Category Archives: Stem Cell Treatment

Vor Biopharma and MaxCyte Announce Clinical and Commercial License Agreement for Engineered Hematopoietic Stem Cells (eHSCs) to Treat Cancer -…

CAMBRIDGE, Mass. & GAITHERSBURG, Md.--(BUSINESS WIRE)--Vor Biopharma, an oncology company pioneering engineered hematopoietic stem cells (eHSCs) for the treatment of cancer, and MaxCyte, Inc., a global cell-based therapies and life sciences company, today announced a clinical and commercial license agreement under which Vor will use MaxCytes Flow Electroporation technology to produce eHSCs and initiate Investigational New Drug (IND)-enabling studies to accelerate its progress towards the clinic.

Under the terms of the agreement, Vor obtains non-exclusive clinical and commercial use rights to MaxCytes Flow Electroporation technology and ExPERT platform to develop up to five engineered cell therapies, including VOR33, Vors lead eHSC candidate, which is in development for acute myeloid leukemia (AML). In return, MaxCyte will receive undisclosed development and approval milestones and sales-based payments in addition to other licensing fees.

Vor will use MaxCytes cell engineering platform to deliver its gene editing machinery into hematopoietic stem cells to remove biologically redundant cell surface proteins that are also expressed on blood cancer cells. Once the eHSCs are transplanted into a cancer patient, these cells are effectively hidden from complementary targeted therapies that target the relevant protein, while diseased cells are left vulnerable to attack. Vors approach thereby could unleash the potential of targeted therapies by broadening the therapeutic window and improving the utility of complementary targeted therapies.

MaxCyte is a leader in GMP electroporation technology, and we are thrilled that this agreement provides us with long-term access to a platform technology applicable to a pipeline of eHSC programs used to treat AML and other blood cancers, said Sadik Kassim, Ph.D., Chief Technology Officer of Vor. As we build on promising in vivo data from our lead candidate VOR33, we can now expand our manufacturing capabilities to support later-stage studies, regulatory filings and commercialization of VOR33.

MaxCytes ExPERT instrument family represents the next generation of leading, clinically validated, electroporation technology for complex and scalable cellular engineering. By delivering high transfection efficiency with enhanced functionality, the ExPERT platform delivers the high-end performance essential to enable the next wave of biological and cellular therapeutics.

We look forward to expanding our relationship with Vor Biopharma as the company pioneers a potential future standard of care in hematopoietic stem cell transplants for cancer patients in need, said Doug Doerfler, President & CEO of MaxCyte. This agreement represents another key business milestone for MaxCyte, emphasizing the value of our technology platform applied to next-generation engineered cell therapies that may make a true difference in patient outcomes.

About VOR33Vors lead product candidate, VOR33, consists of engineered hematopoietic stem cells (eHSCs) that lack the protein CD33. Once these cells are transplanted into a cancer patient, CD33 becomes a far more cancer-specific target, potentially avoiding toxicity to the normal blood and bone marrow associated with CD33-targeted therapies. In so doing, Vor aims to improve the therapeutic window and effectiveness of CD33-targeted therapies, thereby potentially broadening the clinical benefit to patients suffering from AML.

About Vor BiopharmaVor Biopharma aims to transform the lives of cancer patients by pioneering engineered hematopoietic stem cell (eHSC) therapies. By removing biologically redundant proteins from eHSCs, these cells become inherently invulnerable to complementary targeted therapies while tumor cells are left susceptible, thereby unleashing the potential of targeted therapies to benefit cancer patients in need.

Vors platform could be used to potentially change the treatment paradigm of both hematopoietic stem cell transplants and targeted therapies, such as antibody drug conjugates, bispecific antibodies and CAR-T cell treatments. A proof-of-concept study for Vors lead program has been published in Proceedings of the National Academy of Sciences.

Vor is based in Cambridge, Mass. and has a broad intellectual property base, including in-licenses from Columbia University, where foundational work was conducted by inventor and Vor Scientific Board Chair Siddhartha Mukherjee, MD, DPhil. Vor was founded by Dr. Mukherjee and PureTech Health and is supported by leading investors including 5AM Ventures and RA Capital Management, Johnson & Johnson Innovation JJDC, Inc. (JJDC), Novartis Institutes for BioMedical Research and Osage University Partners.

About MaxCyteMaxCyte is a clinical-stage global cell-based therapies and life sciences company applying its proprietary cell engineering platform to deliver the advances of cell-based medicine to patients with high unmet medical needs. MaxCyte is developing novel CARMA therapies for its own pipeline, with its first drug candidate in a Phase I clinical trial. CARMA is MaxCytes mRNA-based proprietary therapeutic platform for autologous cell therapy for the treatment of solid cancers. In addition, through its life sciences business, MaxCyte leverages its Flow Electroporation Technology to enable its biopharmaceutical partners to advance the development of innovative medicines, particularly in cell therapy. MaxCyte has placed its flow electroporation instruments worldwide, including with all of the top ten global biopharmaceutical companies. The Company now has more than 80 partnered programme licenses in cell therapy with more than 45 licensed for clinical use. With its robust delivery technology platform, MaxCyte helps its partners to unlock the full potential of their products. For more information, visit http://www.maxcyte.com.

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Vor Biopharma and MaxCyte Announce Clinical and Commercial License Agreement for Engineered Hematopoietic Stem Cells (eHSCs) to Treat Cancer -...

CALQUENCE Approved in the US for Adult Patients With Chronic Lymphocytic Leukemia – Business Wire

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca today announced that the US Food and Drug Administration (FDA) has approved CALQUENCE (acalabrutinib) for adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The US approval was granted under the FDAs Real-Time Oncology Review and newly established Project Orbis programs.

The approval is based on positive results from the interim analyses of two Phase III clinical trials, ELEVATE-TN in patients with previously untreated CLL and ASCEND in patients with relapsed or refractory CLL. Together, the trials showed that CALQUENCE in combination with obinutuzumab or as a monotherapy significantly reduced the relative risk of disease progression or death versus the comparator arms in both 1st-line and relapsed or refractory CLL. Across both trials, the safety and tolerability of CALQUENCE were consistent with its established profile.

Dave Fredrickson, Executive Vice President, Oncology Business Unit said: With over 20,000 new cases anticipated this year in the US alone, todays approval of CALQUENCE provides new hope for patients with one of the most common types of adult leukemia, offering outstanding efficacy and a favorable tolerability profile. The chronic lymphocytic leukemia patient population is known to face multiple comorbidities, and tolerability is a critical factor in their treatment.

Dr. Jeff Sharman, Director of Research at Willamette Valley Cancer Institute, Medical Director of Hematology Research for The US Oncology Network, and a lead author of the ELEVATE-TN trial, said: Tolerability remains an issue in the current treatment landscape of chronic lymphocytic leukemia, which may require ongoing therapy for many years. In the ELEVATE-TN and ASCEND trials comparing CALQUENCE to commonly used treatment regimens, CALQUENCE demonstrated a clinically meaningful improvement in progression-free survival in patients across multiple settings, while maintaining its favorable tolerability and safety profile.

The results of the interim analysis of the ELEVATE-TN trial will be presented at the upcoming American Society of Hematology congress.

The trial showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for patients treated with either CALQUENCE in combination with obinutuzumab or CALQUENCE monotherapy versus chlorambucil chemotherapy plus obinutuzumab, a current standard-of-care combination used in the control arm.

In the CALQUENCE combination arm, risk of disease progression or death was reduced by 90% (HR 0.10; 95% CI, 0.06-0.17, p<0.0001) and in the monotherapy arm it was reduced by 80% (HR 0.20; 95% CI, 0.13-0.30, p<0.0001).

The median time to disease progression for patients treated with CALQUENCE in combination with obinutuzumab or as a monotherapy has not yet been reached vs. 22.6 months (95% CI, 20-28) for chlorambucil plus obinutuzumab.

ELEVATE-TN safety overview (most common ARs*, 15%):

Adverse reaction

CALQUENCE plus obinutuzumab(n=178)

CALQUENCE monotherapy(n=179)

Chlorambucil plus obinutuzumab(n=169)

Any

Grade 3

Any

Grade 3

Any

Grade 3

Infection

69%

22%

65%

14%

46%

13%

Neutropenia

53%

37%

23%

13%

78%

50%

Anemia

52%

12%

53%

10%

54%

14%

Thrombocytopenia

51%

12%

32%

3.4%

61%

16%

Headache

40%

1.1%

39%

1.1%

12%

0

Diarrhea

39%

4.5%

35%

0.6%

21%

1.8%

Musculoskeletal pain

37%

2.2%

32%

1.1%

16%

2.4%

Fatigue

34%

2.2%

23%

1.1%

24%

1.2%

Bruising

31%

0

21%

0

5%

0

Rash

26%

2.2%

25%

0.6%

9%

0.6%

Arthralgia

22%

1.1%

16%

0.6%

4.7%

1.2%

Dizziness

20%

0

12%

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CALQUENCE Approved in the US for Adult Patients With Chronic Lymphocytic Leukemia - Business Wire

Brooks Koepka Withdraws From Presidents Cup Team – The New York Times

Brooks Koepkas knee injury is bad enough that on Wednesday he withdrew from the Presidents Cup three weeks before it begins.

Koepka, the No. 1 player in the world who led all qualifiers for the American team, said the injury he suffered Oct. 18 at the CJ Cup in South Korea has not healed well enough for him to complete Dec. 12-15 at Royal Melbourne in Australia.

United States captain Tiger Woods replaced him with Rickie Fowler.

I consider it to be a high honor to be part of the 2019 team and I regret not being able to compete, Koepka said in a statement. Since my injury in Korea, I have been in constant contact with Tiger and assured him that I was making every effort to be 100% in time for the Presidents Cup in Australia. However, I need more time to heal.

Koepka was coming off a season in which he won three times, including a second straight P.G.A. Championship, and had runner-up finishes in the Masters and United States Open. When he started the new season in October at Las Vegas, he revealed that he had had stem cell treatment on his left patella the day after the Tour Championship because his knee had been bothering him over the last five months of the season.

Two weeks later, he was walking down a slope off the tee at the par-5 third hole in the second round of the CJ Cup when his right foot hit a wet piece of concrete and he landed hard on his left knee for support. He shot 75 and withdrew after the round, returning to Florida for treatment.

Koepka has not spoken publicly about the nature of the injury. He was in touch with Woods, who had been contemplating alternative plans.

Brooks and I talked, and hes disappointed that he wont be able to compete, Woods said. I told him to get well soon, and that were sorry he wont be with us in Australia. He would clearly be an asset both on the course and in the team room.

Woods, who used one of his four captains picks on himself after winning in Japan, originally left Fowler off the team and said it was the hardest phone call he made when telling prospective players he was not taking them.

Fowler has played on the last two Presidents Cup teams, going 2-0-1 in team play with Justin Thomas at Liberty National in 2017.

When I heard Brooks wasnt going to be ready to play, I was bummed for him and the team, Fowler said. Then I got a call from both Brooks and Tiger. I was humbled and excited to be given the chance. To be picked by Tiger to compete with him and the rest of the team is very special. It is impossible to replace the worlds No. 1, but I can assure my teammates and American golf fans that I will be prepared and ready to do my part to bring home the Presidents Cup.

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Brooks Koepka Withdraws From Presidents Cup Team - The New York Times

Rational discovery of antimetastatic agents targeting the intrinsically disordered region of MBD2 – Science Advances

Abstract

Although intrinsically disordered protein regions (IDPRs) are commonly engaged in promiscuous protein-protein interactions (PPIs), using them as drug targets is challenging due to their extreme structural flexibility. We report a rational discovery of inhibitors targeting an IDPR of MBD2 that undergoes disorder-to-order transition upon PPI and is critical for the regulation of the Mi-2/NuRD chromatin remodeling complex (CRC). Computational biology was essential for identifying target site, searching for promising leads, and assessing their binding feasibility and off-target probability. Molecular action of selected leads inhibiting the targeted PPI of MBD2 was validated in vitro and in cell, followed by confirming their inhibitory effects on the epithelial-mesenchymal transition of various cancer cells. Identified lead compounds appeared to potently inhibit cancer metastasis in a murine xenograft tumor model. These results constitute a pioneering example of rationally discovered IDPR-targeting agents and suggest Mi-2/NuRD CRC and/or MBD2 as a promising target for treating cancer metastasis.

Although at least 650,000 protein-protein interactions (PPIs) might occur in humans, only one PPI inhibitor has been approved for clinical use to treat cancers (1), suggesting that the field of PPI inhibitors remains largely unexplored. A variety of proteins and their PPIs have emerged as prospective drug targets to treat tumors because of the extreme heterogeneity and plasticity of cancer (2, 3). Ligands with the potential of binding to a specific site of a target protein with known structure can be efficiently identified by virtual screening. However, the structural plasticity of target proteins usually works against yielding an effective drug candidate. For example, selected compound treatment of cells/organisms often fails to elicit the anticipated effects due to in vivo structural alterations of the target protein caused by various posttranslational modifications (PTMs) and/or unanticipated interactions of the compound and/or its target protein with other molecules (4, 5). Furthermore, many critical proteins regulating various biological processes do not have unique structures as a whole or in some functionally important regions (6, 7). Structures of these intrinsically disordered proteins (IDPs) or IDP regions (IDPRs) are extremely dynamic, depending on the environment, and might change during function (4, 8). Many signaling IDPs/IDPRs undergo characteristic disorder-to-order transitions (DOTs) upon interactions with specific binding partners and/or through PTMs (9, 10). Targeting the IDPs/IDPRs capable of DOT is generally considered an attractive but challenging task for developing anti-PPI inhibitors. In this regard, a recently identified small-molecule compound, 10058-F4, serves as a pioneering success of anti-PPI inhibitor that binds to an IDPR of c-Myc undergoing a DOT upon binding to its partner Max (11, 12). 10058-F4 was discovered by a random screening using a yeast two-hybrid system (11), followed by experimental identification of its specific binding site (residues 402 to 412 of c-Myc) as an IDPR. Drug leads like 10058-F4 targeting IDPs/IDPRs cannot be found by conventional computational methods that rely on fixed conformations, such as crystallographic structures of target proteins. No computer-aided drug discovery platform is currently available for the systematic exploration of IDPRs as potential drug-target sites (3).

To fill this gap, we developed a novel platform for the discovery of drug leads based on molecular docking and molecular dynamics (MD) simulations of the DOT-associated IDPRs of target proteins. Figure 1A describes this protocol. First, intrinsic disorder predispositions of drug-target proteins are analyzed, and potential disorder-based binding regions that can undergo DOTs are evaluated. A search of the protein structure database [Protein Data Bank (PDB)] is also performed to identify known PPIs and DOTs. Once the potential drug-target sites (DOT-based PPI regions) are determined, the corresponding structures retrieved from the PDB are used for molecular docking with druggable compounds from the ZINC compound library (13). Together with the docking scores, off-target probabilities assessed by the similarity ensemble approach (SEA) (1416) analysis are also considered for selection of lead compounds from the molecular-docked hit compounds. Last, prospected candidate compounds are suggested via MD simulations that evaluate the mode and efficiency of the compound binding.

(A) Flow chart describing the computational process of ligand discovery. (B) Evaluation of the intrinsic disorder propensity of MBD2 (left) and c-Myc (right); disorder scores 1 and 0 mean fully disordered and fully ordered residues, respectively. Pink bars show positions of the determined DOT sites embedded in residues 360 to 393 for MBD2 and 395 to 430 for c-Myc. (C) Chemical structures of the top 10 compounds showing the most favorable binding to the MBD2 target site in the molecular docking screening of ZINC chemical library. (D) Representative structures of protein-ligand complexes obtained from the molecular docking results (original data file 1 for PDB coordinates): 10058-F4:c-Myc402 (top; control experiment), ABA:MBD2369 (middle), and APC:MBD2369 (bottom).

The feasibility of the proposed approach was validated in this study by targeting an IDPR of MBD2 that undergoes a DOT upon association with its binding partner p66 for the integration of the Mi-2/NuRD chromatin remodeling complex (CRC). The integrated Mi-2/NuRD CRC includes one CHD (either CHD3 or CHD4), one HDAC (HDAC1 or HDAC2), two DOC1, three MTA (MTA1, MTA2, and MTA3), six RbAp46/48, two p66 (p66 or p66), and one MBD (MBD2 or MBD3) molecules (17, 18), where the molecular interaction of MBD2 with p66 critically mediates the proper assembly of CRC (17, 19). This CRC performs an important epigenetic function in normal development and differentiation by suppressing gene expression by binding directly to the DNA methylation sites and to the DNA methyltransferases (20, 21).

CRC also contributes to the development of human diseases, including cancer (22, 23); for example, the epigenetic regulation by Mi-2/NuRD CRC includes multiple tumor suppressor genes (23, 24), and several CRC components, including MBD2, were also observed to be oncogenic and/or closely correlated with the aggressiveness of several cancers (23, 25, 26). In particular, the function of Mi-2/NuRD CRC is known to be associated with the cellular process of epithelial-mesenchymal transition (EMT; the conversion of adhesive epithelial cells into migratory, invasive mesenchymal cells) that drives wound healing and cell migration and invasion (27, 28). In cancer, EMT necessarily mediates the metastasis of cancers and thus also enables carcinoma cells to acquire cancer stem cell (CSC) properties, malignancy-associated traits, and drug resistance (2931). Given that the metastasis is responsible for more than 90% of contemporary cancer deaths and yet no marketed antimetastatic drug is currently available (32), developing these drugs to target the cancer spreading is an essential and urgent task for oncological therapy. In this context, functional inhibition of CRC or modulation of its individual components might serve as a novel strategy for effective anticancer therapy to prevent the progression of cancer to metastatic stage. In particular, it has been observed that down-regulation of MBD2 and/or p66, which triggered derepression of epithelial regulators via epigenetic reprogramming of the Mi-2/NuRD CRC into the MBD2-free or disentangled CRC, resulted in promoted epithelial differentiation and loss of tumor-initiating ability. Therefore, targeting MBD2 specifically at its IDPR would be a promising approach to the development of antimetastatic agents by inhibiting its DOT-based PPI with p66 that is essential for the integration of CRC and thus for its critical function in EMT. In addition, no noticeable adverse effects displayed by MBD2 inhibitors can be expected from the fact that down-regulation of MBD2 expression is essential for normal cell differentiation (33), and yet, MBD2 knockout (MBD2/) mice exhibit normal survival and reproduction (34).

Hence, in this study, the MBD2 IDPR and its DOT-based interaction with p66 for the CRC integration were selected as a highly promising target system to evaluate the efficiency of our platform for rational drug discovery. Using this novel approach, we identified two small-molecule compounds capable of inhibiting the PPI of MBD2 and thereby efficiently suppressing the cancer metastatic potentials. In vivo efficacy of both leads in inhibiting cancer metastasis was also evident in a murine xenograft tumor model. Therefore, our novel method renders IDPRs available for rational discovery of anticancer drugs targeting DOT-based PPIs. In particular, the identified compounds provide a basis for the development of previously unidentified inhibitors capable of controlling metastasis of various carcinomas.

As our study was inspired by the discovery of 10058-F4, which binds to the c-Myc IDPR to inhibit its DOT for interaction with Max (11, 12), we compared the PPI site of MBD2 with that of c-Myc using our computational platform. Sequence analysis (see fig. S1 for sequence and structure information) revealed that disorder profiles of the PPI site of MBD2 (residues 360 to 393 for p66 interaction) (17, 35) closely resembled that of c-Myc (residues 400 to 434 for Max interaction) (36, 37) (Fig. 1B), characterized by a positive slope in its disorder profile. As both MBD2 and c-Myc are folded in complexes with their cognate partners (p66 and Max, respectively) (17, 35, 37), this analysis suggests that the PPI sites of MBD2 and c-Myc could undergo a similar type of DOT upon complex formation.

Subsequently, a nuclear magnetic resonance (NMR) ensemble structure of MBD2360393 in its complex with p66138178 (PDB ID: 2L2L) was retrieved, and the lowest-energy conformation of the ensemble was extracted for molecular docking analysis using the four residues (D366, I369, V376, and L383) of MBD2360393 engaged in the coiled-coil interaction, with p66 (35) as the initial target site in the molecular docking. From the molecular dockingbased virtual screening of 2 106 chemical compounds in the ZINC library, 10 promising compounds (compounds #1 to #10 in Fig. 1C) capable of interaction with MBD2 at the designated target site were selected. As a control, the Y402-targeted molecular docking of 10058-F4 to c-Myc395430 (Fig. 1D; note that the key residue for the c-Myc interaction with 10058-F4 is Y402) (35) was compared with the MBD2360393 docking of the 10 selected hit compounds (table S1). The MBD2369-targeted docking of two compounds {compounds #2 and #3 in Fig. 1D named herein ABA [2-amino-N-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-acetamide] and APC [3-(2-amino-acetylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester], respectively} was found as the most favorable. In ABA:MBD2369 and APC:MBD2369 dockings, these compounds formed three intermolecular hydrogen bonds and had relatively low DOCK scores (35.2 and 33.3 kcal mol1, respectively) of the DOCK binding. These binding features could be compared favorably with those of the 10058-F4:c-Myc402 docking, which showed the DOCK score of 6.77 kcal mol1 and just one intermolecular hydrogen bond (table S1).

Concerning the potential side effects of the selected hit compounds, their off-target probabilities were assessed by the SEA analysis (14, 16), which has served as an eminent bioinformatics resource aiding in target identification for drug development by profiling multiple protein targets of chemical compounds as probes (15). For this analysis, the c-Myc inhibitor 10058-F4 and two anticancer drugs, imatinib (Gleevec) and sorafenib (Nexavar), were also compared as controls, and 2060 human proteins in the database were searched as potential targets. Given that a significant binding is feasible when both the Max Tc value more than 0.5 and E value lower than 1010 are relevant, no suggestible off-target was predicted for 7 of the 10 hit compounds including both ABA and APC, whereas four proteins were found as the probable 10058-F4 targets (Fig. 2A and table S2). Two of the other compounds also showed a small number of putative off-target proteins (six and two proteins for compounds #4 and #10, respectively), whereas 35 and 26 targets were suggested for imatinib and sorafenib, respectively (fig. S2A and table S2). Therefore, we screened nine compounds with low off-target probability for cellular activity dysregulating MBD2. In particular, the cell migration assay was used for this preliminary test of the compounds on the basis of the previous observation that knockdown of MBD2 in cancer cell lines resulted in decreased migration of the cells. The result implicated most of the hit compounds in actual suppression of the migration of breast adenocarcinoma MDA-MB-231 (LM1) and colorectal carcinoma HCT116 cells (Fig. 2B and fig. S2B). In particular, ABA (compound #2) and APC (compound #3), which accomplished the most favorable target binding in the aforementioned molecular docking experiments, also showed the least MI50 (concentration for half-inhibition of cell migration) values. Therefore, these two molecules were selected as lead compounds for subsequent evaluation in detail.

(A) Computational analysis for off-target probabilities of the 10058-F4 (control experiment) and two selected lead compounds (ABA and APC). Max Tc and E value of the predicted binding are plotted for the n (number of potential targets predicted) off-target candidates yielded from SEA using 2060 human proteins in the database. See fig. S2 for the other hit compounds. (B) Cell migration inhibition by the hit compounds. The LM1 and HCT116 cancer cells were fixed and stained after 48 hours of Transwell migration in the presence of indicated concentrations of individual compounds, followed by counting the number of migrated cells (n = 2) to yield MI50 value.

To assess target-binding feasibility and mode of binding of the two selected leads, we conducted MD simulation using the structures resulting from the ABA:MBD2369, APC:MBD2369, and 10058-F4:c-Myc402 docking (Fig. 1D) as starting points. In 50-ns MD trajectories, the number of the compound-protein contacts (Fig. 3A) and the compound-protein interaction energies (fig. S3A) over time were steady for 10058-F4:c-Myc402 but showed noticeable fluctuations for ABA:MBD2369 and APC:MBD2369, particularly during the first half of the simulation period, suggesting that the binding of ABA or APC to MBD2360393 might be less persistent than the 10058-F4c-Myc395430 interaction. However, heatmaps representing intermolecular contacts for individual residues (Fig. 3B) indicated frequent contacts of the ABA/APCMBD2360393 interaction comparable to that of the 10058-F4c-Myc395430 interaction. In particular, the highest contact density value at the most contacted residue (D368 contact) in the ABA:MBD2369 trajectory was higher than that (L404 contact) in the 10058-F4:c-Myc402 trajectory, suggesting stronger binding. Next, MD simulations for the ligand:MBD2360393 complex were extended to include D366-, V376-, and L383-targeted docking (Fig. 3C). Consistent with the ABA:MBD2369 trajectory, D368 was the most contacted residue in the heatmaps for heavy atom contacts of the ABA:MBD2376 trajectory, although no preferential contact was found in the other ABA:MBD2360393 trajectories and in the APC:MBD2360393 MD simulation sets. Collectively, the MD simulation indicated that the actual binding of ABA and APC to MBD2360393 would be as promising as the 10058-F4 binding to c-Myc395430, although detailed interaction modes can be different between the two compounds. Therefore, it was subsequently examined whether the targeted binding of the compounds to MBD2 would influence specific PPI of the protein.

(A) Time-course alterations of the number of intermolecular contacts within 3 cutoff in MD simulations. (B) Heatmap describing the number of simulated compound-protein contacts during 50-ns trajectory for individual residues. Each value of a number of contacts was normalized by dividing it by the total number of contacts in each simulation. The already-known critical residues for PPI are shown in darker red. (C) Heatmap of the intermolecular heavy atom contacts between the lead compounds and target proteins during 50-ns trajectory. Number of contacts was normalized by the total number of contacts in each simulation. MBD2 N-terminal two residues, G and S, were from the NMR structure (PDB ID: 2L2L). MBD2 sequence starts from K360, after G, and S.

It has been suggested that 10058-F4 evokes a local conformational change (36) or conformational equilibrium shift (38, 39) of the c-Myc IDPR at its binding sites, and this small but significant alteration is critically involved in the functional inhibition of the DOT-mediated PPI of c-Myc with Max. Detailed inspection of the MD simulation results suggested that the MBD2 IDPR could also undergo a local conformational perturbation upon the binding of ABA and APC. For instance, in the ABA:MBD2369 and APC:MBD2369 trajectories, both and backbone torsion angles of the most contacted residue (D368) in the compound-contacting states were significantly (t test, P < 0.05) different from those in the noncontacting states (fig. S3B). The compound-bound conformation also appeared to be different between ABA and APC, as the D368 angles in the compound-contacting states were significantly different in between ABA:MBD2369 and APC:MBD2369 trajectories, although angle differences were not significant (t test, P = 0.574). Therefore, to further analyze the possible conformational perturbation, we compared the compound-bound ABA:MBD2369 and APC:MBD2369 trajectories with the apo-MBD2 and p66-MBD2 trajectories (fig. S3C). The backbone root mean square fluctuation values of individual residues (fig. S3D) showed that apo-MBD2 underwent stronger backbone fluctuations than compound- or p66138178-bound MBD2360393. This reflects the structural instability of MBD2360393 in the absence of bound molecules (or, conversely, DOT upon complex formation). Notably, the backbone fluctuation was also different between compound- and p66138178-bound MBD2360393, especially at the p66138178-contacting D366 and I369 residues, reflecting the compound-specific local conformational perturbation in MBD2360393. The presence of this compound-specific perturbation was also obvious from torsion angle distributions of the p66138178-interacting D366, I369, V376, and L383 residues (fig. S3E), as the backbone / torsion angles in both ABA:MBD2369 and APC:MBD2369 trajectories were different from those in apo-MBD2 and MBD2-p66 (tables S3 and S4). In addition, comparison between ABA:MBD2369 and APC:MBD2369 MD trajectories revealed that the two compounds likely evoked different local conformational changes at the p66138178-interacting residues of MBD2. In particular, significant difference in of I369 and / of V376 and L383 (table S4), which is distinguished from the similarity in / of D366 and of I369, suggested that I369 served as a turning point for the observed torsion angle differences more evident in its C-terminal region from I369. Collectively, comparative MD simulations of MBD2360393 in different states (apo-, compound-, and p66138178-bound) suggested the compound-specific induction of local conformational perturbation of MBD2, especially at its p66-interacting site, which would most likely interfere with the MBD2-p66 interaction. Therefore, we next examined whether these leads can actually inhibit the PPI of MBD2, with p66 both in vitro and in cell, by fluorescence resonance energy transfer (FRET) and co-immunoprecipitation (co-IP) assay.

As the coiled-coil interaction between MBD2 and p66 occurs in an antiparallel fashion (17), MBD2 was fused with a FRET acceptor protein dTomato at its N terminus, whereas the FRET donor enhanced yellow fluorescent protein (eYFP) was C-terminally fused to p661206 (33) for in vitro FRET. Unfortunately, the full-length p66 was not available for the in vitro FRET studies due to the inclusion body formation in the Escherichia coli system for the recombinant production. The in vitro FRET result evidenced that both ABA and APC efficiently interfere with the MBD2-p66 interaction by provoking significant reduction of FRET, which, at 1 to 1.5 equimolar concentrations of the compounds, reached half of the value recorded for the MBD2-p661206 complex (Fig. 4A and fig. S4A). The FRET analysis in 293T cells by transient cotransfection of eYFP-MBD2 and mCherry-p66 expression constructs also showed the noticeable FRET reduction, which was dependent on the concentrations of the compounds used for the treatment (Fig. 4B and fig. S4B). Furthermore, the half maximal inhibitory concentration (IC50) values determined in this in-cell FRET experiments (1.93 and 1.75 M for ABA and APC, respectively; see Fig. 4B) were in good agreement with the MI50 values determined in the migration assay (2.03 and 2.24 M for ABA and APC, respectively; Fig. 2B). Last, the results of the co-IP assay to capture the endogenous MBD2-p66 complex corroborated the fact that ABA and APC inhibit the MBD2-p66 association with the submicromolar IC50 (Fig. 4C). Therefore, as the interruption of the MBD2-p66 interaction is anticipated to result in the prevention of the proper assembly of Mi-2/NuRD CRC, we subjected the compounds to an in-depth evaluation of biological activities targeting the function of Mi-2/NuRD CRC in cellular EMT and thereby in cancer metastasis.

(A) Inhibition of in vitro FRET dynamics of MBD2 interaction with p66 by ABA and APC. Relative mean FRET values for the corresponding ratios of chemical concentration over MBD2::p661206 were plotted. See fig. S4A for the original data. n = 3. (B) Inhibition of FRET dynamics of MBD2 interaction with p66 by ABA and APC in cells. Quantified FRET activities of mock- and compound-treated samples were obtained, and the relative FRET ratios for compounds were calculated by FRETcomp/FRETmock (see Materials and Methods). See also fig. S4B for representative immunofluorescence microscopic photos of cells. n = 2. (C) Dose-dependent suppression of the endogenous MBD2-p66 association by the ABA and APC compounds revealed by in vivo co-IP. Relative fold changes of MBD2 interaction with p66 (right) were obtained by the quantification of immunoblots (left). Data (means SD) in (A) and (B) were analyzed using Students t test. Ab, antibody; IgG, immunoglobulin G.

The cellular EMT process that drives cell migration and invasion is critical not only for wound healing but also for cancer metastasis, including promotion of CSC and drug-resistant properties of cancer cells (2931). As we have previously observed that the MBD2 and/or p66 down-regulation in cancer cell lines resulted in the depressed EMT and conversely promoted epithelial differentiation, we reasoned that disrupted PPI between MBD2 and p66 by the ABA and APC compounds could result in suppression of metastatic potentials of cancer cells by regulating the Mi-2/NuRD CRCmediated EMT. In agreement with these hypotheses, in mesenchymal type of cancer cells (triple-negative and basal-type breast cancers and aggressive colon cancers) treated with ABA or APC, the increased levels of epithelial markers (CDH1 and CTNNB1) were appreciable, whereas the mesenchymal marker (VIM, SNAIL, SLUG, and CDH2) expressions were suppressed. On the other hand, such an alteration indicative of mesenchymal-epithelial transition (MET) was not apparent in the epithelial cancer cells (luminal breast cancers and less aggressive colon cancer) (Fig. 5, A and B, and fig. S5A). Subsequent analyses confirmed that the compounds suppressed wound healing and migration/invasion abilities of the cancer cells (Fig. 5, C and D, and fig. S5B). In addition, flow cytometric measurements of the cell surface markers CD44 and CD24 indicated that the LM1 cells of the stem-like phenotype (CD44hi/CD24lo) were switched over to the nonstem phenotype (CD44lo/CD24lo) by the compound treatments (Fig. 5E), although the compounds did not induce significant alterations in the proliferation rates and cell cycle progression of the cells tested (Fig. 5, F and G, and fig. S5, C and D). Furthermore, the compound-treated cancer cells showed reduced capability of mammosphere formation (Fig. 5H and fig. S5E), thereby resulting in enhanced susceptibility of the cells to chemotherapeutic drugs including doxorubicin and cisplatin (Fig. 5I and fig. S5F). Last, mRNA sequencing (mRNA-Seq) results showed that global gene expression profiles of the ABA- or APC-treated cells were highly comparable to those of MBD2- or p66-knockdown cells but markedly discriminated from the profiles of nontreated wild-type cells (Fig. 5J), supporting no significant off-target effects as initially predicted by SEA (Fig. 2A). Together, these observations established antimetastatic activity of the lead compounds, ABA and APC, by demonstrating that the compounds actioned so specifically on the MBD2-p66 PPI system that the EMT process was efficiently modulated to induce transition of CSC-like cells from a mesenchymal-like state to a bona fide epithelial state.

(A) Representative images showing immunofluorescent signals for VIM or CDH1 (red) and 4,6-diamidino-2-phenylindole (DAPI) (blue) in LM1 (left) and HCT116 (right) cells treated with 10 M ABA or APC. Photo credit: S.H.S., Hanyang University. (B) Immunoblots showing the expression levels of EMT markers 48 hours after compound (10 M) treatment. ACTB was used as a loading control. A.U., arbitrary units. (C) Effects on wound healing, estimated by the recovered surface areas of scraped cell monolayers, 48 hours after treatment with 10 M ABA or APC. n = 4. (D) ABA and APC (10 M) impact on cell migration (left) and invasion (right) represented by the number of migrated and Matrigel-invaded cells in Transwell plates 48 hours following compound treatments. n = 3. (E) Relative proliferation rates quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay after 2 days. Cells were treated with 10 M ABA or APC. n = 2. (F) Cell cycle analysis by fluorescence-activated cell sorter (FACS). Cells were treated with 10 M ABA or APC. n = 2. (G) Number of spheres counted by the naked eye after 5 days. Cells were treated with 10 M ABA or APC. n = 3. (H) Representative cell population images for the stem-like CD44hi profile of the ABA- or APC-treated LM1 cells analyzed by FACS. Data from one experiment are shown as averages of two technical replicates. (I) Sensitivity to doxorubicin (left) and cisplatin (right) of the 10 M ABA- or APC-treated cells quantified by MTT assay. n = 2. (J) Heatmap of mRNA-Seq data, which demonstrates similarity in gene expression between ABA- or APC-treated cells and MBD2 or p66 knockdown LM1 cells. Data (means SD) in (E) to (I) were analyzed using Students t test. **P < 0.01 and *P < 0.05.

Antimetastatic efficacy of the two selected lead compounds in vivo was analyzed using xenograft mice transplanted with the LM1 cells, which were chosen for its potent ability to readily metastasize to lung in mice (40). Here, ABA (10 g kg1) and APC (20 g kg1) compounds were administered by intravenous injection six times every 3 days from day 10 after the subcutaneous injection of the green fluorescent protein (GFP)tagged LM1 cells, followed by sacrifice of the mice (after 4 days of the last administration) for subsequent analysis of tumors (Fig. 6, A and B). Notably, although growth inhibition of original tumor was not significant (Fig. 6, A, C, and D), both ABA and APC compounds exhibited a potent inhibition of the cancer metastasis to lung (represented by the number of nodules developed in lung; Fig. 6C), with no significant effects on body weight of the xenograft mice (Fig. 6B). It was also confirmed by immunohistochemistry that the injected LM1 cells were responsible for the origination of tumor and the metastasized tumor nodules in lung (Fig. 6D). In contrast, histological properties of major organs (Fig. 6E) and complete blood count (CBC) result (Fig. 6F) of the compound-administered mice remained normal. Thus, both ABA and APC appear to be promising antimetastatic agents that are unlikely to cause adverse effects in normal tissues.

(A) Estimated volume (means SEM; P value for significance test by ANOVA) of original tumor developed during the experimental period with and without the drug administration. n = 8 for each group. (B) Body weights of mice monitored at the starting and ending point of experiment. (C) Effects of the compound administration on the xenograft tumor and its metastasis. Estimated tumor weights are presented for the original tumors, whereas the number of nodules developed by lung metastasis is plotted. (D) Representative photographs for lung nodules acquired 29 days after injection of the LM1 cells. Images of metastasized lung tissue sections illustrated by hematoxylin and eosin (H&E) staining and GFP immunohistochemistry (IHC). Yellow arrowhead represents the tumor nodule, and red dotted area indicates the tumor region. Numbers below the H&E-stained tissue sections indicate the average number of tumor nodules in all mice of the same group. Photo credit: M.Y.K. and S.C., Hanyang University. (E) Representative images of H&E-stained tissue sections for the major organs derived from the xenograft NOD-Prkdcscid IL2rg/ (NPG) mice after completion of the metastasis inhibition tests with the ABA and APC administration (top). Histological scoring (tumor-bearing mice/total mice) for the H&E-stained major organs of the xenograft mice (bottom). Scale bars, 500 m. Photo credit: M.Y.K. and S.C., Hanyang University. (F) CBC analysis of the ABA- and APC-treated xenograft mice. WBC, white blood cell count; RBC, red blood cell count; HGB, hemoglobin; HCT, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RDW, red cell distribution width; PLT, platelet count; N.S., not significant. Data (means SD) in (B) to (D) and (G) were analyzed using Students t test.

IDPs/IDPRs are important not only for normal cellular processes but also for the development of various human diseases. In particular, proteins validated as potential drug targets have been increasingly identified to contain IDPRs crucial for PPI mediation. However, the dynamic structure of IDPs/IDPRs limits their use in rational structure-based drug discovery. There are some successful examples of finding of compounds that can bind to and regulate the IDPR-containing proteins (e.g., the c-Myc IDPR-targeting compound 10058-F4). However, most of the current approaches to discover compounds targeting functional IDPR are based on random screening. Meanwhile, because many IDPRs undergo characteristic DOTs upon specific PPIs (9, 10), related structural information can be retrieved from their complexed structures. This, together with the in-depth insights into the compound binding modes (38) and the rapidly accumulating knowledge of the IDPR structural properties (6, 7), suggests the possibility for utilization of the structure-based rational approach as a feasible route for efficient discovery of drug leads targeting specific IDPRs engaged in DOT-based PPIs.

The present novel approach to an antimetastatic agent development provides a prime example of a collaborative work of in silico, in vitro, in cell, and in vivo analyses to discover the drug candidates targeting a pharmacologically important IDPR. In particular, we propose here a three-step computational platform for finding these drug leads. First, IDPRs with DOT potential are selected as potential drug-target sites. We speculate that these regions can be identified based on the characteristic features of their intrinsic disorder predisposition profiles similar to those observed in the known DOT-based PPI regions of MBD2 (residues 360 to 393) and c-Myc (residues 395 to 430) (Fig. 1B). Second, for virtual screening, ordered conformation is taken from the structure of selected IDPR complexed with binding partner. Third, MD simulation is conducted for the selected drug leads targeting IDPRs. Because the structure of target IDPR is dynamic (6, 7) and because the presumably entropy-driven compound binding also occurs in a dynamic fashion (38), MD simulations of the compound-target complex structures are essential for detailed evaluation of the binding feasibility. In this study, MD simulation indicated the compound bindingspecific conformational perturbations of MBD2, particularly at its critical PPI site with p66, which could provide a structural basis for the molecular inhibition of the DOT-based PPI of MBD2. In general, specific molecular interactions of IDPs/IDPRs are known to be accomplished in distinctive ways such as DOT, avidity, allovalency, and fuzzy binding; the last three involves multivalent binding sites, whereas the first represents a simple two-state binding involving a single binding site (41, 42). The present MD simulation result suggests that the ABA and APC binding of the MBD2 IDPR resembled a dynamic, multivalent interaction at low entropic cost, rather than the DOT-based interaction relevant to its p66 binding. The entropy-driven compound binding and structural multiplicity of the compound-bound IDPR have been identified earlier in the case of 10058-F4 binding to c-Myc402412, which also requires just a few stable atomic interactions (38, 39). In this regard, increased fuzziness of the MBD2 IDPR by the compound binding may conversely lead to decreased propensity for DOT for its p66 interaction, although the exact mode of binding of our compounds to the MBD2 IDPR, which can ultimately underlie their PPI inhibition mechanism, remains to be characterized in detail.

Our computational platform also contains an additional in silico study using the SEA, which was practical to assess off-target probability of the suggested compounds that is potentially associated with adverse effects in actual usage. In subsequent studies, mRNA-Seq results in cells (Fig. 5J) were consistent with the SEA result (Fig. 2A) that predicted no significant off-target probability, and in vivo administration of the suggested compounds raised no significant toxicity in normal tissues (Fig. 6, E and F).

It is generally appreciated that identifying and understanding molecular regulation and signaling network involved in the EMT process are essential to provide a molecular basis for antimetastatic drug development (43, 44). Concerning this study, we have recently identified the MBD2-p66 molecular system in Mi-2/NuRD CRC as a promising target for EMT modulation by observing the induction of MET (conversed process of EMT) by knockdown of MBD2 and/or p66 in cancer cells. Together with this parallel effort, the present discovery of novel antimetastatic agents targeting a component of Mi-2/NuRD CRC validates that this epigenetic machinery can serve as an emerging target system for efficient antimetastatic drug developments. Both ABA and APC disrupting the specific PPI of MBD2 were able to suppress cellular EMT processes, thereby inducing epithelial differentiation of the more aggressive CSCs. Last, our compounds potently inhibited the cancer metastasis in vivo. Furthermore, considering that they raised no noticeable adverse effects on blood and normal tissues, the present results provide a basis for a novel safe control of cancer metastasis. Hence, found in this study, lowmolecular weight (<250 g mol1) compounds constitute a pioneering example of antimetastatic agents acting on a specific Mi-2/NuRD CRC component. In addition, the present observation that the compound treatments rendered the cancer cells more sensitive to anticancer drugs (Fig. 5I) provides important implications in combination therapy for cancer.

In conclusion, this study successfully used a rational approach to search for the novel antimetastatic agents acting via inhibition of the DOT-based PPI in an IDPR. As IDPs/IDPRs play crucial roles in diverse cellular processes (6, 7), we believe that this platform can be applied for the discovery of innovative drug leads targeting DOT-based PPI regions in proteins associated with various cancers and other diseases.

This study was designed to develop a novel platform for the discovery of drug leads based on molecular docking and MD simulations of the DOT-associated IDPRs of target proteins and, as a proof of concept, to identify candidate drugs, suppressing metastatic potentials of cancer cells in vitro and in vivo, by targeting an IDPR of MBD2 that undergoes a DOT upon association with its binding partner p66 for the integration of the Mi-2/NuRD CRC. These objectives were addressed by (i) analyzing intrinsic disorder predispositions of drug-target proteins and evaluating potential disorder-based binding regions (45), (ii) doing molecular docking with druggable compounds from the ZINC compound library to the potential drug-target sites, (iii) selecting two lead compounds based on the docking scores and off-target probabilities and experimental validation of target binding, (iv) evaluating the mode and efficiency of the compound binding via MD simulations, (v) assessing the identified leads for biological effects suppressing metastatic potentials of cancer cells, and (vi) verifying antimetastatic efficacy in a murine xenograft tumor model.

In animal studies, mice were randomly assigned to treatment and control groups. Numbers of tested mice were specified in each figure. Outliers were removed only if mice died at an early stage of the treatment according to the Hanyang University Institutional Animal Care and Use Committee (IACUC) dimension guideline. The primary end points were tumor size and cancer metastasis to lung. Mice were euthanized when moribund or at the end of the prespecified treatment period. All procedures were performed in accordance with institutional protocols approved by the IACUC of the Hanyang University. Pathology analysis was performed in a blinded fashion.

Data were presented as means SE. The sample size for each experiment, n, was included in Results and the associated figure legend. Everywhere in the text, the difference between two subsets of data was considered statistically significant if the one-tailed Students t test gave a significance level P (P value) less than 0.05. Multiple comparisons, more than two means, were performed using a univariate analysis of variance (ANOVA), where a Scheffe posttest was performed in some cases or Kruskal-Wallis test. GraphPad Prism was used to generate MI50 curves for cell lines treated with ABA and APC in vitro. In addition, IC50 curves for FRET assay were also generated by GraphPad Prism. Statistical analyses were performed using IBM SPSS statistics 23.

Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/11/eaav9810/DC1

Supplementary Materials and Methods

Fig. S1. Structural information on MBD2 and c-Myc.

Fig. S2. SEA and cell migration analysis for the nine selected hit compounds targeting MBD2.

Fig. S3. MD simulations of the selected compound-docked structures of MBD2 and c-Myc.

Fig. S4. FRET dynamics of ABA and APC to the MBD2-p66 interaction.

Fig. S5. Effects of ABA and APC on the expression of EMT markers and CSC properties in various breast and colon cancer cells.

Table S1. Molecular docking result (H-bond, hydrogen bond; N/A, not available).

Table S2. Selection of compound by in silico assessment of off-target probability by SEA analysis.

Table S3. Backbone torsion angle variations (95% confidence interval) of the four key residues in the four different MD simulations of MBD2.

Table S4. T test and P values on the backbone torsion angle summarized in table S3.

Table S5. Primer sets for vector construction.

Original data file S1. Figure 1D PDB files.

References (4669)

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Rational discovery of antimetastatic agents targeting the intrinsically disordered region of MBD2 - Science Advances

Bristol-Myers Squibb Announces Update on CheckMate -915 for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Versus Opdivo Alone in Patients with Resected…

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced results for one of the co-primary endpoints from CheckMate -915, a randomized Phase 3 study evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) versus Opdivo alone for the adjuvant treatment of patients who have had a complete surgical removal of stage IIIb/c/d or stage IV (no evidence of disease) melanoma. A statistically significant benefit was not reached for the co-primary endpoint of recurrence-free survival (RFS) in patients whose tumors expressed PD-L1 <1%. The Data Monitoring Committee recommended that the study continue unchanged. The study remains double-blinded and will continue to assess the other co-primary endpoint of RFS in the all-comer (intent-to-treat) population.

About CheckMate -915CheckMate -915 is a Phase 3, randomized, placebo controlled, double-blind study evaluating Opdivo in combination with Yervoy versus Opdivo monotherapy, an approved standard of care, in patients who have had a complete surgical removal of stage IIIb/c/d or stage IV (no evidence of disease) melanoma. Patients enrolled in the trial had no prior anti-cancer treatment for melanoma, except surgery for the melanoma lesion(s) and/or adjuvant radiation therapy after neurosurgical resection for central nervous system lesions. The trial randomized 1,943 patients to receive either Opdivo 240 mg intravenously every two weeks and Yervoy 1 mg/kg every six weeks or Opdivo 480 mg every four weeks for one year.

About MelanomaMelanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs. The incidence of melanoma has been increasing steadily for the last 30 years. In the United States, 91,270 new diagnoses of melanoma and more than 9,320 related deaths are estimated for 2018. Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths. Melanoma is mostly curable when treated in its very early stages; however, survival rates are roughly halved if regional lymph nodes are involved. Patients in the United States diagnosed with advanced melanoma classified as Stage IV historically have a five-year survival rate of 15% to 20% and a 10-year survival of 10% to 15%.

Adjuvant Therapy in MelanomaMelanoma is separated into five staging categories (Stages 0- IV) based on the in-situ feature, thickness and ulceration of the tumor, whether the cancer has spread to the lymph nodes, and how far the cancer has spread beyond lymph nodes.

Stage III melanoma has generally reached the regional lymph nodes but has not yet spread to distant lymph nodes or to other parts of the body (metastasized) and requires surgical resection of the primary tumor as well as the involved lymph nodes. Some patients may also be treated with adjuvant therapy. Despite surgical intervention, most patients experience disease recurrence and progress to metastatic disease.

Stage IV melanoma occurs when the melanoma has spread beyond the original site and regional lymph nodes to more distant areas of the body. The most common sites of metastasis are to vital organs, soft tissues and distant lymph nodes.

Bristol-Myers Squibb: Advancing Oncology ResearchAt Bristol-Myers Squibb, patients are at the center of everything we do. The focus of our research is to increase quality, long-term survival for patients and make cure a possibility. Through a unique multidisciplinary approach powered by translational science, we harness our deep scientific experience in oncology and Immuno-Oncology (I-O) research to identify novel treatments tailored to individual patient needs. Our researchers are developing a diverse, purposefully built pipeline designed to target different immune system pathways and address the complex and specific interactions between the tumor, its microenvironment and the immune system. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines, like I-O, a reality for patients.

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

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

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

U.S. FDA-APPROVED INDICATIONS FOR OPDIVOOPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with unresectable or metastatic melanoma.

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

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

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

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

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

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

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

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

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

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

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on 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.

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

About Yervoy

Yervoy is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types.

Indications and Important Safety Information for YERVOY (ipilimumab)

Indications

YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma in adults and pediatric patients (12 years and older).

YERVOY (ipilimumab) is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 1.7% (2/119) of patients.

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

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 7% (8/119) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of 7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barr syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12% (14/119) of patients. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 1.7% (2/119) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16% (90/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one RCC patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure. Encephalitis occurred in one MSI-H/dMMR mCRC patient (0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barr syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 4.2% (5/119) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

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

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

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue breastfeeding during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 032, serious adverse reactions occurred in 45% of patients receiving OPDIVO (n=245). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, pneumonitis, pleural effusions, and dehydration. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in 2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 017 and 057, the most common adverse reactions (20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 032, the most common adverse reactions (20%) in patients receiving OPDIVO (n=245) were fatigue (45%), decreased appetite (27%), musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%), constipation (20%), and cough (20%). In Checkmate 025, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 214, the most common adverse reactions (20%) reported in patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), decreased appetite (21% vs 29%), dyspnea (20% vs 21%), and vomiting (20% vs 28%). In Checkmate 205 and 039, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (10%) in patients receiving OPDIVO (n=236) were cough and dyspnea at a higher incidence than investigators choice. In Checkmate 275, the most common adverse reactions (20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the most common adverse reactions (20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 238, the most common adverse reactions (20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).

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

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

Checkmate Trials and Patient PopulationsCheckmate 037previously treated metastatic melanoma; Checkmate 066previously untreated metastatic melanoma; Checkmate 067previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 017second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 032small cell lung cancer; Checkmate 025previously treated renal cell carcinoma; Checkmate 214previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 205/039classical Hodgkin lymphoma; Checkmate 141recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275urothelial carcinoma; Checkmate 142MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040hepatocellular carcinoma; Checkmate 238adjuvant treatment of melanoma.

About the Bristol-Myers Squibb and Ono Pharmaceutical CollaborationIn 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol-Myers Squibb further expanded the companies strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies as single agents and combination regimens for patients with cancer in Japan, South Korea and Taiwan.

About Bristol-Myers SquibbBristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

Cautionary Statement Regarding Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, the possibility of unfavorable results from further clinical trials involving the combination treatment described in this release and whether such product candidate for the additional indications described in this release will be successfully developed and commercialized. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol-Myers Squibbs business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol-Myers Squibbs Annual Report on Form 10-K for the year ended December 31, 2018, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol-Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

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Bristol-Myers Squibb Announces Update on CheckMate -915 for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Versus Opdivo Alone in Patients with Resected...

Novocure Announces 43 Presentations on Tumor Treating Fields at 24th Annual Meeting of the Society for Neuro-Oncology – Business Wire

ST. HELIER, Jersey--(BUSINESS WIRE)--Novocure (NASDAQ: NVCR) today announced 43 presentations on Tumor Treating Fields, including three oral presentations, will be featured at the 24th Annual Meeting of the Society for Neuro-Oncology (SNO) on Nov. 20 through Nov. 24 in Phoenix. Presentations on Tumor Treating Fields cover a broad and growing range of topics. External authors prepared 34 of the 43 presentations.

The oral presentations on Tumor Treating Fields include an EF-14 post hoc subgroup analysis on tumor growth rates, and the pilot study results of Tumor Treating Fields combined with radiotherapy and temozolomide for the treatment of newly diagnosed glioblastoma.

Highlights among poster presentations include the combinations of Tumor Treating Fields with other therapies such as radiation and immunotherapies, simulations, health economics and outcomes research, patient advocacy, and research on the mechanism of action.

Year after year, it is amazing to see the continued focus on Tumor Treating Fields at the SNO Annual Meeting, said Novocure CEO Asaf Danziger. From our first presentation at SNO in 2008 to today, more than 250 abstracts on Tumor Treating Fields have been included at one of the most important conferences in neuro-oncology worldwide. I am proud of our team for their relentless focus on innovative research and for their consistent drive in raising awareness of our therapy among the scientific community. We look forward to another productive year at SNO.

Oral Presentations

(Abstract #: ACTR-46) Tumor Treating Fields combined with radiotherapy and temozolomide for the treatment of newly diagnosed glioblastoma: Final results from a pilot study. R. Grossman. 2:45 to 2:50 p.m. MST Nov. 22.

(Abstract #: RTHP-28) TTFields treatment affects tumor growth rates: A post-hoc analysis of the pivotal phase 3 EF-14 trial. Z. Bomzon. 4:05 to 4:10 p.m. MST Nov. 22.

(Abstract #: QOLP-24) Patients/parents experiences of receiving Optune delivered tumor treatment fields: A Pediatric Brain Tumor Consortium Study: PBTC-048. J. Lai. 7:50 to 7:54 p.m. MST Nov. 22.

Poster Presentations

(Abstract #: RDNA-10) TTFields treatment planning for targeting multiple lesions spread throughout the brain. Z. Bomzon. 7:30 to 9:30 p.m. MST Nov. 22. (Radiation Biology and DNA Repair/Basic Science)

(Abstract #: NIMG-20) Evaluation of head segmentation quality for treatment planning of tumor treating fields in brain tumors. Z. Bomzon. 7:30 to 9:30 p.m. MST Nov. 22. (Neuro-Imaging/Clinical Research)

(Abstract #: HOUT-24) Challenges and successes in the global reimbursement of a breakthrough medical technology for treatment of glioblastoma multiforme. C. Proescholdt. 7:30 to 9:30 p.m. MST Nov. 22. (Health Outcome Measures/Clinical Research)

(Abstract #: EXTH-02) The blood brain barrier (BBB) permeability is altered by Tumor Treating Fields (TTFields) in vivo. E. Schulz. 7:30 to 9:30 p.m. MST Nov. 22. (Experimental Therapeutics/Basic Science)

(Abstract #: IMMU-06) TTFields induces immunogenic cell death and STING pathway activation through cytoplasmic double-stranded DNA in glioblastoma cells. D. Chen. 7:30 to 9:30 p.m. MST Nov. 22. (Immunology/Basic Science)

(Abstract #: DRES-06) Prostaglandin E Receptor 3 mediates resistance to Tumor Treating Fields in glioblastoma cells. D. Chen. 7:30 to 9:30 p.m. MST Nov. 22. (Drug Resistance/Basic Science)

(Abstract #: EXTH-34) In vitro tumor treating fields (TTFields) applied prior to radiation enhances the response to radiation in patient-derived glioblastoma cell lines. S. Mittal. 7:30 to 9:30 p.m. MST Nov. 22. (Experimental Therapeutics/Basic Science)

(Abstract #: CSIG-20) Effect of tumor-treating felds (TTFields) on EGFR phosphorylation in GBM cell lines. M. Reinert. 7:30 to 9:30 p.m. MST Nov. 22. (Cell Signaling and Signaling Pathways/Basic Science)

(Abstract #: CBMT-14) The dielectric properties of brain tumor tissue. M. Proescholdt. 7:30 to 9:30 p.m. MST Nov. 22. (Cell Biology and Metabolism/Basic Science)

(Abstract #: CSIG-26) Is intrinsic apoptosis the signaling pathway activated by tumor-treating fields for glioblastoma. K. Carlson. 7:30 to 9:30 p.m. MST Nov. 22. (Cell Signaling and Signaling Pathways/Basic Science)

(Abstract #: ATIM-08) Trial in Progress: CA209-9Y8 phase 2 trial of tumor treating fields (TTFs), nivolumab plus/minus ipilimumab for bevacizumab-nave, recurrent glioblastoma. Y. Odia. 7:30 to 9:30 p.m. MST Nov. 22. (Adult Clinical Trials Immunologic/Clinical Research)

(Abstract #: ACTR-60) A phase 2, historically controlled study testing the efficacy of TTFields with adjuvant temozolomide in high-risk WHO grade II and III astrocytomas (FORWARD). A. Allen. 7:30 to 9:30 p.m. MST Nov. 22. (Adult Clinical Trials - Non-Immunologic/Clinical Research)

(Abstract #: TMIC-54) Comparison of cellular features at autopsy in glioblastoma patients with standard treatment of care and tumor treatment fields. A. Lowman. 7:30 to 9:30 p.m. MST Nov. 22. (Tumor Microenvironment/Basic Science)

(Abstract #: ACTR-26) Safety and efficacy of bevacizumab plus Tumor Treating Fields (TTFields) in patients with recurrent glioblastoma (GBM): data from a phase II clinical trial. J. Fallah. 7:30 to 9:30 p.m. MST Nov. 22. (Adult Clinical Trials Non-immunologic/Clinical Research)

(Abstract #: RBTT-02) Radiosurgery followed by Tumor Treating Fields for brain metastases (1-10) from NSCLC in the phase 3 METIS trial. V. Gondi. 7:30 to 9:30 p.m. MST Nov. 22. (Randomized Brain Tumor Trials in Development/Clinical Research)

(Abstract #: INNV-16) Complete response of thalamic IDH wildtype glioblastoma after proton therapy followed by chemotherapy together with Tumor Treating Fields. M. Stein. 7:30 to 9:30 p.m. MST Nov. 22. (Innovations in Patient Care/Clinical Research)

(Abstract #: INNV-20) A systematic review of tumor treating fields therapy for primary for recurrent and glioblastoma. P. Shah. 7:30 to 9:30 p.m. MST Nov. 22. (Innovations in Patient Care/Clinical Research)

(Abstract #: STEM-16) Dual Inhibition of Protein Arginine Methyltransferase 5 and Protein Phosphatase 2a Enhances the Anti-tumor Efficacy in Primary Glioblastoma Neurospheres. H. Sur. 7:30 to 9:30 p.m. MST Nov. 22. (Stem Cells/Basic Science)

(Abstract #: CBMT-13) 3DEP system to test the electrical properties of different cell lines as predictive markers of optimal tumor treating fields (TTFields) frequency and sensitivity. M. Giladi. 5 to 7 p.m. MST Nov. 23. (Cell Biology and Metabolism/Basic Science)

(Abstract #: EXTH-37) A novel transducer array layout for delivering Tumor Treating Fields to the spine. Z. Bomzon. 5 to 7 p.m. MST Nov. 23. (Experimental Therapeutics/Basic Science)

(Abstract #: NIMG-41) Rapid and accurate creation of patient-specific computational models for GBM patients receiving Optune therapy with conventional imaging (T1w/PD). Z. Bomzon. 5 to 7 p.m. MST Nov. 23. (Neuro-Imaging/Clinical Research)

(Abstract #: HOUT-17) Utilities of rare cancers like malignant pleural mesothelioma and glioblastoma multiforme - do they compare? C. Proescholdt. 5 to 7 p.m. MST Nov. 23. (Health Outcome Measures/Clinical Research)

(Abstract #: INNV-17) Innovative educational approaches to enhance patient and caregiver understanding of Optune for glioblastoma. M. Shackelford. 5 to 7 p.m. MST Nov. 23. (Innovations in Patient Care/Clinical Research)

(Abstract #: EXTH-05) Therapeutic implications of TTFields induced DNA damage and replication stress in novel combinations for cancer treatment. N. Karanam. 5 to 7 p.m. MST Nov. 23. (Experimental Therapeutics/Basic Science)

(Abstract #: EXTH-31) Combination of tumor treating fields (TTFields) and paclitaxel produces additive reductions in proliferation and clonogenicity in patient-derived metastatic non-small cell lung cancer (NSCLC) cells. S. Michelhaugh. 5 to 7 p.m. MST Nov. 23 (Experimental Therapeutics/Basic Science)

(Abstract #: EXTH-53) Tumor Treating Fields leads to changes in membrane permeability and increased penetration by anti-glioma drugs. E. Chang. 5 to 7 p.m. MST Nov. 23. (Experimental Therapeutics/Basic Science)

(Abstract #: RDNA-01) Tubulin and microtubules as molecular targets for TTField therapy. J. Tuszynski. 5 to 7 p.m. MST Nov. 23. (Radiation Biology and DNA Repair/Basic Science)

(Abstract #: SURG-01) OptimalTTF-1: Final results of a phase 1 study: First glioblastoma recurrence examining targeted skull remodeling surgery to enhance Tumor Treating Fields strength. A. Korshoej. 5 to 7 p.m. MST Nov. 23. (Surgical Therapy/Clinical Research)

(Abstract #: ATIM-39) Phase 2 open-labeled study of adjuvant temozolomide plus Tumor Treating Fields plus Pembrolizumab in patients with newly diagnosed glioblastoma (2-THE-TOP). D. Tran. 5 to 7 p.m. MST Nov. 23. (Adult Clinical Trials Immunologic/Clinical Research)

(Abstract #: ACTR-49) Initial experience with scalp preservation and radiation plus concurrent alternating electric tumor-treating fields (SPARE) for glioblastoma patients. A. Song. 5 to 7 p.m. MST Nov. 23. (Adult Clinical Trials - Non-Immunologic/Clinical Research)

(Abstract #: RTHP-25) TTFields dose distribution alters tumor growth patterns: An imaging-based analysis of the randomized phase 3 EF-14 trial. M. Ballo. 5 to 7 p.m. MST Nov. 23. (Radiation Therapy/Clinical Research)

(Abstract #: ACTR-19) Report on the combination of Axitinib and Tumor Treating Fields (TTFields) in three patients with recurrent glioblastoma. E. Schulz. 5 to 7 p.m. MST Nov. 23. (Adult Clinical Trials - Non-Immunologic/Clinical Research)

(Abstract #: PATH-47) TTF may apply selective pressure to glioblastoma clones with aneuploidy: a case report. M. Ruff. 5 to 7 p.m. MST Nov. 23. (Molecular Pathology and Classification Adult and Pediatric/Clinical Research)

(Abstract #: RARE-39) Combination of Tumor Treating Fields (TTFields) with lomustine (CCNU) and temozolomide (TMZ) in newly diagnosed glioblastoma (GBM) patients - a bi-centric analysis. L. Lazaridis. 5 to 7 p.m. MST Nov. 23. (Rare Tumors/Clinical Research)

(Abstract #: ACTR-31) The use of TTFields for newly diagnosed GBM patients in Germany in routine clinical care (TIGER: TTFields in Germany in routine clinical care). O. Bahr. 5 to 7 p.m. MST Nov. 23. (Adult Clinical Trials Non-Immunologic/Clinical Research)

(Abstract #: INNV-09) Clinical efficacy of tumor treating fields for newly diagnosed glioblastoma. Y. Liu. 5 to 7 p.m. MST Nov. 23. (Innovations in Patient Care/Clinical Research)

(Abstract #: EXTH-61) Celecoxib Improves Outcome of Patients Treated with Tumor Treating Fields. K. Swanson. 5 to 7 p.m. MST Nov. 23. (Experimental Therapeutics/Basic Science)

(Abstract #: INNV-23) Glioblastoma and Facebook: An Analysis Of Perceived Etiologies and Treatments. N. Reddy. 5 to 7 p.m. MST Nov. 23. (Innovations in Patient Care/Clinical Research)

(Abstract #: INNV-12) Outcomes in a Real-world Practice For Patients With Primary Glioblastoma: Impact of a Specialized Neuro-oncology Cancer Care Program. N. Banerji. 5 to 7 p.m. MST Nov. 23. (Innovations in Patient Care/Clinical Research)

(Abstract #: RBTT-11): NRG Oncology NRG-BN006: A Phase II/III Randomized, Open-label Study of Toca 511 and Toca FC With Standard of Care Compared to Standard of Care in Patients With Newly Diagnosed Glioblastoma. M. Ahluwalia. 5 to 7 p.m. MST Nov. 23. (Randomized Brain Tumor Trials Development/Clinical Research)

About Novocure

Novocure is a global oncology company working to extend survival in some of the most aggressive forms of cancer through the development and commercialization of its innovative therapy, Tumor Treating Fields. Tumor Treating Fields is a cancer therapy that uses electric fields tuned to specific frequencies to disrupt solid tumor cancer cell division. Novocures commercialized products are approved for the treatment of adult patients with glioblastoma and malignant pleural mesothelioma. Novocure has ongoing or completed clinical trials investigating Tumor Treating Fields in brain metastases, non-small cell lung cancer, pancreatic cancer, ovarian cancer and liver cancer.

Headquartered in Jersey, Novocure has U.S. operations in Portsmouth, New Hampshire, Malvern, Pennsylvania and New York City. Additionally, the company has offices in Germany, Switzerland, Japan and Israel. For additional information about the company, please visit http://www.novocure.com or follow us at http://www.twitter.com/novocure.

Approved Indications

Optune is intended as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM).

Optune with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery, and completion of radiation therapy together with concomitant standard of care chemotherapy.

For the treatment of recurrent GBM, Optune is indicated following histologically- or radiologically-confirmed recurrence in the supratentorial region of the brain after receiving chemotherapy. The device is intended to be used as a monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.

The NovoTTF-100L System is indicated for the treatment of adult patients with unresectable, locally advanced or metastatic, malignant mesothelioma (MPM) to be used concurrently with pemetrexed and platinum-based chemotherapy.

Important Safety Information

Contraindications

Do not use Optune in patients with GBM with an implanted medical device, a skull defect (such as, missing bone with no replacement), or bullet fragments. Use of Optune together with skull defects or bullet fragments has not been tested and may possibly lead to tissue damage or render Optune ineffective. Do not use the NovoTTF-100L System in patients with MPM with implantable electronic medical devices such as pacemakers or implantable automatic defibrillators, etc.

Use of Optune for GBM or the NovoTTF-100L System for MPM together with implanted electronic devices has not been tested and may lead to malfunctioning of the implanted device.

Do not use Optune for GBM or the NovoTTF-100L System for MPM in patients known to be sensitive to conductive hydrogels. Skin contact with the gel used with Optune and the NovoTTF-100L System may commonly cause increased redness and itching, and may rarely lead to severe allergic reactions such as shock and respiratory failure.

Warnings and Precautions

Optune and the NovoTTF-100L System can only be prescribed by a healthcare provider that has completed the required certification training provided by Novocure.

The most common (10%) adverse events involving Optune in combination with chemotherapy in patients with GBM were thrombocytopenia, nausea, constipation, vomiting, fatigue, convulsions, and depression.

The most common (10%) adverse events related to Optune treatment alone in patients with GBM were medical device site reaction and headache. Other less common adverse reactions were malaise, muscle twitching, and falls related to carrying the device.

The most common (10%) adverse events involving the NovoTTF-100L System in combination with chemotherapy in patients with MPM were anemia, constipation, nausea, asthenia, chest pain, fatigue, device skin reaction, pruritus, and cough.

Other potential adverse effects associated with the use of the NovoTTF-100L System include: treatment related skin toxicity, allergic reaction to the plaster or to the gel, electrode overheating leading to pain and/or local skin burns, infections at sites of electrode contact with the skin, local warmth and tingling sensation beneath the electrodes, muscle twitching, medical site reaction and skin breakdown/skin ulcer.

If the patient has an underlying serious skin condition on the treated area, evaluate whether this may prevent or temporarily interfere with Optune and the NovoTTF-100L System treatment.

Do not prescribe Optune or the NovoTTF-100L System for patients that are pregnant, you think might be pregnant or are trying to get pregnant, as the safety and effectiveness of Optune and the NovoTTF-100L System in these populations have not been established.

Forward-Looking Statements

In addition to historical facts or statements of current condition, this press release may contain forward-looking statements. Forward-looking statements provide Novocures current expectations or forecasts of future events. These may include statements regarding anticipated scientific progress on its research programs, clinical trial progress, development of potential products, interpretation of clinical results, prospects for regulatory approval, manufacturing development and capabilities, market prospects for its products, coverage, collections from third-party payers and other statements regarding matters that are not historical facts. You may identify some of these forward-looking statements by the use of words in the statements such as anticipate, estimate, expect, project, intend, plan, believe or other words and terms of similar meaning. Novocures performance and financial results could differ materially from those reflected in these forward-looking statements due to general financial, economic, regulatory and political conditions as well as more specific risks and uncertainties facing Novocure such as those set forth in its Quarterly Report on Form 10-Q filed on July 25, 2019, with the U.S. Securities and Exchange Commission. Given these risks and uncertainties, any or all of these forward-looking statements may prove to be incorrect. Therefore, you should not rely on any such factors or forward-looking statements. Furthermore, Novocure does not intend to update publicly any forward-looking statement, except as required by law. Any forward-looking statements herein speak only as of the date hereof. The Private Securities Litigation Reform Act of 1995 permits this discussion.

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Novocure Announces 43 Presentations on Tumor Treating Fields at 24th Annual Meeting of the Society for Neuro-Oncology - Business Wire

10 promising developments that can help Alzheimer’s patients – ISRAEL21c

November is Alzheimers Awareness Month. Its a fitting time to look at the latest Israeli advances in preventing, diagnosing and treating the progressive and incurable brain disorder.

Alzheimers disease (AD) is the most common cause of the 9.9 million new cases of dementia diagnosed each year worldwide. The disease primarily strikes the elderly population, affecting 30 percent of those over age of 85.

AD impacts memory, thinking and language skills, and even the ability to carry out simple tasks.

The disease occurs when a protein called amyloid beta aggregates in brain tissues. These protein clumps kill nerve cells, leading to damage in the brain-function mechanisms.

Here are 10 examples of promising Israeli approaches reported within the past two years alone.

PREVENTION

Various genetic, lifestyle and environmental factors can put a person at risk for AD. Among them are diabetes, high blood pressure, obesity, smoking, depression, cognitive inactivity or low education, and physical inactivity.

Preventing the onset of AD is the focus of these approaches:

Eitan Okun, Alzheimers disease researcher at Bar-Ilan University. Photo: courtesy

Most vaccines work by mounting an immune response toward a weakened pathogen to boost the immune systems ability to fight the real pathogen.

Okuns approach primes the body to attack amyloid beta protein clumps in the brain, the signature sign of AD.

Following experiments on mice, Okun is preparing for human trials on people at known risk of developing the disease in their 50s or younger: those genetically inclined toward Alzheimers and people with Down syndrome.

These critical trials will determine whether the vaccine actually works in humans, said Okun. Depending on the success rate and side effects from [human] testing, we will be able to know how much more time is needed to make the vaccine available on a global scale.

Okun also is investigating new ways to diagnose AD earlier and more accurately using advanced MRI (magnetic resonance imaging) technologies to detect initial signs of amyloid protein aggregation in the brain.

BGU Prof. Alon Friedman has invented a new treatment to prevent neurological diseases. Photo courtesy of Dr. Merav Shamir

Introduced by BGN Technologies of Ben-Gurion University of the Negev, the novel therapy hinges on the fact that a malfunctioning BBB allows neurotoxic blood products to enter the brain and cause damage leading to neurological diseases.

The lab of Prof. Alon Friedman discovered that treating the BBB at early stages can protect the brain and prevent disease development.

Their proposed treatment would combine Memantine and Losartan, which have been shown in preclinical studies to protect the integrity of the BBB when administered together. Partners are being sought to continue development.

Prof. Ester Segal of the Technion. Photo: courtesy

They reported on this advance in a recent cover story of the journal Small.

Nanoscale silicon chips invented in Prof. Ester Segals lab allow for the direct insertion of neural growth factor protein into the brain and its gradual release into the target tissue, bypassing the BBB (see above). Afterward delivering all the therapeutic protein loaded onto them, the chips safely dissolve.

In a series of experiments, we showed in mice that the two ways of delivering the platform into the brain led to the desired result, said Technion doctoral student Michal Rosenberg.

Our technology has also been tested in a cellular model of Alzheimers disease and indeed, the protein release has led to rescuing the nerve cells.

DIAGNOSIS

PET scans and spinal taps are now the gold standard for diagnosing AD. Theyre both expensive and carry risks.

Cheaper, noninvasive tests being developed in Israel also could be critical in providing a much earlier diagnosis, when treatment would be most effective.

Thats because the same beta-amyloid proteins that clump in the brain of AD patients appear in the retina of the eyes up to 15 years before the onset of AD symptoms.

RetiSpec developed the retinal scanner at the Ontario Brain Institute in Canada. Clinical studies are ongoing in Israel and Canada.

In October, RetiSpec received the Alzheimers Drug Discovery Foundations Diagnostics Accelerator Award to fund continued development of its hyperspectral imaging technology.

This could allow doctors to compare brain scans taken over time from the same patient, and to differentiate between healthy and diseased brain tissue, without resorting to invasive or dangerous procedures such as brain tissue biopsies, explained lead researcher Dr. Aviv Mezer.

Clara is based on a relatively recent understanding that AD affects the brains orientation system before it affects memory.

The overlap between how the self is oriented to the world and the brain mechanisms that are disturbed by Alzheimers disease is astonishing, Arzy told ISRAEL21c.

Clara asks patients questions about themselves and their relationships to people, places and events. It then compares that information to a baseline and generates a computer-based test tailored for the individual that can diagnose very early Alzheimers.

The team from Dr. Shahar Arzys computational neuropsychiatry lab at Hadassah Hebrew University Medical Center in Jerusalem. Photo: courtesy

According to a study Arzys team published in the Proceedings of the National Academy of Sciences and in the American Psychological Associations journal Neuropsychology, Clara is 95 percent accurate.

Clara is now in the midst of a five-year test at Harvard to compare data generated by the system with data from AD markers taken via amyloid PET scan, quantitative and functional MRI and other neuropsychological tests.

Jaul and Oded Meiron (a cognitive neuroscientist who heads the Electrophysiology and Neuro-cognition Lab in Herzogs Clinical Research Center for Brain Sciences) published an articlein the Journal of Alzheimers Disease outlining their discovery of the link between the two conditions.

The reason is that the abnormal changes in the brain that lead to dementia are happening in other parts of the body, including the skin. Skin tissue and brain tissue derive from the same embryonic stem cells.

Jaul and Meiron are working with an American company to develop a test to identify a biomarker for abnormal cell density in the skin of dementia patients. They hope that this skin test could pinpoint an individuals type and stage of dementia. The biomarkers show the most promise in identifying AD, they say.

TREATMENT

A variety of approved medications for AD including Exelon, developed in Israel cannot cure or stop the progression of the disease. They only relieve or delay AD symptoms, such as memory loss and confusion.

A few Israeli pharmaceuticals under development aim to improve Alzheimer treatment options.

Breathing in pure oxygen in a pressurized room or chamber stimulates the release of growth factors and stem cells, which promote healing.

This revolutionary treatment for Alzheimers disease uses a hyperbaric oxygen chamber, which has been shown in the past to be extremely effective in treating wounds that were slow to heal, said lead researcher Prof. Uri Ashery.

Asherys group tested the therapy on a mouse model of Alzheimers disease. The treatment was found to reduce behavioral deficiencies compared to control mice.

Remarkably, the treatment also reduced plaque pathology and neuroinflammation in the test mice by about 40 percent.

Further research will investigate the underlying mechanisms of the therapy and evaluate its beneficial effects in Alzheimer patients.

Yotam Nisemblat, CEO of ProteKt Therapeutics. Photo: courtesy

Incubated at FutuRx in Ness Ziona, ProteKt was spun out of PKR kinase inhibitor research by University of Haifa Prof. Kobi Rosenblum. Inhibition of the enzyme PKR is a unique idea for improving memory consolidation.

Protein aggregation tends to increase with age and can lead to neurodegeneration because proteins can adopt an erroneous configuration, where theyre misfolded, explains Prof. Martin Kupiec.

The paper he and his colleagues published in Molecular Cell describes how removing glucose from a particular aggregated protein made the blob dissolve.

If the results can be replicated in more complex proteins, scientists will have a new research avenue toward treatments that could reverse the neurodegenerative effect of protein aggregates, Kupiec says.

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10 promising developments that can help Alzheimer's patients - ISRAEL21c

Eli Lilly touts $400M manufacturing expansion, 100 new jobs to much fanfare in Indianapolis even though it’s been chopping staff – Endpoints News

Hepatitis delta, also known as hepatitis D, is a liver infection caused by the hepatitis delta virus (HDV) that results in the most severe form of human viral hepatitis for which there is no approved therapy.

HDV is a single-stranded, circular RNA virus that requires the envelope protein (HBsAg) of the hepatitis B virus (HBV) for its own assembly. As a result, hepatitis delta virus (HDV) infection occurs only as a co-infection in individuals infected with HBV. However, HDV/HBV co-infections lead to more serious liver disease than HBV infection alone. HDV is associated with faster progression to liver fibrosis (progressing to cirrhosis in about 80% of individuals in 5-10 years), increased risk of liver cancer, and early decompensated cirrhosis and liver failure.HDV is the most severe form of viral hepatitis with no approved treatment.Approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not appreciably impact HBsAg and have no impact on HDV. Investigational agents in development for HBV target multiple new mechanisms. Aspirations are high, but a functional cure for HBV has not been achieved nor is one anticipated in the forseeable future. Without clearance of HBsAg, anti-HBV investigational treatments are not expected to impact the deadly course of HDV infection anytime soon.

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Eli Lilly touts $400M manufacturing expansion, 100 new jobs to much fanfare in Indianapolis even though it's been chopping staff - Endpoints News

Global Stem Cell Therapy for Osteoarthritis Market 2019 Growth Factors, Technological Innovation and Emerging Trends 2024 – News Appear

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GlobalStem Cell Therapy for Osteoarthritishas witnessed gradual growth in recent years and is expected to witness steady growth in the forecast period.In this report, theStem Cell Therapy for Osteoarthritismarket is valued at USD XX million in 2017 and is expected to reach USD XX million by the end of 2024, growing at a CAGR of XX% between 2019 and 2024.

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Furthermore, manufacturing cost structure combines analysis of key raw materials, their price trends along with labor cost and manufacturing expenses. For market chain analysis, the report covers upstream raw materials, equipment, downstream buyers, marketing channels, and market development trend which more deeply include important information on key distributors/traders, major raw materials suppliers and contact information, major manufacturing equipment suppliers, major suppliers, and key consumers.

The report profiles SWOT analysis and market strategies of the key players. Any individual or organization interested in the report can greatly benefit from it. The market research data added in the study is the result of extensive primary and secondary research activities, surveys, personal interviews, and inputs from industry expert.

Rex is the chief editor of News Appear. He has a stinct experience working as a journalist for Capital and Main.

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Global Stem Cell Therapy for Osteoarthritis Market 2019 Growth Factors, Technological Innovation and Emerging Trends 2024 - News Appear

Shark Tank Season 11 Episode 8 Everything About Gallant Stem Cell Bank For Dogs As Seen on Shark Tank! Unknown Facts – TheNewsCrunch

Gallant Stem Cell Therapy For Dogs is one of the product companies to be featured on Shark Tank Season 11 Episode 8. The story behind the birth of Gallant Stem Cell Therapy For Dogs is pretty interesting. Here are some of the unknown facts about Gallant and its founders, Aaron Hirschhorn.

Aaron Hirschhorn is the founder and former-CEO of the popular dog-sitting marketplace DogVacay. Aaron is a noted entrepreneur with more than 20 years of experience in building companies and investing in them. DogVacay app was launched in 2013 and Aaron managed to raise $47 million from his erstwhile investors.

Aaron was the finalist in the Ernst & Young Entrepreneur of the Year Award 2016. In April 2017, Aarons DogVacay app merged with Rover.com and eventually went on to become a $1 billion pet services marketplace.

Trouble struck Aarons life when he suffered a massive back injury and was forced to undergo stem cell treatment which yielded amazing results to his surprise. Aaron, being an ardent dog lover wondered why this cutting-edge medical technology of stem cell transplants cannot be applied to dogs.

As a result, Gallant was born in the middle of 2018. According to Gallant, Your pups stem cells haveincredible healing power. Extract and store these powerful cells during your pets spay/neuter, so that you can unleash their potential when your best friend needs it most.

Ever since its inception, the mission of Gallant stem cell therapy is to help pets live a healthier life and make use of the epic technology of stem cell therapy in saving the lives of tons of dogs.

Dogs enter their senior years around 7 and begin feeling the effects of aging as early as 4! Traditional methods of treatment for injury and age-related conditions are expensive and can have harmful side effects. Stem cells are incredible natural healers. However, up to 99% of stem cells are lost over time due to aging. This forms the bottomline of Gallants business problem.

Gallant raised $7 million investment in August 2019.

https://gallant.com/

From the moment you entrust Gallant with your dogs stem cells, were actively invested in their long-term health and well-being. Working in tandem with you and your veterinarian, we will collect and store these powerful cells now, so down the road we can help to treat the most common health problems your dog may face. We will also update you on new and potentially life-changing treatments as they become available.

Pick your pups stem cell storage plan you dont have to have a spay/neuter procedure scheduled yet! You can always add that in later. Our proprietary process requires no additional training, so any veterinarian you trust to alter your dog is qualified. Ahead of your dogs spay/neuter, we will connect with your vet and send our collection kit directly to their office.

2. Collect

On the big day, we align with your vet before the procedure and arrange for a courier. During your dogs spay/neuter procedure, your veterinarian will take out the stem cell-rich reproductive tissue they would normally discard into the collection kit.

3. Preserve

Once the tissue is received by our scientists, we send confirmation to both you and your veterinarian. Your dogs tissue is first inspected for quality before isolating the stem cells. The stem cells are then counted and frozen in liquid nitrogen to preserve their potency in our secure, state-of-the-art laboratory. Once this process is complete, you and your veterinarian will be notified that your pets stem cells are safely stored. The cells are then monitored by our team to ensure they stay perfectly preserved.

4. Treat

Your pets stem cells are at the ready to be sent to your veterinarian if/when treatment is needed. Treatments are out-patient procedures and cost about $300. A stem cell procedure is not painful to your pet and does not require anesthesia to administer.

Gallants stem cell therapy is receiving a lot of exciting reviews online. The therapy has been successful in saving scores of dogs with conditions like osteoarthritis, skin conditions, chronic dry eye.

Gallant is offering a $395 off discount for using the code SHARKTANK

How did Gallant fare in Shark Tank Season 11? What did the Sharks have to tell about it? Did Gallant Get a Deal on Shark Tank? More information to be updated soon in this post.

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Shark Tank Season 11 Episode 8 Everything About Gallant Stem Cell Bank For Dogs As Seen on Shark Tank! Unknown Facts - TheNewsCrunch