Synthetic stress hormone dexamethasone could reduce certain breast cancer metastases

The drug dexamethasone supplements cancer treatments to alleviate side effects of chemotherapy such as nausea or inflammation. Researchers at the University of Basel, Switzerland, have now discovered that it also fights metastases in certain types of breast cancer.

The active substance dexamethasone is a synthetic signaling substance with a similar effect to the body's own stress hormone cortisol. A research group at the University of Basel has found evidence that this drug, which has been in use for a long time, could have a new, additional effect on certain treatment-resistant breast cancers.

Breast cancer of the "estrogen receptor-positive" (ER+ for short) subtype can usually be treated with anti-hormonal therapy. The target of this therapy is the estrogen receptor, which is hyperactive in these tumors and drives abnormal cell division. Hormone therapy uses drugs that deactivate or break down the estrogen receptor, thereby slowing the growth of cancer cells. However, this type of tumor sometimes forms metastases that no longer respond to hormone therapy.

Fewer metastases

A research team led by Professor Mohamed Bentires-Alj from the Department of Biomedicine at the University of Basel and the University Hospital Basel reports in the journal EMBO Molecular Medicine that dexamethasone can combat precisely these therapy-resistant metastases. In trials with mice with therapy-resistant ER+ tumors, dexamethasone reduced liver metastases and prolonged the animals' survival.

Further analyses provided more detailed insights into how the drug achieves this effect: dexamethasone activates the glucocorticoid receptor. This, in turn, suppresses the production of the estrogen receptor. "As a result, the cancer cells lose the main driver of tumor growth," explains Dr. Madhuri Manivannan, lead author of the study.

In addition to the trials with mice, the researchers also used patient-derived tumor tissue grown in the laboratory known as organoids. Here, they also observed that the amount of estrogen receptor decreased with the addition of dexamethasone

https://en.wikipedia.org/wiki/Dexamethasone

Synthetic stress hormone dexamethasone could reduce certain breast cancer metastases

U.S. Food and Drug Administration Accepts Bristol Myers Squibb's New Drug Application for Iberdomide in Patients with Relapsed or Refractory Multiple Myeloma

Bristol Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for iberdomide combined with standard treatment (daratumumab + dexamethasone - IberDd) in patients with relapsed or refractory multiple myeloma (RRMM). Iberdomide is part of an investigational, new class of medicines called cereblon E3 ligase modulator (CELMoD) agents. The FDA has granted a Prescription Drug User Fee Act (PDUFA) date of August 17, 2026 for this indication.

• Iberdomide has the potential to be the first approved CELMoD agent
• The U.S. FDA has granted Breakthrough Therapy Designation and Priority Review for this indication and assigned a target action date of August 17, 2026

“The FDA’s acceptance of this application is a testament to the potential of iberdomide, in combination with anti-CD38 monoclonal antibodies, as a novel, potent, oral treatment option, with a manageable safety profile, for patients with multiple myeloma,” said Cristian Massacesi, executive vice president and chief medical officer, Bristol Myers Squibb. “Furthermore, our filing for iberdomide based on the MRD endpoint, underscores our commitment to pioneering new ways of advancing life-saving therapies for patients living with cancer.”

The filing was based on results from a planned analysis of MRD negativity rates in the Phase 3 EXCALIBER-RRMM study evaluating iberdomide as a treatment for RRMM patients. The EXCALIBER-RRMM trial is ongoing and patients continue to be evaluated for progression-free survival (PFS).

The FDA also granted Breakthrough Therapy designation for iberdomide based on these data.

This review is being conducted under the FDA’s Project Orbis initiative, which enables concurrent review by the health authorities in several other countries.

https://en.wikipedia.org/wiki/Iberdomide

U.S. Food and Drug Administration Accepts Bristol Myers Squibb's New Drug Application for Iberdomide in Patients with Relapsed or Refractory Multiple Myeloma

Selinexor Offers Hope Against a Tough-to-Treat Blood Cancer

In continuation of my update on Selinexor

Patients with a form of blood cancer known as multiple myeloma who haven't responded to other therapies might have a new weapon against the disease, researchers say.

A drug called selinexor appeared to help patients with the blood and bone marrow cancer, according to a clinical trial involving 122 people.

"This study proved that a novel, first-in-class drug with a new mechanism of action can kill a patient's cancer cells," said study senior author Dr. Sundar Jagannath. He directs the multiple myeloma program at the Tisch Cancer Institute at Mount Sinai in New York City.

Selinexor also "worked in patients who had exhausted every other treatment and who would have been placed on hospice care otherwise," Jagannath said in a hospital news release.

In the trial, which was funded by the drug's maker, Karyopharm, patients at centers in the United States and Europe received a combination therapy of two pills, selinexor and the standard anti-cancer medicine dexamethasone.

As reported in the Aug. 22 issue of the New England Journal of Medicine, nearly 40% of the patients showed at least a minimal response to the therapy within one or two months. There were "significant" responses in more than a quarter of the patients, the researchers said, and two patients had their cancers go into complete remission.

As the team explained, selinexor works in a new way to fight myeloma, blocking a key mechanism in cancer cell growth and causing the cell to die.

Although the drug caused no toxicity to organs, there were side effects for some patients. These included low blood counts without bleeding, nausea, vomiting, lack of appetite or fatigue.

The U.S. Food and Drug Administration had already approved selinexor in early July to treat patients with multiple myeloma resistant to multiple therapies.

"This study is meaningful for patients with multiple myeloma who haven't had success on multiple other therapies," said study first author Dr. Ajai Chari, director of clinical research in the multiple myeloma program at the Tisch Cancer Institute.

"An increasing number of patients have resistance to the standard drugs used in the treatment of multiple myeloma, and the overall survival in these patients is short, sometimes less than three months," Chari said in the news release.

One myeloma expert unconnected to the research was heartened by the findings.

The trial results are "cautiously positive and very encouraging," said hematologist Dr. Kanti Rai. He works in the CLL Research and Treatment Program at Northwell Health Cancer Institute in New Hyde Park, N.Y.

Rai noted that while newer drugs are helping many multiple myeloma patients, others are still left without viable treatment options.

"The need for better treatments is especially urgent for those patients who are elderly, have compromised functions of other vital organs, have had multiple chemotherapy regimens in the past and still have evidence of progressive disease," he explained. "For such patients, unfortunately, death seems imminent."

Rai called the advent of selinexor "a positive step forward for patients with myeloma who otherwise have no hope for the future."

For their part, the Tisch researchers said they are also assessing selinexor for treatment of multiple myeloma in combination with other approved multiple myeloma drugs, as well for treatment of other cancers such lymphoma and ovarian cancer.

https://en.wikipedia.org/wiki/Selinexor

FDA Approves Xpovio (selinexor) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma

In continuation of my update on Selinexor

Karyopharm Therapeutics Inc. an oncology-focused pharmaceutical company, announced that the U.S. Food and Drug Administration (FDA) has approved oral Xpovio (selinexor), a nuclear export inhibitor, in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The ongoing, randomized Phase 3 BOSTON study evaluating selinexor in combination with Velcade® (bortezomib) and low-dose dexamethasone will serve as the confirmatory trial. The FDA’s Accelerated Approval Program was developed to allow for expedited approval of drugs that treat serious conditions and that fill an unmet medical need.  

Karyopharm expects Xpovio to become commercially available in the U.S. on or before July 10, 2019.  A Marketing Authorization Application for selinexor is also currently under review by the European Medicines Agency.

“With today’s accelerated approval of Xpovio by the FDA, patients with heavily pretreated multiple myeloma will now have a new therapeutic option to treat their disease,” said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. “Discovering, developing and securing FDA approval for XPOVIO with its novel mechanism of action over the past decade required the dedication of many people, including the patients, caregivers and physicians involved in our clinical trials, along with the many employees at Karyopharm.  We are tremendously grateful for everyone’s contributions to this important milestone, and we look forward to the next stage in our pursuit of improving the lives of patients with cancer.”

“The 25.3% response rate seen in the subgroup of 83 patients in the pivotal Phase 2b STORM study that served as the basis for Xpovio's accelerated approval is clinically meaningful and a validated surrogate marker for clinical benefit in our patients with advanced refractory disease,” said Sundar Jagannath, MD, Director of the Multiple Myeloma Program, Professor of Medicine (Hematology and Medical Oncology) at Tisch Cancer Institute at Mount Sinai School of Medicine, and principal investigator of the STORM study.

“Despite recent advances in the treatment of multiple myeloma, almost all our patients will develop disease that is resistant to the five most commonly used anti-myeloma drugs we currently have available, and the prognosis for this patient population is particularly poor.  The accelerated approval of oral Xpovio marks an important advance in the treatment paradigm for patients with relapsed refractory multiple myeloma, and in my view, is an important addition to our therapeutic armamentarium,” said Dr. Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute.

Michael G. Kauffman, MD, PhD, Chief Executive Officer of Karyopharm, commented, “Having worked on novel drugs in myeloma beginning with Velcade in the year 2000, I have been thrilled to see such exciting progress overall in the field where there are substantial increases in patients’ duration and quality of life.  The accelerated approval of oral Xpovio targeting XPO1 represents the first approval against a new target in myeloma since 2015, and we look forward to advancing the further clinical development of Xpovio.”

https://pubchem.ncbi.nlm.nih.gov/compound/Selinexor

Ocular Therapeutix Announces FDA Approval of Dextenza (dexamethasone intracanalicular insert) for the Treatment of Ocular Inflammation Following Ophthalmic Surgery

In continuation of my update on Dextenza 

Ocular Therapeutix™, Inc. ), a biopharmaceutical company focused on the formulation, development, and commercialization of innovative therapies for diseases and conditions of the eye,   announced the U.S. Food and Drug Administration (FDA) approved a Supplemental New Drug Application (sNDA) for Dextenza to include the treatment of ocular inflammation following ophthalmic surgery as an additional indication. With the approval of the sNDA, Dextenza is now approved for the treatment of both ocular inflammation and pain following ophthalmic surgery.

Dextenza is the first FDA-approved intracanalicular insert, a novel route of administration that delivers drug to the surface of the eye without the need for eye drops. Dextenza is a preservative-free, resorbable hydrogel insert that delivers 0.4mg of dexamethasone to treat post-surgical ocular inflammation and pain for up to 30 days with a single administration. Dextenza originally received FDA approval in November 2018 for the treatment of ocular pain following ophthalmic surgery.

“We could not be more excited about both the approval and its earlier-than-expected timing,” said Antony Mattessich, the Company’s President and Chief Executive Officer. “With our C-Code and pass-through payment status effective on July 1, the expanded indication gives us tremendous momentum as we approach our commercial launch.”

The approval of the sNDA is supported by three Phase 3 randomized, vehicle-controlled trials; patients received Dextenza or a vehicle immediately upon completion of cataract surgery. In all three trials, Dextenza had, at a statistically significant level, a higher proportion of patients than the vehicle group who were pain free on post-operative Day 8. On post-operative Day 14, in two of the three studies, Dextenza had a higher proportion of patients than the vehicle group, at a statistically significant level, who had an absence of anterior chamber cells.

http://www.chemdiv.com/dextenza-dexamethasone-ophthalmic-insert-first-intracanalicular-insert-drug-delivery/

Karyopharm Announces FDA Extension of Review Period for Selinexor New Drug Application

  

Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a clinical-stage pharmaceutical company,  announced that the U.S. Food and Drug Administration (FDA) has extended the Prescription Drug User Fee Act (PDUFA) action date for the New Drug Application (NDA) for selinexor. The NDA, which is currently under Priority Review by the FDA, is seeking accelerated approval for selinexor in combination with dexamethasone for the treatment of patients with relapsed refractory multiple myeloma who have received at least three prior therapies and whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and one anti-CD38 monoclonal antibody. The previously disclosed April 6, 2019 PDUFA date has been extended by three months to July 6, 2019.

On February 26, 2019, the FDA'sOncologic Drugs Advisory Committee (ODAC) met to discuss the selinexor NDA and voted 8 to 5 recommending that the FDA wait for the results from Karyopharm's randomized, open-label, Phase 3 BOSTON study evaluating selinexor in patients with relapsed or refractory multiple myeloma, before making a final decision regarding approval.  Although the FDA considers the recommendation of this panel, the final decision regarding the approval of the product is made by the FDA solely, and the recommendations by the panel are non-binding.

Following the ODAC meeting, at the FDA's request,  Karyopharm submitted additional, existing clinical information as an amendment to the NDA, which allowed the FDA to extend the PDUFA action date by three months. "We look forward to the continued collaboration with FDA in trying to meet the needs of patients with relapsed refractory multiple myeloma," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm.

About Selinexor

Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. In 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with triple class refractory multiple myeloma who have been previously exposed to all five of the most commonly prescribed anti-myeloma therapies currently available. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm's New Drug Application (NDA) has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients with triple class refractory multiple myeloma. The Company has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval and was granted accelerated assessment. Selinexor is also being studied in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In 2018, Karyopharm reported positive top-line results from the Phase 2b SADAL study evaluating selinexor in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue. Selinexor has received Fast Track designation from the FDA for the patient population evaluated in the SADAL study.  Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL), and an investigator-sponsored study in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm's clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

https://pubchem.ncbi.nlm.nih.gov/compound/Selinexor#section=2D-Structure

Karyopharm Announces FDA Extension of Review Period for Selinexor New Drug Application

FDA Approves Dextenza (dexamethasone ophthalmic insert) for the Treatment of Ocular Pain Following Ophthalmic Surgery

In continuation of my update on Dexamethasone

Ocular Therapeutix™, Inc. a biopharmaceutical company focused on the formulation, development, and commercialization of innovative therapies for diseases and conditions of the eye, today announced that the U.S. Food and Drug Administration (FDA) has approved Dextenza (dexamethasone ophthalmic insert) 0.4mg for intracanalicular use for the treatment of ocular pain following ophthalmic surgery.

“We are extremely pleased to announce the approval of Dextenza, coming so soon after our pre-approval inspection and approximately one month ahead of the PDUFA date,” said Antony Mattessich, the Company’s President and Chief Executive Officer. “Just over a year ago, we set out to augment our scientific and formulation expertise with individuals who have the skills and experience to create a first-class team to get Dextenza approved and become a commercial stage biopharmaceutical company. We believe this approval is a major external validation of the drug delivery technology platform, and also of the transformation that has taken place at Ocular. While we are excited by the approval of our first drug product, our goal has always been to bring Dextenza to as many patients as possible in the near term and to revolutionize ophthalmic drug delivery by making drops obsolete. We now turn our efforts towards the successful commercial launch of Dextenza.”

Dextenza is the first FDA-approved intracanalicular insert delivering dexamethasone to treat post-surgical ocular pain for up to 30 days with a single administration. The approval of Dextenza was based on (i) demonstrated efficacy in two randomized, vehicle-controlled Phase 3 studies in which a statistically significantly higher incidence of subjects were pain free at day 8 post-cataract surgery compared to the vehicle control group and (ii) safety in the two Phase 3 studies as well as a third randomized, vehicle-controlled Phase 2 study. The Company believes the delivery profile represents a differentiated and potentially transformational new product for patients and physicians. For patients, Dextenza offers the convenience of a full course of post-surgical steroid treatment with a physician’s one-time placement of a single intracanalicular insert. Dextenza has the potential to replace a complex eye drop regimen that under the current standard of care requires up to 70 topical ocular steroid drops.

“Compliance with taking eye drops after eye surgery is very challenging for patients and a concern for surgeons,” said Michael Goldstein, MD, Chief Medical Officer. “The approval of Dextenza offers surgeons the opportunity to treat patients with a preservative-free steroid after surgery with the placement of a single drug insert. With this product, patients may be liberated from having to deal with the burdensome regimen of using steroid eye drops after ophthalmic surgery.”

In connection with the commercial launch of Dextenza, Ocular Therapeutix also submitted an application for transitional pass-through payment status after receiving FDA approval and intends to submit an application for a J-code ahead of the January 2019 deadline.

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FDA Approves Dextenza (dexamethasone ophthalmic insert) for the Treatment of Ocular Pain Following Ophthalmic Surgery

FDA Approves Intravenous Formulation of Akynzeo (fosnetupitant/palonosetron) for Chemotherapy-Induced Nausea and Vomiting

Helsinn, a Swiss pharmaceutical group focused on building quality cancer care products, today announces that the U.S. Food and Drug Administration (FDA) has approved the intravenous formulation of Akynzeo (NEPA, a fixed antiemetic combination of fosnetupitant, 235mg, and palonosetron, 0.25mg) as an alternative treatment option for patients experiencing CINV.

     

The FDA has approved Akynzeo IV (formulation of fosnetupitant first structure  and palonosetron second structure) in combination with dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Akynzeo for injection has not been studied for the prevention of nausea and vomiting associated with anthracycline plus cyclophosphamide chemotherapy.

Oral Akynzeo was previously approved by the FDA as a fixed combination oral agent in 2014 for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Akynzeo is an oral fixed combination of palonosetron and netupitant: palonosetron prevents nausea and vomiting during the acute phase and netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.

The bioequivalence of the IV with the oral formulation of netupitant was demonstrated and the safety of IV NEPA was established through a repeated dose safety study in cancer patients to potentially uncover adverse drug reactions that may appear during subsequent clinical practice. No anaphylactic and injection site reactions related to IV NEPA were reported in this study.

Currently a repeated dose safety study is ongoing in patients receiving anthracycline plus cyclophosphamide to further establish the safety profile in this setting.

The prevention of CINV has been refined in treatment guidelines over the past several decades. Currently the combination treatment of antiemetic medicines with different mechanisms of actions are recommended for the prevention of CINV.

The approval of Akynzeo in IV formulation will offer to US patients and healthcare providers an alternative route of administration of the only fixed antiemetic combination targeting two distinct CINV pathways in a single dose.

Riccardo Braglia, Helsinn Group Vice Chairman and CEO, commented: “The approval of the intravenous formulation of Akynzeo paves the way to bring this important therapeutic option to more patients in a new formulation, and we are delighted that we are now able to push ahead with launching this product in the United States in May 2018”

FDA Approves Intravenous Formulation of Akynzeo (fosnetupitant/palonosetron) for Chemotherapy-Induced Nausea and Vomiting

Tesaro Announces U.S. FDA Approval of Varubi IV for Delayed Nausea and Vomiting Associated With Cancer Chemotherapy

In continuation of my update on Varubi (rolapitant)

Tesaro, Inc.  an oncology-focused biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved Varubi (rolapitant) IV in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Delayed nausea and vomiting can occur anytime between 25 and 120 hours following chemotherapy, and is often extremely debilitating.

About Varubi

Varubi is a highly selective and competitive antagonist of human substance P/neurokinin 1 (NK-1) receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV). With a long plasma half-life of approximately seven days, a single dose of Varubi, as part of an antiemetic regimen, significantly improved complete response (CR) rates in the delayed phase of CINV. Results from three Phase 3 trials of Varubi oral tablets demonstrated a significant reduction in episodes of vomiting or use of rescue medication during the 25- to 120-hour period following administration of highly emetogenic and moderately emetogenic chemotherapy regimens. In addition, patients who received Varubi reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy. Results from a bioequivalence trial demonstrated comparability of the IV and oral formulations of Varubi.

Varubi IV is supplied in ready-to-use vials and does not require refrigerated storage or mixing. As a result, utilization in busy chemotherapy clinics is straightforward and easily adopted into existing practice patterns for administration of antiemetic regimens associated with emetogenic chemotherapy. Varubi IV is to be administered up to two hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone. No dosage adjustment is required for dexamethasone, a CYP3A4 substrate, and Varubi is the first intravenously administered NK-1 receptor antagonist approved by the FDA that does not contain polysorbate 80.

“The approval of Varubi IV represents a significant milestone for TESARO. The majority of NK-1 receptor antagonist doses are administered intravenously in the U.S., and with the introduction of Varubi IV, we now offer healthcare providers a unique, easy-to-use option that fits well into standard operating practices of a chemotherapy clinic or hospital,” said Mary Lynne Hedley, Ph.D., President and COO of TESARO. “We will continue our efforts to expand awareness of delayed chemotherapy-induced nausea and vomiting, and plan to make this important medicine available next month.”

“Many healthcare providers tend to believe that CINV is no longer an unmet need but the reality is that more than half of patients treated with emetogenic chemotherapy experience delayed CINV, even when prescribed standard preventative therapies, such as a 5-HT3 receptor antagonist and dexamethasone,” said Lee Schwartzberg, M.D., Professor of Medicine at University of Tennessee Health Science Center. “The FDA approval of VARUBI IV gives doctors and nurses a new option to help protect their patients from these often preventable side effects.”

Tesaro Announces U.S. FDA Approval of Varubi IV for Delayed Nausea and Vomiting Associated With Cancer Chemotherapy

Tesaro Announces U.S. FDA Approval of Varubi IV for Delayed Nausea and Vomiting Associated With Cancer Chemotherapy

       

In continuation of my update on rolapitant

Tesaro, Inc., an oncology-focused biopharmaceutical company, announced that the U.S. Food and Drug Administration (FDA) has approved Varubi (rolapitant) IV in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Delayed nausea and vomiting can occur anytime between 25 and 120 hours following chemotherapy, and is often extremely debilitating.

About Varubi

Varubi is a highly selective and competitive antagonist of human substance P/neurokinin 1 (NK-1) receptors, which play an important role in the delayed phase of chemotherapy-induced nausea and vomiting (CINV). With a long plasma half-life of approximately seven days, a single dose of Varubi, as part of an antiemetic regimen, significantly improved complete response (CR) rates in the delayed phase of CINV. Results from three Phase 3 trials of Varubi oral tablets demonstrated a significant reduction in episodes of vomiting or use of rescue medication during the 25- to 120-hour period following administration of highly emetogenic and moderately emetogenic chemotherapy regimens. In addition, patients who received Varubi reported experiencing less nausea that interfered with normal daily life and fewer episodes of vomiting or retching over multiple cycles of chemotherapy. Results from a bioequivalence trial demonstrated comparability of the IV and oral formulations of Varubi.

Varubi IV is supplied in ready-to-use vials and does not require refrigerated storage or mixing. As a result, utilization in busy chemotherapy clinics is straightforward and easily adopted into existing practice patterns for administration of antiemetic regimens associated with emetogenic chemotherapy. Varubi IV is to be administered up to two hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone. No dosage adjustment is required for dexamethasone, a CYP3A4 substrate, and Varubi is the first intravenously administered NK-1 receptor antagonist approved by the FDA that does not contain polysorbate 80.

“The approval of Varubi IV represents a significant milestone for TESARO. The majority of NK-1 receptor antagonist doses are administered intravenously in the U.S., and with the introduction of Varubi IV, we now offer healthcare providers a unique, easy-to-use option that fits well into standard operating practices of a chemotherapy clinic or hospital,” said Mary Lynne Hedley, Ph.D., President and COO of TESARO. “We will continue our efforts to expand awareness of delayed chemotherapy-induced nausea and vomiting, and plan to make this important medicine available next month.”

“Many healthcare providers tend to believe that CINV is no longer an unmet need but the reality is that more than half of patients treated with emetogenic chemotherapy experience delayed CINV, even when prescribed standard preventative therapies, such as a 5-HT3 receptor antagonist and dexamethasone,” said Lee Schwartzberg, M.D., Professor of Medicine at University of Tennessee Health Science Center. “The FDA approval of VARUBI IV gives doctors and nurses a new option to help protect their patients from these often preventable side effects.”

The full prescribing information for Varubi IV will be available at www.VarubiRx.com.

Tesaro Announces U.S. FDA Approval of Varubi IV for Delayed Nausea and Vomiting Associated With Cancer Chemotherapy

Study shows three-drug combination delays recurrence and lengthens life for myeloma patients

In continuation of my update on lenalidomide, bortezomib and dexamethasone

The International Myeloma Foundation (IMF) today announced the publication in The Lancet of the results of a randomized, phase III trial, conducted by SWOG, a publicly funded international cancer clinical trials network, and led by IMF chairman of the board Brian G.M. Durie, MD. This important trial compared the effectiveness of two drug regimens in patients undergoing their first round of treatment for multiple myeloma. The trial shows that a three-drug combination - known as VRd - delays recurrence and lengthens life for myeloma patients, indicating a possible new standard of care.

One regimen used in the study was lenalidomide with dexamethasone, a standard first-line treatment for myeloma patients. The other drug regimen also included bortezomib, a second-line drug typically given to myeloma patients whose cancer progresses after initial therapy. SWOG researchers found that the addition of bortezomib earlier made a difference for myeloma patients, giving them about another year of remission and another year of life compared to the standard two-drug regimen.

"Our results are clear. Using bortezomib in combination with lenalidomide and dexamethasone in front-line treatment - hitting the disease early and hard - makes a meaningful difference for myeloma patients," said study principal investigator Dr. Durie, a physician at Cedars-Sinai Outpatient Cancer Center in Los Angeles. "Our results represent a potential new standard of care."

"This is a landmark study that lends clarity to frontline therapy of myeloma," said Dr. S. Vincent Rajkumar of Mayo Clinic and a co-author of the study. "Newer alternatives to VRd may be more expensive, cumbersome, or toxic. These regimens will therefore need to show superiority over VRd in randomized trials."

Also worth noting, Dr. Rajkumar said, is that the VRd regimen will become even more cost effective as the drugs in this combination become generic over time.

 bortezomib     lenalidomide

  dexamethasone

Patients in the trial receiving bortezomib, along with lenalidomide and dexamethasone, in their first six months of treatment had a median remission time of 43 months compared to a median remission of 30 months for patients who received lenalidomide and dexamethasone alone. Researchers also found that patients who received bortezomib lived a median of 75 months, or about six years, after their initial treatment. Patients who received the standard two-drug treatment lived a median of 64 months, or about five years, after initial treatment.

Celebrating its 60th year, SWOG has conducted more than 1,300 cancer trials that have led to FDA approval of 14 new drugs and led to more than 100 changes to cancer standards of care. SWOG is part of the NCI's National Clinical Trials Network (NCTN), the nation's largest and oldest publicly funded cancer research network. SWOG members and other members in the NCTN enrolled 471 eligible and consented adult patients in the study, known as S0777, between February 2008 and February 2012, at 139 institutions across the US.

Patients ranged in age from 28 to 87, had active myeloma, and had not had a stem-cell transplant or any prior treatment for their disease. Patients were randomized into two groups. One group received the standard two-drug treatment for six cycles over six months. That includes lenalidomide, an immunomodulating therapy marketed as Revlimid by Celegene Corporation. The other group received a three-drug combination that included bortezomib, a proteasome inhibitor marketed as Velcade by Millennium Pharmaceuticals. These patients received the triple combination therapy for eight cycles over six months.

Phase I study of triple drug combination shows promise in multiple myeloma patients

In continuation of my updates on Dexamethasone,  Plitidepsin and  Bortezomib 

Dexamethasone    Plitidepsin

 Bortezomib 

PharmaMar (MSE:PHM) announces the positive results from a Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Dr María Victoria Mateos, MD of the Hematological Department of the University Hospital of Salamanca, Spain, the principal investigator of the study, will present the results in an oral session on June 3rd, 2016 during the 52nd Congress of the American Society of the Clinical Oncology (ASCO), taking place in Chicago (USA), June 3 - 7.

The primary objective of this 20-patient study was to identify the recommended dose for the triple combination (dexamethasone / bortezomib / plitidepsin) administered every four weeks. Efficacy and the safety profile were also evaluated. The overall response rate (ORR) was 56%, including very good partial responses (VGPR) in 33% of the patients and a remarkable partial remission in one triple refractory patient. The median progression free survival (PFS) was 8.3 months. Additionally, 90% of the patients showed a DOR of 6 months or more and clinical benefit was observed in 72% of the patients.

Dose limiting toxicities were not seen in any of the evaluated patients; therefore, the full dose of plitidepsin and bortezomib when used alone were established as the recommended dose for the triple combination. The treatment was well tolerated. The hematological toxicity was manageable and the non-hematological toxicity was in general mild, with the exception of one case of creatinine increase.

Out of the 20 patients that participated in the study, 10 are still under the treatment. The median age was 65. All patients had relapsed after previously receiving, on average, 3.5 therapeutic regimens (range 1-10). Forty-five percent of these patients had been subject to a hematopoietic stem cell transplant (8 autologous, 1 allogeneic). Of the 18 patients evaluable for efficacy, 83% (15 patients) had previously received bortezomib and lenalidomide. One was refractory to bortezomib and seven to lenalidomide.

In abstract #8006, Dr María Victoria Mateos and her team explain that despite the recent progress in the treatment of multiple myeloma due to the introduction of proteasome inhibitors (PIs), the new immunomodulatory drugs (IMIDs), and monoclonal antibodies, the illness is still incurable. Therefore, active compounds with novel mechanisms of action and adequate safety profile are needed. Plitidepsin targets the eukaryotic Elongation Factor eEF1A2, an overexpressed protein in multiple myeloma that contributes to its pathogenesis. The positive results from this study will be added to the already extensive data package from Phase II and Phase III trials, where plitidepsin has shown activity and a favorable safety profile in combination with dexamethasone.

One-dose of dexamethasone can improve outcomes of asthmatic patients in ER

In continuation of my update on dexamethasone

Adults with asthma who were treated with one-dose dexamethasone in the emergency department had only slightly higher relapse than patients who were treated with a 5-day course of prednisone. "Enhanced compliance and convenience may support the use of dexamethasone" is the conclusion of a study that was published online Friday inAnnals of Emergency Medicine ("A Randomized Controlled Noninferiority Trial of Single Dose vs. Five Days of Oral Dexamethasone in Acute Adult Asthma").

"Any time we can reduce the role of patient compliance with asthma, we have a chance of improving outcomes," said lead study author Matthew W. Rehrer, MD, of the Department of Emergency Medicine with Kaiser Permanente in Oakland, Calif. "Dexamethasone allows the emergency physician to administer treatment in one dose and doesn't rely on the patient to remember to take her pills for four more days after leaving the ER. A single dose of medication eliminates prescription adherence barriers such as forgetfulness, cost and dose omission."

Plitidepsin in combination with dexamethasone shows top-line results in Phase III multiple myeloma trial

 

In continuation of my updates on  dexamethasone and Aplidin (plitidepsin) 

PharmaMar (MSE:PHM)  announced positive top-line results of its Phase III clinical trial -ADMYRE- with Aplidin (plitidepsin) in combination with dexamethasone versus dexamethasone alone in patients with relapsed/refractory multiple myeloma (MM). Aplidin® has shown a statistically significant 35% reduction in the risk of progression or death over the comparator (p=0.0054). The study has met its primary endpoint.

This pivotal, randomized, open-label, international, multicenter Phase III clinical trial, called ADMYRE, enrolled 255 patients in 83 medical centers across 19 countries (including the U.S, Europe and Asia-Pacific) with relapsed or relapsed and refractory multiple myeloma after at least three but no more than six prior therapeutic regimens.

The efficacy of plitidepsin in combination with dexamethasone versus dexamethasone alone has been evaluated by means of PFS calculated using the IMWG (International Myeloma Working Group) criteria and other secondary efficacy endpoints. A full description of the final ADMYRE data will be submitted for presentation at an upcoming medical meeting.

"Taking into account these positive results, we intend to submit a Marketing Authorization Application to the European Medicines Agency during the last quarter of this year", said Luis Mora, Managing Director of the Oncology Business Unit of PharmaMar, who added "I´d like to thank all the patients, physicians and the dedicated team at PharmaMar who helped participate in the success of this trial. Aplidin® may be our second drug of marine origin in the market".

As previously disclosed PharmaMar has entered into licensing agreements to market and distribute the drug candidate Aplidin with Specialised Therapeutics Asia, covering several Asian countries, Australia and New Zealand; with TTY Biopharm in Taiwan; and with a co-promotion agreement in 8 European countries with Chugai Pharma Europe.

Plitidepsin in combination with dexamethasone shows top-line results in Phase III multiple myeloma trial

Role for carfilzomib in relapsed, refractory multiple myeloma treatment

In continuation of my update on carfilzomib

Carfilzomib significantly improves outcomes in previously treated patients with relapsed or refractory multiple myeloma, shows a head-to-head comparison with bortezomib.

In the ENDEAVOR phase III trial, published in The Lancet Oncology, median progression-free survival (PFS) was 18.7 months for the 464 patients randomly assigned to receive open-label carfilzomib plus dexamethasone. This was significantly longer than the 9.4 months for the 465 participants treated with bortezomib and dexamethasone, and equated to a 47% risk reduction in favour of carfilzomib.

Moreover, a significantly higher proportion of carfilzomib- than bortezomib-treated patients achieved an objective response, at 77% versus 63%, and the duration of response was also longer in the former group, at a respective 21.3 and 10.4 months.

The most common side effects of grade 3 or worse that occurred more frequently in the carfilzomib than the bortezomib treatment arm were anaemia and hypertension, with rates of 14% versus 10% and 9% versus 3%, respectively.

However, peripheral neuropathy of grade 3 was observed in 2% of carfilzomib-treated patients and there were no grade 4 events, compared with 8% of patients in the bortezomib arm who experienced events of grade 3 or 4.

Serious adverse events occurred in 48% of patients in the carfilzomib group and in 36% of those given bortezomib, but Meletios Dimopoulos (National and Kapodistrian University of Athens, Greece) and team note that the number of discontinuations and deaths attributable to adverse events were comparable between the groups.

They conclude that carfilzomib plus dexamethasone could be considered for multiple myeloma patients for whom bortezomib is indicated.

Role for carfilzomib in relapsed, refractory multiple myeloma treatment

Takeda receives FDA approval for NINLARO (ixazomib) capsules to treat patients with multiple myeloma

Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that the U.S. Food and Drug Administration (FDA) has approved NINLARO® (ixazomib) capsules, the first and only oral proteasome inhibitor, indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is a once-weekly pill.

Takeda submitted a New Drug Application for NINLARO to the FDA in July 2015, and in September NINLARO was granted Priority Review status with a PDUFA date of March 10, 2016, reflecting the profound and continuing unmet need for new treatments for multiple myeloma, a devastating, relapsing and incurable rare cancer.

“With the approval of NINLARO, we can now offer patients a once-weekly oral proteasome inhibitor as part of a highly active triplet therapy,” said Paul Richardson, M.D., Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center Institute Physician at Dana-Farber Cancer Institute, and investigator for TOURMALINE-MM1, the pivotal Phase 3 trial on which today’s approval is based. “We, as investigators of the TOURMALINE-MM1 trial, felt it was vital to conduct a comprehensive ‘real world’ evaluation of this combination that included some of the most common patient types in the relapsed/refractory multiple myeloma setting, such as older patients, patients with moderate renal impairment, light chain disease, and high risk cytogenetics. Further, we treated patients until disease progression to determine the sustainability of NINLARO in treating their relapsed/refractory disease. The TOURMALINE-MM1 data demonstrate convincingly that oral NINLARO-based triplet treatment is effective at extending progression-free survival, over and above the clinical benefit seen with lenalidomide and dexamethasone, with a tolerable safety profile.”

Takeda receives FDA approval for NINLARO (ixazomib) capsules to treat patients with multiple myeloma

Ixazomib’s phase 3 study in relapsed/refractory multiple myeloma presented

Takeda Pharmaceutical Company Limited today announced that it will present Phase 3 data from the TOURMALINE-MM1 ixazomib clinical trial at the 57th American Society of Hematology (ASH) Annual Meeting to be held in Orlando, Florida from December 5 to 8, 2015.

A total of 19 company-sponsored abstracts representing the breadth and depth of Takeda’s hematology-oncology portfolio were accepted for presentation at this year’s meeting.

We are particularly looking forward to this year’s ASH annual meeting. We will be presenting pivotal data on the ixazomib program, as well as the five year overall survival data for ADCETRIS in relapsed/refractory Hodgkin lymphoma.

The success of these two programs, in addition to data we will be presenting on VELCADE and our pipeline, is the realization of decades of commitment to patients with hematological malignancies.

Dixie-Lee Esseltine, MD, FRCPC, Vice President, Oncology Therapeutic Area Unit, Takeda.

“This is the first time Phase 3 data will be presented for ixazomib, an oral, once-weekly proteasome inhibitor which, if approved, would enable the first all-oral triplet regimen containing a proteasome inhibitor for the treatment of relapsed/refractory multiple myeloma,” said TOURMALINE-MM1 Principal Investigator Philippe Moreau, M.D., University of Nantes, France.

“In working with Takeda Oncology on the evolution of proteasome inhibition, we continue to strive towards providing new options to address the unmet needs of patients with multiple myeloma.”

Ixazomib is the first oral proteasome inhibitor in late stage clinical development. The TOURMALINE-MM1 study is an international, randomized, double-blind, placebo-controlled Phase 3 clinical trial which was designed to evaluate the superiority of once-a-week oral ixazomib plus lenalidomide and dexamethasone vs. placebo plus lenalidomide and dexamethasone in adult patients with relapsed and/or refractory multiple myeloma.

Ixazomib has been granted Priority Review from the U.S. Food and Drug Administration (FDA) and Accelerated Assessment by the Committee for Medicinal Products for Human Use of the European Medicines Agency , respectively, validating the profound and continuing unmet need for new multiple myeloma treatments.

Ixazomib’s phase 3 study in relapsed/refractory multiple myeloma presented