On May 13, 2016 Diffusion Pharmaceuticals Inc. (OTCQX:DFFN), a clinical stage biotechnology company focused on the development of novel small molecule therapeutics for cancer, reported that data from the Phase 1/2 clinical trial evaluating the safety and efficacy of trans sodium crocetinate (TSC) in newly diagnosed glioblastoma multiforme (GBM) has been published online today in the Journal of Neurosurgery ("JNS"), the official publication of the American Association of Neurological Surgeons (Press release, Diffusion Pharmaceuticals, MAY 13, 2016, View Source [SID:1234512374]).

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As outlined in the JNS article, 36.3% of the full TSC dose patients were alive at two years based on a Kaplan-Meier analysis, compared to reported survival rates for the standard of care (SOC) ranging from 27% to 30%. TSC, the Company’s lead product candidate, is designed to target the tumor’s hypoxic microenvironment, re-oxygenating treatment-resistant tissue and making the cancer cells more susceptible to the therapeutic effects of SOC radiation therapy and chemotherapy.

The article, entitled, "Trans Sodium Crocetinate with Temozolomide and Radiation Therapy for Glioblastoma Multiforme," outlines the results of a Phase 1/2 trial designed to evaluate the therapeutic effect of adding TSC to radiation therapy (RT) in 59 newly diagnosed GBM patients. In the open, single-arm trial, all patients received SOC RT and temozolomide (TMZ) beginning either after an initial resection or biopsy of the tumor to confirm GBM. TSC was administered at a dosage of 0.25 mg/kg IV around 45 minutes before each RT session three days per week during the 6 weeks of radiation therapy. Considerable tumor shrinkage was observed in many patients, with some tumors disappearing completely.

John L. Gainer, Ph.D., Chief Science Officer of Diffusion Pharmaceuticals, remarked, "The peer-reviewed publication in JNS indicates that the Phase 1/2 trial data are very striking and encouraging. These data strongly suggest that adding TSC during radiation therapy is beneficial for the treatment of GBM. TSC offers a novel, easily-implemented way to combat hypoxia in tumor tissue."

Summary of Key Findings

Overall Survival: Overall survival at two years in the Phase 1/2 trial was 36% greater than the historical standard of 26.5% that was established as the SOC in the 2005 Stupp study.

Needle-only biopsy subgroup: Greater survival rates were seen in patients who received only needle biopsies initially, a subgroup thought to fare worse than patients whose tumors have been surgically resected before radiation begins.

73% of the tumors existing at the beginning of radiation therapy decreased in size.

Safety: No serious adverse events were associated with TSC in any patient in the Phase 1/2 trial, and no complications arose in combination with TMZ. This suggests that adding TSC to the SOC could also increase patients’ ability to tolerate the TMZ treatment.

Quality of Life: Quality of life did not diminish in the Phase 1/2 trial as measured by Karnofsky Performance Status (KPS) and QOL questionnaires.
David Kalergis, Chairman and Chief Executive Officer of Diffusion Pharmaceuticals, said, "The publication is a significant milestone for Diffusion in the clinical advancement of TSC. The Phase 1/2 trial results confirm the therapeutic potential of TSC to overcome treatment resistance by re-oxygenating solid cancerous tumors and improving patient survival outcomes without the addition of harmful side effects. We look forward to continuing the clinical development of TSC as we continue the preparations for the Phase 3 GBM trial and continue discussions with the FDA about trial design for a pivotal trial in pancreatic cancer."

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 on hypoxia and the resultant changes in the tumor microenvironment cause "treatment-resistance" 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 patients’ life expectancy. Oxygen levels of normal tissue remain unaffected upon administration of TSC, thereby avoiding the introduction of harmful side effects.

On May 13, 2016 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported that it has completed patient enrollment of FRESCO, its Phase III pivotal trial of fruquintinib (HMPL-013) in third-line locally advanced or metastatic colorectal cancer ("CRC") in China, where an estimated 390,000 new cases of CRC were diagnosed in 2012 (Press release, Hutchison China MediTech, MAY 13, 2016, http://www.chi-med.com/enrolled-416-crc-pts-in-ph-3-fresco-trial/ [SID:1234512368]).

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Fruquintinib is a highly selective small molecule drug candidate that has been shown to inhibit vascular endothelial growth factor receptors (VEGFR) 24 hours a day via an oral dose, without known off-target toxicities. The FRESCO trial is evaluating the efficacy of fruquintinib versus placebo, with all patients receiving best supportive care ("BSC"). The primary endpoint is overall survival ("OS").

"Completing enrollment of our first Phase III clinical trial is an important milestone for our company," said Christian Hogg, Chief Executive Officer of Chi-Med. "We believe fruquintinib has the potential to significantly improve outcomes in several types of solid tumors. While we wait for the FRESCO CRC data to mature over the balance of the year, we are focused on accelerating the ongoing Phase III FALUCA pivotal trial in non-small cell lung cancer ("NSCLC"), and launching additional studies of fruquintinib, including a Phase II study in gastric cancer in combination with paclitaxel, new studies in the U.S., and certain exploratory studies in combination with other oncology agents."

The FRESCO trial was launched following a 71-patient, randomized, double-blind Phase II trial of fruquintinib as a third-line treatment for metastatic CRC. The study met its primary endpoint of progression free survival ("PFS") of 4.73 months for patients receiving fruquintinib versus 0.99 month for the placebo arm, with a hazard ratio of 0.30 (p<0.001), and had no unexpected safety issues. The positive data resulted in a US$18 million payment to Chi-Med from its partner, Eli Lilly and Company ("Lilly").

About the FRESCO CRC Trial

FRESCO is a randomized, double-blind, placebo-controlled, multicenter, Phase III pivotal trial in patients with locally advanced or metastatic CRC who have failed at least two prior systemic antineoplastic therapies (i.e. third-line), including fluoropyrimidine, oxaliplatin and irinotecan. The results of the preceding Phase II trial were presented at the 2015 European Cancer Congress (ESMO; see poster).

The first patient was dosed on December 12, 2014. A total of 416 patients were randomized at a 2:1 ratio to receive either: 5mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus BSC; or placebo plus BSC.

The primary endpoint is OS, with secondary endpoints including PFS, objective response rate, disease control rate and duration of response. Once a pre-specified number of OS events (deaths) have occurred, data analysis will commence. We expect to publish top-line results at the end of 2016 or in early 2017.

Additional details of the FRESCO study may be found at clinicaltrials.gov, using identifier NCT02314819.

According to the 2012 Chinese Cancer Registry annual report, CRC was 10.3% of the total China cancer incidence, or about 390,000 new cases.

Other Fruquintinib Clinical Development Overview

In addition to CRC, fruquintinib is also in clinical development for lung cancer and gastric cancer.

Lung: In June 2014, Chi-Med initiated a second proof-of-concept ("POC") Phase II trial of fruquintinib in third-line NSCLC patients in China. 91 patients received fruquintinib plus BSC or placebo plus BSC at a 2:1 ratio. Top-line results demonstrated that the trial succeeded in meeting the primary efficacy endpoint of PFS, with no unexpected safety issues. Detailed results will be presented at an upcoming scientific conference in 2016. The positive results of this trial triggered a US$10 million payment from Lilly and the initiation of FALUCA in December 2015, a 520-patient Phase III pivotal study of fruquintinib in third-line NSCLC patients in China. Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02691299.

Gastric: Chi-Med is nearing completion of a Phase Ib dose-finding study of fruquintinib, in combination with paclitaxel, in second-line gastric cancer patients and plans to initiate a Phase II POC study in 2016. Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02415023.

Chi-Med receives reimbursement for costs associated with clinical development in China from Lilly according to a pre-specified cost-sharing rate.

On May 13, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that in a Phase III clinical study (Study 304) of its in-house developed anticancer agent eribulin mesylate ("eribulin", product name: Halaven ) in patients with locally recurrent or metastatic breast cancer in China, eribulin demonstrated a statistically significant extension in the study’s primary endpoint of progression free survival (PFS) over the comparator treatment vinorelbine (Press release, Eisai, MAY 13, 2016, View Source [SID:1234512341]).

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Conducted in China, Study 304 was a multicenter, open-label, randomized parallel group Phase III clinical study to evaluate the efficacy and safety of eribulin and vinorelbine in 530 female subjects with locally recurrent or metastatic breast cancer, previously treated with at least two and a maximum of five prior chemotherapy regimens, including an anthracycline and a taxane. In this study, the primary objective was to assess PFS in both treatment groups. In addition, the most common adverse events observed in the eribulin group were neutropenia, anaemia, pyrexia, and fatigue/asthenia, which was consistent with the known side-effect profile of eribulin. Detailed results of the study have been submitted for presentation at an upcoming academic conference.
Based on the results of this study, Eisai intends to submit a New Drug Application to the China Food and Drug Administration during the first half of fiscal 2016.

The number of women diagnosed with breast cancer in China has been increasing in recent years,1 with an estimated 272,400 new cases of invasive breast cancer and 70,700 related deaths in 2015. 2 Breast cancer is now the most frequently diagnosed cancer in Chinese women. 1

Halaven is a halichondrin class microtubule dynamics inhibitor with a distinct binding profile. Recent non-clinical studies showed that Halaven is associated with increased vascular perfusion and permeability in tumor cores.3 Halaven promotes the epithelial state and decreases the capacity of breast cancer cells to migrate. 4 First approved in the United States for use in the treatment of breast cancer in November 2010, Halaven is currently approved in approximately 60 countries worldwide, including Japan and countries in Europe, the Americas and Asia.

Eisai remains committed to providing further clinical evidence for Halaven aimed at maximizing value of the drug as it seeks to contribute further to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare providers.

About Halaven (eribulin mesylate) Halaven is the first in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally Halaven is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Halaven is believed to work by inhibiting the growth phase of microtubule dynamics which prevents cell division. In addition, recent non-clinical studies showed that Halaven is associated with increased vascular perfusion and permeability in tumor cores.3 Halaven promotes the epithelial state and decreases the capacity of breast cancer cells to migrate.4

Halaven was first approved as a treatment in the United States in November 2010 for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Halaven is currently approved for use in the treatment of breast cancer in approximately 60 countries worldwide, including Japan and countries in Europe, the Americas and Asia. In Japan, Halaven has been approved to treat inoperable or recurrent breast cancer and was launched in the country in July 2011. Halaven has also been approved in countries in Europe and Asia indicated as a treatment for patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments.

Regarding soft tissue sarcoma, Halaven was approved in the United States for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen in January 2016, approved in Japan for the treatment of soft tissue sarcoma in February 2016, and approved in the EU for the treatment of adult patients with unresectable liposarcomas who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease in May 2016. Applications seeking approval for use in the treatment of soft tissue sarcoma are currently under review throughout the world including Switzerland, Russia, Australia, Brazil, Malaysia, and the Philippines. Furthermore, Halaven has been designated as an orphan drug for soft-tissue sarcoma in the United States and Japan.

About Study 304
Conducted in China, Study 304 was a multicenter, open-label, randomized, parallel group Phase III clinical study to evaluate the efficacy and safety of eribulin and vinorelbine in 530 female subjects with locally recurrent or metastatic breast cancer, previously treated with at least two and a maximum of five prior chemotherapy regimens, including an anthracycline and a taxane. Patients received either eribulin (1.4 mg/m2 administered intravenously on Day 1 and Day 8) or vinorelbine (25 mg/m2 administered intravenously on Day 1, Day 8 and Day 15) every 21 days until disease progression.

From the results for the study, eribulin demonstrated a statistically significant extension in the study’s primary endpoint of progression-free survival (PFS) over the comparator treatment vinorelbine. The study’s secondary endpoints were overall survival (OS) and objective response rate (ORR). The most common adverse events observed in the eribulin arm were neutropenia, anaemia, pyrexia, and fatigue/asthenia, which was consistent with the known side-effect profile of eribulin.