem cells altogether by inducing mature cells to proliferate.However, a recent study by Bonventre, HSCI Affiliated Faculty member Benjamin Humphreys, MD, PhD, HSCI Executive Committee Member Andrew McMahon, PhD, and their team went a long way toward understanding how the tubules repair themselves.

By tagging the mature epithelial cells that form the tubule walls with a red fluorescent protein, the HSCI team was able to demonstrate that the replacement cells after injury are coming from the epithelium itself rather than from circulating stem cells that enter the kidney or local tissue specific stem cells in the tissue between the tubules. These stem cells might not be sitting on the sidelines, however. Other evidence suggests that they may be offering some assistance in causing the epithelial cells to multiply.

The Harvard Stem Cell Institute basically has allowed us to look at kidney disease in a different and, in many cases, quite definitive way. Joseph Bonventre, MD, PhD

In over 35 years of studying the repair of damaged kidneys, Bonventre suggests that the field may be reaching an inflection point. The Harvard Stem Cell Institute basically has allowed us to look at kidney disease in a different and, in many cases, quite definitive way, said Bonventre. Were understanding the processes much better so that we can now focus on the cell biology related to the intrinsic capacity for the kidney to renew itself.

Collaboration among HSCI researchers has been key to advancing this understanding by sharing expertise as well as findings from model organisms such as the mouse and the zebrafish. Andy McMahon is a world class investigator who has made enormous contributions to the understanding of the way the kidney matures during development, said Bonventre. It has been very productive to apply this knowledge to understanding repair in the adult organ. The team is also using knowledge of the kidneys ability to renew itself to find out how to protect it from further damage. We have found in mice that we can precondition the kidney to be protected against a subsequent injury simply by temporarily cutting off blood flow to parts of the organ and coming back one to two weeks later and finding that when we cut off blood supply again the kidney is not damaged, said Bonventre. We want to understand what causes the protection against the second injury. Is there a cell that goes into the kidney, or some other factor involved? If these protective factors can be found, they could potentially be developed as drugs or treatments that prevent kidney damage in highrisk individuals.

Another use of kidney cells grown in the laboratory is in screens for the potential toxicity of drugs before they are introduced into animals or humans. There really is no good model for in vitro kidney toxicity screening today, because the cells tend to lose their differentiated state and become less kidney-like or less epithelial-like outside the body. Bonventre and colleagues are working on ways to control cell behavior and maintain their state to make better predictive screens. We will be working with Lee Rubins group at the HSCI Therapeutic Screening Center to help us screen for molecules that will keep cells differentiated in culture. If we can do that, we can use them for toxicology and for more sophisticated kidney assist devices, said Bonventre.

Taking that technology back inside the body, one might even use the differentiated cells to create artificial tubules and nephrons with the help of bioengineered materials - completing the regeneration that the kidney is unable to do on its own.

Patients might not have to wait too long to see the benefits of this research. Based on animal studies that suggested an indirect role for stem cells in kidney repair, clinical trials aimed at preventing or rolling back kidney damage in cardiac patients have already begun.

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The kidney repair shop | Harvard Stem Cell Institute (HSCI)

Mark Humayun University of Southern California Phase 1 Active, not recruiting 16 Tippi MacKenzie University of California, San Francisco Phase 1 Recruiting 10 Ralph Kern BrainStorm Cell Therapeutics Phase 3 Recruiting 200 Clive Svendsen Cedars-Sinai Medical Center Phase 1/2 Active, not recruiting 18 Crystal Mackall Stanford University Phase 1 Recruiting 57 Thomas Kipps University of California, San Diego Phase 1/2 Recruiting 156 Ed Conner Sangamo BioSciences, Inc. Phase 1/2 Recruiting 6 Edward Kavalerchik Angiocrine Bioscience, Inc. Phase 1 Launching N/A Thomas Kipps University of California, San Diego Phase 1 Active, not recruiting 29 Irving Weissman Stanford University Phase 1 Completed 88 Paul Finnegan Angiocrine Bioscience, Inc. Phase 1 Launching N/A Michael Pulsipher Children's Hospital of Los Angeles Phase 1/2 Launching N/A Anthony Gringeri ImmunoCellular Therapeutics Phase 3 Suspended 414 Christine Brown City of Hope, Beckman Research Institute Phase 1 Recruiting 92 Mark Chao Forty Seven Inc. Phase 1/2 Recruiting 112 Linda Marban Capricor, Inc Phase 2 Completed 25 Rachel Smith Capricor, Inc Phase 2 Active, not recruiting 134 Mehrdad Abedi University of California, Davis Phase 1/2 Recruiting 18 Geoff Symonds Calimmune, Inc. Phase 1/2 Completed 12 John Zaia City of Hope, Beckman Research Institute Phase 1 Active, not recruiting 12 Vicki Wheelock University of California, Davis Phase 1/2 Completed 29 Everett Meyer Stanford University Phase 1 Launching N/A Jeffrey Lawson Humacyte, Inc. Phase 3 Active, not recruiting 355 Samuel Strober Stanford University Phase 1 Active, not recruiting 15 Jeffrey Lawson Humacyte, Inc. Phase 3 Recruiting 240 Scott Batty Medeor Therapeutics, Inc. Phase 3 Recruiting 75

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Funding Clinical Trials | California's Stem Cell Agency

TREATMENTS

Regenerative revolutionary cord blood stem cell therapies along with PRP therapy that are effective, nonsteroidal, outpatient & repairdamaged tissue.

Repair and regenerate damaged joints, tendons, ligaments and cartilage from sports injuries or arthritis. Back and neck pain, COPD, Kidney/Heart Failure and more!

Your most common questions answered about cord blood regenerative therapies and how they can help you obtain relief, increase function and avoid potentially risky surgery.

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Stem Cell Therapy Has Been Groundbreaking For Pain Relief

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The procedure is carried out in one day as an outpatient, and patients generally do not need an overnight stay with us.

We need some blood tests for anesthetic safety. Once we are happy with these, we administer a short general anesthetic. Typically this lasts 30 to 90 minutes.

We need to take x-rays of the affected areas and also a chest x-ray. Where recent x-rays are available from your own vet, we will not need to repeat these.

We then harvest approximately 40 grams of fat from a site behind the shoulder or just inside the tummy. At this time we may inject Platelet Rich Plasma (PRP) into the affected joints. This reduces inflammation and pain in the joint and prepares it to receive stem cells, should they be required. Your pet is then woken from the anesthetic. There may be a few stitches that need to come out in 10 days.

The fat is processed in our lab to isolate, concentrate and activate stem cells and this takes 10-14 days. Once we have the healthy stem cells, we organise a second appointment for a sedative to allow us to inject the cells directly into the affected joints.

Well then book you follow up consultations at 30, 60 and 90 days.

We ask you to send us follow up videos and updates on a weekly basis so we can keep a close eye on progress.Where repeat visits are difficult because of travel distances, we can arrange telephone consultations.

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Stem Cell Vet UK Treat Arthritis in Dogs & Cats

Welcome to Stem Cell Consults

Stem Cell Center offers a complete scope of stem cell solutions in India for the treatment of various types of diseases. Our main focus is helping people get back to good health through stem cell treatment. Our organization associated with so many hospitals, medical tourism company and also has our own stem cell research labs in India to provide best quality of stem cells in this advanced stem cell treatment field to provide best quality of treatment for all needed patients al over the world.

We also provide complete stem cell lab set up in all over the world and started some other stem cells labs in other countries via our best and experienced team. We have more than 10 years stem cell research experience and treated more than thousand patients for various diseases and even provide stem cell services to various hospitals in all over the world.

We at stem cell center can proudly say that we give the best stem cells in India. Our years of research, hard work and trials have helped us pioneer and accomplish amazing results when required. Your precious cells are processed utilizing our restrictive technology to guarantee they have the best features required for treatment. Undeveloped cell focus are completely anchored, non-lethal and totally without reactions with an excellent probability of homing and tissue or organ.

We are giving advanced Stem Cell Therapy in India where all other medical treatment fail then this stem cell treatment apply to cure such non-treatable maladies or diseases.

As the main healthcare consultant, stem cell center in India takes care of each and every section of the Medical Tourism Trip to entire India. We guarantee, our patients get the best healthcare service by getting in place, the renowned specialty hospitals, latest stem cell treatments, economical housing and alternatives for the patients.

Our organization is giving best stem cell therapy in India and furthermore has perfection in stem cell treatment in Uttar Pradesh, Delhi NCR and all other all major cities of India for the required patients in all those application which can treat by stem cell therapy. We have stem cells in various forms to improve the better recuperation of patient and refer the best stem cell solutions after the evaluation of patient case study by our experts. Our experts in stem cell cooperate with patients however the total understanding to offer you more peace of mind to develop clear evidence based path. We have highly experts in our team and our experts are strong in research and clinical research from the two perspectives.

Our mission is to offer best stem cell therapy at sensible price not only in India but also throughout the entire world so that every required patients can get best stem cell therapy to enhance his life.

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15 Aug Stem Cell Therapy for Kidney Failure

As Type-2 diabetes and high blood pressure continue to plague the world, the demand for kidney transplants is increasing by the day. Owing to a shortage of organ donors to meet this requirement, stem cell therapies emerge as a hope to cure thousands of patients as an alternative treatment.

Our kidneys are designed to prevent toxins build up in our bodies. Kidneys help remove a lot of waste, cleansing our bodies from within so that no harmful toxins and chemicals destroy our vital organs. Our kidneys also produce hormones to control other body functions.

When more than a third of your kidney function is impaired, chronic kidney disease begins to take place. Other diseases such as diabetes also contribute to worsening this condition. When left untreated, chronic kidney disease gradually worsens and may result in kidney failure in some cases.

When this happens, patients have to rely on a kidney transplant and dialysis to stay alive and perform day to day activities.

Stem cells possess the unique capacity to self-renew if they are provided the right environment. Therefore, stem cells are used to replace or repair damaged tissues. This is why stem cells can be of significant help in treating kidney failure.

There has been a lot of research to study the effects of stem cells to regenerate a damaged kidney and re-establish its lost function. The past few decades have shown a substantial improvement in identifying how stem cells can play their role in treating several medical conditions such as kidney failure.

Researchers have concentrated on focusing on how human induced pluripotent stem cells and bone marrow mesenchymal stem cells (MSCs) can deliver maximum results in restoring kidney function.

Mesenchymal stem cells regenerate into several different types of stem cells. These cells can be incorporated into the renal tubular cells and develop into mesangial cells. Moreover, these cells revitalize the kidneys stem cells and support the survival of renal cells by discharging growth stimulants, to initiate the natural recovery process.

Cases in which stem cells are taken from bone marrow and fat to treat patients suffering from chronic nephritis (resulting in kidney failure) have revealed positive outcomes.

The treatment involves delivering the mesenchymal stem cells and the bone marrow directly into the kidneys to begin repairing the damage on their own.

In the same way, stem cell therapy is also useful in treating complicated conditions such as multiple myeloma, (which also leads to a kidney failure), by transplanting bone marrow stem cells.

Although we are yet to declare the stem cell therapy to be the ultimate treatment for kidney failure, it is definitely useful in slowing down and sometimes suspending the progression of CKD.

Modern stem cells therapies that are currently available utilize stem cells to repair and regenerate damaged renal cells and improve the function of the kidney to slow down the diseases progression.

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Stem Cell Chicago | Stem Cell Therapy for Kidney Failure

Its important for people suffering from kidney disease to know theyre not alone. Heres a list of todays celebrities and athletes who have suffered from kidney disease.

Peter Burns, singer for the band, Dead or Alive, acute kidney failure caused by several kidney stones

Nick Cannon, singer, actor, suffers from lupus nephritis

Grizzwald Chapman, actor in 30 Rock, kidney failure due to hypertension, transplant recipient

Natalie Cole, singer, kidney failure after treatment for hepatitis C, transplant recipient

Lucy Davis, actress in The Office, kidney failure due to diabetes, transplant recipient

Aron Eisenberg, actor in Star Trek: Deep Space Nine, born with one partially functioning kidney, transplant recipient

Sean Elliott, basketball player, suffered from FSGS, transplant recipient

Freeway, rap musician, kidney failure due to diabetes, waiting for a kidney transplant

Stephen Furst, actor, diabetic, transplant recipient

Jennifer Harman, professional poker player, hereditary kidney disease, two-time transplant recipient

Ed Hearn, baseball player, suffered from FSGS, three-time transplant recipient

Ken Howard, actor in 30 Rock, kidney failure caused by a misdiagnosed blockage, transplant recipient

Paul Hutchins, football player, FSGS, received double kidney transplant

Sarah Hyland, actress, suffered from kidney dysplasia, received a kidney from her father

Donald Jones, football player, IgA nephropathy, received a kidney from his father and is playing baseball post-transplant

Chris Kemoeatu, football player, hereditary kidney disease, received a kidney from his brother, also a football player

Jonah Lomu, New Zealand rugby player, kidney failure due to nephrotic syndrome, sadly passed away in November 2015 while waiting for another kidney transplant

George Lopez, comedian, hereditary kidney disease, transplant recipient

Scott MacIntyre, American Idol singer, family history of kidney disease, transplant recipient, now in need of another kidney transplant

Aries Merritt, Olympic hurdler, rare congenital kidney disease, transplant recipient

Tracy Morgan, actor in 30 Rock, kidney failure due to diabetes, transplant recipient

Alonzo Mourning, basketball player, suffered from FSGS, transplant recipient

Jeremy Newberry, football player, kidney disease caused by painkillers

Liam Payne, singer for the band, One Direction, born with partially functioning kidney

Pele, soccer legend, had a kidney removed in the 1970s, recently underwent surgery for kidney stones

Phillip Phillips, singer, chronic kidney stones

Amy Purdy, athlete and actress, kidneys failed two years after hospitalization for septic shock, received a kidney from her father

Jon Rankin, Olympic athlete, FSGS

Bobby Rydell, singer,kidney failure caused by liver disease, transplant recipient

Neil Simon, playwright, suffered from PKD, transplant recipient

Clyde Simms, pro soccer player, FSGS

Dayna Stephens, jazz musician, diagnosed with FSGS, in need of kidney transplant

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