On February 1, 2016 Nektar Therapeutics (Nasdaq: NKTR) reported the publication in Clinical Cancer Research of pre-clinical findings for NKTR-214 (Press release, Nektar Therapeutics, FEB 1, 2016, View Source [SID:1234508925]).

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The paper, titled "NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models," (Charych et al., Clin Cancer Res, doi:10.1158/1078-0432.CCR-15-1631) documents a broad set of pre-clinical data supporting the clinical advancement of NKTR-214. Among the findings reported, treatment with NKTR-214 led to durable and specific anti-tumor immunity in multiple syngeneic mouse models both as a single agent and as combination therapy with checkpoint inhibitors. In addition, treatment with single-agent NKTR-214 in tumor-bearing mice resulted in a controlled, sustained, and biased T-cell activation leading to a 450:1 mean ratio of CD8-positive effector T cells to T-regulatory cells in the tumor microenvironment, while maintaining more balanced ratios in non-tumor tissues and circulation.

"NKTR-214 allows us to capture and harness the power of the IL-2 biological pathway, which is known to promote T cell growth, to stimulate the body’s own immune system to target and fight cancer. The design of NKTR-214 gives it a combination of biophysical, biochemical, and pharmacological properties that translate into a desirable anti-tumor immune profile," said Stephen Doberstein, Ph.D., Senior Vice President and Chief Scientific Officer of Nektar Therapeutics.

The newly published data documented in the paper also support the favorable safety profile of NKTR-214. The compound was well-tolerated in rodents and in non-human primates (NHPs). Importantly, these pre-clinical safety studies showed that NKTR-214 did not lead to hypotension or vascular leak syndrome at predicted clinical therapeutic doses.

As documented in the new publication, in a pre-clinical tumor re-challenge study in an EMT6 mouse breast cancer model, dosing of NKTR-214 in combination with anti-CTLA-4 antibody resulted in durable and complete responses lasting up to 170 days (5.5 months). When tumor-free animals were re-challenged with the same tumors with no additional treatment, the complete responders demonstrated sustained vaccine-like resistance. These results suggest that NKTR-214 provides a complementary mechanism of immune activation when used concurrently with approved antibody therapies.

"We are pleased that the unique mechanism, efficacy and safety of NKTR-214 are now described and published in a prestigious peer-reviewed journal that is widely read by oncologists, scientists and physician-scientists," said Dr. Doberstein. "We are continuing to advance NKTR-214 in an ongoing Phase 1/2 clinical trial in cancer patients and we expect to have preliminary top-line results from the first stage of this study in the second half of 2016."

About the NKTR-214 Phase 1/2 Clinical Study

NKTR-214 is currently being evaluated in a Phase 1/2 clinical study in patients with advanced solid tumors, including melanoma, renal cell carcinoma and non-small cell lung cancer. The ongoing study is being conducted at MD Anderson Cancer Center and Yale Cancer Center and is comprised of two stages. The first stage is an open-label, multi-dose, dose-escalation study evaluating single-agent NKTR-214 treatment in approximately 20 patients with solid tumors. The primary objective of the first stage of the study is to evaluate the safety and efficacy of NKTR-214, and to define the recommended Phase 2 dose. In addition, the study will assess preliminary anti-tumor activity, including objective response rate (ORR). The immunologic effect of NKTR-214 on tumor-infiltrating lymphocytes (TILs) and other immune cells in both blood and tumor tissue will also be assessed. Following the dose-escalation stage of the study, dose expansion cohorts are planned to evaluate NKTR-214 in specific tumor types, including melanoma, renal cell carcinoma and non-small cell lung cancer.

For more information on the ongoing NKTR-214 Study, please visit the "Clinical Trials" section of www.mdanderson.org using identifier 2015-0573 or visit View Source

About NKTR-214

NKTR-214 is a CD122-biased immune-stimulatory cytokine, which is designed to stimulate the patient’s own immune system to kill tumor cells. By biasing activation to the CD122 receptor, NKTR-214 enhances CD8+ effector T cells (tumor-killing cells) in the tumor. In pre-clinical studies, a single dose of NKTR-214 resulted in a 400-fold AUC exposure within the tumor compared with an equivalent dose of the existing IL-2 therapy, enabling, for the first time, an antibody-like dosing regimen for a cytokine.

On February 1, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported positive overall survival (OS) results from METEOR, the phase 3 pivotal trial comparing cabozantinib to everolimus in 658 patients with advanced renal cell carcinoma (RCC) who have experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor (TKI) (Press release, Exelixis, FEB 1, 2016, View Source [SID:1234508924]). In a second interim analysis for OS, a secondary endpoint of the trial, the results showed a highly statistically significant and clinically meaningful increase in OS for patients randomized to cabozantinib as compared to everolimus. Ongoing study monitoring did not identify any new safety signals. Exelixis intends to present these data at a medical meeting later this year.

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"With these results, cabozantinib is now the first and only therapy evaluated in a large, pivotal study in previously treated patients with advanced renal cell carcinoma to demonstrate a benefit in all three key efficacy parameters – overall survival, progression-free survival and objective response rate," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "This is an important moment for the kidney cancer community, including the patients, clinical investigators, and Exelixis team members who made the METEOR trial possible. Exelixis will share these new results with regulators as part of ongoing review processes in the United States and European Union. Our highest priority is to bring this new option for advanced RCC to patients as quickly as possible."

In late December 2015, Exelixis announced that it completed the submission of its rolling New Drug Application (NDA) for cabozantinib as a treatment for patients with advanced RCC who have received one prior therapy; the U.S. Food and Drug Administration (FDA) recently granted Priority Review to the application and set a Prescription Drug User Fee Act action date of June 22, 2016. The FDA previously granted Breakthrough Therapy and Fast Track designations to cabozantinib for its potential advanced RCC indication.

On January 28, 2016, the European Medicines Agency (EMA) validated Exelixis’ Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma who have received one prior therapy. The MAA has been granted accelerated assessment, making it eligible for a 150-day review, versus the standard 210 days (excluding clock stops when information is requested by the EMA’s Committee for Medicinal Products for Human Use).

Both regulatory applications are based on the results of METEOR. In July 2015, Exelixis announced top-line results from METEOR demonstrating that the trial had met its primary endpoint of improving progression-free survival; compared with everolimus, a standard of care therapy for second line RCC, cabozantinib was associated with a 42% reduction in the rate of disease progression or death. Median PFS for cabozantinib was 7.4 months as compared to 3.8 months with everolimus (HR=0.58, 95% CI 0.45-0.75, p < 0.001). Cabozantinib also significantly improved the objective response rate as compared to everolimus. These data were later presented at the European Cancer Congress in September 2015 and concurrently published in The New England Journal of Medicine.

Cabozantinib is currently marketed in capsule form under the brand name COMETRIQ in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. COMETRIQ is not indicated for patients with RCC. In the METEOR trial, and all other cancer trials currently underway, Exelixis is investigating a tablet formulation of cabozantinib distinct from the COMETRIQ capsule form. The tablet formulation of cabozantinib is the subject of the NDA and MAA for advanced RCC.

About the METEOR Phase 3 Pivotal Trial

METEOR is an open-label, event-driven trial with the primary endpoint of progression-free survival (PFS). The target enrollment for METEOR was 650 patients, and 658 patients were ultimately randomized. The trial was conducted at approximately 200 sites in 26 countries, and enrollment was weighted toward Western Europe, North America, and Australia. Patients were randomized 1:1 to receive 60 mg of cabozantinib daily or 10 mg of everolimus daily, and were stratified based on the number of prior VEGF receptor TKI therapies received, and on commonly applied RCC risk criteria developed by Motzer et al. No cross-over was allowed between the study arms.

Secondary endpoints for METEOR include OS and objective response rate. The secondary endpoint of OS assumed a median of 15 months for the everolimus arm and 20 months for the cabozantinib arm. The study was designed to observe 408 deaths in the entire intent-to-treat population of 650 planned patients, providing 80% power to detect a HR of 0.75. An interim analysis of OS at the 2-sided 0.0019 level employing a Lan-DeMets O’Brien-Fleming alpha-spending function was planned at the time of the primary analysis for PFS, if the trial met the primary PFS endpoint. This analysis showed a strong trend in OS favoring cabozantinib (HR=0.67, 95% CI 0.51-0.89, p=0.005), although the p-value of 0.0019 to achieve statistical significance was not reached at that time. Based upon these results and after consulting with the FDA and EMA, a second interim analysis was undertaken; the results of this second interim analysis crossed the boundary for early declaration of statistical significance.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2015 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.3

Until the introduction of targeted therapies into the RCC setting a decade ago, treatments for metastatic RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon). In the second and later-line settings, which encompass approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,4 two small-molecule therapies and an immune checkpoint inhibitor have been approved for the treatment of patients with advanced RCC who have received prior systemic therapy. The currently approved small-molecule agents have shown little differentiation in terms of efficacy and have demonstrated only modest progression-free survival benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau protein function, either due to gene inactivation or epigenetic silencing, resulting in a stabilization of the hypoxia-inducible transcription factors and consequent up-regulation of VEGF, MET and AXL.5 The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype and reduced overall survival. 6 Up-regulation of MET and AXL in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET and AXL in the development of resistance to these therapies.7

About Cabozantinib

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and maintenance of the tumor microenvironment.

Cabozantinib, marketed under the brand name COMETRIQ, is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.

Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.

COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.

Wound complications have been reported with COMETRIQ.

COMETRIQ treatment results in an increase in hypertension.

Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.

The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.

Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.

Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

COMETRIQ can cause fetal harm when administered to a pregnant woman.

Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf

Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted

Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that Eisai has entered into an exclusive license agreement with HUYA Bioscience International, LLC (Headquarters: San Diego, California, United States, President, CEO, Executive Chairman & Founder: Dr. Mireille Gillings, "HUYA") to develop and market the oral histone deacetylase (HDAC) inhibitor HBI-8000 in Japan, South Korea, Thailand, Malaysia, Indonesia, Philippines, Vietnam and Singapore (Press release, Eisai, FEB 1, 2016, View Source [SID:1234508923]).

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HBI-8000 is an oral HDAC inhibitor approved in China for use in the treatment of peripheral T-cell lymphoma (PTCL). Non-clinical data suggest HBI-8000 has epigenetic properties that work to regulate tumor cell growth, and the agent is believed to have immunomodulatory properties as well. HBI-8000 is at the clinical stage of testing in Japan as a treatment for PTCL, a type of non-Hodgkin’s lymphoma, under orphan drug designation from the regulatory authority in Japan. Meanwhile, a Phase I clinical study of the agent in solid tumors has been completed in the United States.

Under the agreement, Eisai has exclusive rights to develop and market HBI-8000 in the licensed territories. However, for PTCL and adult T-cell leukemia-lymphoma, HUYA will complete development of the agent for these indications and Eisai will be responsible for commercialization. According to the agreement, Eisai will pay HUYA upfront, development and commercial milestone payments as well as royalties over the term of the license, respectively.

Eisai positions oncology as a key franchise area, and is committed to providing new treatment options for patients with cancer in order to further contribute to addressing unmet medical needs that exist in the treatment of cancer as well as increase the benefits provided to patients and their families.

About HBI-8000
HBI-8000 is a member of the benzamide class of histone deacetylase (HDAC) inhibitors designed to block the catalytic pocket of Class I HDACs. HBI-8000 is an orally bioavailable, low-nanomolar inhibitor of cancer-associated HDAC enzymes with favorable pharmacology and safety profiles. HBI-8000 inhibits cancer-associated Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10 at nanomolar concentrations and stimulates accumulation of acetylated histones H3 and H4 in tumor cells. Studies with human-derived tumor cell lines suggest that HBI-8000 inhibits the growth of many tumor cell lines via multiple mechanisms of action, including epigenetic regulation of tumor cell growth and apoptosis as well as immunomodulatory effects regulating antitumor activity.
To date, HBI-8000 has been dosed in various types of hematological and solid tumors in several clinical trials, including a Phase I trial completed in the United States. HBI-8000 is approved for the treatment of peripheral T-cell lymphoma (PTCL) in China. A Phase I clinical study of the agent in non-Hodgkin’s lymphoma is underway in Japan under orphan drug designation as a treatment for PTCL by the regulatory authority in Japan.

About HDAC
Removing acetyl groups from lysine amino acids on histones to encourage stronger binding of chromatin structures to suppress gene transcription, and adding acetyl groups to weaken binding of chromatin structures to promote transcriptional activity play an important role in regulation of gene transcription on histones. HDAC are enzymes that remove acetyl groups from lysine amino acids on histones, and it is thought that by inhibiting HDAC to allow acetyl groups to accumulate on histones and relax chromatin structures promotes gene transcription activity. In tumor cells, inhibiting HDAC suppresses tumor growth by facilitating the transcriptional activity of cancer suppressing genes and inducing both apoptosis in tumor cells as well as cell cycle arrest.

On February 1, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) reported that the U.S. Food and Drug Administration (FDA) has completed its review of the Company’s Investigational New Drug (IND) application for AP32788, a tyrosine kinase inhibitor (TKI) designed as a targeted therapy for patients with non-small cell lung cancer (NSCLC) with specific mutations in EGFR or HER2 (Press release, Ariad, FEB 1, 2016, View Source [SID:1234508922]). ARIAD anticipates initiation of its Phase 1/2 clinical trial of AP32788 in patients with NSCLC in the second quarter of 2016.

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                  Schedule Your 30 min Free Demo!ent targeted treatment options. ARIAD estimates that there are approximately 6,000 patients in the United States living with EGFR exon 20 or HER2 point mutations, based on a broader data set of 175,000 patients with stage IIIb or IV NSCLC living in the U.S. in 2015, according to Kantar Health.

About AP32788

AP32788 is an investigational oral tyrosine kinase inhibitor (TKI) of activating mutations in EGFR and HER2. The molecule was designed to address the unmet need in patients with non-small cell lung cancer (NSCLC) driven by exon 20 insertion mutations in EGFR and HER2, and is ARIAD’s fourth internally discovered oncology IND to be cleared for clinical development.