On October 16, 2017 Fennec Pharmaceuticals Inc. (NASDAQ: FENC, TSX: FRX), a specialty pharmaceutical company focused on the development of PEDMARKTM (a unique formulation of sodium thiosulfate (STS)) for the prevention of platinum-induced ototoxicity in pediatric patients, reported data from its Phase 3 SIOPEL 6 study presented during the late breaker session on Saturday, October 14, 2017 at SIOP 2017 in Washington, DC (Press release, Fennec Pharmaceuticals, OCT 16, 2017, View Source [SID1234520965]).

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Top Line Efficacy Data

The SIOPEL 6 study met its primary endpoint. The study demonstrated that the addition of STS significantly reduces the incidence of cisplatin-induced hearing loss without any evidence of tumour protection. Among the 99 evaluable patients, hearing loss occurred in 30/45=67% treated with Cisplatin (Cis) alone and in 20/54=37.0% treated with Cis+STS, corresponding to a relative risk of 0.56(P=0.0033).

Fennec plans to pursue regulatory approval for PEDMARKTM based on the data from the SIOPEL 6 study along with the proof of principle data from COG ACCL0431. STS has received Orphan Drug Designation in the US in this setting and plans to pursue European Market Exclusivity for Pediatric Use upon approval.

"I am absolutely delighted that after 30 years of research we have found a safe way to reduce ototoxicity in children receiving platinum containing chemotherapy," said Penelope Brock, M.D., PhD, International Chair of SIOPEL. "This means that children who are cured from cancer after receiving platinum treatment can look forward to a normal healthy life, fully integrated into society. I believe this marks a new standard of care in pediatric oncology."
The Company also reported top-line data for secondary endpoints Event Free Survival (EFS) and Overall Survival (OS). The combination of Cis+STS was generally well tolerated. With a follow up of 52 months, 3yr EFS is Cis 78.8% and Cis+STS 82.1%; 3yr OS is Cis 92.3% and Cis+STS 98.2%.

"We are very pleased with the results of this study," stated Rosty Raykov, CEO of Fennec. " We would like to thank all the patients and their families who participated in this trial, physicians, the entire SIOPEL 6 team, and Dr. Neuwelt and his research team at OHSU. We believe that if approved PEDMARK would be an important therapy for patients and caregivers where currently there are no treatment options."

Safety and Tolerability

In the study, the results presented showed that treatment was well tolerated and acute toxicity similar and expected between arms. The table below presents the toxicities of the two arms:

Adverse event Grade CIS CIS+STS
N % N %
Febrile neutropenia 3 7 13.5 5 8.8
4 - - - -
Infection 3 5 9.6 6 10.5
4 - - - -
Hypomagnesemia 3 1 1.9 1 1.8
4 - - - -
Hypernatremia 3 - - 1 1.8
4 - - - -
Vomiting 3 1 1.9 3 5.3
4 - - - -
Nausea 3 3 5.8 2 3.5
4 - - - -

SIOP 2017 Presentation

Fennec will provide access to the recording of SIOP 2017 late breaker presentation on the Company’s website.

To access the archived recording, visit the Fennec website at www.fennecpharma.com.

SIOPEL 6

SIOPEL 6 is a multi-centre open label randomized phase 3 study evaluating the efficacy of STS in reducing ototoxicity in patients receiving cisplatin monotherapy for standard risk hepatoblastoma. From the beginning of 2007 to the end 2014, 52 sites from 11 countries enrolled 113 evaluable patients. The study is closed to recruitment and all protocol pre-specified IDMC safety reviews are now complete. The primary efficacy hearing endpoint analysis can be performed once patients have reached 3.5 years of age and an audiometry test can be carried out. The SIOPEL 6 study trial was designed with 80% power and a 5% significance level to detect an absolute 25% reduction in the rate of Brock grade ≥1 hearing loss with a chi-square test, from a 60% hearing loss in Cis alone arm to a 35% hearing loss in Cis+STS arm. The primary endpoint is the rate of Brock grade ≥ 1 hearing loss determined after the end of treatment at the age of ≥3.5 years by pure tone audiometry.

About PEDMARKTM (sodium thiosulfate/STS)

Cisplatin and other platinum compounds are essential chemotherapeutic components for many pediatric malignancies. Unfortunately, platinum-based therapies cause ototoxicity in many patients, and are particularly harmful to the survivors of pediatric cancer.

In the U.S. and Europe there is estimated that over 7,000 children are diagnosed with local cancers that may receive platinum-based chemotherapy. Localized cancers that receive platinum agents may have overall survival rates of greater than 80% further emphasizing the quality of life after treatment. The incidence of hearing loss in these children depends upon the dose and duration of chemotherapy, and many of these children require lifelong hearing aids. There is currently no established preventive agent for this hearing loss and only expensive, technically difficult and sub-optimal cochlear (inner ear) implants have been shown to provide some benefit. Infants and young children at critical stages of development lack speech language development and literacy, and older children and adolescents lack social-emotional development and educational achievement.

STS has been studied by cooperative groups in two Phase 3 clinical studies of survival and reduction of ototoxicity, The Clinical Oncology Group Protocol ACCL0431 and SIOPEL 6. Both studies are closed to recruitment. The COG ACCL0431 protocol enrolled one of five childhood cancers typically treated with intensive cisplatin therapy for localized and disseminated disease, including newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma, neuroblastoma, and medulloblastoma. SIOPEL 6 enrolled only hepatoblastoma patients with localized tumors. COG ACCL0431 final results were published in the Lancet Oncology.

In May 2017, Fennec announced the launch of a Named Patient Program in Europe. European based Healthcare Professionals can obtain details about STS Named Patient Program by emailing [email protected].

On 16 October, 2017 Ipsen (Euronext: IPN; ADR: IPSEY) and its partner Exelixis (NASDAQ: EXEL) reported that its global phase 3 CELESTIAL trial met its primary endpoint of overall survival (OS), with cabozantinib providing a statistically significant and clinically meaningful improvement in median OS compared to placebo in patients with advanced hepatocellular carcinoma (HCC) (Press release, Ipsen, OCT 16, 2017, View Source [SID1234520945]). The independent data monitoring committee for the study recommended that the trial should be stopped for efficacy following review of the second planned interim analysis. CELESTIAL is a randomized, global phase 3 trial of cabozantinib versus placebo in patients with advanced HCC who have been previously treated with sorafenib. The safety data in the study were consistent with the established profile of cabozantinib.

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In line with and in collaboration with our partner Exelixis, Ipsen expects to file in the first half of 2018 a variation of the initial application to the EMA and other relevant regulatory agencies and to evaluate potential next steps in the development strategy for cabozantinib outside the United States and Japan as a treatment for advanced HCC in patients who have been previously treated. Detailed results from CELESTIAL will be submitted for presentation at a future medical conference.

Alexandre Lebeaut, MD, Executive Vice-President, R&D, Chief Scientific Officer, Ipsen, said: "Liver cancer is one of the leading causes of cancer deaths worldwide and more effective treatment options are urgently needed. We are pleased to report that in the CELESTIAL clinical study cabozantinib has been shown to provide a survival benefit and therefore has the potential to bring a new oral systemic treatment to previously treated patients with advanced liver cancer. "

About the CELESTIAL Study

CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who previously received sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017, and 773 patients were ultimately randomized. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms.

The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and progression-free survival. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

Based on available clinical trial data from various published trials conducted in the second-line setting of advanced HCC, the CELESTIAL trial statistics for the primary endpoint of OS assumed a median OS of 8.2 months for the placebo arm. A total of 621 events provide the study with 90 percent power to detect a 32 percent increase in median OS (HR = 0.76) at the final analysis. Two interim analyses were planned and conducted at 50 percent and 75 percent of the planned 621 events.

About HCC

Hepatocellular Carcinoma (HCC) is the most common form of liver cancer in adults.1 The disease originates in cells called hepatocytes found in the liver. With approximately 800’000 new cases diagnosed each year, HCC is the sixth most common cancer and the second-leading cause of cancer deaths worldwide.2,3 According to the GLOBOCAN data, it is estimated that across the European Union (EU-28) nearly 60’000 new patients will be diagnosed with liver cancer in 2020.4 Without treatment, patients with the disease in advanced stage usually survive between 4 and 8 months.5

About CABOMETYX (cabozantinib)

Cabometyx is an oral small molecule inhibitor of receptors, including VEGFR, MET, AXL and RET. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

In February of 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan. This agreement was amended in December of 2016 to include commercialization rights for Ipsen in Canada. On April 25, 2016, the FDA approved Cabometyx tablets for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy and on September 9, 2016, the European Commission approved Cabometyx tablets for the treatment of advanced RCC in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland. Cabometyx is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

Ipsen also submitted to European Medicines Agency (EMA) the regulatory dossier for cabozantinib as a treatment for first-line advanced RCC in the European Union on August 28, 2017; on September 8, 2017, Ipsen announced that the EMA validated the application.

Cabozantinib is not approved for the treatment of advanced hepatocellular carcinoma.

On October 16, 2017 Atossa Genetics (NASDAQ:ATOS), a clinical-stage pharmaceutical company developing novel therapeutics and delivery methods for breast cancer and other breast conditions, reported that the Ernest Mario School of Pharmacy at Rutgers, The State University at New Jersey, plans to conduct a study utilizing Atossa’s intraductal microcatheter technology (Press release, Atossa Genetics, OCT 16, 2017, View Source [SID1234520936]).

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The Rutgers researchers believe that directly administering drugs into the breast duct where breast cancer grows, by inserting microcatheters into the nipple, is a better alternative than systemic administration, because the drugs will be directly delivered to the tissue. The Rutgers program uses a unique directed delivery system comprised of nanoscale pharmaceutical carriers loaded with single drugs. The long-term goal of the research program is to develop a locally administered drug delivery system that selectively targets and delivers pathway-specific targeting therapeutics to eliminate breast cancer cells and cancer stem-like cells while sparing normal breast cells.

"We are encouraged that a leading research institution like Rutgers recognizes the potential merit of our microcatheter technology. Atossa fully supports additional research utilizing our patented microcatheter technology," stated Steven Quay, MD, PhD, Atossa CEO and President.

The Rutgers program is in the research and development phase and has not been approved by the FDA or any other regulatory body. Studies demonstrating safety and efficacy, among other things, and regulatory approvals will be required before commercialization.