On July 25, 2016 Halozyme Therapeutics, Inc. (NASDAQ: HALO) reported that it has resumed the enrollment and dosing of patients in its ongoing Phase 1b trial evaluating its investigational new drug, PEGPH20, in combination with KEYTRUDA (pembrolizumab) in patients with advanced non-small cell lung and gastric cancers under a revised clinical protocol (Press release, Halozyme, JUL 25, 2016, View Source [SID:1234514020]).

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The revised protocol has been submitted to all institutional review boards (IRB) and is pending feedback from the FDA. The majority of IRBs have completed their review and approved the revised protocol allowing the study to resume.

The Phase 1b study will enroll up to approximately 80 patients at a number of leading sites in the United States. For more information, go to www.clinicaltrials.gov and reference NCT02563548.

For information on KEYTRUDA, please go to www.keytruda.com.

About PEGPH20

PEGPH20 (PEGylated recombinant human hyaluronidase) targets the degradation of hyaluronan (HA), a chain of natural sugars that can accumulate around cancer cells, inhibiting other therapies. By degrading HA, PEGPH20 may increase the access of co-administered chemotherapeutic and immunotherapeutic agents.

FDA granted orphan drug designation to PEGPH20 for treatment of pancreatic cancer and fast track for PEGPH20 in combination with gemcitabine and nab-paclitaxel for the treatment of metastatic pancreatic cancer. Additionally, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency, designated investigational drug PEGPH20 an orphan medicinal product for the treatment of pancreatic cancer.

On July 25, 2016 Celsion Corporation (NASDAQ:CLSN) reported data from the second cohort of patients in its Phase Ib dose escalating clinical trial (the OVATION Study) combining GEN-1, the Company’s DNA-based immunotherapy, with the standard of care for the treatment of newly-diagnosed patients with advanced ovarian cancer who will undergo neoadjuvant chemotherapy followed by interval debulking surgery (Press release, Celsion, JUL 25, 2016, View Source [SID:1234514019]). In the first six patients dosed, GEN-1 plus standard chemotherapy produced impressive results, with no dose limiting toxicities and highly promising efficacy signals in this difficult to treat cancer.

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"The totality of study data available to date suggests that GEN-1 holds great potential to serve as an effective, safe IL-12 immunotherapy in ovarian cancer," said Dr. Premal Thaker, Associate Professor in Gynecologic Oncology, Washington University School of Medicine and OVATION Study Investigator. "Notably, we have seen dramatic decreases of 95% or greater in CA-125 protein levels, which serve as a key indicator of the presence of ovarian cancer cells, as well as impressive pathological response data, which is associated with prolonged survival. We look forward to the completion of this study, and to learning more about how GEN-1 performs in this patient population."

The OVATION Study is designed to enroll three to six patients per dose cohort, and will continue into 2016 at higher doses of GEN-1 with the goal to identify a safe, tolerable and therapeutically active dose of GEN-1 by recruiting and maximizing an immune response. The first two cohorts each enrolled three patients. Enrollment in the third cohort is ongoing, and Celsion expects to complete the OVATION Study this year. Future studies of GEN-1 will include a Phase I/II study combining GEN-1 with Avastin and Doxil.

OVATION Study – Results to Date

Of the first six patients dosed, one patient demonstrated a complete response (CR), two patients demonstrated partial response (PR) and three patients demonstrated stable disease (SD), as measured by RECIST criteria.

Five patients had successful resections of their tumors, with two patients having an R0 resection, which indicates a microscopically margin-negative resection in which no gross or microscopic tumor remains in the tumor bed and three patients with a R1 resection, indicating microscopic residual tumor. One patient in the second cohort is currently ineligible for debulking surgery due to a medical complication unrelated to the study or the study drug.

Of the five surgically treated and evaluable patients, one patient demonstrated a pathological complete response (pCR), two patients (40%) demonstrated a micro pathological response (microPR), and two patients (40%) demonstrated a macroPR. These data compare favorably to historical data, which indicate that pCRs are typically seen in less than 7% of patients receiving neoadjuvant chemotherapy followed by surgical resection. pCRs have been associated with a median overall survival of 72 months, which is more than three years longer than those who do not experience a pCR. In addition, microPRs are seen in approximately 30% of patients, and are associated with a median overall survival of 38 months&supl;.
"GEN-1 continues to demonstrate impressive activity in patients with advanced Stage III and IV ovarian cancer, a population clearly in need of effective therapies," said Nicholas Borys, M.D., Celsion’s chief medical officer. "We anticipate completion of enrollment in the third patient cohort in the coming weeks, and will continue to assess a potential accelerated clinical development path for GEN-1. In parallel, we are currently evaluating translational data from the study, which we expect to report before the end of the third quarter."

On July 25, 2016 BIND Therapeutics, Inc. (NASDAQ:BIND), a biotechnology company developing targeted and programmable therapeutics called ACCURINS, reported that it has received two bids that are qualified to participate in the Court authorized auction beginning at 10 a.m. EST on July 25, 2016 (Press release, BIND Therapeutics, JUL 25, 2016, View Source [SID:1234514017]). The bids are in addition to Pfizer Inc.’s initial stalking horse bid of approximately $20 million under Section 363 of the U.S. Bankruptcy Code.

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The U.S. Bankruptcy Court has authorized BIND to proceed with an auction on July 25, 2016 and the Company intends to select the highest and best offer at the conclusion of the auction. The winning bid is subject to U.S. Bankruptcy Court approval and a hearing is scheduled to take place on July 27, 2016.

BIND initiated voluntary Chapter 11 bankruptcy protection on May 1, 2016 and is conducting a sale of assets pursuant to Section 363 of the Bankruptcy Code.

On July 25, 2016 Merrimack Pharmaceuticals, Inc. (Nasdaq: MACK) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion for ONIVYDE (irinotecan liposome injection), also known as "nal-IRI", in combination with fluorouracil (5-FU) and leucovorin for the treatment of patients with metastatic pancreatic adenocarcinoma who have progressed after gemcitabine-based therapy (Press release, Merrimack, JUL 25, 2016, View Source [SID:1234514014]). The CHMP positive opinion for ONIVYDE will now be reviewed by the European Commission (EC) for marketing authorization. Shire plc (LSE: SHP, NASDAQ: SHPG) is responsible for the development and commercialization of ONIVYDE outside of the United States and Taiwan pursuant to an exclusive licensing agreement with Merrimack.

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"This recommendation advances our mission to expand the availability of the ONIVYDE regimen to metastatic pancreatic cancer patients worldwide," said Robert Mulroy, President and CEO of Merrimack. "The CHMP’s positive opinion is further validation of the clinical importance of the ONIVYDE regimen. We are grateful to all of the patients, families and investigators who contributed to the development of ONIVYDE, and to our partner Shire, together with whom we are committed to advancing the availability of this important therapy to patients facing this devastating disease with few treatment options."

"This regulatory milestone is an important step for patients with metastatic pancreatic adenocarcinoma who have progressed after gemcitabine-based therapy," said Philip J. Vickers, Ph.D., Head of R&D, Shire. "There has been little improvement in prognosis for patients in this setting for over 20 years, and given this high unmet need we look forward to receiving the final approval decision from the European Commission."

The opinion was based on data from the pivotal Phase 3 NAPOLI-1 study, which demonstrated that ONIVYDE in combination with 5-FU and leucovorin met its primary endpoint of significantly increased overall survival when compared to 5-FU and leucovorin alone: 6.1 months vs 4.2 months (p=0.012, unstratified hazard ratio (HR) =0.67, 95% CI: [0.49-0.92]) i. Findings from an updated analysis of the NAPOLI-1 data showed that one in four patients treated with the ONIVYDE combination regimen survived a milestone one year or more: 12-month overall survival estimates of 26% (95% CI, 18-35%) were observed in the ONIVYDE combination treatment arm representing a 63% improvement when compared to 16% (95% CI, 10-24%) for 5-FU and leucovorin aloneii. This updated analysis was presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Gastrointestinal Cancers Symposium.

The primary NAPOLI-1 study results were the basis for the October 2015 U.S. Food and Drug Administration (FDA) and Taiwan FDA approvals of the ONIVYDE combination regimen for the treatment of patients with metastatic pancreatic adenocarcinoma whose disease progressed after gemcitabine-based therapy. It is the first and only U.S. FDA-approved therapy in this setting. The ONIVYDE combination is also designated as a category 1 treatment option in the 2016 National Comprehensive Cancer Network (NCCN) guidelines for pancreatic adenocarcinoma in the U.S. as well as a category 2B status in the 2015 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) clinical practice guidelines in the EU.

About Pancreatic Cancer

Pancreatic cancer is a rare and deadly disease with only 7% of all patients surviving five years or longeriii. There are approximately 50,000 patients diagnosed with pancreatic cancer each year in the United Statesiv, the overwhelming majority of which have adenocarcinomav. Globally there are approximately 338,000 new cases each yearvi. Most patients receive gemcitabine-based therapy during either adjuvant/neoadjuvant treatment for locally advanced disease or during first- or second-line therapy for metastatic diseasevii, but are left with no standard of care therapy upon progression. ONIVYDE in combination with 5-FU and leucovorin is approved in the United States and Taiwan for these patients whose disease has progressed following gemcitabine-based therapy.

About ONIVYDE [pronounced \ ‘on – ih – vide \]

ONIVYDE (irinotecan liposome injection), also known as MM-398 or "nal-IRI," is a novel encapsulation of irinotecan in a liposomal formulation. The activated form of irinotecan is SN-38, which functions by inhibiting topoisomerase I (an essential enzyme involved in DNA transcription and replication) and promoting cell death. ONIVYDE was approved by the U.S. FDA in combination with fluorouracil and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. For full prescribing information, including Boxed WARNING, please visit www.ONIVYDE.com.

IMPORTANT SAFETY INFORMATION – UNITED STATES

INDICATION
ONIVYDE (irinotecan liposome injection) is indicated, in combination with fluorouracil (5-FU) and leucovorin (LV), for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA
Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with fluorouracil (5-FU) and leucovorin (LV). Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment.
Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with 5-FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity.
CONTRAINDICATION
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl.

WARNINGS AND PRECAUTIONS

Severe Neutropenia
ONIVYDE can cause severe or life-threatening neutropenia and fatal neutropenic sepsis. In a clinical study, the incidence of fatal neutropenic sepsis was 0.8% among patients receiving ONIVYDE, occurring in 1/117 patients in the ONIVYDE/5-FU/LV arm and 1/147 patients receiving ONIVYDE as a single agent. Severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE/5-FU/LV vs 2% of patients receiving 5-FU/LV. Grade 3/4 neutropenic fever/neutropenic sepsis occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not occur in patients receiving 5-FU/LV.

In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian (18/33 [55%]) vs White patients (13/73 [18%]). Neutropenic fever/neutropenic sepsis was reported in 6% of Asian vs 1% of White patients.

Severe Diarrhea
ONIVYDE can cause severe and life-threatening diarrhea. Do not administer ONIVYDE to patients with bowel obstruction. Severe and life-threatening late-onset (onset > 24 hours after chemotherapy) and early-onset diarrhea (onset ≤24 hours after chemotherapy, sometimes with other symptoms of cholinergic reaction) were observed. An individual patient may experience both early- and late-onset diarrhea.

In a clinical study, Grade 3/4 diarrhea occurred in 13% of patients receiving ONIVYDE/5-FU/LV vs 4% receiving 5-FU/LV. Grade 3/4 late-onset diarrhea occurred in 9% of patients receiving ONIVYDE/5-FU/LV vs 4% in patients receiving 5-FU/LV; the incidences of early-onset diarrhea were 3% and no Grade 3/4 incidences, respectively. Of patients receiving ONIVYDE/5-FU/LV, 34% received loperamide for late-onset diarrhea and 26% received atropine for early-onset diarrhea.

Interstitial Lung Disease (ILD)
Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD.

Severe Hypersensitivity Reactions
Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction.

Embryo-Fetal Toxicity
Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during and for 1 month after ONIVYDE treatment.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions in which patients receiving ONIVYDE/5-FU/LV experienced a ≥5% higher incidence of any Grade vs the 5-FU/LV arm, were diarrhea (any 59%, 26%; severe 13%, 4%) (early diarrhea [any 30%, 15%; severe 3%, 0%], late diarrhea [any 43%, 17%; severe 9%, 4%]), fatigue/asthenia (any 56%, 43%; severe 21%, 10%), vomiting (any 52%, 26%; severe 11%, 3%), nausea (any 51%, 34%; severe 8%, 4%), decreased appetite (any 44%, 32%; severe 4%, 2%), stomatitis (any 32%, 12%; severe 4%, 1%), pyrexia (any 23%, 11%; severe 2%, 1%).
Of less common ( < 20%) adverse reactions, patients receiving ONIVYDE/5-FU/LV who experienced Grade 3/4 adverse reactions at a ≥2% higher incidence of Grade 3/4 toxicity vs the 5-FU/LV arm, respectively, were sepsis (3%, 1%), neutropenic fever/neutropenic sepsis (3%, 0%), gastroenteritis (3%, 0%), intravenous catheter-related infection (3%, 0%), weight loss (2%, 0%), and dehydration (4%, 2%).
The laboratory abnormalities in which patients receiving ONIVYDE/5-FU/LV experienced a ≥5% higher incidence vs the 5-FU/LV arm, were anemia (any 97%, 86%; severe 6%, 5%), lymphopenia (any 81%, 75%; severe 27%, 17%), neutropenia (any 52%, 6%; severe 20%, 2%), thrombocytopenia (any 41%, 33%; severe 2%, 0%), increased alanine aminotransferase (any 51%, 37%; severe 6%, 1%), hypoalbuminemia (any 43%, 30%; severe 2%, 0%), hypomagnesemia (any 35%, 21%; severe 0%, 0%), hypokalemia (any 32%, 19%; severe 2%, 2%), hypocalcemia (any 32%, 20%; severe 1%, 0%), hypophosphatemia (any 29%, 18%; severe 4%, 1%), hyponatremia (any 27%, 12%; severe 5%, 3%), increased creatinine (any 18%, 13%; severe 0%, 0%).
ONIVYDE can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early-onset diarrhea. Grade 1/2 cholinergic symptoms other than early diarrhea occurred in 12 (4.5%) ONIVYDE-treated patients.
Infusion reactions, consisting of rash, urticaria, periorbital edema, or pruritus, occurring on the day of ONIVYDE administration were reported in 3% of patients receiving ONIVYDE or ONIVYDE/5-FU/LV.
The most common serious adverse reactions (≥2%) of ONIVYDE were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.
DRUG INTERACTIONS
Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme-inducing therapies ≥2 weeks prior to initiation of ONIVYDE. Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy.

USE IN SPECIFIC POPULATIONS

Pregnancy and Reproductive Potential
Advise pregnant women of the potential risk to a fetus. Advise males with female partners of reproductive potential to use effective contraception during and for 4 months after ONIVYDE treatment.

Lactation
Advise nursing women not to breastfeed during and for 1 month after ONIVYDE treatment.

Pediatric
Safety and effectiveness of ONIVYDE have not been established in pediatric patients.

DOSAGE AND ADMINISTRATION
The recommended dose of ONIVYDE is 70 mg/m2 intravenous (IV) infusion over 90 minutes every 2 weeks, administered prior to LV and 5-FU. The recommended starting dose of ONIVYDE in patients known to be homozygous for the UGT1A1*28 allele is 50 mg/m2 administered by IV infusion over 90 minutes. There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal. Premedicate with a corticosteroid and an anti-emetic 30 minutes prior to ONIVYDE. Withhold ONIVYDE for Grade 3/4 adverse reactions. Resume ONIVYDE with reduced dose once adverse reaction recovered to ≤Grade 1. Discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction and in patients with a confirmed diagnosis of ILD.

Do not substitute ONIVYDE for other drugs containing irinotecan HCl.

Please see full U.S. Prescribing Information for ONIVYDE.

Global Partnerships

In 2014, Merrimack and Shire plc entered into an exclusive licensing agreement for the development and commercialization of ONIVYDE outside of the United States and Taiwan. PharmaEngine, Inc. (Taipei, Taiwan) holds the rights to commercialize ONIVYDE in Taiwan and received the Taiwan FDA approval of ONIVYDE in October 2015.

On July 25, 2016 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical-stage pharmaceutical company focused on discovering and developing novel small molecule drugs directed against tumor metabolism and tumor immunology targets for the treatment of cancer, reported that the U.S. Food and Drug Administration (FDA) has accepted the company’s Investigational New Drug (IND) application for CB-1158 for the treatment of solid tumors (Press release, Calithera Biosciences, JUL 25, 2016, View Source [SID:1234514013]). CB-1158 is a first-in-class, orally available small molecule inhibitor of the enzyme arginase.

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"We are pleased to be advancing the first arginase inhibitor into clinical trials. Arginase is a novel target in metabolic immuno-oncology, and these studies will allow us to assess the safety, pharmacokinetics and pharmacodynamics of this exciting new agent," said Susan M. Molineaux, Ph.D., founder, Chief Executive Officer and President of Calithera Biosciences. "CB-1158 has demonstrated significant anti-tumor activity in preclinical models, and we look forward to reporting initial clinical results with this compound in 2017."

Arginase exerts its immunosuppressive effect by depleting the amino acid arginine in the tumor microenvironment and prevents activation and proliferation of the immune system’s cytotoxic T-cells and natural killer (NK) cells. Inhibition of arginase activity reverses this immunosuppressive block and restores T-cell function. The Phase I clinical trial will enroll patients with advanced solid tumors treated with CB-1158 as a monotherapy, as well as in combination with an anti-PD1 antibody.