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Dual Publications in the New England Journal of Medicine Highlight Transformative Potential of Imetelstat in Hematologic Myeloid Malignancies

On September 02, 2015 Geron Corporation (Nasdaq:GERN) reported the publication of two papers in The New England Journal of Medicine (NEJM) in which the company’s telomerase inhibitor, imetelstat, was shown to have disease-modifying activity thought to be associated with selective inhibition of the malignant progenitor cell clones responsible for the underlying disease in two hematologic myeloid malignancies, essential thrombocythemia (ET) and myelofibrosis (MF) (Press release, Geron, SEP 2, 2015, View Source [SID:1234507389]). The papers are available online in the September 3rd issue at www.NEJM.org.

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"The data in the ET and MF study publications in The New England Journal of Medicine provide compelling evidence that use of a telomerase inhibitor, such as imetelstat, may result in ground-breaking changes in how we approach the future treatment of hematologic myeloid malignancies," said John A. Scarlett, Geron’s President and Chief Executive Officer.

In the Phase 2 clinical study evaluating imetelstat in ET, all patients achieved a hematologic response, with the majority achieving a hematologic complete response. Rapid and substantial molecular responses observed in the study suggested therapeutic activity of imetelstat on the growth of malignant progenitor cell clones that drive ET. The safety and efficacy results reported in the NEJM publication are consistent with the preliminary data from this study previously presented in part at the annual meetings of the American Society of Hematology (ASH) (Free ASH Whitepaper) in December 2012 and December 2014, and the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting in June 2013.

"This study was a first look at what happens when you treat ET patients with a drug that has a totally novel mechanism of action," said Dr. David Snyder, City of Hope, Duarte, CA, and co-principal investigator of the ET study. "In the study, imetelstat had a clinically significant effect on disease burden in ET patients."

"The molecular responses suggest that imetelstat may have broad activity across hematologic myeloid malignancies which warrants further clinical study in other myeloproliferative neoplasms," noted Prof. Dr. med. Gabriela M. Baerlocher, Inselspital, Bern University Hospital and University of Bern, Switzerland, and co-principal investigator of the ET study.

In the Phase 2 pilot study evaluating imetelstat in MF patients, unprecedented complete and partial remissions, including reversal of bone marrow fibrosis and molecular responses, were observed. These results suggest the potential value of telomerase-targeting strategies for the treatment of MF, and identify imetelstat as an active drug in this disease. The safety and efficacy results reported in the NEJM publication are consistent with the preliminary data from this study previously presented in part at the annual meetings of the American Society of Hematology (ASH) (Free ASH Whitepaper) in December 2013 and December 2014.

"The clinical and molecular remissions seen in the study suggest selective anti-clonal activity, not previously documented in current drug treatment of MF," commented Dr. Ayalew Tefferi, Mayo Clinic, Rochester, MN, and principal investigator of the MF pilot study. "A much larger multi-center clinical study is needed to confirm these findings and to further investigate the mechanism by which imetelstat induces clinical responses in some patients."

Future Clinical Development of Imetelstat in Collaboration with Janssen

In November 2014, Geron entered into an exclusive license and collaboration agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize imetelstat worldwide for indications in oncology, including hematologic myeloid malignancies, and all other human therapeutics uses. Under the collaboration with Janssen, development of imetelstat initially will proceed under a mutually agreed clinical development plan which includes a Phase 2 study in MF and a Phase 2 study in myelodysplastic syndrome (MDS). In addition, the clinical development plan may also include additional, possible registration studies in MF and MDS, and possible exploratory Phase 2 and potential follow on Phase 3 studies in acute myeloid leukemia (AML). Certain regulatory, development, manufacturing and promotional activities are being managed through a joint governance structure, with Janssen responsible for these activities.

In July 2015, Janssen initiated IMbark, a Phase 2 clinical study to evaluate the activity of two dose levels of imetelstat in patients with DIPSS intermediate-2 or high-risk MF who have relapsed after or are refractory to a JAK inhibitor. Up to approximately 80 medical centers across North America, Europe and Asia are planned to participate in this clinical study and currently sites are open to patient enrollment. The study is designed to enroll approximately 200 patients (approximately 100 patients per dosing arm). For more information about the IMbark study, please visit View Source

A Phase 2 clinical study in MDS, to be conducted by Janssen, is expected to open for patient enrollment by the end of 2015.

About Imetelstat

Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary data suggest that imetelstat shows disease-modifying activity by affecting the malignant clones associated with hematologic myeloid malignancies. Most commonly reported adverse events in imetelstat clinical studies conducted to date include fatigue, gastrointestinal symptoms and cytopenias. Patients in these studies also experienced elevated liver enzymes, which resolved to normal or baseline in the majority of patients followed after imetelstat treatment was withdrawn. Imetelstat has not been approved for marketing by any regulatory authority.

TESARO Announces U.S. FDA Approval of VARUBI(TM) (rolapitant) for Nausea and Vomiting Associated With Cancer Chemotherapy

On September 2, 2015 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has approved VARUBI (rolapitant) 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 (Press release, TESARO, SEP 2, 2015, View Source [SID:1234507385]).

VARUBI is a selective and competitive antagonist of human substance P/neurokinin 1 (NK-1) receptors, with a plasma half-life of approximately seven days. Results from three Phase 3 trials of VARUBI 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. A 180 milligram dose of VARUBI is to be administered approximately one to two hours prior to chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone. No dosage adjustment is required for dexamethasone, a CYP3A4 substrate, when administering VARUBI.

"The approval of VARUBI, our first product, represents a significant milestone in TESARO’s evolution into an integrated biopharmaceutical company with strong development and commercialization capabilities," said Lonnie Moulder, CEO of TESARO. "Results from the Phase 3 trials of VARUBI demonstrated that patients receiving emetogenic chemotherapy agents, including platinum and cyclophosphamide-containing regimens, benefitted from the addition of VARUBI to their antiemetic regimen. Data from multiple well-controlled trials demonstrate that patients who receive only a 5-HT3 receptor antagonist and dexamethasone often continue to suffer from nausea and vomiting for several days following chemotherapy administration. Patient surveys and our primary market research also point to the high rate of CINV and its potentially debilitating effects. We look forward to expanding the awareness of CINV and working with healthcare providers to make this important medicine available to patients during the fourth quarter."

"While important strides in preventing nausea and vomiting associated with chemotherapy have been made, still up to half of patients receiving emetogenic cancer chemotherapy can experience delayed CINV," said Richard J. Gralla, M.D., Professor of Medicine at Albert Einstein College of Medicine in New York. "Because NK-1 receptors are key drivers of CINV, especially in the delayed Phase, NK-1 receptor antagonists such as VARUBI, when combined with a 5-HT3 receptor antagonist and a corticosteroid, provide enhanced protection from CINV, and do so in the delayed timeframe where the most help is needed."

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

About Chemotherapy-Induced Nausea and Vomiting (CINV)

Chemotherapy-induced nausea and vomiting is a debilitating, yet often preventable, side effect of chemotherapy.

Up to 50% of patients undergoing highly or moderately emetogenic chemotherapy experience delayed CINV (25 to 120 hours post chemotherapy)—even when prescribed a 5-HT3 receptor antagonist and corticosteroid.

Blocking both 5-HT3 and NK-1 receptors has been shown to offer better control of nausea and vomiting than inhibiting 5-HT3 receptors alone. Adding a single dose of VARUBI to an antiemetic regimen, including a 5-HT3 receptor antagonist and corticosteroid, further improves prevention of CINV in the delayed Phase following chemotherapy.

About the VARUBI (Rolapitant) Clinical Program

The superior efficacy of VARUBI was established in multiple randomized, well-controlled, blinded clinical trials that enrolled more than 2,500 patients. VARUBI, when administered in combination with a 5-HT3 receptor antagonist and dexamethasone, was superior to a 5-HT3 receptor antagonist and dexamethasone in preventing CINV in patients receiving either moderately or highly emetogenic chemotherapy.

The clinical profile of VARUBI in cisplatin-based highly emetogenic chemotherapy (HEC) was confirmed in two identical Phase 3 studies: HEC1 and HEC2. Both trials met their primary endpoint of complete response (CR), and demonstrated statistical superiority of rolapitant 180 mg compared to active control (5-HT3 receptor antagonist + dexamethasone) in the delayed Phase (25-120 hours) of CINV. In HEC1, 264 patients received rolapitant 180 mg and 262 received control. The proportion of patients achieving a CR was 72.7% vs. 58.4% (p= < 0.001). In HEC2, 271 patients received rolapitant and 273 received control. The proportion of patients achieving a CR was 70.1% vs. 61.9% (p=0.043). The most common adverse reactions (≥3%) among patients receiving cisplatin-based chemotherapy were neutropenia (9% VARUBI vs. 8% control), hiccups (5% vs. 4%), and abdominal pain (3% vs. 2%).

A Phase 3 trial was also conducted to evaluate rolapitant 180 mg compared to active control in 1,332 patients receiving moderately emetogenic chemotherapy regimens, including anthracycline/cyclophosphamide combinations, carboplatin, irinotecan, pemetrexed, oxaliplatin, and doxorubicin. This trial met its primary endpoint of CR, and demonstrated statistical superiority of rolapitant 180 mg compared to active control (5-HT3 receptor antagonist + dexamethasone) in the delayed Phase of CINV. The proportion of patients achieving a CR was 71.3% vs 61.6% (p= < 0.001). The most common adverse reactions (≥3%) among patients receiving these chemotherapies were decreased appetite (9% VARUBI vs. 7% control), neutropenia (7% vs. 6%), dizziness (6% vs. 4%), dyspepsia (4% vs. 2%), urinary tract infection (4% vs. 3%), stomatitis (4% vs. 2%), and anemia (3% vs. 2%).

Primary data from the three Phase 3 studies have recently been published online ahead of print in Lancet Oncology, the analysis of the non-AC MEC population was presented at the 2015 annual meeting for the Multinational Association for Supportive Care in Cancer, and commentary has been provided in Nature Reviews Clinical Oncology.

VARUBI Additional Safety Information

VARUBI is contraindicated in patients receiving thioridazine, a CYP2D6 substrate with a narrow therapeutic index.

Use of VARUBI should be avoided in patients who are receiving pimozide, a CYP2D6 substrate with a narrow therapeutic index. Adverse reactions should be monitored if concomitant use of VARUBI and other CYP2D6 substrates with a narrow therapeutic index cannot be avoided. The inhibitory effect of VARUBI on CYP2D6 lasts for at least 7 days and may last longer after administration of a single dose of VARUBI.

VARUBI is available by prescription only.

About VARUBI

VARUBI is a substance P/neurokinin-1 (NK-1) receptor antagonist indicated 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. NK-1 receptors are highly concentrated in the brain and bind neurokinin substance P. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by emetogenic stimuli, including certain cancer chemotherapies. A Positron Emission Tomography (PET) study with rolapitant in normal, healthy volunteers demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK-1 receptors at high levels for up to 120 hours. VARUBI has a half-life of approximately 7 days, which may contribute to the ability of a single dose of VARUBI to cover the entire delayed CINV Phase (25-120 hours).

An intravenous formulation of rolapitant is also being developed. TESARO licensed exclusive rights for the development, manufacture, commercialization and distribution of VARUBI (rolapitant) from OPKO Health, Inc.

Loxo Oncology Announces FDA Orphan Drug Designation Granted to LOXO-101 for Treatment of Soft Tissue Sarcoma

On September 2, 2015 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company focused on the discovery, development, and commercialization of targeted cancer therapies, reported that the United States Food and Drug Administration (FDA) has granted the company orphan drug designation for LOXO-101 for treatment of patients with soft tissue sarcoma (Press release, Loxo Oncology, SEP 2, 2015, View Source [SID:1234507381]).

Soft tissue sarcomas are cancers of the body’s connective or supportive tissues, such as cartilage, fat, muscle, fibrous tissue, and blood vessels. The FDA’s Office of Orphan Drug Products grants orphan drug designation to support the development of medicines for underserved patient populations, or rare disorders, that affect fewer than 200,000 people in the United States. Orphan drug designation provides to Loxo certain benefits, including market exclusivity upon regulatory approval if received, exemption of FDA application fees and tax credits for qualified clinical trials.

About LOXO-101

LOXO-101 is a potent, oral, selective inhibitor of tropomyosin receptor kinase (TRK) signaling molecules. The TRK family (TRKA, TRKB, and TRKC) has been implicated in diverse tumor types such as lung cancer, head and neck cancer, melanoma, colorectal cancer, sarcoma, and breast cancer. LOXO-101 was built specifically to inhibit TRK and is currently the only selective TRK inhibitor in clinical development. LOXO-101 is currently being evaluated in a Phase 1 dose escalation trial for patients with advanced solid tumors.

Incyte Announces Global License Agreement with Jiangsu Hengrui Medicine for SHR-1210, an Investigational Anti-PD-1 Monoclonal Antibody

On September 2, 2015 Incyte Corporation (Nasdaq: INCY) reported a global license and collaboration agreement with Jiangsu Hengrui Medicine Co., Ltd. for the development and commercialization of SHR-1210, an investigational anti-PD-1 monoclonal antibody (Press release, Incyte, SEP 2, 2015, View Source [SID:1234507380]).

Under the agreement, Incyte will have the exclusive development and commercialization rights to SHR-1210 worldwide, with the exception of Mainland China, Hong Kong, Macau, and Taiwan. SHR-1210 is expected to enter proof-of-concept studies for the treatment of patients with advanced solid tumors in the coming months.

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"The addition of this anti-PD-1 candidate to our early stage portfolio reinforces our commitment to cancer patients and further diversifies our clinical development programs," stated Hervé Hoppenot, President and Chief Executive Officer of Incyte. "We continue to make excellent progress in the multiple clinical trials underway across our existing portfolio, including our strategic collaborations."

Piaoyang Sun, Chairman of the Board of Hengrui, added, "Both Incyte and Hengrui are dedicated to cancer immunotherapy and are investigating several relevant biological targets in the area. The addition of SHR-1210 is an excellent fit to Incyte’s oncology portfolio, and we are pleased to see Incyte’s commitment to this PD-1 program. Combining the expertise and resources of both companies can accelerate the development of SHR-1210."

Terms of the Agreement

Under the terms of the agreement, Incyte will acquire development and commercialization rights to SHR-1210 worldwide, with the exception of Mainland China, Hong Kong, Macau, and Taiwan, in exchange for an upfront payment of $25 million. The terms also include potential milestone payments of up to $770 million to Hengrui, consisting of $90 million for regulatory approval milestones, $530 million for commercial performance milestones, and $150 million based on clinical superiority. The terms also include tiered royalties to Hengrui on net sales of SHR-1210 in Incyte territories. Under the Agreement, Incyte and Hengrui will assume all financial obligations associated with the development and commercialization of SHR-1210 in their respective territories.

About Anti-PD-1 Monoclonal Antibodies

Monoclonal antibodies targeting PD-1 enhance anti-tumoral immunity and are being developed for the treatment of cancer. Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand. Inhibition of the interaction between PD-1 and PD-L1, known as immune checkpoint blockade, can enhance T-cell responses and mediate preclinical antitumor activity.1

For this transaction, Incyte was advised by Morgan Lewis, and Hengrui was advised by Wilson Sonsini Goodrich & Rosati.

EISAI CLEARS ALL-CASE SURVEILLANCE CONDITION FOR APPROVAL OF ANTICANCER DRUG GLIADEL(R) 7.7MG IMPLANT

On September 2, 2015 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has received notification from Japan’s Ministry of Health, Labour and Welfare (MHLW) to the effect that the "all-case surveillance" survey condition required for approval of Gliadel 7.7mg Implant (carmustine, "Gliadel") has been lifted (Press release, Eisai, SEP 2, 2015, View Source [SID:1234507378]).

In September 2012, the MHLW approved Gliadel indicated for malignant glioma with the following condition for approval: "Because of the very limited number of subjects treated in the Japanese clinical trials, the applicant is required to conduct all-case drug use-results survey until data from a certain number of patients are accumulated after market launch, in order to identify the background information of patients treated with the product and collect safety and efficacy data on the product in the early post-marketing period, and thereby take necessary measures to ensure proper use of the product."

The MHLW lifted this condition for approval after evaluating safety and efficacy data submitted by Eisai from patients with malignant glioma (558 cases for safety analysis, 536 cases for efficacy analysis). According to the results of the evaluation, the MHLW determined that the conditions for approval have been met.

Gliadel is the only sustained-release formulation approved for intracranial implantation in Japan. Each wafer contains the nitrosourea alkylating agent carmustine distributed in a biodegradable polymer matrix. Implanting the agent into the brain following surgical removal of malignant glioma allows for direct delivery of chemotherapy to the tumor site, allowing the agent to be used prior to initiating radiation, chemotherapy and other standard therapies. Gliadel is manufactured and distributed by Eisai, and the product is co-promoted by Eisai and Nobelpharma Co., Ltd.

Eisai will continue to promote and provide information on the proper use of Gliadel while making further contributions to improve the quality of life of patients.