On October 17, 2017 Ignyta, Inc. (Nasdaq: RXDX), a biotechnology company focused on precision medicine in oncology, reported that the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) designation for entrectinib in the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumours in adult and paediatric patients who have either progressed following prior therapies or who have no acceptable standard therapy (Press release, Ignyta, OCT 17, 2017, View Source [SID1234520979]). Through the PRIME initiative, Ignyta will have enhanced EMA support, including optimizing the entrectinib development pathway, potentially accelerating assessment of the Marketing Authorisation Application (MAA), and engaging in early discussion with EMA and health technology assessments (HTAs) regarding reimbursement pathways. PRIME designation for entrectinib was substantially based on data from the Phase 2 global study, STARTRK-2.

“We are pleased and grateful that the EMA has accepted entrectinib into its PRIME program, which is analogous to the Breakthrough Therapy Designation from the U.S. FDA that entrectinib received earlier this year. This PRIME designation recognition is the result of the efforts of Ignyta’s team to ensure that entrectinib development was global in nature from its earliest days, and further validates the broad potential of entrectinib as a novel treatment for patients, regardless of age, with NTRK-positive tumors, a group of cancers for which there currently is no approved treatment,” said Jonathan Lim, M.D., chairman and CEO of Ignyta. “We look forward to collaborating with the EMA, as well as other global regulatory authorities, on the accelerated assessment of entrectinib with the goal to provide a new therapy for patients in need.”

Entrectinib is an investigational, orally available, CNS-active tyrosine kinase inhibitor targeting tumors that harbor NTRK1/2/3 or ROS1 gene fusions. Entrectinib was previously granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumors in adult and pediatric patients who have either progressed following prior therapies or who have no acceptable standard therapies in May 2017.

About the Priority Medicines (PRIME) Initiative
The PRIME initiative was launched in 2016 by the EMA to support the development and accelerate the review of new therapies to treat patients with unmet medical need. The criteria for the PRIME initiative require early clinical evidence that the therapy offers a therapeutic advantage over existing treatments or benefits patients without treatment options. This designation provides appointment of a rapporteur, early dialogue and scientific advice at key development milestones, and the potential to qualify products for accelerated review earlier in the application process.

About Entrectinib
Entrectinib is an investigational, CNS-active, potent, and selective small molecule tyrosine kinase inhibitor of the TRK (tropomyosin receptor kinase) family of tyrosine kinase receptors (TRKA/B/C) and ROS1 proteins, which is in a Phase 2 clinical study and two Phase 1 clinical studies in molecularly defined adult patient populations for the treatment of solid tumors, and a Phase 1/1b clinical study in pediatric patients with advanced solid tumor malignancies.
LOGO

About STARTRK-2
STARTRK-2 is an open-label, multicenter, global Phase 2 basket study of entrectinib for the treatment of patients with locally advanced or metastatic solid tumors that harbor NTRK1/2/3, ROS1, or ALK rearrangements. The basket design screens patient tumor samples for the relevant targets to take full advantage of entrectinib’s demonstrated preliminary clinical activity across a range of different tumor types and molecular targets.

On October 17, 2017 Diffusion Pharmaceuticals Inc. (NASDAQ:DFFN) (“Diffusion” or “the Company”), a clinical-stage biotechnology company focused on extending the life expectancy of cancer patients, reported that it has received final protocol guidance from the U.S. Food and Drug Administration (FDA) for a Phase 3 clinical trial with the Company’s lead compound trans sodium crocetinate (TSC) in patients newly diagnosed with inoperable glioblastoma multiforme (GBM), a type of brain cancer (Press release, Diffusion Pharmaceuticals, OCT 17, 2017, View Source [SID1234520978]). The Company has responded to all outstanding points raised by the FDA and plans to begin the trial under the protocol agreed to by the FDA by the end of 2017. The trial will compare survival at two years of patients receiving TSC concurrent with chemotherapy and radiation (standard of care, or SOC), with patients receiving SOC alone.

“Following a series of interactions with the FDA, we are gratified to have an agreed-upon protocol and to be preparing to start our TSC Phase 3 trial in patients newly diagnosed with inoperable GBM,” said David Kalergis, Chief Executive Officer of Diffusion Pharmaceuticals. “As previously announced, we have engaged the contract research organization to oversee this trial and have completed the Phase 3 TSC drug production run to FDA standards. On our way to opening an anticipated total of 100 sites across the U.S. and Europe, we have 17 initial sites selected in the U.S., all under one Institutional Review Board, and first patients are expected to be enrolled this year.”

Mr. Kalergis continued, “This Phase 3 study will focus on treating newly diagnosed GBM patients who have been judged by their medical team to be inoperable because of the size or location of the tumor. In Diffusion’s Phase 2 proof-of-concept trial, the inoperable GBM patients who were treated with TSC plus standard of care showed a nearly four-fold increase in survival at two years compared with standard of care patients only. Due to their poor prognoses, inoperable patients are often excluded from GBM clinical trials and have usually been treated with radiation and chemotherapy only. We are excited to bring a new treatment possibility to patients with inoperable GBM, and look forward to beginning the trial.”

About the Glioblastoma Multiforme Phase 3 Trial

The Phase 3 trial is a randomized, controlled registration trial with TSC and SOC chemotherapy and radiation, compared with SOC alone in newly diagnosed inoperable GBM patients. The primary endpoint is overall survival, either after a predetermined number of patient deaths or following successful results of an optional interim analysis. Secondary endpoints include progression-free survival (PFS) and objective response rate (ORR; tumor response) using RANO criteria, as well as patient performance scoring (Karnofsky Performance Scale; KPS), Quality of Life (EQ-5D-5L questionnaire) and corticosteroid and anticonvulsant usage.

A total of 236 patients will be randomized 1:1 at 100 clinical sites (54 U.S., 46 EU). TSC will be dosed three times each week for six weeks concurrent with standard radiation and chemotherapy as initial treatment. This will be followed by one month of rest and then adjuvant chemotherapy consisting of six monthly cycles of TSC and temozolomide given for the first week of each cycle. As such, 18 doses of TSC will be administered during initial treatment and another 18 doses will be administered during adjuvant treatment to those so randomized.

About Treatment-Resistant Cancers and TSC

Oxygen deprivation at the cellular level (hypoxia) is the result of rapid tumor growth, causing the tumor to outgrow its blood supply. Cancerous tumor cells thrive with hypoxia and the resultant changes in the tumor microenvironment cause the tumor to become resistant to radiation therapy and chemotherapy. Using a novel, proprietary mechanism of action, Diffusion’s lead drug TSC counteracts tumor hypoxia – and therefore treatment-resistance – by safely re-oxygenating tumor tissue, thus enhancing tumor kill and potentially prolonging patient life expectancy. Oxygen levels of normal tissue remain unaffected upon administration of TSC, thereby avoiding the introduction of harmful side effects.

On October 17, 2017 Celsion Corporation (NASDAQ:CLSN), an oncology development company, reported a summary of ThermoDox related presentations made during the Company’s Research and Development (R&D) Day held on Thursday, October 12, 2017 (Press release, Celsion, OCT 17, 2017, View Source [SID1234520977]). This summary is intended to provide easy access to pertinent, top line information discussed during the conference. A complete webcast of the presentations is available on Celsion’s website at www.celsion.com under the heading News & Investors / Financial Events / Featured Events – October 12, 2017 – Celsion to Host Research and Development Update.

The presentations focused on the Company’s research and development program using ThermoDox, Celsion’s proprietary heat-activated liposomal encapsulation of doxorubicin, for the treatment of primary liver cancer, also known as hepatocellular carcinoma or HCC. Leading OPTIMA Study clinical investigators representing various geographical regions (Asia-Pacific and Europe) and multiple medical disciplines (hepatology, interventional radiology and surgery) presented their past and current experiences with ThermoDox for the treatment of primary liver cancer.

— Nicholas Borys, M.D., Celsion’s Senior Vice President & Chief Medical Officer, presented the following:
ThermoDox’s mechanism of action and how it utilizes tumor biology to deliver high concentrations of drug (Doxorubicin) directly to the tumor site and the importance of heating time.

Key learnings from the Company’s 701 patient HEAT Study including results from (i) computer simulation studies, (ii) preclinical animal studies and (iii) a post hoc subgroup analysis, all of which establishes a clear understanding of a key ThermoDox heat-based mechanism of action: the longer the target tissue is heated, the greater the doxorubicin tissue concentration.

Hypothesis prompted by the HEAT Study post-hoc findings: ThermoDox, when used in combination with Radiofrequency Ablation (RFA) standardized to a minimum dwell time of 45 minutes (sRFA > 45 min), appears to increase the overall survival (OS) of patients with HCC.

Results from an independent retrospective analysis conducted by the National Institutes of Health on the intent-to-treat population of the HEAT Study which sought to evaluate the correlation between RFA burn time per tumor volume (min/ml) and clinical outcome. The analysis concluded that increased RFA “burn time” per tumor volume significantly improved overall survival (OS) in patients with solitary lesions treated with sRFA + ThermoDox compared to patients treated with sRFA alone.

Update on the current enrollment status of the OPTIMA Study which is approaching 70% of the 550 patients necessary to ensure that its primary end point, overall survival, can be evaluated with statistical significance. The statistical plan for the OPTIMA Study calls for two interim efficacy analyses by the IDMC. The Company projects full patient enrollment by mid-2018 and the first pre-planned efficacy analysis after 118 overall survival events by the first quarter of 2019.

— Won Young Tak, M.D., Ph.D., Professor Internal Medicine, GI & Hepatology Kyungpook National University Hospital Daegu, Republic of Korea presented the following:

RFA has limited efficacy in larger tumors due to microsatellite nodules or viable tumors.
Patients treated with ThermoDox in the HEAT Study had excellent survival outcome. Two cases presented for the HEAT Study showed five and nine year survival benefit for patients treated with ThermoDox plus sRFA.

— Stephen N. Wong, M.D., Principal Investigator OPTIMA, Chinese General Hospital, Philippines presented the following:

HEAT Study patients treated with ThermoDox demonstrated a high complete response rate compared to other studies

A strong correlation exists between complete response and better survival.

— Robert M. Eisele, M.D., Deputy Head of Department, Dept. of General, Visceral, Vascular and Pediatric Surgery, Medical Faculty of the University of Saarland, Homburg, Germany presented the following:
HCC is a worldwide problem with high incidence that continues to rise.

Treatment strategies for treating HCC should be tailored.

Until ThermoDox, RFA was insufficient in treating intermediate to large tumors.
Data from the HEAT Study suggests a new role for RFA plus ThermoDox in HCC – a “promising option.”

About the OPTIMA Study
The Phase III OPTIMA Study is expected to enroll up to 550 patients in up to 70 clinical sites in the United States, Europe, China and Asia Pacific, and will evaluate ThermoDox in combination with optimized RFA, which will be standardized to a minimum of 45 minutes across all investigators and clinical sites for treating lesions three to seven centimeters, versus optimized RFA alone. The primary endpoint for the trial is Overall Survival, which is supported by post-hoc analysis of data from the Company’s 701 patient HEAT Study, where optimized RFA has demonstrated the potential to significantly improve survival when combined with ThermoDox. The statistical plan calls for two interim efficacy analyses by an independent Data Monitoring Committee.

ThermoDox has received U.S. FDA Fast Track Designation and has been granted orphan drug designation for primary liver cancer in both the U.S. and Europe. Further, the U.S. FDA has provided ThermoDox with a 505(b)(2) registration pathway. Subject to a successful trial, the OPTIMA Study has been designed to support registration in all key primary liver cancer markets. Celsion fully expects to submit registrational applications in the USA, Europe and China. The Company believes that applications will be accepted in South Korea, Taiwan and Vietnam, three other large and important markets for ThermoDox subject to approval in Europe, China or the USA.

On October 17, 2017 Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, reported that its license partner, Janssen Biotech, Inc., presented a poster with initial data from an ongoing first-in-human Phase 1 dose finding trial to evaluate JNJ-64041757 (also known as ADU-214 ), a live, attenuated double-deleted Listeria monocytogenes (LADD)-based immunotherapy in development for the treatment of advanced or metastatic non-small cell lung cancer (Press release, Aduro Biotech, OCT 17, 2017, View Source [SID1234520976]). The data were presented at the International Association for the Study of Lung Cancer’s World Conference being held in Yokohama, Japan.

The Phase 1 first-in-human, open label dose-finding trial included nine patients with advanced stage relapsed or refractory non-small cell lung cancer. Patients were administered either 1×108 or 1×109 colony-forming units infused intravenously over one hour every 21 days. Of the nine patients treated with JNJ-64041757 monotherapy, five experienced a best response of stable disease. The maximum number of cycles administered to a single patient was 25 cycles at the time of the clinical data cut off. Additionally, biomarker data showed evidence of activation of innate immunity with transient cytokine increases in all patients as well as induction of mesothelin-specific T cell immunity in a subset of patients. The immunotherapy was generally well-tolerated with transient mild to moderate adverse events, including headache, nausea, pyrexia and vomiting.

“These are encouraging early data which we believe may support clinical activity of our listeria-based immunotherapy for lung cancer,” said Dirk Brockstedt, executive vice president of research and development at Aduro Biotech. “We look forward to Janssen initiating a combination trial of JNJ-64041757 with other agents, based on synergistic combination data from preclinical mouse tumor models.”

In October 2014, Aduro entered into its second agreement with Janssen Biotech, Inc., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, granting an exclusive, worldwide license to JNJ-64041757 and other product candidates engineered for the treatment of lung cancer and certain other cancers based on its novel LADD immunotherapy platform. Under the agreement facilitated by the Johnson & Johnson Innovation center in California, Aduro received a $30 million up-front payment and has received $21 million in milestone payments upon the completion of various development activities. Aduro is eligible to receive future development, regulatory and commercialization milestone payments up to a potential total of $766 million. In addition, Aduro is eligible to receive royalties at a rate ranging from high single-digits to low teens on worldwide net sales upon successful launch and commercialization.

About LADD
LADD is Aduro’s proprietary platform of live-attenuated double-deleted Listeria monocytogenes strains that have been engineered to induce a potent innate immune response and to express tumor-associated antigens to induce tumor-specific T cell-mediated immunity.

On October 17, 2017 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to improve the survival and quality of life of cancer patients, reported payment of a $6 million milestone to Infinity Pharmaceuticals, Inc., representing the first milestone under the duvelisib license agreement between Verastem and Infinity (Press release, Verastem, OCT 17, 2017, View Source [SID1234520973]). This milestone is based on the achievement of positive top-line results from the Phase 3 DUO study evaluating the efficacy and safety of duvelisib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

In addition, Verastem drew an additional advance of $7.5 million from its existing $25 million loan and security agreement, dated March 21 2017, with Hercules Capital, Inc. (the Term Loan Facility). The proceeds will be used to pay the $6 million milestone payment to Infinity, for ongoing research and development programs, and for general corporate purposes. Verastem has drawn a total of $10 million under the Term Loan Facility, leaving $15 million in available additional advances, subject to certain conditions of funding.

“Payment of this milestone to Infinity reflects the attainment of a critical milestone for the duvelisib development program, positive data from the Phase 3 DUO study in CLL/SLL,” said Julie B. Feder, Chief Financial Officer of Verastem. “We have elected to employ the non-dilutive option of drawing a second tranche of funding under our Term Loan Facility. We believe this approach is a prudent use of the strategic financial tools that we have at hand as we advance the program towards a potential NDA filing in H1 2018.”

In September 2017, Verastem reported that the Phase 3 DUO study met its primary endpoint with oral duvelisib monotherapy demonstrating superiority over ofatumumab for progression free survival (PFS) in patients with CLL/SLL. In this study, duvelisib achieved a statistically significant improvement in median PFS of 13.3 months, compared to 9.9 months for ofatumumab with a hazard ratio (HR) of 0.52 (p<0.0001), representing a 48% reduction in the risk of progression or death. Verastem plans to share these clinical data with the U.S. Food and Drug Administration (FDA) during Q4 2017 with the goal of filing a New Drug Application (NDA) with the FDA during the first half of 2018. The duvelisib NDA submission will also be supported by favorable results from the Phase 2 DYNAMO study in indolent non-Hodgkin’s lymphoma (iNHL), which also achieved its primary endpoint with an ORR of 46% (p<0.0001).