On October 10, 2016 Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM) (NASDAQ:PPHMP), a biopharmaceutical company committed to improving patient lives by manufacturing high quality products for biotechnology and pharmaceutical companies and advancing its proprietary R&D pipeline, reported that top-line data from the Phase III SUNRISE trial of bavituximab in patients with previously treated locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) were presented in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress (Press release, Peregrine Pharmaceuticals, OCT 10, 2016, View Source [SID:SID1234515714]). The presentation included interim efficacy and safety outcomes, as well as initial findings from the company’s ongoing biomarker analysis of samples collected during the study. The SUNRISE Phase III trial was discontinued earlier this year based on a pre-specified interim analysis although patient treatment and follow-up in the study were allowed to continue. The pre-planned biomarker analysis has been taking place as patient follow-up has continued and available results were evaluated as part of the recent top-line data analysis.

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The study protocol pre-specified the collection of thousands of patient samples for exploratory analyses over a wide range of possible biomarkers, including pre-treatment levels of beta-2 glycoprotein-1 (β2GP1). Data presented at ESMO (Free ESMO Whitepaper) demonstrated that patients with pre-treatment β2GP1 levels between 200 and 240 (representing approximately 30% of randomized patients) achieved a statistically significant, 5.5-month improvement (13.2 months vs. 7.7 months) in median overall survival (OS) as compared to patients in the control group with the same range of β2GP1 levels [p = 0.049; hazard ratio (HR) = 0.67]. A similar trend was observed with pre-treatment β2GP1 levels ≥ 200 µg/mL (representing approximately 50% of randomized patients) with 11.9 months vs. 10.1 months median OS in favor of the bavituximab-containing group (p = 0.155; HR = 0.81). Taken together, this strongly suggests β2GP1 levels may be useful for identifying patients who are more likely to benefit from a bavituximab containing therapeutic regimen. Numerous additional biomarkers are currently being analyzed with the goal of developing a multi-marker signature that can potentially identify patients that are likely to receive significant clinical benefit from a bavituximab-containing therapeutic regimen.

Top-line results reported at ESMO (Free ESMO Whitepaper) today were based on a data cut-off after 70% (330/473) of the targeted OS events had been reached and demonstrated the addition of bavituximab to docetaxel did not result in improvement of the study’s primary endpoint of OS in the intent-to-treat population. Median OS for the bavituximab plus docetaxel group was 10.7 months as compared to 10.8 months for the placebo plus docetaxel control group (HR = 1.110; p = 0.382). Median progression free survival (PFS) for the bavituximab-containing group was 4.1 months compared to 3.9 months for the control group (HR = 0.97; p = 0.803). Objective response rates based on independent central review are currently 13% and 11% (p = 0.53) for the bavituximab-containing and control groups, respectively. Additionally, the safety profile of the combination of bavituximab with docetaxel was similar to placebo plus docetaxel.

"With every clinical trial we conduct, we are constantly reminded of the difficulty involved in treating patients with non-small cell lung cancer. This continues to prove to be a very challenging cancer to combat and the need for effective treatments remains high," David R. Spigel, MD, chief scientific officer and program director of Lung Cancer Research at the Sarah Cannon Research Institute and one of the lead investigators in the SUNRISE trial. "The findings with regard to β2GP1 that have been collected as part of the ongoing SUNRISE trial data analysis are interesting and support further investigation."

Peregrine intends to further evaluate the role of β2GP1 levels in response to bavituximab therapy in future clinical trials. The company has filed a new patent application directed to the use of this initial biomarker discovery. Additional patient sample testing and analysis is ongoing and may result in other biomarkers of importance.

"We would once again like to thank all of the patients, clinical investigators and scientists who participated in the SUNRISE trial and have made it possible for us to continue to collect and analyze a range of key data from the study. While we were disappointed with the trial being discontinued earlier in the year, we are excited by the fact that we are beginning to learn important information from the trial through the ongoing biomarker analysis program that will be critical in helping guide the future clinical development of bavituximab," said Joseph Shan, vice president of clinical and regulatory affairs at Peregrine. "It is encouraging that the initial biomarker analysis has identified an important biomarker early in the process and we are optimistic that additional biomarkers associated with improved outcomes for bavituximab-containing treatments will be identified as the analysis continues. We expect to be able to share the emerging data over the coming months at scientific and medical conferences as the more
results become available."

Mr. Shan continued, "It is not uncommon in the cancer field for therapeutic candidates to suffer clinical trial setbacks as researchers continue to learn more about the most appropriate patient populations for those drugs. In this landscape, biomarkers play an increasingly important role in helping identify specific patient characteristics that may impact responses to a treatment. This has been seen historically with targeted cancer treatments, as well as more recently with checkpoint inhibitors including PD-1 inhibitors. We look forward to identifying the equivalent markers for bavituximab that will help guide its clinical development."
Bavituximab is an investigational chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab is believed to override PS mediated immunosuppressive signaling by blocking the engagement of PS with its receptors as well as by sending an alternate immune activating signal. PS targeting antibodies have been shown to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses.

Peregrine’s clinical development strategy for bavituximab is currently focused on small, early-stage proof-of-concept trials evaluating the drug in combination with other cancer treatments. The intent behind this strategy is to control research and development costs, while continuing to generate clinical data to further validate bavituximab’s combination potential that will be critical to bringing onboard a partner to help advance the program.

On October 10, 2016 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP) reported the presentation of preliminary data from the Company’s Phase 1b/2 study of Ad-RTS-hIL-12 + veledimex following standard chemotherapy for the treatment of patients with locally advanced or metastatic breast cancer (Press release, Ziopharm, OCT 10, 2016, View Source [SID:SID1234515715]). The poster presentation, titled "Phase 1b/2 study of intratumoral Ad-RTS-hIL-12+veledimex in patients with chemotherapy-responsive locally advanced or metastatic breast cancer," was presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress today in Copenhagen, Denmark.

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The study, which is being conducted at the Memorial Sloan Kettering Cancer Center in New York, is designed to examine the safety, tolerability and efficacy of Ad-RTS-hIL-12 immunotherapy in up to 40 women with locally advanced or metastatic breast cancer of all subtypes. Ad-RTS-hIL-12 + veledimex is a novel gene therapy which controls local expression of IL-12. The ability to regulate the production of IL-12 by modulating veledimex dosing is designed to improve its therapeutic index with standard of care.

Following entry into the trial, patients go on a chemotherapy holiday and enter an immunotherapy phase of treatment. A single cycle of Ad-RTS-hIL-12, along with the oral activator ligand veledimex, is given during the immunotherapy phase, with the goal of maintaining or improving pre-study response.

As of August 30, 2016, a total of nine patients were available for initial assessment. Results show that Ad-RTS-hIL-12 + 7 days of veledimex consistently elicited production of IL-12 which in turn produced IFNγ. It was notable that the intratumoral influx of CD8+ T cells and IFNγ were present six weeks after completion of veledimex consistent with the ability of Ad-RTS-hIL-12 to favorably impact the tumor environment over the long term. In two patients, Ad-RTS-hIL-12 + veledimex provided a meaningful drug holiday, with durable responses for 18 and 35 weeks. In all patients, disease control rate (DCR) was 44% at Week 6 and 22% at Week 12. Overall response rate (ORR), defined as achieving a partial response (PR) or better, was 11% at Week 12. Most toxicities promptly reversed upon discontinuation of veledimex, including cytokine release syndrome (grade 1-2 CRS), observed in six of nine patients. The higher than expected incidence of CRS was likely related to CYP-3A4 drug interactions with veledimex (80 mg) which resulted in enhanced peak cytokine expression.

"These data provide additional evidence that IL-12 expression and corresponding downstream signaling is activated using Ad-RTS-hIL-12 + veledimex, consistent with results observed in other studies and tumor types," said Francois Lebel, M.D., Executive Vice President, Research and Development, Chief Medical Officer at ZIOPHARM. "Early results from this study are promising, providing further support and validation for our ongoing study of Ad-RTS-hIL-12 in glioblastoma, a program we anticipate moving into a pivotal trial."

ESMO Presentation Details

Title: Phase 1b/2 study of intratumoral Ad-RTS-hIL-12+veledimex in patients with chemotherapy-responsive locally advanced or metastatic breast cancer
Abstract Number: 280P
Date and Time: October 10, 2016, 1:00-2:00p CET
Location: Hall E

On October 10, 2016 Panther Biotechnology, Inc. reported that a request for a Pre-IND (Investigational New Drug) meeting with the Division of Oncology Products 1 (DOP1) of the Center for Drug Evaluation and Research (CDER) of the U.S. Food and Drug Administration ("FDA") has been submitted (Press release, Panther Biotechnology, OCT 10, 2016, View Source [SID1234517403]). The purpose of the requested meeting is to obtain FDA’s input regarding Panther’s plans for the development of TRF-DOX, Panther’s novel transferrin-doxorubicin conjugate for the treatment of platinum-resistant ovarian cancer. In preparation for the meeting, Panther is preparing a Pre-IND Package to be submitted to FDA that describes the information Panther intends on submitting in the TRF-DOX IND planned for submission in 2017. The IND is the regulatory vehicle that will allow for the initiation of clinical trials with TRF-DOX for the treatment of ovarian cancer.

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FDA will specifically review Panther’s manufacturing, preclinical pharmacology and toxicology, and clinical plans for TRF-DOX and provide specific feedback to Panther prior to the meeting.

TRF-DOX binds to transferrin receptors on tumor cells, inhibits cancer cell proliferation and causes cell death. TRF-DOX has been shown to exhibit increased cytotoxicity relative to unconjugated doxorubicin toward a variety of cancer cell lines and reduced cytotoxicity to normal cells. In addition to improvements in cytotoxicity and selectivity, TRF-DOX exhibits cytotoxic effects in many multidrug-resistant cells in vitro. Tumor targeting of doxorubicin to transferrin receptors on the cell membranes of tumor cells is intended to improve the therapeutic index of doxorubicin and to reduce the development of doxorubicin resistance. Panther is proposing to conduct an open label, multiple ascending dose study to investigate the safety, pharmacokinetics and preliminary efficacy of TRF-DOX in patients with platinum-resistant ovarian cancer.

On October 10, 2016 Galena Biopharma, Inc. (NASDAQ:GALE), a biopharmaceutical company committed to the development and commercialization of hematology and oncology therapeutics that address unmet medical needs, reported that it has presented interim safety data from the Company’s NeuVax (nelipepimut-S) Phase 2b combination study with trastuzumab at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen, Denmark (Press release, Galena Biopharma, OCT 10, 2016, View Source [SID:SID1234515719]). The clinical trial is a randomized, multicenter, investigator-sponsored, 300 patient Phase 2b study. It is currently enrolling HER2 1+ and 2+ node positive, and high-risk node negative patients to study NeuVax in combination with trastuzumab to prevent breast cancer recurrence.

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Poster #1069P, entitled "Interim safety analysis of a phase II trial combining trastuzumab and NeuVax, a HER2-targeted peptide vaccine, to prevent breast cancer recurrence in HER2 low expression," demonstrated that this novel combination of trastuzumab and NeuVax in HER2 low-expressing (LE) patients is well-tolerated and the cardiac effects of trastuzumab are not impacted by the addition of NeuVax.

In March 2016, the 150th patient was randomized into the trial, triggering this pre-specified safety analysis (Vaccine Group (VG) n=81, Control Group (CG) n=69). There were no significant differences in treatment factors, but a significant difference in node positivity appreciated between the groups. The sponsor expects this randomization imbalance to equalize over the duration of the study. Cardiac ejection fraction (EF) was assessed at baseline and serially throughout treatment. The majority of toxicities were Grade 1 and 2, and there was no difference between treatment arms. There was no difference in EF over time (baseline (T0) to 6mo (T6)) between VG v CG (T0: 61.4+0.6%, T6: 60.5+0.9% v T0: 61.6+0.7%, T6: 60.7+1.0%, p=0.9). There was one CG patient who experienced a grade 3 cardiac adverse event, but their EF returned to baseline after discontinuation of trastuzumab.

"This pre-specified, interim safety analysis is crucial to this trial to ensure that the combination of NeuVax and trastuzumab is well-tolerated in patients, and importantly that it does not increase the cardio-toxicity effects known to be associated with trastuzumab," said Bijan Nejadnik, M.D., Executive Vice President and Chief Medical Officer. "There is a growing consensus that combination therapies may yield the greatest clinical benefit, and this Phase 2b trial remains ongoing with enrollment expected to complete by the end of this year. As a result, we expect to report our first interim efficacy and immunologic outcomes after 12 months of follow-up, currently expected at the end of 2017. We are grateful to Dr. George Peoples and his team who continue this groundbreaking work."

Disease-free, HLA-A2+, A3+, A24+, or A26+, HER2 LE breast cancer patients at high risk for recurrence were enrolled after standard of care treatment and randomized to vaccine group (VG) receiving trastuzumab and NeuVax or control group (CG) receiving trastuzumab and GM-CSF only. Trastuzumab dosing was 8mg/kg loading, then 6mg/kg every 3 weeks. Patients received 6 total inoculations of NeuVax or GM-CSF, one every 3 weeks starting with the third trastuzumab infusion, followed by four booster inoculations administered every 6 months. Demographic and safety data were collected and analyzed with appropriate statistical tests.

The poster presentation from the conference will be available on Galena’s website here.
Abstract #3981 can be found on the conference website here.

About NeuVax (nelipepimut-S)

NeuVax (nelipepimut-S) is a first-in-class, HER2-directed cancer immunotherapy under evaluation to prevent breast cancer recurrence after standard of care treatment in the adjuvant setting. It is the immunodominant peptide derived from the extracellular domain of the HER2 protein, a well-established target for therapeutic intervention in breast carcinoma. The nelipepimut-S sequence stimulates specific CD8+ cytotoxic T lymphocytes (CTLs) following binding to specific HLA molecules on antigen presenting cells (APC). These activated specific CTLs recognize, neutralize and destroy, through cell lysis, HER2 expressing cancer cells, including occult cancer cells and micrometastatic foci. The nelipepimut-S immune response can also generate CTLs to other immunogenic peptides through inter- and intra-antigenic epitope spreading. In clinical studies, NeuVax is combined with recombinant granulocyte macrophage-colony stimulating factor (GM-CSF).

NeuVax is currently in two breast cancer studies in combination with trastuzumab (Herceptin; Genentech/Roche): a Phase 2b trial in node positive and triple negative HER2 IHC 1+/2+ (clinicaltrials.gov identifier: NCT01570036); and, a Phase 2 trial in high risk, node positive or negative HER2 IHC 3+ patients (clinicaltrials.gov identifier: NCT02297698). Phase 2 clinical trials with NeuVax are also planned in patients with ductal carcinoma in situ (DCIS), and in patients with gastric cancer.

About HER2 1+/2+ Breast Cancer

According to the National Cancer Institute, over 230,000 women in the U.S. are diagnosed with breast cancer annually. Of these women, only about 25% are HER2 positive (IHC 3+). NeuVax targets approximately 50%-60% of these women who are HER2 low to intermediate (IHC 1+/2+ or FISH < 2.0) and achieve remission with current standard of care, but have no available HER2-targeted adjuvant treatment options to maintain their disease-free status.

On October 10, 2016 Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), the leading RNAi therapeutics company, reported that the Data Monitoring Committee (DMC) for the Phase 3 APOLLO study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN) met on October 7, 2016 and recommended continuation of the trial without modification (Press release, Alnylam, OCT 10, 2016, View Source;p=RssLanding&cat=news&id=2210373 [SID:SID1234515688]). The APOLLO DMC met at the request of the Company following the decision – announced on October 5, 2016 – to discontinue development of revusiran for the treatment of hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM). The DMC will continue to meet periodically per their remit to monitor the overall safety of patisiran in the APOLLO study through its completion.

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The APOLLO study has completed enrollment of 225 patients at 44 sites in 19 countries, between December 2013 and January 2016.

"As part of our vigilance around patient safety, we felt it was important to take immediate action and requested that the APOLLO DMC convene to evaluate accumulated safety data from the randomized, placebo-controlled Phase 3 study of patisiran," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer at Alnylam. "We’re pleased to learn of the DMC’s recommendation that dosing can continue in APOLLO, and we look forward to the top-line data readout from that study expected in mid-2017. There is substantial unmet need in hATTR-PN and we are committed to advancing patisiran through development in hopes of bringing a new and needed treatment option to patients."

About ATTR Amyloidosis

ATTR amyloidosis is a progressively debilitating and often fatal disease caused by deposition of transthyretin (TTR) in peripheral tissues. TTR protein is produced primarily in the liver and is normally a carrier of vitamin A. In hereditary ATTR amyloidosis (hATTR), mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy. Hereditary ATTR amyloidosis represents a major unmet medical need with significant morbidity and mortality; hATTR amyloidosis with polyneuropathy (hATTR-PN) – also known as familial amyloidotic polyneuropathy (FAP) – affects approximately 10,000 people worldwide. hATTR-PN patients have a life expectancy of 5 to 15 years from symptom onset, and the only approved treatment options for early stage disease are liver transplantation and tafamidis (approved in Europe, certain countries in Latin America and Japan, where it is approved for all stages of disease). There is a significant need for novel therapeutics to treat patients with ATTR amyloidosis.

Sanofi Genzyme Alliance

In January 2014, Alnylam and Sanofi Genzyme, the specialty care global business unit of Sanofi, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. Alnylam retains product rights in North America and Western Europe, while Sanofi Genzyme obtained the right to access certain programs in Alnylam’s current and future Genetic Medicines pipeline in the rest of the world (ROW) through the end of 2019, together with certain broader co-development/co-commercialization rights and global rights for certain products. In the case of patisiran, Alnylam will advance the product in North America and Western Europe, while Sanofi Genzyme will advance the product in the ROW.

About RNAi

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About LNP Technology

Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.