First-Line Treatment With Merck’s KEYTRUDA (pembrolizumab) Doubled Five-Year Survival Rate (31.9%) Versus Chemotherapy (16.3%) in Certain Patients…

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced five-year survival results from the pivotal Phase 3 KEYNOTE-024 trial, which demonstrated a sustained, long-term survival benefit and durable responses with KEYTRUDA, Mercks anti-PD-1 therapy, versus chemotherapy as first-line treatment in patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (tumor proportion score [TPS] 50%) with no EGFR or ALK genomic tumor aberrations. At five years, the overall survival (OS) rate was twice as high for patients who received KEYTRUDA (31.9%; n=154) versus chemotherapy (16.3%; n=151). KEYTRUDA also reduced the risk of death by 38% (HR=0.62 [95% CI, 0.48-0.81) versus chemotherapy, with a median OS of 26.3 versus 13.4 months. Results from KEYNOTE-024 represent the longest follow-up and first-ever five-year survival data for an immunotherapy in a randomized Phase 3 study for the first-line treatment of NSCLC.

Before 2014, the five-year survival rate for patients in the U.S. with advanced non-small cell lung cancer was only 5%. Data presented today from KEYNOTE-024 showed that 31.9% of patients treated with KEYTRUDA were alive at five years, said Martin Reck, M.D., Ph.D., Lung Clinic Grosshansdorf, German Center of Lung Research. Survival outcomes in these patients with metastatic lung cancer did not seem possible to many oncologists, including myself, several years ago. The long-term survival benefit achieved with KEYTRUDA as a single agent in this study is a great example of the progress we have made in lung cancer to provide patients with more time without disease progression and a chance at a longer life.

KEYTRUDA has become foundational in the treatment of metastatic lung cancer based on the sustained, long-term survival benefit demonstrated in our clinical trials. These new, first-of-their-kind five-year survival results from KEYNOTE-024 add to our understanding of the important role that KEYTRUDA now has in the treatment of lung cancer, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. It is particularly noteworthy that at five years, 81.4% of patients who completed two years of treatment with KEYTRUDA were alive and nearly half of these patients remained treatment-free, representing an encouraging new precedent in the first-line metastatic non-small cell lung cancer setting. We are grateful to the many patients and health care providers in this trial and our other trials for their essential role in these studies and in advancing cancer care.

These late-breaking data were presented as a proffered paper at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 on Monday, Sept. 21 (Abstract #LBA51). As announced, data spanning more than 15 types of cancer will be presented from Mercks broad oncology portfolio and investigational pipeline at the congress. A compendium of presentations and posters of Merck-led studies is available here. Follow Merck on Twitter via @Merck and keep up to date with ESMO news and updates by using the hashtag #ESMO20.

Five-Year Overall Survival Data From KEYNOTE-024 (Abstract #LBA51)

New data from KEYNOTE-024 (ClinicalTrials.gov, NCT02142738) demonstrated a sustained, long-term survival benefit with KEYTRUDA versus chemotherapy after 59.9 months of median follow-up (range, 55.1 to 68.4). The pivotal Phase 3, randomized, open-label trial evaluated KEYTRUDA monotherapy versus standard of care platinum-based chemotherapy as first-line treatment in patients with metastatic NSCLC whose tumors express high levels of PD-L1 (TPS 50%) with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA reduced the risk of death by 38% (HR=0.62 [95% CI, 0.48-0.81]) versus chemotherapy alone, with a median OS of 26.3 versus 13.4 months. The five-year OS rate was 31.9% for patients who received KEYTRUDA versus 16.3% for those who received chemotherapy. The OS benefit was observed, despite a 66% (n=99/150) effective crossover rate from chemotherapy to subsequent anti-PD-1/PD-L1 therapy. KEYTRUDA also reduced the risk of disease progression or death by half (HR=0.50 [95% CI, 0.39-0.65]) versus chemotherapy as assessed by investigators, with a median progression-free survival of 7.7 versus 5.5 months. The objective response rate (ORR) was 46.1% for KEYTRUDA versus 31.1% for chemotherapy. The median duration of response was 29.1 months (range, 2.2 to 60.8+) for KEYTRUDA versus 6.3 months (range, 3.1 to 52.4) for chemotherapy.

Of the patients who completed two years of treatment with KEYTRUDA (n=39/154), 81.4% were alive at five years and nearly half (46%) remained treatment-free. These data suggest that patients who completed two years of treatment with KEYTRUDA experienced a long-term OS benefit. The ORR was 82% for patients who completed two years of treatment with KEYTRUDA. Additionally, 12 patients received a second course of therapy.

No new safety signals for KEYTRUDA were identified with long-term follow-up. Among all patients who were treated, 31.2% of those who received KEYTRUDA and 53.3% of those who received chemotherapy experienced Grade 3-5 treatment-related adverse events (TRAEs). Among patients who completed two years of treatment with KEYTRUDA, Grade 3-5 TRAEs occurred in 15.4%.

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. Before 2014, the five-year survival rate for patients diagnosed in the U.S. with NSCLC and SCLC was estimated to be 5% and 6%, respectively.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

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 1,200 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 patient's 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 1 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.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient 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.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

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).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. 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 TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

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 adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). 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 adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or 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 with advanced NSCLC; 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%).

See more here:
First-Line Treatment With Merck's KEYTRUDA (pembrolizumab) Doubled Five-Year Survival Rate (31.9%) Versus Chemotherapy (16.3%) in Certain Patients...

Coronavirus, Charity, and the Trolley Problem – Crooked

I signed up to be a bone marrow donor in 2016, after an anonymous strangers marrow saved my father. It started out easy enough: The registry mailed me a kit to swab my cheeks, I mailed it back, and then I heard nothing for years. This wasnt unusual. Marrow transplantation requires finding complex and rare genetic matches; according to Be The Match, only about one out of every 430 people who sign up will ever go on to donate. I expected it would be a while before I got to pay my dads transplant forward. It did not occur to me that my opportunity might arise at the height of a global coronavirus pandemic.

The coronavirus created a tangle of moral dilemmas that most Americans never expected to face. At the extremes, weve resolved these dilemmas easily. Weve designated whole categories of labormostly underpaid, perennially underappreciatedessential because we accept that even with a plague lurking, people must eat and medicate and have working showers in which to cry. On the opposite end of the spectrum, weve trained our online shaming apparatus on the most reckless and selfish offendersthe wealthy New Yorkers who fled to the Hamptons, the house parties posted to Instagram with weak defensive captions (we only took our masks off for the body shots).

The longer we live in the shadow of an uncontained virus, the more agonizing the in-between dilemmas become. How long should people be expected to remain isolated from their loved ones? Is there a point at which the negative effects of physical distancing begin to outweigh the toll of the disease itself? On the one hand, we should do everything in our power to protect the most vulnerable in our communities. On the other hand, what should we tell the vulnerable seniors who feel they dont have endless spare months to let pass without embracing their grandchildren? Are our individual mitigation responsibilities lessened by the fact that we all made sacrifices to buy an incompetent president time to get this under control, and he squandered it? Are we that much more obligated to pick up the slack?

In some sort of sick philosophical joke, the moral waters get even murkier when you throw altruism into the mix. For all of the guidance reminding us of the impact of our selfish choices on strangersyou might not kill your own grandmother by going to that dive bar, but think of the bartenders roommates grandmothermoral experts have had far less to say about the boundaries around charitable acts. How should we think about helping strangers when doing so requires a dangerous level of social interaction? How should we measure the suffering of the people we want to help against the harm we risk causing to unseen others in the process? That quandary leads to another awful question that most people should never have to confront: When does human life become too risky to save?

Be The Match first notified me that it had identified me as a potential match in June, when coronavirus cases in Los Angeles, where I live, had just begun to spike. By the time I was confirmed as the patients best match and asked to proceed with a donation several weeks later, the city had become a full-blown hotspot. The idea of navigating the whole process in plague conditions made me nervous, but underneath the anxiety was a distinct whiff of relief. Like a lot of people, Id spent the last few months in a horrified daze, helpless to do anything but stay home, donate money, and cyberbully the mayor. Here, finally, was a task that felt equal to the urgency of the moment. Here was somethingsomeonereal. I just wasnt allowed to know who.

Be The Match will put donor and recipient in contact one year after the transplant, if both have consented; until then, everything is completely anonymous. I was told that my recipient was a man in the United States, along with his age (surprisingly young), and diagnosis (a type of blood cancer). Because matches are typically found within shared ancestries, I assume that he is, like me, an Ashkenazi Jew, and because he needed a bone marrow transplant, his situation must have been dire.

Fortunately, helping people like him has become simpler. When most people think of donating for a bone marrow transplant, they imagine general anesthesia; a very big needle; a painful recovery. This is one of the two ways to donate, but its grown much less common. Ninety percent of donors (including me) are instead asked to donate peripheral blood stem cells (PBSC), through a process called apheresis. While a donor is awake and watching Party Down, their blood flows through a tube attached to one arm, gets spun around in a centrifuge that separates out the extra blood-forming stem cells, and is returned through a tube into the other arm. This can take several hours, but its painless, and neednt even happen at a hospital. Usually.

(Sarah Lazarus)

On August 13, two nurses met me at the San Bernardino blood bank where I was scheduled to donate later that month. We were all there for an assessment, to make sure my arm veins could handle the apheresis needles. It was a weird little ritual. The two women bent on either side of me, intently tapping along my upturned arms in total silence as if waiting for something to tap back. They then switched sides, tapped the opposite arm, and issued their verdict: Too small. I would need to donate through a central line placed in one of my larger veins, and that could only happen at a hospital. I would probably be sent to a medical center two hours south in La Jolla, they told me.

This was a complication, but not necessarily a big deal. Be The Match footed the bill for all of my donation-related expenses, including the fancy car service that seemed safer, COVID-wise, than using Lyft. (I am a genius who moved to Los Angeles without a drivers license. A worse essay for another time.) Donating at the La Jolla hospital would mean a longer commute, maybe even one night in a hotel, but that was about it.

Later that morning I was waiting for my next appointment at an urgent care center when Heather, my donor coordinator, called to tell me that La Jolla didnt have an opening on the right day. Neither did the next-closest option, she told me as I paced around the parking lot, and the patients team couldnt shift his treatment schedule.

So my question for you is, would you feel comfortable flying to Boise, Idaho?

I went back inside to the busy waiting room and reclaimed my seat. Across the room, a man in a UPS uniform freed his nose to rest obscenely on top of his mask. I hunched over my phone and googled, Boise coronavirus. My phone informed me that it was dying. The UPS man coughed. On a TV in the corner, the president admitted he was sabotaging the post office to steal the election. I googled, airports coronavirus. At last, a nurse called me back and started checking my vitals.

Your heart rate is really elevated, she said, frowning at the reading. Any idea why?

As of this writing, Be The Matchs COVID-19 FAQ page was last updated on April 6. Heres part of the section on air travel:

Q: Are there alternatives to donors traveling for donation? A: Possibly. If you feel uncomfortable traveling, we respect your decision. However, it is extremely important that you tell us right away so we can look for alternatives. Donation is time-sensitive, and any delay can have a negative impact on the recipients wellbeing. It may be possible to arrange for donation to occur somewhere within driving distance.

There was an alternative to Boise, it turned out, if I felt uncomfortable. I could donate at the La Jolla hospital a day later than originally planned. My cells would be cryogenically frozen and given to the patient a week or two later, instead of immediately. Heather told me that the patients team preferred me to stick with the original date, that a delayed transplant would be riskier for him, but, for confidentiality reasons, they couldnt tell me how much riskier.

We dont want you to feel pressured, Heather emphasized. You should only agree to travel if you feel comfortable.

Did I feel comfortable? It depended on the circumstances, which I wasnt allowed to know. The window of risks were willing to take expands as the stakes get higher; anyone who showed up to a Black Lives Matter protest this summer or signed up to be a poll worker this fall can attest to that. I wouldnt feel at all comfortable flying for the heck of it, but I would certainly do it to save a life. This fell somewhere on the vast spectrum in between, but I had no idea where.

How do you make a call about your personal risk tolerance when its also a choice about the course of a strangers cancer treatment? If the pandemic had taught us all a valuable lesson about the interconnectedness of our fates, I was now being beaten over the head with it. Stuck without enough facts to make an informed decision, I thought about my dads old hospital room in Baltimore, the airlock separating his ward from the rest of the building because any mundane microbe could kill the patients on the other side. I imagined a somber-looking doctor walking through those doors to give my vulnerable recipient the news.

Im afraid theres been a change of plans, he would say, removing his glasses. It seems your donor is a pussy-ass bitch.

I called Heather back and told her to arrange my donation in Boise.

In most respects, my pre-donation medical screening was extremely, almost ludicrously thorough. I submitted vials and vials of blood to check for a host of diseases and disorders. I peed in a cup to make sure I wasnt pregnant. I had more blood drawn, to make sure I really wasnt pregnant. After the second pregnancy test confirmed the results of the first pregnancy test, I got the following email from Heather:

The result of your repeat pregnancy test on 8/13 was negative, but we are still required to complete our pregnancy assessment with you today. The assessment consists of a single question Is there any chance you could be pregnant? Please respond via email when convenient.

I have not touched another person in five months, I wrote back.

Thank you for completing the pregnancy assessment, Heather replied.

In one respect, my pre-donation medical screening seemed oddly lax. I wasnt tested for coronavirus until the day before my flight, and only then because I panicked.

(Sarah Lazarus)

The PBSC donation process begins in earnest a few days before the stem cells are actually collected, with five rounds of filgrastim injections. Its a drug normally given to cancer patients to bring up low white-blood cell counts after chemo or radiation. In my case, it would send my healthy bone marrow into overdrive, to produce enough cells for the donation. The injections have a few side effects: bone pain, fatigue, headaches, nausea. Essentially, filgrastim makes you feel like you have the flua particularly special feeling in the year of our lord 2020. My side effects were mild and I knew to expect them, and I was managing them fine until an extra one showed up.

The night after receiving my second round of shots, I went for a walk around my neighborhood. It was a hot night, and I was tired and achy from the medication; this was not a fast walk. And yet within a few blocks I noticed that my breathing was quick and shallow, and my heart was pounding as if Id just run a sprint. When I tried to take a deep breath, it felt like there was an elastic band cinched around my chest.

Shortness of breath was not on my list of filgrastim side effects. Neither were the heart palpitations, which continued long after I went home and collapsed on my bed.

I put an empty Gatorade bottle on my stomach and watched it pulse up and down as I considered how fucked I was. I had assumed my fatigue and body aches were side effects; what if those were symptoms, too? I mentally tallied up my appointments from over the past week. I had been to five different medical facilities, been a passenger in three different cars. Of course I had caught it. How stupid to think I wouldnt catch it.

The timing was a nightmare. At some point while I was receiving the filgrastim injections, the patient began a course of high-dose chemo to kill off his own blood-forming stem cells in preparation for the transplant. If I had to back out of donating after that treatment began, the patient would die quickly.

For a few desperate minutes, I thought about keeping these symptoms to myself. I didnt have a fever. As long as I didnt develop one, maybe I could get to Boise and finish the donation leaving no one the wiser. What was the moral math, I wondered, of proceeding with travel plans that might seed multiple new outbreaks (but also might not) and lead to numerous deaths (but maybe none), knowing that if I didnt, one person would certainly die? Had anyone solved that particular trolley problem? My heart palpitations got worse. This was insane. I texted Heather everything and asked if she could arrange for a rapid coronavirus test the next day.

It was nearly 11 p.m. by this point, later in Heathers time zone. She made sure my shortness of breath wasnt an emergency, then said shed see how I was feeling in the morning to assess whether a test was necessary.

I went to bed and thought about what they would tell the patient. Would his doctors be allowed to explain why I couldnt donate? Would he think I had just bailed? Would he and his family hate me? What did it say about my motivations that I was fixated on this? Probably nothing good. I drifted off into a stress dream, and then it was dawn.

My breathing was still labored in the morning, and now, compounding my dread, I had a definite tickle in my throat that verged on a cough. Heather and the medical team decided this did indeed warrant a coronavirus test, and went about setting one up. In the meantime, Heather told me, I should proceed with my third day of filgrastim.

When my home nurse Maria arrived at 8 a.m. to do the honors, I stopped her outside to inform her that I might be a vector of death. She was unimpressed. (Ok, sweetie. Can I come in and wash my hands?) Soon afterwards, Heather called to let me know she had found a doctors office that would send someone to test me at my apartment, and deliver results within 24 hoursjust fast enough that I could still make my flight if I tested negative. Be The Match picked up the tab for this, too, but the receipt came to my email. The cost of a rapid PCR test, antibody test, and home visit came out to a cool $900.

The unaffordable testing nurse arrived an hour later cloaked in full PPE. She coached me on how to swab my own mouth and throat for the diagnostic test, then we made small talk while waiting for the little white antibody tray, which looked for all the world like yet another pregnancy test, to reveal either one or two lines. She had been doing these home visits for two weeks, she told me, and none of her patients had yet tested positive for an infection. For no good reason at all, this made me feel better. The antibody test came up negative. The nurse wished me luck with my other results and headed off to her next appointment, leaving me alone with my wonderful thoughts.

I had nothing to do for the rest of the day but wait. By late afternoon my throat felt better, and my breathing had become less conspicuous. At one point I started to pack a bag, wondered if I was jinxing it, and unpacked the bag. At 10 p.m., less than 12 hours after my throat swab, the results arrived in my inbox. NOT DETECTED. I texted Heather a screenshot and lay down on the floor, awash with relief.

(Sarah Lazarus)

The travel and donation themselves were mercifully uneventful. My parents, who were very pleased that I was donating and terrified that I was flying, had shipped me a steady stream of hand sanitizer, KN95 masks, surgical masks, disinfectant wipes, face shields, safety glasses, and gloves. I wore only some of this to the airport, unless you are my parents, in which case I wore all of it. In any event, I felt protected. My terminal at LAX was deserted, and Heather had booked me a first class seat on Delta, which limits capacity to 50 percent. After barely leaving my immediate neighborhood for half a year, the feeling of takeoff, even for a two-day trip to Boise, was sensational.

The next day I arrived at the hospital at 7:15 a.m. By 8:30 Id had a central line inserted above my collarbone, in a painless 15-minute procedure under local anesthesia. The song We Are Young was playing, and the doctors threading a tube into my neck were chatting quietly about a patient whod given them trouble over the weekend. (Im just saying, if youre cussing people out and trying to beat me up, you probably didnt have too bad of a stroke.) Ive had much less pleasant mornings.

By 9:30 I was in bed and hooked up to the apheresis machine, where I would remain for the next seven hours. At one point my calcium levels dropped too low and I threw up; this was the excitement peak of the day. I spent the rest of the time comfortably reading or watching Netflix, keeping an eye on the stem cells slowly collecting in the bag above my head, and carefully avoiding any RNC coverage that might cause the nausea to recur. At around 4:30 I was loosed from the machine, and after waiting a couple more hours while the lab made sure I had forked over enough cells, the nurse removed my central line and I was officially done.

I was exhausted that evening, but the next day felt well enough to go for a walk along the Boise River, where I took 50 terrible photos of a great blue heron. My shortness of breath, whatever it had been, was gone. The day after that I was just a little more fatigued than usual, and by day three I was back to my 2020-adjusted tiredness baseline.

Coronavirus complications aside, the actual donation process was remarkably easy; shockingly easy, when you consider the scale of what it means for the recipient. It was a time commitment for a few weeksIm lucky to have employers who were happy to give me the necessary leaveand involved some mild discomfort, but as a baby about both pain and scheduling, I would not hesitate to do this again.

I also came away with a clearer sense of how to approach the kind of altruistic acts that standard social-distancing guidelines say we shouldnt engage in. The people and organizations that facilitate charity, particularly sensitive medical charity, have existing support systems that theyve retrofitted to help mitigate the extra risks. Those systems may be imperfect and require some self-advocacy, but when combined with ones own diligence and added layers of protection (and, if one is lucky, a concerned Jewish mother), its possible to get help to the people who need it with risk levels not much higher than we tolerate in normal times. There is a way to be selfless without being self-sacrificing, or worse, becoming an inadvertent menace.

Even so, pandemic experiences like this one wont be universally feasible. One might live with immunosuppressed family members or roommates, or have care-taking responsibilities, or lack the spare emotional bandwidth, or have any number of circumstances more complex than my own. And thats finethere will still be people in need of a lifeline on the other side of this crisis, and that lifeline will be no less appreciated.

I asked my dad, Mitchell Lazarus, what he thought potential donors should know about the recipient experience. He sent me this:

The diagnosis is, literally, a death sentence: you will soon die. Word of a matching donor who has agreed to participate is a reprieve the only possible reprieve. I have felt relief many times in my life, but except possibly for the safe birth of my children, nothing like that. I was in a chemo chair when they came by and told me. I called my wife and said, I have a donor, and I started to cry.

Patients in the transplant ward talk a lot about our donors, despite not knowing who they are. Everybody everybody! tears up when talking about their donors.

True story: I was in the hallway on the transplant floor, talking with the woman in the room next to mine. A nurse walking by stopped and said, Mr. Lazarus, are you having trouble with allergies? (which would require attention). I said no, I was talking about my donor. No other explanation needed. She patted my arm and walked on.

I am a chimera. The rest of me has my own DNA, but my blood cells carry my donors DNA, not mine. Somebody elses blood pumps through my body, keeping me alive, not just through treatment, but every second of every day for the rest of my life. How can you not be grateful to someone who literally gave you the rest of your life?

At some point during the 24 hours after I was unhooked from the machine, a volunteer courier arrived at the hospital in Boise. He or she or they retrieved the bag of my donated cells, flew with it to wherever the recipient is located, and hand-delivered it to his hospital. The patient almost certainly received the transplant before I made it back to Los Angeles. If all goes well, my stem cells will navigate their way into his bone marrow, where theyll settle in, multiply, and start producing healthy blood cells. If all goes well, this perfect stranger will eventually have my blood type, and potentially even my childhood immunitieshe might soon, in other words, have my immune system. If all goes well, may that sucker protect us both.

View original post here:
Coronavirus, Charity, and the Trolley Problem - Crooked

Royal Biologics Announces the Acquisition of FIBRINET – PRNewswire

HACKENSACK, N.J., Sept. 1, 2020 /PRNewswire/ --Royal Biologics, an ortho-biologics company specializing in the research and advancement of autologous and live cellular solutions, today announced the completed acquisition of FIBRINET, from Vertical Spine LLC. The acquisition comes as part of Royal Biologics' strategic initiative to add novel technologies to its growing portfolio of autologous and live cellular solutions to support orthopedic and spinal fusion.

The FIBRINET system utilizes a patient's own autologous blood to create a platelet-rich fibrin matrix/membrane (PRFM). During this process, a patient's autologous platelets are harvested first through centrifugation and then combined with a proprietary solution to solidify into a fibrin clot/membrane. PRFM can be used to help augment spinal fusions and provide surgeons a new and novel biologic option. FIBRINET is the first commercialized system that utilizes a non-thrombin solution to create a reproducible platelet-rich fibrin matrix. The use of its proprietary solution to solidify a fibrin membrane provides the unique advantage of creating a biologic reservoir of growth factors and stem cells that can be held and used at the point of care for spinal fusion.

"We are extremely excited to add FIBRINET to our growing portfolio of autologous and live cellular therapies," says Salvatore Leo, Royal Biologics Chief Executive Officer. "FIBRINET'S technology now allows surgeons to harvest a patient's autologous cells and create a unique platelet-rich fibrin membrane-scaffold to be used at the point of care in most spinal fusion procedures. When added to our current product portfolio of autologous and live cellular therapies, we feel that providing each patient an opportunity to harvest their own unique cells for treatment is a superior option in many surgical settings."

FIBRINET has shown promising results and has been adopted into major orthopedic institutions in the United States. Hospitals such as Hospital for Special Surgery, Mount Sinai, NY Presbyterian and Connecticut's Orthopaedic Institute have all adopted FIBRINET into their spine services portfolio of approved products for use.

In a recent European Spine Journalstudy, at a one-year follow-up, FIBRINET demonstrated over a 92.4% radiographic fusion, and there was a significant improvement recorded in VAS scores for both back and leg pain. Compared to baseline figures, the number of patients using opioid analgesics at 12 months decreased by 38%. While the majority (31/50) of patients that participated in the study were retired, 68% of the employed patients were able to return to work.1

"FIBRINET presents itself as a low-cost option to obtain premium, high-quality viable cells from the patient for each fusion procedure," comments Dr. James Yue, Co-Chief and Orthopedic Spine Surgeon at Midstate Medical Center. "During this pandemic, a time when patients are having difficulty receiving operations in major hospital systems, the transition of procedures to ambulatory surgery centers has become even more desired and essential. FIBRINET's low-cost bundle provides surgeons the ability to offer a live viable cell product, point of care in a streamlined and safe environment for spinal fusion."

As part of a national re-launch plan for FIBRINET, Royal Biologics has just launched a new 3D animated moviethat demonstrates the unique features and benefits of FIBRINET's technology. "We wanted to show surgeons, distributors and our peers a new and creative take on Autologous & Live Cellular therapy," comments Leo. "With the recent pandemic and industry environment, we felt it was necessary to help create a unique viewing experience of the FIBRINET system."

FIBRINET comes after two other recent product launches from Royal Biologics in Q1 of 2020. Magnus, a live viable cellular allograft, and Cryo-Cord, a live cellular umbilical cord, were launched in the first quarter of 2020. Both products focus on providing live cellular therapies without the use of traditional toxic cyro-protectants. Both products are new, novel approaches to preserving live cells in a cryo-protected format.

Royal Biologic's FIBRINET is available for U.S. national distribution. Please contact [emailprotected] for more information.

1"Singlecenter, consecutive series study of the use of a novel plateletrich fibrin matrix (PRFM) and betatricalcium phosphate in posterolateral lumbar fusion," European Spine Journal https://doi.org/10.1007/s00586-018-5832-5, July 16, 2018.

SOURCE Royal Biologics

Home

Read the original:
Royal Biologics Announces the Acquisition of FIBRINET - PRNewswire

Targeted Approach Considered for the Treatment of Accelerated/Blast Phase MPNs – Targeted Oncology

Standard treatment for accelerated or blast phase myeloproliferative neoplasms (MPNs) consists of hypomethylating agents (HMAs) or intensive induction chemotherapy and transplant. However, newer studies have suggested that accelerated or blast phase MPNs, such as acute myeloid leukemia (AML), can be treated with molecularly driven targeted therapies.

Srdan Verstovsek, MD, explained the current treatment paradigm for patients with accelerated or blast phase MPNs as well as emerging therapies in this setting in a presentation during the Texas Virtual MPN Workshop.1

Current Paradigm and Unmet Needs

Verstovsek, professor in the Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, explained that there are 3 phases of MPNs: chronic, accelerated, and blast (or post-MPN AML), which are determined by the percentage of blasts in the peripheral blood or bone marrow. These phases affect each type of MPN: essential thrombocytopenia (ET), polycythemia vera (PV), and myelofibrosis. In the chronic phase there are less than 10% blasts found in the peripheral blood or bone marrow, and in the blast phase theres 20% or more.

Blast-phase MPNs are associated with a very poor prognosis. It unfortunately has not changed very much over many yearswe have a lot to do, Verstovsek said.

Additionally, those with blast-phase MPNs show limited responses to conventional treatments for AML. In an analysis of 91 patients who developed post-MPN AML, patients who were treated with conventional treatments did not show significant survival differences compared with those who were not treated. The median survival among patients who received induction chemotherapy was 3.9 months compared with 2.1 months for those who did not receive any chemotherapy.2

Stem cell transplant, however, does have a more significant impact on survival following induction chemotherapy. Only patients that achieve complete response [CR] and go for transplant do well, Verstovsek said.

One analysis showed that the rate of overall survival (OS) among patients who did not achieve a CR from induction chemotherapy prior to transplant was 22% compared with 69% among patients who did have a CR (P = .008).3 He said that overall, the chance of achieving a CR with induction chemotherapy is approximately 35% to 40%.4

An alternative to induction chemotherapy is azacitidine, which has shown comparable survival rates to chemotherapy in post-MPN AML. In a study of 73 patients with post-MPN AML, no statistically significant difference was observed in either event-free survival or OS between those treated with chemotherapy or azacitidine. The event-free survival was 4.2 months with induction chemotherapy and 5.8 months with azacitidine (P = .4443) and the median OS was 8.3 and 7.9 months, respectively (P = .9842). Response rates were also similar at 58.8% with chemotherapy and 54.6% with azacitidine.5

The patients that transform from chronic phase MPN to blastic phase MPN actually pass through accelerated phase MPN. That is rather a rule. Its extraordinarily rare that overnight the patient comes from chronic phase to blastic phase, usually you see blasts coming up, Verstovsek said. That is useful because we dont want to wait for patients to transform. If we can follow patients closely, we would be intervening with hypomethylating agents in the accelerated phase.

Research suggests that patients benefit more from HMAs in the accelerated phase than in the blast phase. A retrospective study of patients with high-risk myelofibrosis in the accelerated or blast phase who were treated with decitabine showed that the OS among patients in the blast phase was 6.9 months, but those in the accelerated phase had a median OS of 9.7 months. Among those who responded to decitabine, the median OS was 10.5 months for those in the blast phase and 11.8 months for those in the accelerated phase.6

As ruxolitinib (Jakafi) is standard of care in treating patients with myelofibrosis, the JAK inhibitor has been investigated in clinical trials in combination with HMAs for the treatment of patients with accelerated and blast phase MPNs. When we talk about transformation to accelerated/blastic phase, we are usually talking about [patients with] myelofibrosis transforming, they are in bad physical shape, they have a very big spleen, very big liver, so there is utility perhaps in giving them ruxolitinib, Verstovsek said.

In a phase 1/2 study of ruxolitinib and decitabine in 29 patients with blast phase MPN, treatment with up to 50 mg of ruxolitinib twice daily and 20 mg/m2 of intravenous decitabine for 5 days on a 4 to 6 week schedule led to a response rate of 45%, which included a CR rate of 7%. The median OS for patients who responded to treatment was 9.4 months compared with 6.2 months in those who did not respond.7

We already know that ruxolitinib is not active in preventing progression. On its own its not active in accelerated or blast phasethats already well known, Verstovsek said.

The National Comprehensive Cancer Network (NCCN) guidelines for MPNs now include that ruxolitinib or fedratinib (Inrebic) can be given close to the start of conditioning treatment for the improvement of splenomegaly or disease-related symptoms.8

Overall, Verstovsek suggested starting with HMAs for 2 to 3 cycles because it canbedelivered in the outpatient setting and is not as toxic as chemotherapy, leading to better quality of life for the patient.

Moving Toward a Molecularly Targeted Approach

New medications are being developed for de novo acute myeloid leukemia, so why not use some of them in the setting of post-MPN AML or even in accelerated phase MPN? Verstovsek suggested.

Mutational analyses have shown a significant difference in the mutation frequency found between de novo AML and accelerated or blast phase MPNs. One mutation that is found more often in accelerated or blast phase MPN is IDH1/2, and agents are already available to target these alterations.

Small studies have already shown promise for this approach of treating patients with IDH1/2-mutant accelerated or blast phase MPNs with an IDH1/2 inhibitor. In a small study of 12 patients with IDH1/2-mutant post-MPN AML treated with IDH1/2 inhibitorbased regimens, 3 of 7 patients treated in the frontline setting had a CR and a median duration of response of 17.5+ months was reported. Two patients treated in the frontline and 3 in the relapsed/refractory setting also had stable disease.1

Targeted agentsis the way of the futureidentifying patients based on genetic profile and targeting those mutations for which we have medications, Verstovsek said.

A study has also considered treatment with venetoclax (Venclexta)based combination regimens. The study included 29 patients treated in the frontline or relapsed/refractory setting. Six of the 14 patients treated in the frontline setting achieved a CR or complete response with incomplete hematologic recovery from treatment with the venetoclax regimen and showed a median duration of response of 6 months. However, there was a high degree of infections and mortality in the first 60 days of treatment.1

Additionally, when comparing the venetoclax regimen to other treatment regimens, no survival benefit was found with the use of venetoclax.

Verstovsek summarized that those with targetable mutations, such as IDH1/2 or FLT3 mutations, should receive these targeted treatments, and those with no targetable mutation should receive HMA-based therapy or intensive chemotherapy, and all patients are recommended to undergo allogeneic stem cell transplant if they achieve a complete response and are eligible for transplant.

References:

1. Verstovsek S. Therapy Strategies for Accelerated and Blastic Phase MPN. Presented at: Texas Virtual MPN Workshop; August 27-28, 2020; Virtual.

2. Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105(3):973-977. doi:10.1182/blood-2004-07-2864

3. Alchalby H, Zabelina T, Stubig T, et al; Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Bio Blood Marrow Trasplant. 2014;20(2):279-281. doi:10.1016/j.bbmt.2013.10.027

4. Mascarenhas J. A concise update on risk factors, therapy, and outcome of leukemic transformation of myeloproliferative neoplasms. Clin Lymph Myel Leuk. 2016;16(suppl):S124-S129. doi:10.1016/j.clml.2016.02.016

5. Venton G, Courtier F, Charbonnier A, et al. Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms. Am J Hematol. 2018;93(3):330-338. doi:10.1002/ajh.24973

6. Badar T, Kantarjian HM, Ravandi F, et al. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase. Leuk Res. 2015;39(9):950-956. doi:10.1016/j.leukres.2015.06.001

7. Bose P, Verstovsek S, Cortes JE, et al. A phase 1/2 study of ruxolitinib and decitabine in patients with post-myeloproliferative neoplasm acute myeloid leukemia. Leukemia. 2020;34(9):2489-2492. doi:10.1038/s41375-020-0778-0

8. NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 1.2020. Accessed August 28, 2020. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf

See original here:
Targeted Approach Considered for the Treatment of Accelerated/Blast Phase MPNs - Targeted Oncology

Novel Targets Outside of JAK Inhibition Inching into Myelofibrosis Treatment Landscape – Targeted Oncology

Experts in myeloproliferative neoplasms find janus kinase (JAK) inhibitors to be particularly important to the armamentarium for the treatment of myelofibrosis (MF). With only 2 FDA-approved agents, fedratinib (Inrebic) and ruxolitinib (Jakafi), and the inevitability that not all patients will derive benefit, and some will develop resistance, the option of moving beyond JAK inhibition is widely discussed.

During a presentation at the 1st annual Texas Virtual MPN Workshop, Naveen Pemmaraju, MD, associate professor, Department of Leukemia, University of Texas MD Anderson Cancer Center discussed the novel therapies beyond JAK inhibitors that are making their way into the treatment landscape of MF.1

Currently, novel agents are showing promise in phase 3 clinical trials, include pacritinib (SB1518) in the phase 3 PACIFICA study (NCT03165734), momelitinib (formerly GS-0387) is being evaluated in the phase III MOMENTUM study (NCT04173494), and fedratinib, although approved in the frontline setting, is now being evaluated as second-line treatment.

Modern JAK Inhibition Combinations

Ruxolitinib remains the standard-of-care treatment for patients with MF, even with the emergence of novel therapies, Pemmaraju noted. To improve upon outcomes in the patient population, ruxolitinib is now being rechallenged in patients or combined with other drugs. One study for which data were published in a 2018 issue of Blood, explored the addition of ruxolitinib to the chemotherapy agent azacitidineazacitidine (Vidaza).

The phase 2 study of ruxolitinib plus azacitidineazacitidine included 44 patients with MF whose median age was 66 years (range, 48-87 years). At baseline, 36 patients (82%) had intermediate-2 (int-2)/high IPSS score, 29 patients (66%) had splenomegaly, and 24 patients (55%) were positive for a JAK V61F mutation.

Thirty-nine patients were evaluable for response. The median follow-up time was 20.4 months (range, 0.5-3.7). The results showed objective response in 33 patients (72%) which included 2 partial responses and clinical improvement in 31 patients. The median time to response was 1.8 months (range, 0.7-19 months). In addition, the combination of ruxolitinib and azacitidine led to spleen response in 21 (61%) of the 34 patients who had splenomegaly > 5cm. In 3 other patients whose splenomegaly was 5 to 10 cm at baseline, there was a 50% reduction in spleen size following treatment with the ruxolitinib combination.

Another phase 2 clinical trial evaluated treatment with ruxolitinib plus navitoclax in patients with JAK2-resistant MF (NCT03373877). The combination demonstrated clinical activity in these patients, according to findings presented at the 2019 American Society of Hematology Annual Meeting. In 30% of the study population, there was a spleen volume response of greater than 35%. In addition, there was a 65% reduction in symptoms and 35% of patients had a reduction in total symptom score (TTS) of more than 50%.

Pemmeraju also noted an ongoing phase 1b study of ruxolitinib plus PU-H71 in patients with MF and polycythemia vera (PV, NCT03373877). In addition, the add-on strategy is being explored with lenalidomide (Revlimid), thalidomide (Thalomid), pracinostat, CPI-0610, sotatercept (ACE-011) plus luspatercept (Reblozyl), as well as in combination with a PI3k (phosphoinositide 3-kinase) inhibitors and interferon inhibitors.

Possible Modern JAK Inhibition Strategies

Targeting JAK is no longer the only strategy available for MF in 2020, Pemmaraju explained. Research has shown that there are possibilities for targeting apoptosis and cell death pathways, telomerase, hematopoietic stem cell, and microenvironments, the TP53 pathway, and targeting fibrosis, cytokines, epigenetics, and other pathways.

In relation to targeting apoptosis and cell death pathways, the phase 2 study of single-agent LCL-161 (NCT02098161) investigated 50 patients with primarily relapsed/refractory MF. A phase 2 open-label study of navitoclax alone or in combination with ruxolitinib (NCT03222609) is also testing out this strategy. The telomerase inhibitor, imtelestat, was also studied in this patient population in phase 2 study (NCT02426086).

There are 2 ongoing trials (NCT02268253 and NCT03373877) investigating the targeting of hematopoietic stem cell/microenvironment. One study is also assessing the targeting of the TP53 pathway in patients with MPNs as well as post-MPN acute myeloid leukemia (AML). Other trials that Pemmaraju mentioned that are investigating fibrosis, cytokines, epigenetics, and other pathways as targets include the phase 2 study of pentraxin (PRM-151, NCT01981850), as well as the studies of sotatercept/luspatercept, alisertib (MLN8237), CPI-0610, and PSD1 inhibition.

Promise of MF Treatment Beyond JAK Inhibition

Multiple treatment strategies have shown positive results in clinical trials as treatment of patients with high-risk MF, Pemmaraju shared. First, he shared results of the phase 1/2 trial of a novel CD123-directed therapy, which was designed to address the CD123 expression seen in many myeloid malignancies, including MF.

Tagraxofusp

In the phase 1/2 trial of tagraxofusp, 32 patients were included in the safety analysis for the study, and more than 10% experienced treatment-related adverse events (TRAEs). The most common TRAEs of any grade were hypoalbuminemia (25%), headache (16%), alanine aminotransferase increased (16%), anemia (14%), and thrombocytopenia (14%).

At baseline, 18 patients had splenomegaly 5 cm, and of those patients, 10 (56%) had spleen reductions. Additionally, 2 patients had spleen reductions of greater than 50%. Among patients with thrombocytopenia and platelet counts <100 109/L 8 patients (62%) had spleen size reduction as did 4 patients (57%) with thrombocytopenia and platelets < 50 109/L. Subjects with monocytosis whose monocytes were 1 109/L. In addition, 46% of the 24 patients evaluated to efficacy had a reduction in their TTS.

In terms of survival, the median OS observed was 30.5 months at a median follow-up time of 27 months (range, 0.6-50.3 months).

According to Pemmaraju, the subsets of patients with MF who had thrombocytopenia, monocytosis, or accelerated phase disease are areas of ongoing research.

LCL161

LCL161 was the second agent Pemmaraju noted as a potential new treatment for high-risk MF. The agent was assessed in a phase 2 clinical trial which was launched to address the unfavorable survival outcomes in the patient population. In addition, no JAK inhibitors are approved by the FDA as treatment of this particular group of patients with MF.

In 50 patients, the objective response rate was 30%, leading clinical improvements in 11 patients with symptoms, 6 patients with anemia, and 1 pain with splenomegaly. Additionally, 1 patient achieved a cytogenetic remission.

The survival data show that 34 patients (68%) were still alive at data cutoff. The median duration of response was 1.4 months (95% CI, 0.9-9.1 months). There was also a number of longer-term responses (n = 8) who experienced a response for 1 year or more. At data cutoff, long-term responses were ongoing in 4 patients. The median OS was not reached in the study.

Based on these data, Pemmaraju stated that LCL161 may be a viable option for older patients, those who failed prior JAK inhibitors, and those with thrombocytopenia that limit entry into clinical trials.

Luspatercept

Data presented previously at the 2018 American Society of Hematology (ASH) Annual Meeting showed that a phase 2 study of luspatercept was positive for its primary and secondary end points of transfusion independence.1,2

In a cohort of 22 patients who were not receiving ruxolitinib and had no red blood cell transfusion for 12 consecutive weeks, 14% achieved the primary end point and 18% achieved the secondary end point. In a separate cohort of 21 patients who were not receiving ruxolitinib and had been transfusion dependent for 12 consecutive weeks, 10% were positive for the primary end point and 38% were positive for the secondary end point. In the cohort of 14 patients who were receiving a stable dose of ruxolitinib and were transfusion independent of 12 consecutive weeks, 21% reached the primary end point and 64% achieved the secondary end point. Finally, in the cohort of 19 patients who received a stable dose of ruxolitinib but were transfusion-dependent for 12 consecutive weeks, 32% achieved the primary end point and 53% achieved the secondary end point.

CPI-0610

Preliminary results for CPI-0610 were also presented at ASH in 2019. In the phase 2 study CPI-0610 was combined with ruxolitinib in treatment-nave patients with MF.1,3

Compared with baseline measurements, an 80% SVR35 (spleen volume reduction) response was observed at week 12, demonstrating a median change from baseline of -49.7% (range, -80.8% to -17.0%). Responses were also observed in high-risk patients including 86.7% of those with DIPSS Dynamic Prognostic Scoring System (DIPPS) int-2, 80% with hemoglobin < 10g/dL, and 53.3% of patients with high molecular risk (HMR) positivity.

In terms of total symptom score (TSS) improvement, it was observed that 71.4% of patients had a TSS response at week 12, and this included the treatment nave population with an improvement of 45.9%.

Navitoclax

In another phase 2 study, navitoclax with or without ruxolitinib demonstrated promise in patients with primary of secondary MF. The drug specifically helped patients overcome resistance to ruxolitinib which resulted in splenomegaly improvement.1,4

Out of 30 patients assessed, SVR35 at week 24 was 43% in 13 patients and 30% in 9 patients. In addition, resolutions of palpable splenomegaly were observed in 53% of patients. Twenty-five percent of patients also demonstrated reductions in bone marrow fibrosis per local assessment.

Imetelstat

A randomized phase 2 study of imetelstat as treatment of patients with intermediate-2 or high-risk MF who were relapsed or refractory to JAK inhibition induced responses and a survival benefit.1,5

In a pool of 107 patients, 6 patients (10%) had 35% SVR at week 24 and 23 patients (37%) had a 10% SVR at week 24.

Imetelstat also achieved a median OS of 19.9 months (95% CI, 17.1-not evaluable [NE]) when administered at a dose of 4.7 mg.kg and the median OS climbed to 29.9 months (95% CI, 22.8-NE) when Imetelstat was administered at 9.4 mg/kg.

Pemmaraju noted that a review of the existing and ongoing research on targeting beyond JAK inhibition in patients with MF was recently published in Current Hematologic Malignancy Reports. The paper states that because of the different mechanisms of action other the novel therapies in MPNs, they can improve outcomes in the field when use alone or in combination with ruxolitinib.6

References:

1. Pemmaraju N, et al. Novel Targeted Therapies Beyond JAK Inhibitors. Presented at: Texas Virtual MPN Workshop; August 2728, 2020; Virtual.

2. Gerds AT, Vannucchi AM, Passamonti F, et al. A Phase 2 Study of Luspatercept in Patients with Myelofibrosis-Associated Anemia. Blood. 2019;34(supplement_1):557. doi: 10.1182/blood-2019-122546

3. Mascarenhas J, Kremyanskaya M, Hoffman R, et al. MANIFEST, a Phase 2 Study of CPI-0610, a bromodomain and extraterminal domain inhibitor (beti), as monotherapy or "add-on" to ruxolitinib, in patients with refractory or intolerant advanced myelofibrosis. Blood. 2019; 134 (Supplement_1): 670. doi: /10.1182/blood-2019-127119

4. Harrison CN, Garcia JS, Mesa RS, et al. Results from a phase 2 study of navitoclax in combination with ruxolitinib in patients with primary or secondary myelofibrosis. Blood. 2019;134(supplement_1):671. doi: 10.1182/blood-2019-130158

5. Mascarenhas J, Komrokji RS, Cavo M, et al. Imetelstat is effective treatment for patients with intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to janus kinase inhibitor therapy: results of a phase 2 randomized study of two dose levels. Blood. 2018;132(supplement_1):685. doi: 10.1182/blood-2018-99-115163

6. Economides, M.P., Verstovsek, S. & Pemmaraju, N. Novel therapies in myeloproliferative neoplasms (mpn): beyond jak inhibitors.Curr Hematol Malig Rep.2019;14,460468. doi: 10.1007/s11899-019-00538-4

The rest is here:
Novel Targets Outside of JAK Inhibition Inching into Myelofibrosis Treatment Landscape - Targeted Oncology

MaaT Pharma to Announce Clinical Data with its Lead Microbiota Biotherapeutic in Intestinal Acute GvHD at Virtual 46th Annual Meeting of the European…

LYON, France--(BUSINESS WIRE)--MaaT Pharma announced today that clinical data from 11 patients treated with the companys lead microbiome restoration biotherapeutic, MaaT013, will be presented in an e-poster at the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) to be held virtually from August 29 September 1, 2020. MaaT013 is an enema formulation of a microbiota biotherapeutic characterized by a consistent richness of microbial species derived from pooled healthy donors to treat patients with intestinal acute Graft-versus-Host-Disease (aGvHD) following allogeneic Hematopoietic Stem-Cell Transplantation (allo-HSCT). MaaT Pharma provided MaaT013 to hospitals as part of its compassionate use program for patients who had previously received and failed up to five previous systemic treatments for GvHD. MaaT Pharma will share the results through a press release on Monday, August 31, 2020.

As the event is held virtually this year, the presentation will take the form of an e-poster with commentary. The abstract of the presentation is available using the following link, https://www.professionalabstracts.com/ebmt2020/iPlanner/#/presentation/5171.

e-Poster presentation details:

Title: Successful and Safe Treatment of Intestinal Graft-Versus-Host Disease (GvHD) with Pooled-Donor Full Ecosystem Microbiota Biotherapeutics Presenter: Dr. Florent Malard, Associate Professor of Hematology at the Saint-Antoine Hospital and Sorbonne University Session Name: e-Experimental Transplantation Date/Time: Saturday, August 29, 2020 / 12:30 PM 06:30 PM CET Location: e-Poster area

After the e-presentation, MaaT Pharma will provide the poster on the company website under News.

In addition to the compassionate use program, MaaT Pharma is currently investigating MaaT013 in a multi-center, single-arm, open-label, Phase II clinical trial called HERACLES to evaluate the safety and efficacy of MaaT013 in gastrointestinal-predominant, steroid-refactory, acute GvHD (GI SR-aGvHD) patients (NCT03359980). The acute form of GvHD is a serious, often fatal syndrome typically involving the gut, skin and liver. MaaT Pharma has established the most complete approach to restoring patient-microbiome symbiosis in the gut to improve efficacy of cancer treatments and survival outcomes in life-threatening diseases. MaaT013 has been granted Orphan Drug Designation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

About MaaT Pharma

MaaT Pharma, a clinical stage company, has established the most complete approach to restoring patient-microbiome symbiosis to improve survival outcomes in life-threatening diseases. Committed to treating cancer and graft-versus-host disease (GvHD), a serious complication of allogeneic stem cell transplantation, MaaT Pharma has already achieved proof of concept in acute myeloid leukemia patients and a Phase 2 clinical trial in acute GvHD is ongoing. Supporting the further expansion of our pipeline into larger indications, we have built a powerful discovery and analysis platform, GutPrint, to evaluate drug candidates, determine novel disease targets and identify biomarkers for microbiome-related conditions. Our therapeutics are produced through a standardized cGMP manufacturing and quality control process to safely deliver the full diversity of the microbiome. MaaT Pharma benefits from the commitment of world-leading scientists and established relationships with regulators to spearhead microbiome treatment integration into clinical practice.

More here:
MaaT Pharma to Announce Clinical Data with its Lead Microbiota Biotherapeutic in Intestinal Acute GvHD at Virtual 46th Annual Meeting of the European...

The Inside Story Of Biotechs Barnum And His Covid Cures – Forbes

Billionaire Patrick Soon-Shiongs radical cancer treatments made him one of the wealthiest physicians on Earth. Now the master of medical marketing believes his drug therapies could defeat the crisis of our time.

Patrick Soon-Shiong knows when he realized that the Covid-19 pandemic was going to pose a serious threat. It was February 24, and the part-owner of the L.A. Lakers was at the Staples Center in Los Angeles for Kobe Bryants memorial service.

With sudden, untimely demise on his mind, he found himself thinking about the emerging pandemic. Even though Covid-19 hadnt yet caused a single reported death in the United States, Soon-Shiong was worried. He recalls turning around to California Governor Gavin Newsom and telling him, Were in trouble.

His sense of urgency hasnt gone away. If I thought I was scared on February 24, he says, Im more scared now. The reason, he explains, is that what weve learned is that this virus acts like cancer. He says he has left his house only once since Bryants memorial, and that was to film a video about the coronavirus for the Los Angeles Times, which he bought, along with The San Diego Union-Tribune, for $600 million two years ago. I shut myself off from the world, he says.

And so one of the planets richest medical doctors, who made a $6.7 billion fortune developing breakthrough treatments for cancer and diabetes, seeks to battle the pandemic. The weapons in his arsenal: the cancer treatments he has spent the past decade and a half developing. Hes aiming them at all aspects of the coronavirus, from a vaccine to treatments for mild cases to therapies targeted toward patients on ventilators.

Its an enormously ambitious plan from a man who has often been accused of being a hype artist. In an earlier incarnation, Soon-Shiong was a respected surgeon and professor at UCLA Medical School, but throughout his wildly successful entrepreneurial second act, he has been derided as more showman than scientist, thought guilty of overinflating results and taking undue credit. A few years ago, for example, he boasted about using a breast cancer drug to treat a patient with cervical cancerbut other groups were already seeing similar successes. As we wrote in a 2014 cover story, While hes undeniably brilliant, Soon-Shiong is equally undeniably a blowhard.

But he also has fierce defenders of his approach to both cancer and Covid-19, including former Senate majority leader Harry Reid, who says the 68-year-old South Africaborn doctor saved my life in 2019 by providing an experimental treatment for his stage IV pancreatic cancer. Researchers say his methods are conceptually grounded in good science, though the verdict on his work will ultimately depend on results.

Weve been tracking and seeing an increase in the number of these cell-based therapies, whether theyre being repurposed from oncology or even other disease conditions, says Esther Krofah, a senior analyst who monitors the clinical development pipeline for Covid-19 vaccines and therapies for the Milken Institute. A number of themfrom large pharmaceuticals and small biotech startups alikeare going into clinical trials. For many of the latter, the pandemic offers a chance to show what their treatments can do in a shorter time frame than cancer drugs typically require. For small companies, its a worthwhile exercise to see if its successful, Krofah says.

It may seem counterintuitive, but advances in knowledge about the immune system, and how it might help kill cancer, have real applications for infectious diseases. To me, a cancer cell and a virus-infected cell are one and the same, says Dr. Wayne Marasco, an immunologist at Harvard Medical School who is currently researching coronavirus treatments. The immune system, he adds, seems to think the same way. Which is a good reason to take Patrick Soon-Shiong seriously.

Born in Port Elizabeth, South Africa, in 1952, Soon-Shiong is no stranger to the intersection of the immune system, cancer and infectious disease. Having graduated from medical school at age 22, he focused his early surgical career on transplants and cancer, both of which involve a complex pas de deux with the immune system. Crossing disciplines, he says, led him to look at the body as a system, not a single little cell. We are a biological system.

Such interdisciplinary thinking may be what led to the medicine that made his fortune: Abraxane, which took an existing chemotherapy drug, Toxol, but wrapped it in protein that made it easier to deliver to tumors. Its now used to treat advanced cases of lung, breast and pancreatic cancer. In 1998, to develop Abraxane, he purchased Fujisawa, a small, publicly traded business that sold injectable generic drugs. Soon-Shiong used its revenues to quickly move Abraxane through the regulatory process. The FDA approved it in 2005, and in 2007 Soon-Shiong split the business in two, spinning out a company called Abraxis that focused on the new cancer drug. He sold the generics business to Fresenius in 2008 for $4.6 billion. Two years later, he sold Abraxis to Celgene for $4.5 billion. Celgene, itself acquired by Bristol Myers Squibb in November 2019, reports that sales of Abraxane exceed $1 billion annually.

Soon-Shiong at Nants Los Angeles headquarters in 2017. I see [the complexity of the immune system] like an orchestra, but the challenge is to separate the violin from the cello from the drums.

The complex business deals that went into Abraxane, however, left Soon-Shiong with a reputation as more of a wheeler-dealer than a scientist, as we noted in 2014. Back then, he posted to Twitter under the grandiose handle @solvehealthcare, but today he simply uses his name. Over several recent Zoom conversations, he evinces very little showmanship. Hes visibly tired, exhibiting the most excitement when he starts talking about intricate scientific details. Im burning out a little bit, he candidly admits, adding that hes been getting only about four to six hours of sleep a night since February. Over that time, he says, his companies have concentrated on both continuing to develop his cancer treatments and working to employ them against Covid-19. He peppers his statements about his companys approach to both cancer and the coronavirus with qualifiers about the results of pending studies, carefully avoiding seeming to overpromise.

Soon-Shiong has multiple interrelated businesses organized in a complex corporate structure that would have puzzled the Byzantines. But his Covid-19 efforts come from the two companies he founded that work on developing cancer immunotherapies: NantKwest, a publicly traded outfit based in San Diego, and the privately held ImmunityBio.

Cancer immunotherapy is based on the notion that the bodys own immune system can be stimulated to treat the disease. That idea dates to the 19th century, when scientists first observed tumors getting smaller after patients developed a type of skin infection. This led to some of the first experiments in which the immune system of cancer patients was stimulated. Early efforts proved difficult to reproduce, though, and the field got sidetracked by advances in chemotherapy and radiation. Interest spiked anew in 1959, when a paper showed that the tuberculosis vaccine inhibited tumor growth in mice. After decades of intense research, the first cancer immunotherapy was approved by the FDA in 1986.

Other types of immunotherapies followed, ranging from purified antibodies that attack cancer to drugs that turn off the chemical switches that let tumor cells hide from the immune system. The latest advances involve CAR-T cell therapy, which first gained FDA approval in 2017 and involves genetically engineering immune cells from patients so that they attack certain targets found in tumor cells.

Founded in 2002, Soon-Shiongs company NantKwest focuses on developing so-called natural killer (NK) cells, which the immune system uses to destroy virally infected cells as well as early-stage tumors. The company has been working to develop a line of off-the-shelf NK cells called NK-92, which can be used to treat certain cancers as well as viral infections.

The company, which has yet to post any meaningful revenue, has lost nearly $400 million since it went public at $25 a share (a $2.6 billion market cap) in 2015. The stock has recently traded in the $10.50 range, off a bottom of around $1 a share in 2019. One reason for the stocks surge, says Jefferies analyst Biren Amin, is the companys reported research into the coronavirus pandemic. The second, he suggests, involves former Senator Reids cancer treatment, which made use of the companys products.

Harry Reid, who represented Nevada in the upper chamber from 1987 to 2017, was diagnosed with pancreatic cancer in 2018 and started chemotherapy that July. He didnt respond well. I was so sick they stopped the chemo that October, he says. In July 2019, a scan of his liver showed that the cancer had spread. That meant his only option was more chemotherapy. Around the same time, Joe Kiani, founder and CEO of Irvine, Californiabased health IT company Masimo, met with Soon-Shiong to discuss acquiring $50 million worth of assets from NantHealth. During that initial meeting, the conversation turned to Soon-Shiongs other projects, which later led Kiani to phone the former senator. I called up Harry and I said, Look, I just left this meeting. This person could have the cure. I dont know if he does, but what do you have to lose? Reach out to him and see what happens, Kiani recalls.

Two weeks later, Soon-Shiong and a doctor from NantKwest named Leonard Sender were working with Reid, using treatments from NantKwest as well as Soon-Shiongs ImmunityBio. Those treatments arent yet officially approved but were permitted under the FDAs compassionate-use rules. Reid was treated with a combination of Abraxane, NantKwests natural killer cells and a drug from ImmunityBio called N-803, which stimulates the immune system to produce its own killer cells. Soon-Shiong compares it to the triangle offense often employed by the Lakers. In November 2019, Reid reported that his scans were completely clear, showing no signs of cancer. I admire Dr. Soon-Shiong a great deal, he tells Forbes. Both for what hes done for me personally and what hes done for the health-care delivery system in this country.

Former Senator Harry Reid, pictured the same month he began treatment for pancreatic cancer with Soon-Shiong, says being in remission a few months later was kind of like a miracle.

Reids is an extraordinary story, as pancreatic cancer remains one of the deadliest forms of the disease. Within five years of diagnosis, it kills some 90% of patients, accounting for 7% of cancer deaths globally. Jeopardy! host Alex Trebek, who also suffers from pancreatic cancer, has received the same treatment, as have two other unidentified patients. But Sender cautions against declaring a cure. Its too early to tell, because this is a very nasty form of cancer, he says. Thats why NantKwest is now focused on a new randomized clinical trial, he adds, which is looking to recruit nearly 300 pancreatic cancer patients with advanced forms of the disease. Those who sign up will be given a course of treatment similar to the one Reid received.

As part of these treatments development, Soon-Shiong has spent the past five years working with the National Cancer Institute. His companies have a collaborative agreement with the NCI involving several types of treatments, including NK-92 and N-803, as well as some vaccines against two kinds of tumors. Dr. Jeffrey Schlom, chief of the NCIs laboratory of tumor immunology and biology, recalls being in sync with Soon-Shiong from the start. At our first official creative meeting, we presented our slides of our approach, he says. And then he got up and presented his approach, and they were almost identical. Schloms group has since published in peer-reviewed journals 15 papers regarding Soon-Shiongs treatments, in both preclinical and clinical settings.

Since February, NantKwest and ImmunityBio have redirected some of their attention toward the coronavirus pandemic, using a number of weapons in their collective arsenal. The first is a vaccine, based on the system Soon-Shiongs companies are developing for cancer, that has already shown positive results against Covid-19 in a study involving mice. Its also being studied in monkeys as a part of the federal governments Operation Warp Speed. As for human trials, Soon-Shiong says hes ready to go. My timeline is now dependent on the FDA letting me get out of the gate, he says. Im in the gate, the bell hasnt rung and the racehorse is frothing at the mouth.

This vaccine is delivered to the body in a common cold virus called an adenovirus that has been stripped of all the parts that can cause harm to people or trigger the body to attack it. That modified virus contains two individual segments of the Covid-19 coronavirus: the spike protein, the surface protein on the virus that triggers an antibody response; and a nucleocapsid protein, which is found in the center of the virus. Most of the more than 100 vaccines that are currently in clinical development for Covid-19 focus on the spike protein to generate an immune response. Soon-Shiong thinks that wont be enough, though, which is why hes including the nucleocapsid protein. My concern is that the spike protein mutates, he says. Its mutated even through this pandemic.

Beyond potential mutations, another concern about merely eliciting an antibody response is that from the data seen so far, antibodies to the Covid-19 virus just dont last very long. Levels of antibodies in the blood are really low after a few months, says Marasco, whos not associated with Soon-Shiongs companies or their vaccine research. I think its uncertain how long immunity will remain after successful vaccination. Using the nucleocapsid protein couldnt hurt, he adds, and it could elicit not only antibodies but virus-killing T-cells as well.

The second weapon is the application of NantKwests NK-92 and ImmunityBios N-803 against Covid-19. NK-92 is being adapted to directly attack virus-infected cells, while the N-803 stimulates the patients immune system to produce its own natural killer cells against the virus. The treatments might be used either together or separately depending on the particular patient, Soon-Shiong says. Human trials of these treatments have already begun. Its a fantastic thing that theyre applying them to infectious disease to see how patients fare, says Gigi Gronvall, an immunologist at Johns Hopkins Center for Health Security, who is not involved in the research. The concept is great, she adds, cautiously, but we need to see what the data says.

The third weapon NantKwest and ImmunityBio are developing to combat Covid-19 involves the use of mesenchymal stem cells, which are derived from bone marrow. This type of stem cell has been investigated over the past decade for diseaseslike Covid-19that can cause the bodys immune system to go into overdrive and attack itself. This treatment would be for the most severely sick Covid-19 patients, who are experiencing a cytokine storm, in which the immune system overreacts. Small-scale studies have suggested this might be an effective treatment, and several companies, including Melbourne, Australiabased Mesoblast, are already in late-stage clinical trials for severe Covid-19 patients. Soon-Shiongs companies are working with hospitals to recruit patients for human trials.

If Soon-Shiongs approaches to Covid-19 bear fruit in clinical trials, the next step may prove harder still: getting those treatments to needy patients. This is especially so for the vaccine, because at the moment neither NantKwest nor ImmunityBio has the resources to scale up manufacturing. Im now behind the eight ball, Soon-Shiong admits, because theres no way I could have 100 million doses unless somebody supports me. Maybe I have a million doses or 2 million doses. He expresses some frustration at the government: Billions of dollars are going to companies that have billions [in] revenues. Hes not wrong about that. In July, pharma giant Pfizer (2019 revenue: $51.8 billion) received a $2 billion federal contract to manufacture a vaccine its developing.

Things are brighter for the companies N-803 and NK-92 products, as NantKwest has the ability to manufacture at scale, but these treatments will face certain competition from others being developed by a number of pharmaceutical companies. I think there are a lot of alternatives that are more practical than a cellular therapy for an acute infectious disease, Marasco says, though he does acknowledge that the companies plans to use stem cells against the more severe cases of disease have potential.

Despite his frustrations, Soon-Shiong appears determined to do his part in the health-care industrys war against the coronavirus. This is the crisis of our time, he says. Its almost existential. The United States could have 20 to 30 million infected. You could have a million deathsthis is not a joke.

Link:
The Inside Story Of Biotechs Barnum And His Covid Cures - Forbes

Mustang Bio: Slow, Steady Progress Towards Multiple Gene And CAR-T Therapy Goals – Seeking Alpha

Investment Thesis

Mustang Bio share price performance since joining Nasdaq. Source: TradingView

Mustang Bio (MBIO) is looking like an increasingly attractive investment opportunity within the gene and CAR-T therapy space.

Mustang is a wholly owned subsidiary of Fortress Bio, and operates the same strategy as its parent company, identifying promising therapeutic candidates at research centers and medical establishments and in-licensing them or acquiring an ownership interest, in exchange for funding research and development, and milestone and royalty payments in the event the candidates are eventually out-licensed or brought to market.

Mustang has an experienced management team and is focused on developing next-generation therapies for patients with cancer and rare genetic diseases, working alongside the St. Jude Children's Research Hospital ("St. Jude") on a lentiviral vector treatment of X-linked severe combined immunodeficiency ("XSCID"), and with City of Hope National Medical Center ("COH"), Fred Hutchinson Cancer Research Center ("Fred Hutch") and Nationwide Children's Hospital ("Nationwide") on a number of CAR-T therapies targeting hematologic malignancies and solid tumors.

Mustang leases a 27,000 square foot cell processing and translational research facility situated on the University of Massachusetts ("U-MASS") Medical School campus and is progressing 8 candidates in total, all of which have completed or entered phase 1 clinical trials. As such, the company has numerous milestones upcoming in the remainder of this year and throughout the next 24-month period.

Mustang Bio near-term goals. Source: corporate presentation.

The company's MB107 and MB207 XSCID treatments are both due to enter pivotal trials in 2020, with a real chance of becoming the new standard of care for this ultra-rare disease in which affected patients rarely live beyond infancy without treatment, whilst its CAR-T programs - which target far larger markets, will present data readouts related to ongoing trials of patients with Non-Hodgkin's Lymphoma ("NHL"), Prostate Cancer, and Acute Myeloid Lymphoma ("AML") in early 2021.

Meanwhile, in Q320 Mustang plans to submit an IND filing for CD20-targeting candidate MB106, for NHL and Chronic Lymphocytic Leukemia ("CLL"), and present first data from its NHL trial in Q420, and treat the first patient in a multi-center trial of CD-123-targeting MB-102 in blastic plasmacytoid dendritic cell neoplasm ("BPDCN"), acute myeloid lymphoma ("AML"), and high-risk myelodysplastic syndrome (hrMDS) in Q320.

In Q420, Mustang will also leverage City of Hope's IND for MB108, a C134 oncolytic virus, for a combination trial with its IL13R2-specific candidate MB101, targeting glioblastoma multiform ("GBM").

CAR-T therapy is a highly competitive space, with a host of big pharma firms and early stage biotechs chasing approvals for a range of different modalities, hence there is no guarantee that Mustang can win a race to market, or even if it does, that it can convert an approval into meaningful sales volumes. The only 2 CAR-T treatments to have been approved to date, Gilead's Yescarta and Novartis' Kymriah, made <$750m of sales between them in FY19.

In truth, however, Mustang/Fortress would be most likely look to out-license an approved treatment, and from an investor's perspective, progression to late-stage CAR-T trials would provide price catalysts that could double or triple the current share price, as well as bringing the prospect of a money-spinning acquisition into play, such as Gilead's (GILD) $11.9bn deal to acquire Kite Therapeutics in August 2017, or Celgene's (CELG) $9bn purchase of Juno Therapeutics in 2018.

In the near term, Mustang's XSCID opportunity is its best prospect for approval, and although this market may be small, with just 20 newly-diagnosed patients per annum, it will constitute a significant win for the company and its partners, and vindicate Mustang's approach.

Mustang's shares gained 124% back in April 2019 when the company released positive trial data relating to 8 patients who successfully cleared previous infections and had begun to grow normally, after receiving Mustang/St Jude's therapy.

Share price performance of Fortress Bio, Mustang Bio, other Fortress affiliates (OTC:CKPT), (ATXI) and TG Therapeutics (TGTX). Source: TradingView.

As we can see above, Fortress Bio, its listed affiliates Avenue Therapeutics (ATXI), Checkpoint Therapeutics (OTC:CKPT) and another company, TG Therapeutics (TGTX), led by Michael D. Weiss - Fortress' Executive Vice Chairman and Board member - have enjoyed mixed fortunes over the past 5 years.

Whilst Avenue shares are up 94% on the promise of its schedule IV (low potential for abuse) Tramadol pain treatment, and TG Therapeutics up 85% as its flagship MS and cancer drugs ublituximab and umbrasilib inch towards approval, Fortress itself, Mustang and solid tumor treatment developer Checkpoint Therapeutics are down 24%, 73% and 71% respectively.

Whilst it would be misleading to compare companies targeting very different indications, it may be instructive to note that Fortress' overall approach involves regularly tapping investors for funding via share offerings - Mustang has an at-the-market offering agreement in place to sell up to $75m of its securities - and its development cycles - as you might expect for early stage drug-developers - can be very slow - a frustrating combination for investors.

On balance, however, I rate Mustang's CAR-T pipeline as promising based on its diversity and impressive early data and in comparison with the progress being made by rival companies, and the front-running MB-107 and MB-207 opportunity provides an obvious route to market within the next 12-18 months, providing a strong near-term catalyst to support the progress of the more lucrative opportunities.

Ultimately, I believe that Fortress, its portfolio of companies and management team are beginning to demonstrate that they are capable of rewarding patient investors, and given all of the above, I feel bullish about Mustang's upside potential.

In the rest of this article I will take a deeper dive look at the company and its candidates, and attempt to provide justification for my thesis that, as Fortress' portfolio company's development cycles progress, they tend to reward their long-term stock holders, thanks to a disciplined and painstaking approach that is well suited to the biotech industry.

Mustang Bio was incorporated in Delaware in March 2015, and is headquartered in Worcester, Massachusetts. The company began trading on the Nasdaq in August, 2017, debuting at a price of $11. At the time of writing, Mustang's shares trade at $3.58, representing a 207% decline.

Mustang is led by Manuel Litchman, MD, who joined the company in 2017 from biotech Arvinas (ARVN), where he helped advance the company's pipeline of protein-degradation therapeutics, working in collaboration with Merck (MRK) and Genentech. Prior to that, Litchman spent 18 years at Novartis (NOVN) focused on its oncology pipeline.

Nearly all of Mustang's senior management team have joined since 2019, and combine a wealth of biotech and big-pharma experience. Chief Technology Officer Knut Niss joined Mustang from Biogen (BIIB), where he worked on hematopoietic stem cell and lentiviral gene therapy programs, and Head of Regulatory Affairs Lynn Bayless also joined from Biogen, developing phase 3 drug candidate programs, and has also overseen development programs at Voyager Therapeutics (VYGR) and Shire.

Mustang's various licensing agreements with St. Jude, COH, Fred Hutch and Nationwide are complex but are generally based upon an up-front payment, ongoing milestone payments, and in most cases, royalty sharing agreements should commercialization be achieved.

Fortress Biotech owns 29.9% of Mustang (according to Fintel), and City of Hope has a 5.1% holding, however Fortress controls a voting majority of Mustang's stock, meaning it is able to control or significantly influence all matters requiring approval by stockholders, and also receives an annual grant of 2.5% of any equity or debt financing carried out by Mustang, adding to overall shareholder dilution.

Mustang is certainly well-funded however, so investors need not be too concerned. The company reported cash of $85.4m in Q220 (according to its 10Q submission), total assets of $96.8m, and total liabilities of just $25.8m. In the first 6 months of 2020, Mustang's net losses were $26.4m, which suggests that the company may not require further funding until 2022, although costs are likely to ramp up as the company embarks on more of its own clinical trials, as opposed to leveraging the work of its early-stage development partners.

Mustang candidates, partners and development schedule. Source: company presentation.

Earlier this month, Mustang's thinly traded - and therefore volatile - stock leapt 16% on the news that the FDA had awarded Rare Pediatric Disease Designation to its lead gene therapy candidate, MB107, for treatment of XSCID, and granted the company a priority review voucher that can be used to accelerate a future application, or sold to a third party.

XSCID is a genetic disease that causes disturbed development of functional T cells and B cells making patients - usually newborn males - extremely vulnerable to all types of infectious disease, hence it's being termed as "Bubble Boy" disease. Patients with XSCID who remain untreated usually do not survive beyond their first year of life.

The current standard of care treatment for XSCID is allogeneic hematopoietic stem cell transplant ("HSCT"), which works most effectively when there is a matched sibling donor. This only occurs 15% of the time on average, however (according to a Mustang corporate presentation), and when unavailable, mortality rates can fall to ~50% if there are severe infections present at the time HSCT is initiated, whilst even a successful treatment can cause life-long complications.

Mustang licensed its gene therapy treatment MB-107 in August 2018 from St Jude Children's Research Hospital for a $1m up front payment plus an annual maintenance fee of $0.1 million, up to $13.5 million of milestone payments, and royalty payments in the mid-single digits on all net sales of the product if it secures FDA approval.

Lentiviruses - which are responsible for AIDS and other diseases - work by inserting DNA into a host cell's genome, but can be adapted to act as a vector and insert beneficial genes into cells. Using lentiviral transduction of hematopoietic stem cells, MB107 is able to insert a normal copy of the mutated c gene present in XSCID into patients, which leads to the encoding of a normal c receptor chain, allowing patients' immune systems to stage a recovery.

The results of the first early stage trials have been impressive. 24 patients were treated, either at St Jude's, or as part of a single-center trial at the National Institutes of Health ("NIH"). Eight of these patients have been followed for a period of 3-7 years, with 7 experiencing increased host T cells chimerism from 0-2% to 28-93%, and normalized IgM levels, with 4 able to discontinue immunoglobulin replacement therapy. Additionally, patients were able to recover from illnesses including norovirus and malabsorption, and growth retardation.

MB 107 clinical outcomes show promise. Source: company presentation.

Mustang has since developed a refined enhanced transduction ("ET") procedure using 2 transduction enhancers: LentiBoost 1:100 and dimethyl prostaglandin 2 (dmPGE2; 1mM), which has shown a substantial clinical improvement over baseline, and significant biomarker improvement.

The company expects to begin a pivotal trial of newly diagnosed XSCID patients before the end of the year, subject to FDA approval, and will file an Investigational New Drug ("IND") application for a pivotal trial of a second product, designated MB-207 in previously transplanted patients, also before the end of the year. This trial will enroll 20 patients and compare results to matched historical control patients who have undergone a second HSCT.

XSCID is diagnosed in ~20 new patients per annum and Mustang has proposed a reimbursement model where payers could pay for success, following the example of Orchard Therapeutics' Strimvelis treatment, approved for a similar condition, SCID, in 2016. Mustang has hinted at a price-point of $2m for MB-107/MB-207 in the past, which could be paid out over a period of 10 years+ as the patient recovers from the disease.

It is also possible that Mustang could uncover a "reservoir" of ~400 US and ~650 overseas patients whose HSCT treatments have failed, and enhanced screening for the disease may also increase the overall market for XSCID treatments.

Development hasn't all been straightforward for Mustang and there is still a way to go to prove that its enhanced therapy can be safe and effective over a prolonged period, but at this stage, the signs point to an eventual approval in 2022.

MB-107 was acquired in part to provide a faster route to market than Mustang's CAR-T portfolio, and as well as providing a much needed treatment upgrade for a devastating disease, it ought to pique investor's excitement sufficiently to give Mustang further fundraising opportunities, at a higher price, without damaging its reputation.

Mustang has signed an exclusive, worldwide licensing agreement with Fred Hutch to develop MB-106, a CAR-T therapy targeting CD20, a commercially validated target for B-cell lymphomas, including NHL, which has shown an in vivo anti-tumor effect which compares favorably with CD-19-targeting therapies.

Together, Mustang and Fred Hutch have developed an optimized cell-processing technique for MB-106, which had originally shown limited efficacy in the first 3 cohorts of a phase 1/2 trial. Under an amended IND, using the lowest dose possible (due to the expected increase in potency of the CAR-T cells), and a chemotherapy regime of cyclophosphamide + fludarabine, the first patient dosed - suffering from follicular lymphoma - achieved a complete response, with no cytokine release syndrome or neurologic toxicity reported.

Fred Hutch intends to enroll up to 30 patients on this trial, whilst Mustang plans to submit its own IND in the first quarter of 2021, and initiate a clinical trial in patients with NHL, and CLL. These are large markets: ~70,000 people are diagnosed with NHL in the US annually, and the disease causes 19,000 mortalities per annum.

Around 45% of NHL cases are untreatable with current therapies, with the exception, in some cases, of allogeneic hematopoietic stem cell transplant ("allo-SCT"). allo-SCT carries a significant risk of morbidity or mortality however, hence, Mustang will hope to position MB-106 as an alternative treatment option, as well as a second or third-line treatment for relapsed or refractory aggressive B-cell lymphomas.

MB-105 is being developed for the treatment of prostate and pancreatic cancer, targeting the prostate stem cell antigen ("PSCA") that tends to be overexpressed on solid tumors. The first patient enrolled in a phase 1 trial being conducted by COH experienced a significant reduction in PSA at day 28. A third cohort of the trial is currently underway, and further data is expected in Q121. Meanwhile, Mustang is awaiting a funding decision over an initiation of its own trial, in pancreatic cancer, and plans to submit an IND in Q421.

Prostate (164,000 new cases per annum in US), and pancreatic (55,000) cancers are highly prevalent and there are few advanced stage CAR-T therapies in development with Autolus (my July note here) perhaps presenting the biggest challenge to Mustang. Additionally, PSCA is also expressed in bladder, placenta, colon, kidney, and stomach cancers, making it an attractive target.

MB-101 targets the membrane-bound protein IL13Ra2 and was licensed from COH in 2017, alongside MB-102, in a deal that may provide up to $14.5 million to COH based on 8 development milestones, plus royalty payments in the mid-single-digit percentages of net sales should the products become commercialized. Mustang made payments to COH totaling $0.3m in the first 6 months of 2020.

IL13Ra2 is considered an attractive target for brain cancers and is over-expressed on the surface of >50% of glioblastomas - the most common form of brain and central nervous system cancers.

A phase 1 dose-escalation study involving 60 patients has now completed, and COH/Mustang have subsequently identified 3 potential areas of interest. A pilot trial is planned for Q320, using CAR-T therapy alone in leptomeningeal disease, which affects cerebrospinal fluid (CSF), whilst 2 combination trials are also planned. The first is in combination with C-134 oncolytic virus (Mustang candidate MB-108) for treatment of glioblastoma multiform ("GBM"), and the second in combination with checkpoint inhibitors such as PD-L1, with a trial slated to begin in Q220.

GBM is diagnosed in ~11,800 patients in the US annually, and Mustang is the only company currently working on a CAR-T therapy to address this illness.

MB-102 targets CD-123, and addresses BPDCN, AML and high-risk myelodysplastic syndrome ("MDS"). These diseases affect around 500-1,000, 20,000 and 15,000 patients in the US respectively, and median survival rates are generally less than 1 year.

Mustang's IND for MB-102 was approved in Q319, and the company expects to dose its first patient in BPDCN in Q320, using optimized CAR-T cells, and with a reduced dose of 50% of that used by COH in its trials, which have shown promising results, with 2 complete responses in AML, and 1 in BPDCN.

MB-102 has secured an orphan drug designation for treatment of BPDCN, and has presented a manageable toxicity profile to date, with no grade 4 or above incidents reported. CD-123 is a competitive space for CAR-T therapies, with one approved treatment for BPDCN, Stemline's Elzonris, which made sales of $43.2m in FY19.

Finally, Mustang has paid COH $0.8m and will contribute R&D costs of up to $2.4m for MB-104, a CS1 (NK cell receptor regulating immune functions) targeting treatment for multiple myeloma, whilst MB-103 is undergoing phase 1 trials at COH for metastatic breast cancer, using the human epidermal growth factor receptor 2 ("HER2"), with Mustang contributing $0.3m towards R&D as part of a wider $14.9m deal, plus mid-single digit royalty payments.

As mentioned in my intro, Mustang and its parent Fortress are more likely to reward the patient investor, although, owing to the regular news flow from trials and progress with regulators, there are generally short-term price catalysts for more active traders to consider.

Regular fund-raisings and dilution can be frustrating, but Mustang's strong management team has the experience and know-how to be able to convert promising early stage candidates into late-stage ones, in my view.

Mustang has no fewer than 8 "shots at goal", plenty of funding, and an influential Board that is practicing a similar development strategy - acting as a middleman between research and medical institutions and regulatory authorities and big pharma - at a host of other companies, some of whose share prices have demonstrated very strong upside as its candidates have blossomed.

CAR-T candidates are particularly difficult to develop and haven't set the market on fire in recent years, but there is no doubt that the major pharma companies will still be prepared to pay a huge premium to acquire promising treatments - the cost of a successful treatment being acquired by a rival is almost as great as the cost of purchasing a treatment that ultimately fails to make it to commercialization.

Since I have some faith in Mustang's/Fortress approach and based on the progress of the candidates' described above, and the very low current price of Mustang shares compared to their Nasdaq trading debut, I recommend that risk-on biotech investors carefully consider opening a position.

Analysts are setting a consensus price target of $10. I would be surprised if this was achieved within the next 12 months, but I would also be surprised if the share price has not doubled in that period on slow and steady progression towards later stage trials for a handful of its candidates and the increasing likelihood of an approval for an XSCID treatment.

Gain access to all of the market research and financial analytics used in the preparation of this article plus exclusive content and pharma, healthcare and biotech investment recommendations and research / analytics by subscribing to my channel,Haggerston BioHealth.

Disclosure: I/we have no positions in any stocks mentioned, but may initiate a long position in MBIO over the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Read more here:
Mustang Bio: Slow, Steady Progress Towards Multiple Gene And CAR-T Therapy Goals - Seeking Alpha

Study sheds light on why retinal ganglion cells are vulnerable to glaucoma – Jill Lopez

Millions of sufferers of glaucoma might someday benefit from a study released today inSTEM CELLSin which a "disease in a dish" stem cell model was used to examine the mechanism in glaucoma that causes retinal ganglion cells (RGCs) to degenerate, resulting in loss of vision. The knowledge the study provides could result in new therapeutic approaches for this leading cause of blindness worldwide.

RGCs are a group of nerve cells located in the retina that send images to the brain and enable you to see. Glaucoma attacks these cells and, once they die, they are not replaced. However, why and how glaucoma causes the RGCs to degenerate is something of a mystery.

Stem cell modeling of the disease may shed light on this. Over the past decade, significant progress has been made using induced pluripotent stem cell (iPSC) technology to mimic glaucoma. This includes the generation of human RGCs from iPSCs, which led to the development of a disease model for primary open angle glaucoma (POAG) -- the most common form of glaucoma -- as well as an optic nerve model that demonstrated the supportive role of mTOR signaling in the regeneration of hRGC axons following chemical axotomy.

"However, both these models can be improved by characterizing the developmental trajectories of control and disease-specific RGCs," said Iqbal Ahmad, Ph.D., of the University of Nebraska Medical Center. He and his UNMC colleagues, Pooja Teotia, Ph.D., and Meng Niu, Ph.D., conducted the study reported on inSTEM CELLS.

Dr. Ahmad continued, "This characterization includes the generation of hRGCs through normal developmental time and stages containing a complement of different subtypes, against which the developmental aspects of RGC abnormality in a disease model can be evaluated. Information about different RGC subtypes is not only important from a functional viewpoint, but also for understanding the underlying mechanism of glaucomatous degeneration, given the emerging evidence that the susceptibility and resistance of RGCs are subtype dependent."

In developing their model, the researchers used a single cell transcriptome analysis of human RGCs generated from normal (controls) and SIX6 risk allele iPS cells. (Previous studies have identified a significant association between POAG and SIX6, a gene that plays a role in ocular development.)

They observed that the developmental trajectories, beginning from neural stem cells to RGCs, were similar between SIX6 risk allele and control RGCs.

"However," Dr. Ahmad said, "we observed that the differentiation of SIX6 risk allele RGCs was stalled at the retinal progenitor cell stage, keeping them immature and deficient in subtype composition, compared to the controls. This was likely due to dysregulated mTOR and Notch signaling pathways that play an important role in RGC development. Furthermore," he added, "SIX6 risk allele RGCs, as compared to controls, expressed fewer genes corresponding to RGC subtypes that are preferentially resistant to degeneration.

"The immature phenotype of SIX6 risk allele RGCs with under-represented degeneration-resistant subtypes, may make them vulnerable to glaucomatous degeneration," he concluded.

"This study demonstrates the power of single cell sequencing methods for providing new insights into POAG pathology at the cellular and molecular level, which is necessary for formulation of new therapeutic approaches", said Dr. Jan Nolta, Editor-in-Chief ofSTEM CELLS. "This is truly remarkable and something that we could have not imagined was feasible thirteen years ago until the concept of patient specific iPSC disease modelling was invented. This is an excellent step forward and a phenomenon we will see becoming a daily reality in disease phenotyping and drug discovery."

View original post here:
Study sheds light on why retinal ganglion cells are vulnerable to glaucoma - Jill Lopez

Coronavirus Thursday update: UMN announces new stem cell treatment – TwinCities.com-Pioneer Press

Doctors at the University of Minnesota are the first in the U.S. to treat a critical COVID-19 patient suffering from lung failure using stem cells.

A Food and Drug Administration-approved study will examine a new treatment using mesenchymal stem cells to intervene when a COVID-19 patients immune system becomes overactive and can lead to organ damage and often lung failure. This cytokine storm has been one of the more perplexing and fatal complications of a coronavirus infection.

The inflammation seen in patients with severe COVID-19 can be devastating, Dr. David Ingbar, a critical care and pulmonary physician at the M Health Fairview University of Minnesota Medical Center, said in a statement. The cytokine storm can rapidly lead to shock, massive fluid buildup in the tissues, and direct severe tissue injury, most often in the lungs.

A team of researchers at the university developed the treatment and are leading a study of its effectiveness with other clinicians around the country. Mesenchymal stem cells have been used successfully with other inflammatory conditions including in COVID-19 patients in Italy and China.

Researchers hope the stem cells will slow the cytokine storm and protect lung tissue from damage.

In order to determine the real benefit of MSCs in these very ill patients, patients will be randomized to receive three doses of MSC 48 hours apart or a placebo solution, said John E. Wagner, MD, cancer researcher and director of the Institute for Cell, Gene and Immunotherapy at the University of Minnesota.

The cells being used in this treatment were produced at the universitys molecular and cellular therapeutics center which develops materials such as cells, tissues, antibodies and proteins to be used in clinical trials.

The new treatment being studied at the University of Minnesota was announced as state health officials recorded seven new COVID-19 fatalities on Thursday. Those whose deaths were reported ranged in age from their 40s to their 90s.

The states death toll has reached 1,685 people with another 46 fatalities suspected to have been caused by COVID-19, but the patient did not have a positive coronavirus test.

With 697 new cases announced Thursday, Minnesota now has 62,993 laboratory-confirmed infections with cases in all 87 counties. Most patients are in the Twin Cities metro, but rural counties with meat processing facilities have the most cases per capita.

Health officials reported the results of 15,271 tests Thursday, a marked increase from earlier this week when the number of test results was lower than average.

Minnesota has screened 1.2 million samples from 963,096 patients since local testing started in March. The test positivity rate stands at about 5.3 percent.

Originally posted here:
Coronavirus Thursday update: UMN announces new stem cell treatment - TwinCities.com-Pioneer Press