publication date: Apr. 7, 2017

Drugs and Targets

Novartis drug combination Tafinlar + Mekinist receives EU approval for BRAF V600-positive advanced NSCLC

Novartis said the European Commission has approved Tafinlar(dabrafenib) in combination with Mekinist (trametinib) for the treatment of patients with BRAF V600-positive advanced or metastatic non-small cell lung cancer.

The approval marks the first targeted treatment approved for the patient population, who previously had few treatment options, in all 28 member states of the European Union, plus Iceland and Norway.

Every year, it is estimated, up to about 36,000 people, or about 1-3% of patients with lung cancer, are diagnosed with BRAF V600-positive NSCLC worldwide.

EU approval follows a positive opinion granted in February by the Committee for Medicinal Products for Human Use, which was based on safety and efficacy of dabrafenib in combination with trametinib in a phase II, three-cohort, multicenter, non-randomised and open-label study in which patients with stage IV BRAF V600E mutant NSCLC were enrolled (36 treatment-naïve [previously untreated] and 57 previously treated with chemotherapy).

For the primary endpoint of investigator-assessed overall response rate (ORR), 36 treatment-naïve patients receiving 150 mg of Tafinlar twice daily and 2 mg of Mekinist once daily demonstrated an ORR of 61.1% (95% confidence interval: 43.5%, 76.9%).

In this population, 68% of patients had not progressed after 9 months. The median duration of response (DoR) and progression free survival in the previously untreated population were not yet reached at the time of approval.

In the previously treated population receiving the same dosage, patients demonstrated an ORR of 66.7% (95% CI: 52.9%, 78.6%). The response was durable with a median DoR reaching 9.8 months (95% CI:  6.9, 16.0).

An in-depth analysis of data from the treatment-naïve cohort will be presented at an upcoming medical meeting.

The most common adverse events (incidence >20%) were pyrexia, nausea, vomiting, peripheral edema, diarrhea, dry skin, decreased appetite, asthenia, chills, cough, fatigue, rash, and dyspnea.

FDA granted Tafinlar + Mekinist Breakthrough Therapy designation for advanced or metastatic BRAF V600E-positive NSCLC patients in 2015 and Priority Review in November 2016.

Combination use of Tafinlar + Mekinist is approved in the US, Europe, Australia, Canada, and additional countries for patients with unresectable or metastatic melanoma whose tumors tested positive for the BRAF V600 mutation.


FDA accepts for review the application of Ibrutinib for cGVHD after failure of systemic therapy

Janssen Research & Development, LLC said FDA has accepted for review a supplemental New Drug Application for ibrutinib (Imbruvica) for the treatment of patients with chronic graft-versus-host-disease after failure of one or more lines of systemic therapy.

Imbruvica is jointly developed and commercialized by Janssen Biotech Inc. and Pharmacyclics LLC, an AbbVie company.

The sNDA is supported by data from a single-arm Phase 1b/2 trial (PCYC-1129) examining the safety and efficacy of ibrutinib in patients with cGVHD who have failed first-line corticosteroid therapy and require additional therapy.

The data was accepted as a late-breaker and presented at the American Society of Hematology annual meeting in December 2016 and the Blood and Marrow Transplantation Tandem Meeting in February 2017.

Based on this data, a phase III study was initiated to evaluate ibrutinib with corticosteroid versus placebo with corticosteroid as a first-line therapy for patients with new onset moderate or severe cGVHD; the trial is currently ongoing.

FDA granted Breakthrough Therapy designation and Orphan Drug designation in June 2016 for ibrutinib as a potential treatment for cGVHD after failure of one or more lines of systemic therapy. Approximately 30-70 percent of post-allogeneic transplant patients develop cGVHD.


Amgen seeks to expand XGEVA indications to multiple myeloma in the US, Europe

Amgen announced the submission of a supplemental Biologics License Application to FDA and the European Medicines Agency for XGEVA (denosumab).

The submissions to regulatory authorities seek to expand the currently approved XGEVA indication for the prevention of skeletal-related events in solid tumors to include patients with multiple myeloma. The applications include new data from the pivotal phase III head-to-head ‘482 study, the largest international multiple myeloma trial ever conducted.

XGEVA is a fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL)—a protein essential for the formation, function and survival of osteoclasts, which break down bone—thereby inhibiting osteoclast-mediated bone destruction.

XGEVA is indicated for the prevention of SREs in patients with bone metastases from solid tumors based on results from three previous pivotal phase III head-to-head studies. In these phase III studies, XGEVA demonstrated superiority in the solid tumors studied compared to zoledronic acid.

In the U.S., XGEVA has a limitation of use noting that it is not indicated for the prevention of SREs in patients with multiple myeloma. The sBLA is based on efficacy and safety data from the pivotal phase III ‘482 study, which demonstrated that XGEVA is non-inferior to zoledronic acid in delaying the time to first on-study SRE in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01).

The secondary endpoints of superiority in delaying time to first SRE and delaying time to first-and-subsequent SRE were not met in this study. Overall survival, another secondary endpoint, was also in favor of XGEVA over zoledronic acid (HR=0.90, 95 percent CI: 0.70, 1.16; p=0.41); however, it was not statistically significant. The hazard ratio of XGEVA versus zoledronic acid for progression-free survival was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036). The median PFS difference between arms was 10.7 months in favor of XGEVA.

Adverse events observed in patients treated with XGEVA were consistent with the known safety profile of XGEVA. The most common adverse events (greater than 25 percent) were diarrhea (33.5 percent XGEVA and 32.4 percent zoledronic acid) and nausea (31.5 percent XGEVA and 30.4 percent zoledronic acid).


RedHill receives orphan drug designation for Yeliva

RedHill Biopharma Ltd., a specialty biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for gastrointestinal and inflammatory diseases and cancer, said FDA has granted Yeliva (ABC294640) Orphan Drug designation for the treatment of cholangiocarcinoma.

Yeliva is a phase II, proprietary, first-in-class, orally-administered sphingosine kinase-2 (SK2) selective inhibitor with anticancer and anti-inflammatory activities, targeting multiple oncology, inflammatory and gastrointestinal indications. By inhibiting the SK2 enzyme, Yeliva blocks the synthesis of sphingosine 1-phosphate, a lipid signaling molecule that promotes cancer growth and pathological inflammation, the company said.

Cholangiocarcinoma is a highly lethal malignancy for which there is a strong need for more effective systemic treatments. Approximately 8,000 people are diagnosed with intrahepatic and extrahepatic bile duct cancers annually in the U.S., with recent studies showing an increased incidence of cholangiocarcinoma, mainly attributed to recent advancements in diagnosis of this disease.

Surgery with complete resection remains the only curative therapy for cholangiocarcinoma, however only a minority of patients are classified as having a resectable tumor at the time of diagnosis. Additional treatment options include radiation therapy and chemotherapy; however, the efficacy of these treatments in cholangiocarcinoma patients is also limited. Despite overall advances in the ability to diagnose and treat patients with cholangiocarcinoma, the prognosis for these relapse patients who have failed initial chemotherapy remains very poor, with an overall median survival of approximately one year.

The 5-year relative survival rates of intrahepatic and extrahepatic cholangiocarcinoma patients range between 2% to 30%, depending on the tumor type and stage at diagnosis.  Final results from the phase I study with YELIVA in patients with advanced solid tumors confirmed that the study, conducted at the Medical University of South Carolina Hollings Cancer Center, successfully met its primary and secondary endpoints, demonstrating that the drug is well-tolerated and can be safely administered to cancer patients at doses that provide circulating drug levels that are predicted to have therapeutic activity.

Of the three patients with cholangiocarcinoma treated in the Phase I study, all of whom had prior therapy, one subject achieved a sustained partial response (Overall Survival = 20.3 months) and the other two subjects had prolonged stable disease (OS = 17.6 and 16.3 months).

RedHill said it plans to initiate a phase IIa clinical study with Yeliva in patients with advanced, unresectable, intrahepatic and extrahepatic cholangiocarcinoma in the third quarter of 2017. The single-arm study will evaluate Yeliva as a single agent in cholangiocarcinoma patients with a primary endpoint of determining the response rate of cholangiocarcinoma to this treatment.

A phase II study with Yeliva for the treatment of advanced hepatocellular carcinoma (HCC) is ongoing at MUSC Hollings Cancer Center. The study is supported by a $1.8 million grant from the NCI, awarded to MUSC, which is intended to fund a broad range of studies on the feasibility of targeting sphingolipid metabolism for the treatment of a variety of solid tumor cancers, with additional support from RedHill.

A phase Ib/II study with Yeliva for the treatment of refractory or relapsed multiple myeloma is ongoing at Duke University Medical Center. The study is supported by a $2 million grant from the NCI Small Business Innovation Research Programawarded to Apogee Biotechnology Corp., in conjunction with Duke University, with additional support from RedHill.

A phase I/II clinical study evaluating YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma as well as Kaposi sarcoma patients is ongoing at the Louisiana State University Health Sciences Center. The study is supported by a grant from the NCI awarded to Apogee, with additional support from RedHill. A phase Ib study to evaluate Yeliva as a radioprotectant for prevention of mucositis in head and neck cancer patients undergoing therapeutic radiotherapy is planned to be initiated in the third quarter of 2017, the company said.


ESSA Pharma receives $1.2 million grant payment from CPRIT

ESSA Pharma Inc., a pharmaceutical company focused on the development of novel small molecule drugs for the treatment of prostate cancer, announced today the receipt of a $1.2 million payment from the Cancer Prevention Research Institute of Texas.

The payment is part of a total non-dilutive grant of $12.0 million originally awarded in July 2014, and is repayable out of potential future product revenues. The payment recognizes eligible expenditures made by ESSA in conducting the phase I dose escalation clinical trial currently underway, and also costs incurred in preparation for the phase II dose expansion clinical trial expected to begin later this year.

The company is eligible to receive a further $229,200 upon completion of financial and compliance filings with CPRIT.

“The financial support from CPRIT since 2014 has been instrumental to ESSA in building a top-tier team in Houston to guide the clinical development of EPI-506,” said David Parkinson, ESSA president and CEO.

The company initiated the phase I/II clinical trial of EPI-506 in late 2015 and continues to expand dosing patients in the Phase 1 portion of the study at sites in the U.S. and Canada. The clinical trial is designed to demonstrate the safety, tolerability, maximum tolerated-dose, pharmacokinetics and efficacy of EPI-506 in the treatment of prostate cancer patients who have failed treatments using abiraterone or enzalutamide or both, the current standard-of-care drugs in metastatic castrate-resistant prostate cancer.


MD Anderson, Oncora Medical cooperate on precision radiation oncology

Oncora Medical, a precision radiation oncology software company, and MD Anderson Cancer Center announced a strategic alliance focusing on building the next generation of precision medicine software for radiation oncology.

During phase I, MD Anderson oncologists and information technology professionals will work with Oncora’s team of data scientists and engineers to install Oncora’s Precision Radiation Oncology Platform, a software system built to assist radiation oncologists in the development of personalized treatment plans based on outcome predictions.

Oncora’s platform will be fueled by data from MD Anderson’s electronic medical record system, tumor registry, radiation therapy planning system, and Brocade, an innovative software product developed by MD Anderson in 2014. Brocade was developed by Benjamin Smith, associate professor of radiation oncology, and author of a study published in the April 2016 issue of the Journal of the American College of Radiology that demonstrated a 70 percent reduction in the time physicians spend documenting clinical data using Brocade.

Brocade, a web-based clinical documentation tool used by MD Anderson radiation oncologists, enables intuitive collection of structured data about patient diagnosis, treatment and radiation side effects, and generates narrative-style clinical documentation for medical records. Oncora will engineer complete interoperability between their Precision Radiation Oncology Platform and Brocade to explore the potential value of a combined product.

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