Potential ‘Achilles heel’ in brain cancer

Paul B. Fisher, M.Ph., Ph.D., F.N.A.I., Thelma Newmeyer Corman Endowed Chair in Cancer Research and member of the Cancer Molecular Genetics research program at VCU Massey Cancer Center

Scientists at Virginia Commonwealth University believe they have uncovered an “Achilles heel” of glioblastoma multiforme (GBM), the most common and deadly form of brain cancer. Their study published this week in the Proceedings of the National Academy of Sciences details how a mechanism that protects glioma stem cells can potentially be exploited to develop new and more effective treatments for GBM.

Autophagy is a process in which cells get rid of unnecessary or dysfunctional components. It can be toxic to the cells, or it can serve a protective role. The researchers demonstrated that protective autophagy allows glioma stem cells to resist anoikis, which is a form of programmed cell death (apoptosis) that occurs when cells detach from the extracellular matrix, or the collection of molecules that helps support and protect cells within the body. The study found that this protective mechanism is regulated by the gene MDA-9/Syntenin.

“We discovered that when we blocked the expression of MDA-9/Syntenin, glioma stem cells lose their ability to induce protective autophagy and succumb to anoikis, resulting in cancer cell death,” says Paul B. Fisher, M.Ph., Ph.D., F.N.A.I., Thelma Newmeyer Corman Endowed Chair in Cancer Research and member of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, chairman of the Department of Human and Molecular Genetics at VCU School of Medicine and director of the VCU Institute of Molecular Medicine. Fisher originally discovered the MDA-9/Syntenin gene, and he and others have shown it to be overexpressed in a majority of cancers.

Fisher, in collaboration with Webster K. Cavenee, Ph.D., Distinguished Professor, Ludwig Institute for Cancer Research, University of California San Diego (UCSD) and other colleagues, found that MDA-9/Syntenin maintains protective autophagy by activating BCL2, a gene that regulates cell death. Additionally, they showed that MDA-9/Syntenin suppresses high levels of autophagy that would be toxic to the cell through epidermal growth factor receptor (EGFR) signaling. Excessive EGFR signaling has been shown to contribute to tumor growth in a wide variety of cancers.

“In the absence of MDA-9/Syntenin, EGFR can no longer maintain protective autophagy. Instead, highly elevated and sustained levels of toxic autophagy ensue that dramatically reduce cancer cell survival,” says Fisher. “This is the first study to define a direct link between MDA-9/Syntenin, protective autophagy and anoikis resistance. We’re hopeful we can exploit this process to develop new and more effective treatments for GBM and possibly other cancers.”

Using GBM cells from patients who underwent surgical removal of their tumors, the scientists demonstrated the loss of these protective biological functions in the absence of MDA-9/Syntenin through laboratory experiments involving glioma stem cell cultures. These findings were then tested in mouse models of human stem cells, where an increase in survival occurred following MDA-9/Syntenin inhibition.

This study builds on an extensive line of research by Fisher and his colleagues into the role of MDA-9/Syntenin in cancer development and progression. Moving forward, they hope to determine if the process they uncovered in this research applies to stem cells from other cancer types. They also plan to continue developing new ways to block the expression of MDA-9/Syntenin. Fisher described one such approach in a recent study demonstrating the effectiveness of an experimental inhibitory drug known as a PDZ1i in reducing MDA-9/Syntenin’s ability to promote invasion of GBM cells in vitro (outside of a living organism) and in vivo (in a living organism).

More information: Sarmistha Talukdar et al. MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1721650115

https://bit.ly/2HkfYyL

#ASCO18: Rare gain for tough-to-treat pancreatic cancer

Patients with pancreatic cancer that hadn’t spread lived substantially longer on a four-drug combo than on a single standard cancer drug, a rare advance for a tough-to-treat disease, researchers reported Monday.

The results indicate the powerful chemotherapy treatment known as folfirinox will likely become standard of care for the minority of patients whose pancreatic canceris diagnosed early enough to be removed by surgery, experts not involved in the study said.

After an average three years of follow-up, almost 40 percent of the folfirinox patients were disease-free compared with about 20 percent who had the standard drug, Gemzar. Overall, almost two-thirds of folfirinox patients were still alive compared with almost half of Gemzar patients, unexpectedly good results, said Dr. Thierry Conroy, the lead author and a cancer specialist at the Cancer Institute of Lorraine in Vandoeuvre-les-Nancy, France.

Results were presented Monday at an American Society of Clinical Oncology conference in Chicago.

Dr. Richard Schilsky, the group’s chief medical officer, called the research an “immediately practice-changing study” and said it’s the biggest advance for pancreatic cancer in 25 years.

Folfirinox is already standard treatment for patients whose pancreatic cancer has spread.

The outlook has been bleak for patients with pancreatic cancer , an uncommon disease for which there is no screening. Symptoms including fatigue, weight loss and abdomen pain often don’t occur until late, after the disease has spread.

About 330,000 cases are diagnosed each year worldwide, including about 55,000 in the United States. About half are diagnosed after the disease has spread; most die within a year of diagnosis and only about 6 percent survive for five years.

About 15 percent of patients are candidates for surgery; generally their disease was detected early and has not spread widely beyond the pancreas.

The new results are “reassuring for a disease where unfortunately on average people only live several months rather than several years. This is a new standard of care for this illness,” said Dr. Andrew Epstein, an expert at Memorial Sloan Kettering Cancer Center in New York.

Nearly 500 patients at 77 centers in France and Canada were enrolled in the study from spring 2012 through fall 2016. They either received the four-drug combo through an IV every two weeks for about six months or Gemzar three times a month for six months. The study was funded by philanthropic groups in France and Canada.

Participants had early ductal tumors, the most common kind of pancreatic cancer.

Side effects are common for both drugs including low blood counts, fatigue and diarrhea, and they occurred more often in folfirinox patients. There was one death in the study in the Gemzar group.

Folfirinox and Gemzar are available as generics. Schilsky said both treatments are “pretty inexpensive” since the drugs are available as generics. Insurance typically covers both for metastatic cancer and gemcitabine for operable cancer, and it’s likely it would cover folfirinox for operable cancer if guidelines are revised and it becomes standard of care, which several experts say is expected.

https://bit.ly/2JfFgzA

Agios leukemia data ‘support frontline use’: Piper

Agios’ ivosidenib combo data support use in frontline AML, says Piper Jaffray. Piper Jaffray analyst Tyler Van Buren noted that the combo of ivosidenib plus Vidaza demonstrated “robust” clinical activity, including the rough doubling of ORR and CR rates compared to Vidaza monotherapy, and he believes the data shared at ASCO are supportive of the combination being used in the frontline AML setting. If these earlier trial results are replicated in the AGILE Phase 3 study, Van Buren sees a high probability of this combo being approved and used in the frontline AML setting, he tells investors. He maintains an Overweight rating on shares of Agios Pharmaceuticals, which are down 5% to $91.92 in afternoon trading.

https://bit.ly/2syoqpm

Amedisys to repurchase 50% of shares held by KKR

Amedisy (AMED) announced it has purchased 2,418,304 of its common shares from KKR (KKR), representing one-half of their holdings in the company and 7.1% of the aggregate outstanding shares of the Company’s common stock. The Company repurchased the shares at 96% of the closing price of the Company’s common stock on June 4, 2018. KKR will maintain its presence on the Amedisys Board of Directors for at least twelve months following the transaction. The aggregate value of the transaction is approximately $178M and will be financed through the use of $140M of available cash with the remainder funded by borrowings under the Company’s existing revolving credit facility. For Amedisys, this transaction will be immediately 6% to 7% accretive to earnings per common share. Post transaction, the Company’s available cash will be approximately $20M and its outstanding borrowings under the credit facility will be $128M resulting in a net leverage ratio of approximately 0.7x. The company is also in advanced discussions with its lenders to significantly expand its borrowing capacity under its senior secured credit facility to allow it to capitalize on its active acquisition pipeline. Following this transaction, Amedisys will have approximately 32M of outstanding shares of common stock.

https://bit.ly/2HjIyQF

Mylan Confirms FDA Approval of Biocon’s Fulphila, the First Biosimilar to Neulasta

Mylan N.V. (NASDAQ: MYL) and Biocon Ltd. today announced that the U.S. Food and Drug Administration (FDA) has approved Mylan’s Fulphila™ (pegfilgrastim-jmbd), a biosimilar to Neulasta® (pegfilgrastim), co-developed with Biocon. Fulphila has been approved to reduce the duration of febrile neutropenia (fever or other signs of infection with a low count of neutrophils, a type of white blood cells) in patients treated with chemotherapy in certain types of cancer.

Fulphila is the first FDA-approved biosimilar to Neulasta and the second biosimilar from Mylan and Biocon’s joint portfolio approved in the U.S. Mylan anticipates launching Fulphila in the coming weeks, representing the first alternative, more affordable treatment option to Neulasta for oncology patients. A suite of patient services also will be available at launch to further support patients and caregivers with treatment.

Neulasta had U.S. sales of $4.2 billion for the 12 months ending March 31, 2018, according to IQVIA.

https://bit.ly/2swje5B

#ASCO18: Fabre, Idera, Kyowa Kirin, Portola

There’s plenty of news coming out of the American Society of Clinical Oncology (ASCO)Annual Meeting behind held in Chicago. Here’s a look at a few more of the top stories.

Pierre Fabre and Array BioPharma Update Phase III Melanoma Trial Data

The two companies announced results from the Phase III COLUMBUS trial in BRAF-mutant advanced melanoma. The median overall survival (mOS) was 33.6 months for patients receiving the combination of encorafenib and binimetinib compared to 16.9 months for patients receiving vemurafenib as a monotherapy. The combination also reduced the risk of death compared to vemurafenib monotherapy. The two-year OS with the combination was 58 percent.

Idera Pharmaceuticals’ ILLUMINATE-204 Trial Looks Good in Melanoma

Idera Pharma presented results from its ongoing ILLUMINATE-204 clinical trial of tilsotolimod, its intratumorally-delivered Toll-like Receptor (TLR) 9 agonist in combination with Yervoy (ipilimumab). The data showed an overall response rate (ORR) of 38 percent for the combination, including two complete responses and an ongoing partial response (PR) for 12 months. “We have clinical evidence that tilsotolimod activates both the innate and adaptive immune responses, and when used in combination with a checkpoint inhibitor like ipilimumab, triggers immune responses in previously resistant tumors,” said Adi Diab, lead trial investigator, assistant professor, Department of Melanoma Medical Oncology for University of Texas, MD Anderson Cancer Center, in a statement. “In patients with metastatic melanoma receiving premborlizumab who switched to single agent tipilimumab at the time of disease progression the reported ORR was 13 percent. The ORR was 38 percent observed in the ILLUMINATE-204 study and the duration of response, which is ongoing in most of the responders, is particularly encouraging and suggests that the combination of tilsotolimod and ipilimumab is a very promising strategy for treating patients with metastatic melanoma whose cancer does not respond to PD-1 therapy alone.”

Kyowa Kirin’s Mogamulizumab has Positive Progression Free Survival in Mycosis Fungoides

Tokyo’s Kyowa Hakko Kirin presented additional data from the pivotal MAVORIC trial. The Phase III trial evaluated mogamulizumab versus vorinostat to treat adults with relapsed or refractory mycosis fungoides (MF) or Sezary syndrome (SS) after at least one prior systemic therapy. MF and SS are the most common subtypes of cutaneous T-cell lymphoma (CTCL). The primary endpoint was PFS, which had a clinically relevant and statistically significant increase over vorinostat.

Portola Pharmaceuticals’ SYK-JAK Inhibitor Shows Efficacy in Pre-Treated B- and T-Cell Cancers

Portola Pharma announced new interim results from its ongoing Phase IIa trial of cerdulatinib, an oral SYK/JAK inhibitor, in patients with specific subtypes of B and T-cell Non-Hodgkin Lymphoma (NHL), including relapsed/refractory follicular lymphoma (FL) and peripheral T-cell lymphoma (PTCL), and chronic lymphocytic lymphoma/small lymphocytic lymphoma (CLL/SLL). Seven of the 20 patients in the PTCL cohort had a complete response. “Cerdulatinib continues to demonstrate promising results across a wide range of B- and T-cell malignancies, including early indications of the potential for durable responses,” said Paul Hamlin, medical director for the David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center, in a statement. “The new signals in relapsed/refractory PTCL and CTCL are particularly compelling when you consider the limited treatment options for patients that fail front-line therapy.”

Agios Pharmaceuticals’ Invosidenib in Early Trial in Acute Myeloid Leukemia Looks Promising

Agios Pharma presented data from a Phase I trial looking at ivosidenib (AG-120) or enasidenib (AG-221) in combination with azacitidine in newly diagnosed isocitrate dehydrogenase (IDH) mutant acute myeloid leukemia (AML). “Patients with newly diagnosed AML who are ineligible for intensive ‘7+3’ chemotherapy typically have poor outcomes and few available treatment options,” said Courtney DiNardo, lead investigator and assistant professor, department of leukemia at the University of Texas MD Anderson Cancer Center, in a statement “With additional patients now treated in the ivosidenib arm of this Phase I study, the updated combination data demonstrate a favorable safety profile and impressive response rates versus those expected with azacitidine alone. I look forward to further demonstrating the clinical benefit of utilizing an IDH inhibitor in combination with traditional frontline AML treatment as part of the ongoing Phase I and randomized trials.”

https://bit.ly/2xHpdJJ

#ASCO18: Genomic Health Up As TAILORx Data Clarifies Oncotype DX Utility

Genomic Health’s stock skyrocketed Monday on the news of a study in the New England Journal of Medicine that finally answered the question of how doctors should interpret and act upon an intermediate result from the firm’s Oncotype DX breast cancer risk test.

The company’s stock rose nearly 20 percent to $47.49 in afternoon trading on the Nasdaq.

The data, which was also presented over the weekend at the American Society for Clinical Oncology annual meeting in Chicago, showed that women with Oncotype DX recurrence scores from a low-risk threshold of 11 up to a high-risk threshold of 25 appear to benefit equally when treated with endocrine therapy alone compared to hormonal therapy with added chemotherapy, as long as they are over 50 years of age. Though doctors had known from previous studies that a low-risk score could be prognostic and a high-risk score could be predictive, the intermediate scores were trickier to interpret.

Researchers presenting the study estimated that the new classification architecture means that the percentage of individuals with early-stage hormone-receptor positive, HER-2 negative tumors who can confidently avoid chemo is about 70 percent overall.

In a note to investors on Sunday evening, Canaccord Genuity analyst Mark Massaro reiterated his Buy rating for Genomic Health and raised his price target on the firm’s stock to $45 from $41, noting that the TAILORx data “is at least ‘good enough’ to drive some incremental boost to Oncotype DX volumes globally, and perhaps more obviously, turn on reimbursement where coverage is limited (particularly in Germany).”

Genomic Health’s management believes that capitalizing on the TAILORx data can help the firm hit the high end of its 2018 revenue guide, Massaro added, and the company is looking to create some targeted digital ads to drive new doctor ordering for the test. The firm is also expecting payor decisions from France this summer, from Germany in the fall, and from the UK in September that could be affected by the study’s results.

Overall, Massaro is modeling 13 percent growth in revenues for Genomic Health in 2018, driven in part by the TAILORx results.

Cowen analyst Doug Schenkel in a note to investors on Monday added that the study “solidifies the utility of Oncotype in women with early-stage breast cancer, and it could drive increased ordering of Oncotype. Put simply, we see potential material upside to our volume and revenue per test forecasts in the US and abroad over the next several years.”

Schenkel also noted that Genomic Health believes it now has some power with insurers to improve reimbursement prices for its test, which could be important when its commercial contracts come up for renewal.

“We are currently forecasting that the Invasive Breast average revenue per test will increase by 3 percent in 2020 relative to 2018 levels. Based on company commentary and the disproportionate number of patients that are commercially covered (about 80 percent), we believe this forecast is very achievable if not beatable,” he wrote. “An increase in the reimbursement rate of 10 percent compared to today’s levels would lead to a $30 million increase in our 2020 estimated revenues, with all other assumptions unchanged.”

https://bit.ly/2HhgTzL