On June 30, 2015 CytRx reported unveiled its proprietary LADR (Linker Activated Drug Release) technology platform, a discovery engine designed to leverage the Company’s expertise in albumin biology and linker technology for the development of a new class of anti-cancer therapies (Press release, CytRx, JUN 30, 2015, View Source [SID:1234506012]). Schedule your 30 min Free 1stOncology Demo! CytRx expects the LADR platform to rapidly expand its pipeline of oncology drug candidates, providing an avenue for the development of propriety drug candidates that complement its global Phase 3 aldoxorubicin program. Among the cancers being pursued are liver, pancreatic, and non-small cell lung cancer.
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"LADR is a creative, novel approach to the development of next-generation therapeutic drug conjugates, which we have rationally designed to control release in tumors of high-potency chemotherapeutics that are attached to either albumin or anti-cancer antibodies," stated Dr. Felix Kratz, Vice President of Drug Discovery at CytRx. "These therapies have release properties that minimize their toxic effects on non-cancerous cells, may substantially reduce drug resistance and maximize their anti-cancer potency. With the first drug candidates from this platform expected to enter the clinic in 2016, we look forward to further validating the great potential of this platform in the near future. Our LADR Technology can also be easily combined with immunotherapies to potentially improve outcomes."
"CytRx is committed to improving and extending the lives of patients with cancer through the development of new and innovative therapies," said Steven A. Kriegsman, Chairman and CEO of CytRx. "LADR is an important platform, one that combines our deep knowledge of albumin biology with cutting-edge chemistry and linker technology to deliver a highly potent next-generation albumin and antibody drug conjugate (ADC) drug candidates for cancer treatment. We believe this platform provides us with a number of avenues for near- and long-term value creation."
LADR Platform Mechanism
LADR technology was invented and developed by CytRx at its laboratories in Freiberg, Germany. The platform employs a portfolio of novel linker molecules that bind to albumin in the blood and could also be tied to a variety of antibodies, including antibodies directed at cancer targets. Because of the linker’s ability to modulate release of the highly potent chemotherapy drugs attached to them at the site of cancer cells, it may be possible to reduce toxicity and increase efficacy using these conjugates.
As Dr. Kratz has previously demonstrated, these drug conjugates can form a covalent bond to albumin, the most abundant protein in the blood stream, almost instantaneously. The cytotoxic drug is then held inactive while it circulates throughout the body. Due to highly dysfunctional vasculature surrounding tumors, macromolecules like albumin are able to leak out of the blood vessel and into the tumor itself. This allows for the albumin-bound drug conjugate to accumulate at the tumor but avoid concentration in less permeable normal tissues. The linkers then allow the controlled release of selected payload agents under a variety of conditions that are present in tumors, such as low pH levels. Cleaving of the linker occurs within specific compartments in the cancer cells or can occur in the acidic conditions in and around the tumor. Since most normal tissues are not acidic, the linker does not release the drug, thereby minimizing toxicity to healthy tissues.
Once released in the tumor, the payload induces cell death based on the selected molecule. In current candidates under preclinical development, CytRx has bound very high potency drugs (10-1,000x more potent than standard chemotherapeutics), as well as modified standard chemotherapeutics that are able to avoid drug resistance mechanisms. The first group of these drugs are expected to enter the clinic in 2016.
Broad Intellectual Property Portfolio Covering LADR Technology
CytRx has filed a patent application including comprehensive claims directed to the LADR (Linker Activated Drug Release) technology platform, and compositions of matter and methods related to the technology.
Author: [email protected]
8-K – Current report
On June 29, 2015 Cellular Biomedicine Group reported it has completed the previously announced acquisition of Blackbird Bio Finance and University of South Florida’s ("Licensor") next generation GVAX vaccine’s ("CD40LGVAX") related technologies and technical knowledge (Filing, 8-K, Cellular Biomedicine Group, JUN 29, 2015, View Source [SID:1234506026]). With the close of this acquisition, management believes that the Company will be able to offer comprehensive immuno-oncology cell therapy portfolios, as well as a broad set of options for patients.
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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
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Dr. William (Wei) Cao, Chief Executive Officer of CBMG, commented: "We are extremely pleased with this strategic acquisition which strengthens our cancer immunotherapy vaccine and vaccine combination technology platform. This inroad into the U.S. market is a significant strategic milestone for the Company and we look forward to seeking approval to conduct international clinical trials with leading medical centers."
Under the terms of the agreement, CBMG will pay an initial consideration of $2.5 million in cash and up to $1.75 million in shares of the Company’s Common Stock which is based on the 20-day volume weighted average price ("VWAP") of the Company’s Common Stock on the closing date of June 29, 2015. As a licensee of CD40LGVAX, the Company could pay potentially more than $25M in future milestone and sales royalty payments to the Licensor. Additional information can be found in the Form 8-K filed by Cellular Biomedicine Group with the Securities and Exchange Commission on June 12, 2015.
Epizyme to Present Clinical Data from Ongoing Phase 1 Dose Escalation Trial of Tazemetostat (EPZ-6438) at the European Cancer Congress
On June 29, 2015 Epizyme reported that updated data from the phase 1 portion of its ongoing phase 1/2 study of tazemetostat will be presented during the European Cancer Congress 2015, hosted by the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper), to be held in Vienna, Austria, September 25-28, 2015 (Press release, Epizyme, JUN 29, 2015, View Source [SID:1234506010]). Tazemetostat is a first-in-class EZH2 inhibitor that Epizyme is currently studying in patients with relapsed or refractory B-cell non-Hodgkin lymphomas (NHL) and advanced solid tumors, including INI1-deficient tumors.
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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
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A Phase 1 Study of EPZ-6438 (E7438), an Enhancer of Zeste-Homolog 2 (EZH2)
Inhibitor: Preliminary Activity in INI1-negative Tumors
Speaker: Antonine Italiano, M.D., Ph.D., Institut Bergonié, Bourdeaux, France
Session Title: Proffered Paper Session: Early Drug Development (Hall C1)
Session Date/Time: Saturday, September 26, 10:30 a.m. -12:30 p.m. CET
About EZH2 in Cancer
EZH2 is a histone methyltransferase (HMT) that is increasingly understood to play a potentially oncogenic role in a number of cancers. These include non-Hodgkin lymphomas, INI1-deficient cancers such as malignant rhabdoid tumors, epithelioid sarcomas and synovial sarcoma; and a range of other solid tumors.
About Tazemetostat
Epizyme is developing tazemetostat for the treatment of non-Hodgkin lymphoma patients and patients with INI1-deficient solid tumors. Tazemetostat is a first-in-class small molecule inhibitor of EZH2 created by Epizyme using its proprietary product platform. In some human cancers, aberrant EZH2 enzyme activity results in misregulation of genes that control cell proliferation resulting in the rapid and unconstrained growth of tumor cells. Tazemetostat is the WHO International Non-Proprietary Name (INN) for compound EPZ-6438.
Tazemetostat is the second HMT inhibitor to enter human clinical development (following Epizyme’s DOT1L inhibitor, pinometostat, also known as EPZ-5676).
Additional information about this program, including clinical trial information, may be found here: View Source
CBMG Completes Acquisition of CD40LGVAX Vaccine
On June 29, 2015 Cellular Biomedicine Group reported it has completed the previously announced acquisition of Blackbird Bio Finance and University of South Florida’s ("Licensor") next generation GVAX vaccine’s ("CD40LGVAX") related technologies and technical knowledge (Press release, Cellular Biomedicine Group, JUN 29, 2015, View Source [SID:1234506003]). With the close of this acquisition, management believes that the Company will be able to offer comprehensive immuno-oncology cell therapy portfolios, as well as a broad set of options for patients.
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Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
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Dr. William (Wei) Cao, Chief Executive Officer of CBMG, commented: "We are extremely pleased with this strategic acquisition which strengthens our cancer immunotherapy vaccine and vaccine combination technology platform. This inroad into the U.S. market is a significant milestone for the Company and we look forward to seeking approval to conduct international clinical trials with leading medical centers."
Under the terms of the agreement, CBMG will pay an initial consideration of $2.5 million in cash and up to $1.75 million in shares of the Company’s Common Stock, which is based on the 20-day volume, weighted average price ("VWAP") of the Company’s Common Stock on the closing date of June 26, 2015. As a licensee of CD40LGVAX, the Company could pay potentially more than $25M in future milestone and sales royalty payments to the Licensor. Additional information can be found in the Form 8-K filed by Cellular Biomedicine Group with the Securities and Exchange Commission on June 12, 2015.
Merck Announces Phase 3 Study of Single-Dose EMEND® (fosaprepitant dimeglumine) for Injection Regimen Met Primary Endpoint in Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy
On June 29, 2015 Merck reported results from a Phase 3 study investigating the safety and efficacy of single-dose EMEND (fosaprepitant dimeglumine) for Injection, Merck’s substance P/neurokinin (NK-1) receptor antagonist, in combination with other anti-vomiting medicines, for the prevention of chemotherapy-induced nausea and vomiting (CINV) in adult cancer patients receiving moderately emetogenic (vomit-inducing) chemotherapy (MEC) (Press release, Merck & Co, JUN 29, 2015, View Source [SID:1234506001]). In the study, the first to evaluate an intravenous NK-1 receptor antagonist for the prevention of CINV associated with MEC, the single-dose EMEND for Injection regimen provided greater protection from nausea and vomiting following administration of chemotherapy versus an active control of placebo with other anti-vomiting medicines. These data were presented in an oral session at the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Annual Meeting on Supportive Care in Cancer (Abstract #27-02-O) in Copenhagen (June 25-27, 2015).
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"The results from this important Phase 3 trial are very encouraging as they are the first study to evaluate EMEND for Injection in a combination regimen for the prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy – and show the potential to use a single day antiemetic regimen," said Dr. Bernardo L. Rapoport, principal investigator for the study and chief medical oncologist, Medical Oncology Centre of Rosebank, Johannesburg, South Africa.
"Nausea and vomiting remain a significant burden for patients receiving chemotherapy and we look forward to submitting these data for EMEND for Injection to the U.S. Food and Drug Administration," said Stuart Green, vice president, clinical research, Merck Research Laboratories. "This study builds on our decade of research for EMEND and Merck’s overall commitment to help people with cancer."
EMEND for Injection, a substance P/Neurokinin-1 (NK1) receptor antagonist approved for use in combination with other antiemetic agents, is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer (HEC) chemotherapy, including high-dose cisplatin; and for prevention of nausea and vomiting associated with initial and repeat courses of MEC. EMEND has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND is not recommended.
In the U.S., the single-dose regimen of EMEND for Injection is approved for use associated with HEC. Merck plans to submit these recent data to the Food and Drug Administration in the second half of 2015 to seek approval for a regimen containing single-dose EMEND for Injection for the prevention of CINV associated with MEC.
About Phase 3 Study for Single-Dose EMEND for Injection in MEC
In this global randomized, Phase 3, double-blind study, more than 1,000 patients receiving MEC were randomly assigned to receive either single-dose EMEND for Injection (150 mg) in combination with ondansetron capsules (16 mg) and dexamethasone capsules (12 mg) (n=504) on day one (followed by oral placebo for ondansetron on days two and three) or an active control regimen consisting of placebo (saline IV) in combination with ondansetron (16 mg) and dexamethasone (20 mg) (n=497) on day one (followed by 8 mg ondansetron on days two and three). The primary endpoint of the study was complete response (CR) (as measured by no vomiting and no use of rescue medication for nausea or vomiting) in the delayed phase (25 to 120 hours following initiation of chemotherapy). The secondary endpoints were CR after the first dose of chemotherapy in the acute phase (0 to 24 hours) and in the overall phase (0-120 hours), as well as no vomiting in the overall phase.
Single-Dose EMEND for Injection Regimen Achieved Superior Control of CINV
For the primary study endpoint, EMEND for Injection regimen provided higher incidence of CR in days 2 through 5 – with CR observed in 78.9 percent of patients receiving the EMEND for Injection regimen versus 68.5 percent in the active control group (p <0.001). For the secondary endpoints, in the acute phase, CR was observed in 93.2 percent of patients receiving the EMEND for Injection regimen versus 91 percent in the active control group (p = 0.184). In the overall phase, the incidence of CR was observed in 77.1 percent of patients receiving the EMEND for Injection regimen versus 66.9 percent in the active control group (p <0.001). Additionally, a significantly greater proportion of patients receiving the EMEND for Injection regimen experienced no vomiting in the overall phase (82.7 percent with EMEND vs 72.9 percent in the active control group) and delayed phase (83.9 percent with EMEND vs 75.1 percent in the active control group) (both p <0.001) – with a favorable trend in the acute phase (94.8 percent with EMEND vs 92 percent in the active control group).
The most common adverse events (across all grades) in the EMEND for Injection regimen and active control group included fatigue (15.1 percent and 12.9 percent), diarrhea (12.7 percent and 11.3 percent), and constipation (9.3 percent and 10.5 percent). Treatment-related adverse events were observed in 8.5 percent of patients receiving the EMEND for Injection regimen and in 9.1 percent of patients in the active control group. Serious treatment-related adverse events were observed in 0.2 percent of patients receiving the EMEND for Injection regimen and in 0.4 percent of patients in the active control group.
Selected Important Safety Information for EMEND (fosaprepitant dimeglumine) For Injection
EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions.
Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions.
EMEND for Injection should be used with caution in patients receiving concomitant medications, including chemotherapy agents that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND for Injection could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND for Injection is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND for Injection is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant.
Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine.
Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied.
There have been isolated reports of immediate hypersensitivity reactions, including flushing, erythema, dyspnea, and anaphylaxis, during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who have experienced these symptoms during first-time use.
Coadministration of EMEND for Injection with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND for Injection with each chemotherapy cycle.
The efficacy of hormonal contraceptives (including birth control pills, skin patches, implants, and certain IUDs) may be reduced during coadministration with and for 28 days after the last dose of EMEND for Injection. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND for Injection.
Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use.
In clinical trials of EMEND in patients receiving HEC, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence of 1% or greater, were hiccups (4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue (2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST (1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5% vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%), and anorexia (2.0% vs 0.5%).
In a clinical trial evaluating safety of the 1-day regimen of EMEND for Injection compared with the 3-day regimen of EMEND, the safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients who received fosaprepitant (3.0%) than in those who received aprepitant (0.5%). Those infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.
About Chemotherapy Induced Nausea and Vomiting (CINV)
Chemotherapy Induced Nausea and Vomiting (CINV) is a common side effect of chemotherapy caused by injured stomach cells that start the process of nausea and vomiting and can directly activate the area of the brain responsible for producing nausea and vomiting. The two main types of CINV are acute and delayed. Acute happens within the first 24 hours of receiving chemotherapy. Delayed happens from day 2 to day 5 after chemotherapy. The amount and timing of CINV can vary. Some chemotherapies cause acute nausea and vomiting. Others cause acute nausea and vomiting followed by another period of delayed nausea and vomiting.