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RedHill Biopharma Receives Additional U.S. Patent Covering RHB-105 Ahead of Confirmatory Phase III Study for H. pylori Infection

On July 21, 2016 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), a biopharmaceutical company primarily focused on development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for inflammatory and gastrointestinal diseases and cancer, reported that it has received a Notice of Allowance from the United States Patent and Trademark Office (USPTO) for a new patent covering RHB-105, a proprietary, fixed-dose, oral combination therapy for the eradication of H. pylori infection (Press release, RedHill Biopharma, JUL 21, 2016, View Source [SID:1234513989]).

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The patent application, entitled "Pharmaceutical Compositions For The Treatment Of Helicobacter Pylori" expands RedHill’s patent portfolio covering RHB-105 and is expected to be valid until 2034, once granted. The Company is currently prosecuting additional U.S. and international patent applications covering RHB-105.

"The grant of this new patent is an important addition to RedHill’s expanding IP portfolio covering RHB-105. On top of its extensive patent estate, RHB-105 was granted FDA QIDP designation under the Gain Act, providing for a total of 8 years of U.S. market exclusivity," said Danielle Abramson, Ph.D., RedHill’s Director of Intellectual Property & Research. "We are making good progress with preparations for the confirmatory Phase III study with RHB-105 for eradication of H. pylori, which follows the successful first Phase III study with RHB-105 and a positive meeting with the FDA regarding the path to marketing approval."

H. pylori bacterial infection is a major cause of chronic gastritis, peptic ulcer disease, gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. H. pylori infection is estimated to affect half of the adult population worldwide[1]. The growing resistance of the H. pylori bacteria to metronidazole and clarithromycin has resulted in increasing failure rates of current standard-of-care therapies (SoC) for H. pylori eradication, reaching an estimated 30%[2]. Despite the strong unmet medical need, no new drug has been approved by the FDA for this indication in over a decade. The 2015 U.S. and global market potential for H. pylori eradication therapies, at current branded prices, were estimated at approximately $1.45 billion and $4.83 billion, respectively, and could potentially grow with increasing awareness of the health risks associated with H. pylori infection and the benefits of its eradication[3].

RedHill announced in April 2016 that it had concluded a positive Type B Meeting with the U.S. Food and Drug Administration (FDA) regarding the path to U.S. marketing approval of RHB-105 and the planned confirmatory Phase III study. As a result of the productive and supportive feedback received from the FDA, RedHill is preparing for a confirmatory Phase III randomized, double-blind, active comparator, two-arm clinical study, comparing RHB-105 against a high dose amoxicillin and omeprazole regimen.

Subject to a successful outcome, the confirmatory Phase III study, and the supportive PK program to be completed prior to its initiation, are expected to complete the clinical package required for a U.S. New Drug Application (NDA) for RHB-105.

RHB-105 was previously granted Qualifying Infectious Disease Product (QIDP) designation by the FDA, providing a Fast-Track development pathway, as well as NDA Priority Review status, potentially leading to a shorter NDA review time by the FDA, if filed. If approved, RHB-105 will also receive an additional five years of U.S. market exclusivity, in addition to the standard exclusivity period, for a total of 8 years of U.S. market exclusivity.

With RHB-105, RedHill is pursuing an indication of first-line treatment of H. pylori infection, regardless of ulcer status, a significantly broader indication than current standard treatments for H. pylori, which are typically indicated only for patients with active or recent history of duodenal ulcer disease. If approved, RHB-105 may be the first H. pylori eradication therapy to target this broader indication, which would significantly expand the potential patient population for this drug candidate.

About RHB-105:
RHB-105 is a new and proprietary fixed-dose oral combination therapy of two antibiotics and a proton pump inhibitor (PPI) in an all-in-one oral capsule with a planned indication for the treatment of H. pylori infection. H. pylori bacterial infection is a major cause of chronic gastritis, peptic ulcer disease, gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. A first Phase III study with RHB-105 was completed in the U.S. with positive results (the ERADICATE Hp study). The study demonstrated an overall success rate of 89.4% in eradicating H. pylori, and met its protocol-defined primary endpoint of superiority in eradication of H. pylori infection over historical standard of care efficacy levels of 70%, with high statistical significance (p < 0.001) . A confirmatory Phase III study is planned to be initiated in the U.S. Additional studies may be required, subject to FDA feedback. RHB-105 has been granted Qualifying Infectious Disease Product (QIDP) designation by the FDA, providing a Fast-Track development pathway, as well as NDA Priority Review status, potentially leading to a shorter NDA review time by the FDA, if filed. If approved, RHB-105 will also receive an additional five years of exclusivity, in addition to the standard exclusivity period, for a total of 8 years of U.S. market exclusivity.

Puma Biotechnology Submits New Drug Application for PB272 (Neratinib) to U.S. FDA for Extended Adjuvant Treatment of HER2-Positive Early Stage Breast Cancer

On July 21, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for its lead product candidate PB272 (neratinib) for the extended adjuvant treatment of patients with early stage HER2-overexpressed/amplified breast cancer who have received prior adjuvant trastuzumab (Herceptin)-based therapy (Press release, Puma Biotechnology, JUL 21, 2016, View Source [SID:1234513987]).

"We are very pleased to announce this important regulatory milestone," said Alan H. Auerbach, Chief Executive Officer and President of Puma. "Although the use of trastuzumab in the adjuvant setting has led to a reduction in disease recurrence in patients with early stage HER2-positive breast cancer, there remains an unmet clinical need to further reduce the risk of recurrence and improve outcome following trastuzumab therapy. We believe that neratinib may be able to provide this type of improvement to further help patients with this disease. We look forward to working with the FDA during their review of this submission."

The submission is supported by the results of the ExteNET Phase III study, in which treatment with neratinib resulted in a 33% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.67, p = 0.009). The 2-year invasive disease free survival (DFS) rate for the neratinib arm was 93.9% and the 2-year invasive DFS rate for the placebo arm was 91.6%. For the pre-defined subgroup of patients with hormone receptor positive disease, the results of the trial demonstrated that treatment with neratinib resulted in a 49% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.51, p = 0.001). For the patients with hormone receptor positive disease, the 2-year invasive DFS rate for the neratinib arm was 95.4% and the 2-year invasive DFS rate for the placebo arm was 91.2%.

Results of the study were published online in The Lancet Oncology on February 10, 2016.

The most frequently observed adverse event for the neratinib-treated patients was diarrhea, with approximately 39.9% of the neratinib-treated patients experiencing grade 3 or higher diarrhea (1 patient (0.1%) had grade 4 diarrhea). Patients who received neratinib in the ExteNET trial did not receive any prophylaxis with antidiarrheal agents to prevent the neratinib-related diarrhea. In patients with HER2-positive early stage breast cancer who have previously been treated with adjuvant trastuzumab and received anti-diarrheal prophylaxis with loperamide, interim results of a Phase II study of neratinib monotherapy demonstrated that treatment with prophylactic loperamide reduced the rate of grade 3 or higher diarrhea to between 13.0% and 18.5%.

About ExteNET

The ExteNET trial is a double-blind, placebo-controlled, Phase III trial of neratinib versus placebo after adjuvant treatment with trastuzumab (Herceptin) in women with early stage HER2-positive breast cancer. The trial randomized 2,840 patients in 41 countries with early-stage HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab. After completion of adjuvant treatment with trastuzumab, patients were randomized to receive extended adjuvant treatment with either neratinib or placebo for a period of one year. Patients were then followed for recurrent disease, ductal carcinoma in situ (DCIS), or death for a period of two years after randomization in the trial. The primary endpoint of the trial was invasive DFS.

DelMar Pharmaceuticals Announces Presentation at the European Association of Neuro-Oncology (EANO) Annual Meeting in October 2016

On July 21, 2016 DelMar Pharmaceuticals, Inc. (NASDAQ: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that it will present an abstract at the 12th Meeting of the European Association of Neuro-Oncology (EANO) taking place in Mannheim, Germany from October 12 – 16, 2016 (Press release, DelMar Pharmaceuticals, JUL 21, 2016, View Source [SID:1234513983]).

DelMar will present an abstract entitled: "Dianhydrogalactitol (VAL-083) causes bifunctional alkylation leading to irreparable DNA double-strand breaks, S/G2 phase cell-cycle arrest and tumor cell death in an MGMT independent manner offering a unique treatment paradigm for GBM."

The Company’s EANO presentation will further elucidate how VAL-083 attacks cancer cells utilizing a mechanism of action distinct from other chemotherapies used in the treatment of glioblastoma multiforme (GBM), the most common and aggressive form of brain cancer. Specifically, DelMar will present data supporting the potential of VAL-083 to treat patients whose tumors exhibit features correlated with resistance to the chemotherapies currently used in the treatment of GBM.

About VAL-083

VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments.

VAL-083 has received an orphan drug designation in Europe for the treatment of malignant gliomas; and the U.S. FDA Office of Orphan Products has granted an orphan designation to VAL-083 for the treatment of glioma, medulloblastoma and ovarian cancer.

DelMar presented data from a recently completed Phase I/II clinical trial in refractory GBM at the 2016 American Association of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual meeting. In summary, the Company reported that:

Median survival of 22 patients receiving an assumed therapeutic dose of VAL-083 (≥20mg/m2) was 8.35 months following bevacizumab (Avastin) failure compared to published literature where survival of approximately three to five months has been reported.
A dose of 40 mg/m2/day VAL-083 administered on the first three days of every three-week cycle is well tolerated in refractory GBM patients and has been selected for study in subsequent clinical trials.
DelMar believes that these data support the potential of VAL-083 as a new chemotherapy that may offer improved outcomes in the treatment of GBM. The Company recently announced the completion of a successful end of Phase II meeting with the U.S. FDA and plans to advance VAL-083 into a pivotal clinical trial for GBM patients following bevacizumab failure.

DelMar’s advanced development program will feature a single randomized Phase III study measuring survival outcomes compared to a "physicians’ choice" control, which, if successful, would serve as the basis for a New Drug Application (NDA) submission for VAL-083. The control arm will consist of a limited number of salvage chemotherapies currently utilized in the treatment of Avastin-failed GBM. The final pivotal trial design will be confirmed with the FDA following further discussions with the Company’s clinical advisors.

In addition to the pivotal trial, DelMar also plans to initiate two separate Phase II clinical trials in earlier-stage GBM patients.

In collaboration with the University of Texas MD Anderson Cancer Center: A non-comparative, biomarker-driven, Phase II study to determine if treatment of MGMT-unmethylated recurrent GBM with VAL-083 or CCNU improves overall survival at 9 months, compared to historical control in bevacizumab naïve patients. (clinicaltrials.gov identifier: NCT02717962)
In collaboration with Sun-Yat Sen University and Guangxi Wuzhou Pharmaceutical (Group) Co.: A single arm Phase II clinical trial to confirm the tolerability of DelMar’s dosing regimen in combination with radiotherapy (XRT) and to explore the activity of VAL-083 in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high levels of MGMT.
DelMar believes that data from these clinical trials, if successful, will form the basis of a new paradigm in the treatment for all GBM patients who fail, or whose tumors exhibit features that make them unlikely to respond to, currently available chemotherapy.

Puma Biotechnology Announces Interim 5-Year Disease Free Survival Data from Phase III Trial of PB272 (Neratinib) in Extended Adjuvant HER2-Positive Early Stage Breast Cancer (ExteNET Trial)

On July 21, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported updated results from the Phase III clinical trial of Puma’s investigational drug PB272 (neratinib) for the extended adjuvant treatment of HER2-positive early stage breast cancer (ExteNET trial) (Press release, Puma Biotechnology, JUL 21, 2016, View Source [SID:1234513986]). The ExteNET trial is a double-blind, placebo-controlled, Phase III trial of neratinib versus placebo after adjuvant treatment with trastuzumab (Herceptin) in women with early stage HER2-positive breast cancer.

The ExteNET trial randomized 2,840 patients in 41 countries with early-stage HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab. After completion of adjuvant treatment with trastuzumab, patients were randomized to receive extended adjuvant treatment with either neratinib or placebo for a period of one year. Patients were then followed for recurrent disease, ductal carcinoma in situ, or death for a period of two years after randomization in the trial. The primary endpoint of the trial was invasive disease free survival (DFS). The results of the trial demonstrated that treatment with neratinib resulted in a 33% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.67, p = 0.009). The 2-year invasive DFS rate for the neratinib arm was 93.9% and the 2-year invasive DFS rate for the placebo arm was 91.6%. These results were previously reported at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting and updated results, including interim 3-year invasive DFS data, were presented at the 2015 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS).

As part of the data analysis for the New Drug Application (NDA) filing in the United States and the Marketing Authorisation Application (MAA) submission in Europe, an updated analysis that included an interim 5-year invasive DFS analysis was performed. This data analysis was performed in order to examine the durability of treatment effect beyond the 2-year data included in the primary analysis. This interim analysis was not a pre-planned analysis in the statistical analysis plan for the trial. For the primary endpoint of the trial, invasive DFS, the 5-year interim results of the trial demonstrated that treatment with neratinib resulted in a 26% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.74, p = 0.017). The 5-year interim invasive DFS rate for the neratinib arm was 90.4% and the 5-year interim invasive DFS rate for the placebo arm was 87.9%. Additional updated results for the 3-year invasive DFS rate and 4-year invasive DFS rate are shown in the table below:

DFS for Intent to Treat (ITT) Population
3-Year DFS 4-Year DFS 5-Year Interim DFS
Neratinib 92.5% 91.4% 90.4%
Placebo 90.3% 89.2% 87.9%
Absolute invasive DFS
Difference 2.2% 2.2% 2.5%

As an inclusion criteria for the ExteNET trial, patients needed to have tumors that were HER2 positive using local assessment. In addition, as a pre-defined subgroup in the trial, patients had centralized HER2 testing performed on their tumor as well. To date, centralized HER2 testing has been performed on 2,140 (75%) of the patients in the ExteNET trial, and further central testing on available samples is currently ongoing. For the 1,777 patients whose tumors were HER2 positive by central confirmation, the interim results of the trial demonstrated that treatment with neratinib resulted in a 30% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.70, p = 0.026). The 5-year interim invasive DFS rate for the centrally confirmed patients in the neratinib arm was 90.8% and the 5-year interim invasive DFS rate for the centrally confirmed patients in the placebo arm was 88.1%.

For the pre-defined subgroup of 1,631 patients with hormone receptor positive disease, the interim results of the trial demonstrated that treatment with neratinib resulted in a 41% reduction of risk of invasive disease recurrence or death versus placebo (hazard ratio = 0.59, p = 0.002). The 5-year interim invasive DFS rate for the neratinib arm was 91.7% and the 5-year interim invasive DFS rate for the placebo arm was 86.9%. Additional updated results for the 3-year invasive DFS rate and 4-year invasive DFS rate are shown in the table below:

DFS for Hormone Receptor Positive (HR-positive) Population
3-Year DFS 4-Year DFS 5-Year Interim DFS
Neratinib 93.8% 92.9% 91.7%
Placebo 89.9% 88.6% 86.9%
Absolute invasive DFS
Difference 3.9% 4.3% 4.8%

"We are very pleased with the interim 5-year invasive DFS results from the ExteNET trial with neratinib," said Alan H. Auerbach, Chief Executive Officer and President of Puma. "We believe these results support the long term clinical benefit of neratinib in the extended adjuvant treatment of patients with early stage HER2-positive breast cancer who have completed prior trastuzumab-based adjuvant therapy. We look forward to obtaining the full 5-year DFS data, which we anticipate will be available in 2017."

Mylan and Biocon Announce Regulatory Submission for Proposed Biosimilar Pegfilgrastim Accepted for Review by European Medicines Agency

On July 21, 2016 Mylan N.V. (NASDAQ, TASE: MYL) and Biocon Ltd. (BSE code: 532523, NSE: BIOCON) reported that the European Medicines Agency (EMA) has accepted for review, Mylan’s Marketing Authorization Application (MAA) for our proposed biosimilar Pegfilgrastim, which is used to reduce the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes) (Press release, Mylan, JUL 21, 2016, View Source [SID:1234513985]).

Mylan and Biocon, who have co-developed the proposed biosimilar, received EMA’s acceptance of the submission for review. In addition to analytical, functional and pre-clinical data, the application includes clinical data from pivotal Pharmacokinetic / Pharmacodynamic (PK / PD) and confirmatory efficacy, safety and immunogenicity studies completed earlier in 2016. The results from the studies are expected to be presented at the prestigious European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress to be held in Copenhagen in Oct. 2016.

Arun Chandavarkar, CEO and Joint Managing Director, Biocon, said: "The regulatory submission of biosimilar Pegfilgrastim with the EMA by our partner Mylan marks another significant milestone in our journey to develop affordable biologics for cancer patients. Once approved, this product will enable enhanced access to a cost-effective alternative for patients undergoing chemotherapy in the EU. We are committed to bring a diversified portfolio of high-quality, life-enhancing biosimilars to patients globally."
Mylan President Rajiv Malik commented: "We continue to make great progress across our biosimilars portfolio, which represents one of the industry’s largest and most diversified portfolios in development. This milestone in our Pegfilgrastim program represents yet another important step in bringing more affordable versions of these critical products to market, with Europe representing an exciting opportunity for Mylan in this area."

Pegfilgrastim is prescribed for cancer patients to help them with some of the side-effects of their treatment. It reduces the duration of neutropenia (low levels of neutrophils, a type of white blood cell that fights infections) and the incidence of febrile neutropenia (neutropenia with fever) that are a result of their chemotherapy treatment.
Biocon and Mylan are exclusive partners on a broad portfolio of biosimilars and generic insulin analogs. The proposed biosimilar Pegfilgrastim is one of the six biologic products co-developed by Mylan and Biocon for the global marketplace. Mylan has exclusive commercialization rights for the proposed biosimilar Pegfilgrastim in the U.S., Canada, Japan, Australia, New Zealand and in the European Union and European Free Trade Association countries. Biocon has co-exclusive commercialization rights with Mylan for the product in the rest of the world.