Debiopharm International SA Announces Clinical Collaboration with the Merck-Pfizer Alliance in Cancer Immunotherapy

On October 20, 2016 Debiopharm International (Debiopharm – www.debiopharm.com) reported that it has entered into a collaboration agreement with Merck and Pfizer (NYSE:PFE) to evaluate Debio 1143, an oral, small molecule inhibitor of IAPs (Inhibitor of Apoptosis Proteins), in combination with avelumab, an investigational fully human anti-PD-L1 IgG1 monoclonal antibody, in patients with advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) (Press release, Debiopharm, OCT 20, 2016, View Source [SID1234525193]). Debio 1143 is currently in Phase II development for Head & Neck and Ovarian Cancer. Avelumab is under clinical investigation across a broad range of tumor types by the Merck-Pfizer Alliance. Under the terms of the agreement, Debiopharm will be responsible for conducting the Phase I/Ib clinical trial in NSCLC.

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"We are delighted to initiate this collaboration in immuno-oncology with the Merck-Pfizer Alliance. It is a great opportunity to explore in the clinic the immunomodulatory properties of Debio 1143 observed in preclinical studies," said Dr Chris Freitag, Vice President, Clinical Research & Development, Debiopharm International SA. "We are hopeful that the immunosensitizing effect of our compound in combination with avelumab may translate into a potentially better treatment outcome for patients suffering from this major debilitating disease."

Globally, lung cancer is the leading cause of cancer death among both men and women, responsible for more deaths than colon, breast and prostate cancer combined.1 NSCLC is the most common type of lung cancer, accounting for 80-85% of all lung cancers.2 The 5-year survival rate for people diagnosed with late-stage lung cancer that has spread (metastasized) to other areas of the body is 4%.3

"Inhibition of the PD-1/PD-L1 pathway has shown promising activity in patients with advanced NSCLC," said Alise Reicin, M.D., Head of Global Clinical Development in the biopharma business of Merck. "We hope that our exploration of avelumab as a combination therapy with Debio 1143 will generate results that could potentially one day make a real difference to patients fighting this deadly cancer."

"Investigating the potential of combination therapy is an important strategic focus for the Merck-Pfizer Alliance," said Chris Boshoff, M.D., Ph.D., Head of Immuno-Oncology, Early Development, and Translational Oncology at Pfizer. "This collaboration with Debiopharm provides a significant opportunity to explore the potential synergistic effects of these two agents in combination."

About Debio 1143
Debio 1143 is an oral, small molecule inhibitor of IAPs (Inhibitor of Apoptosis Proteins) that promotes apoptosis of cancer cells by mimicking the activity of the natural Second Mitochondrial-derived Activator of Caspases (SMAC). Evasion of apoptosis is a hallmark of cancer and a common mechanism of resistance to current treatments and Debio 1143 is being investigated as chemo- and radio-sensitizer in Ovarian Cancer and Head & Neck Cancer. In addition, like other members of the class, Debio 1143 displays strong immunomodulatory properties that make it a natural candidate for combination with Immune Checkpoint Inhibitors.

About Avelumab
Avelumab (also known as MSB0010718C) is an investigational, fully human antibody specific for a protein found on tumor cells called PD-L1, or programmed death ligand-1. Avelumab is thought to have a dual mechanism of action which may enable the immune system to find and attack cancer cells. By binding to PD-L1, avelumab is thought to prevent tumor cells from using PD-L1 for protection against white blood cells such as T-cells, exposing them to anti-tumor responses. Avelumab is also thought to help white blood cells such as natural killer (NK) cells find and attack tumors in a process known as ADCC, or antibody-dependent cell-mediated cytotoxicity. In November 2014, Merck, the science and technology company, and Pfizer announced a strategic alliance to
co-develop and co-commercialize avelumab.

Synaffix Enters into a Commercial License Agreement with ADC Therapeutics

On October 20, 2016 Synaffix BV reported it has entered into a Commercial License Agreement with ADC Therapeutics for its proprietary GlycoConnect and HydraSpace site-specific antibody-drug conjugate technologies (Press release, Synaffix, OCT 20, 2016, View Source [SID1234522092]).

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Under the terms of the agreement, ADC Therapeutics has been granted a single-target license for one of its preclinical programs and has also been granted an option to take a limited number of additional single-target licenses for potential future programs.

Floris van Delft, CSO at Synaffix said,

"We are delighted that ADC Therapeutics has recognized the value of our proprietary antibody-drug conjugate technologies and has elected to incorporate Synaffix technology into one of its preclinical programs."

"The experience of Synaffix and its partners has consistently confirmed that, in preclinical models, our proprietary GlycoConnect and HydraSpace technologies significantly improved both efficacy and safety as compared to other mainstream site-specific conjugation approaches."

"We look forward to working closely with the ADC Therapeutics team to advance these promising therapeutics to the patients who need them."

Synaffix is eligible to receive upfront, milestone and royalty payments on a per-target basis.

About GlycoConnect and HydraSpace

The Synaffix technology platforms include GlycoConnect, the site-specific and stable antibody conjugation technology that involves proprietary enzymes and metal-free click conjugation reagents, and HydraSpace, the antibody-drug conjugate enhancing spacer technology.

GlycoConnect was shown to be capable of significantly enhancing the therapeutic index of an antibody-drug conjugate on its own. The highly polar properties of HydraSpace improve the solubility and stability of the payload and the resulting antibody-drug conjugate product, thus enhancing further the therapeutic index of the antibody-drug conjugate.

Both technologies have demonstrated compatibility with all antibody-drug conjugate payload classes and all IgG isotypes without requiring antibody engineering.

Amgen Announces Positive Top-Line Results From XGEVA® (Denosumab) Phase 3 Trial For Delay Of Bone Complications In Multiple Myeloma Patients

On October 20, 2016 Amgen (NASDAQ:AMGN) reported that a Phase 3 study evaluating XGEVA (denosumab) versus zoledronic acid met the primary endpoint of non-inferiority (hazard ratio = 0.98, 95 percent CI, 0.85 – 1.14) in delaying the time to first on-study skeletal-related event (SRE) in patients with multiple myeloma (Press release, Amgen, OCT 20, 2016, View Source [SID1234515927]). The secondary endpoints of superiority in delaying time to first SRE and delaying time to first-and-subsequent SRE were not met. The hazard ratio of XGEVA versus zoledronic acid for overall survival was 0.90 (95 percent CI, 0.70 – 1.16).

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Adverse events observed in patients treated with XGEVA were generally consistent with the known safety profile of XGEVA. The most common adverse events (greater than 25 percent) in the XGEVA arm of the study were diarrhea and nausea.

"Bone complications like fracture, spinal cord compression and radiation or surgery to bone are devastating for multiple myeloma patients. Many of these patients suffer from renal impairment, which has limited their treatment options," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "XGEVA’s unique mechanism of action has the potential to prevent bone complications in multiple myeloma patients regardless of their renal status, fulfilling an important unmet medical need."

Detailed results will be submitted to a future medical conference and for publication. The Company plans to submit these data to regulatory authorities.

About ‘482 Study (NCT01345019)
The ‘482 study was an international, randomized, double-blind, multicenter trial of XGEVA compared with zoledronic acid in the prevention of bone complications in patients with newly diagnosed multiple myeloma. In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks. The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study SRE (fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of XGEVA versus zoledronic acid with respect to time to first on-study SRE and first-and-subsequent on-study SRE and overall survival.The safety and tolerability of XGEVA were also compared with zoledronic acid.

About Multiple Myeloma and Bone Complications
Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow.1,2 Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.2

Bone lesions frequently accompany multiple myeloma and can increase the risk of bone complications.3,4 Approximately 75 percent of multiple myeloma patients are treated for the prevention of bone complications.5 Preventing bone complications is an important aspect of caring for patients with multiple myeloma, because these events can cause significant morbidity.6

About XGEVA (denosumab)
XGEVA targets the RANK ligand pathway to prevent the formation, function and survival of osteoclasts, which break down bone. XGEVA is indicated for the prevention of SREs in patients with bone metastases from solid tumors and for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. XGEVA is also indicated in the U.S. for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. XGEVA is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

U.S. Important Safety Information

Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity
XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.

Drug Products with Same Active Ingredient
Patients receiving XGEVA should not take Prolia (denosumab).

Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has occurred in patients receiving XGEVA, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroid, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA and periodically during XGEVA therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA. Consider temporarily interrupting XGEVA therapy if an invasive dental procedure must be performed.

Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Embryo-Fetal Toxicity
XGEVA can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA is expected to result in adverse reproductive effects. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least five months after the last dose of XGEVA. Apprise the patient of the potential hazard to a fetus if XGEVA is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA.

Adverse Reactions
The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea.

The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis of the jaw and tooth abscess or tooth infection.

The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Denosumab is also marketed as Prolia in other indications.

Please visit www.amgen.com or www.xgeva.com for Full U.S. Prescribing Information.

TG Therapeutics, Inc. Announces the Launch of the Phase 1/2 Study of TGR-1202 and Carfilzomib in Patients with Relapsed or Refractory Lymphoma

On October 20, 2016 TG Therapeutics, Inc. (NASDAQ:TGTX) reported the launch of a Phase 1/2 study to evaluate the safety and efficacy of TGR-1202, the Company’s oral PI3K delta inhibitor in combination with carfilzomib, the FDA-approved proteasome inhibitor, in patients with relapsed or refractory lymphoma (Press release, TG Therapeutics, OCT 20, 2016, View Source [SID1234515923]).

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The rationale for combining these two agents is based on extensive preclinical work conducted as part of a research collaboration supported by TG Therapeutics at the Center for Lymphoid Malignancies, Columbia University Medical Center. Portions of this work were presented in an oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting in December 2015, by Dr. Changchun Deng of the Center for Lymphoid Malignancies. The presentation contained data demonstrating that the combination of TGR-1202 and carfilzomib was uniquely synergistic as compared to any other combination of a PI3K-delta inhibitor and proteasome inhibitor, including the combination of idelalisib and carfilzomib and idelalisib and bortezomib. Of particular interest, the combination of TGR-1202 and carfilzomib was found to potently inhibit cap dependent translation of c-Myc in all cell lines tested, including diffuse large B-Cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma, T-cell lymphoma, and chronic lymphocytic leukemia (CLL) cells. A more in depth presentation of the preclinical work has been submitted to a leading medical journal and is awaiting publication.

In the Phase 1 portion, the study will evaluate the safety, tolerability, and appropriate dose of carfilzomib when combined with 800mg of TGR-1202. Once a recommended Phase 2 dose is identified, the Phase 2 portion will further evaluate the safety and effectiveness of the combination at the chosen dose. TG Therapeutics will supply the TGR-1202 and assume up to 50% for the cost for the trial.

"We are very excited about the launch of this combination study, building on the extensive preclinical work completed by Dr. Deng, Dr. Owen A. O’Connor and the team from Columbia Presbyterian Medical Center, allowing us to move the science from bench to bedside and into patients in need of combination therapies. TGR-1202 continues to exhibit best-in-class safety and efficacy results and has demonstrated itself as a uniquely combinable PI3k-delta inhibitor. Our hope is that combination therapies with TGR-1202 could significantly improve the outcomes for patients with lymphoma," stated Michael S. Weiss, the Company’s Executive Chairman and Interim Chief Executive Officer."

"C-myc continues to be one of the most challenging tumor mutations to target. C-myc tumors include some of the most difficult to treat, including double hit lymphoma and triple negative breast cancer, which are generally resistant to currently available therapies leading to very poor outcomes for patients. The work we completed at Columbia appears to identify a novel mechanism for targeting c-myc by combining these two agents and we are eager to see if the work in the lab translates into helping these patients. We look forward to working with TGR-1202 and carfilzomib in this important clinical research project," stated Dr. Owen O’Connor, Director Lymphoid Malignancies at Columbia Presbyterian Medical Center.

This study is currently open to enrollment at the Center for Lymphoid Malignancies, Columbia Presbyterian Medical Center, New York, NY. More information on this clinical study can be found at www.clinicaltrials.gov.

Advaxis Initiates Combination Portion of Phase 1/2 Study with Merck

On October 20, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported the commencement of Part B of the KEYNOTE-046 clinical trial evaluating Advaxis’ Lm immunotherapy candidate, ADXS-PSA, in combination with KEYTRUDA (pembrolizumab) in patients with previously treated, metastatic castration-resistant prostate cancer (mCRPC) (Press release, Advaxis, OCT 20, 2016, View Source [SID1234515920]). In Part A of the Phase 1/2 study, 14 patients were treated with ADXS-PSA monotherapy across three dose levels, with no dose limiting toxicities, paving the way for initiating Part B of the study.

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KEYNOTE-046 is a multicenter, open-label, nonrandomized, dose determining, Phase 1/2 trial evaluating the safety of ADXS-PSA. Part B of the study is evaluating the tolerability of ADXS-PSA in combination with KEYTRUDA in 30 patients with mCRPC. Secondary objectives for this study are to evaluate antitumor activity and progression-free survival of ADXS-PSA. KEYNOTE-046 is the first-in-human study of Advaxis’ Lm immunotherapy candidate for prostate cancer. It is the second study initiated to evaluate the use of KEYTRUDA in the treatment of advanced prostate cancer.

Advaxis also announced initiation of its Phase 3 AIM2CERV study, a multicenter, placebo-controlled, randomized study of axalimogene filolisbac, or AXAL, administered in the adjuvant setting following chemotherapy and radiation in women with high-risk, locally advanced cervical cancer (HRLACC). The primary objective of the trial is disease-free survival, with secondary objectives including examining overall survival and safety. In July 2016, Advaxis received a Special Protocol Assessment for the AIM2CERV trial, as well as Fast Track designation for AXAL as an adjuvant therapy for HRLACC patients.

Several trial sites have been opened for both studies and locations are currently screening patients for enrollment. For more information on Advaxis clinical trials, visit clinicaltrials.gov.