On July 18, 2016 Aeglea BioTherapeutics, Inc., (NASDAQ:AGLE) a biotechnology company committed to developing enzyme-based therapeutics in the field of amino acid metabolism to treat rare diseases and cancer, reported a regulatory and clinical update for its AEB1102 program (Press release, Aeglea BioTherapeutics, JUL 18, 2016, View Source [SID:1234513934]). AEB1102, the company’s lead investigational molecule, is a recombinant human enzyme designed to degrade the amino acid arginine and is being developed to treat two extremes of arginine metabolism.

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"We have developed a clinical program for AEB1102 with three ongoing clinical trials. The momentum for this program continues to build with AEB1102 receiving Fast Track designation from the FDA for hyperargininaemia in May and also receiving a positive opinion for Orphan Drug Designation from the European Medicines Agency this month," said David G. Lowe, Ph.D., co-founder, president and chief executive officer at Aeglea. "We believe this molecule has great potential for patients with rare diseases and cancer, and we look forward to gathering critical data as we continue to advance our programs."

AEB1102 for the Treatment of Rare Diseases

The European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending Orphan Drug Designation for AEB1102 for the treatment of hyperargininaemia in the European Union.

The EMA’s Orphan Drug Designation provides benefits, such as protocol assistance, fee reductions and ten years of market exclusivity upon regulatory approval, to companies working to develop treatments for life-threatening or chronically debilitating conditions that affect no more than five in 10,000 people in the EU and where no satisfactory treatments are available.

Additionally, Aeglea’s Phase 1 open-label, dose escalation study of AEB1102 for the treatment of patients with Arginase I deficiency has been initiated. The single arm study will enroll up to six patients to assess the safety, tolerability and pharmacokinetics of AEB1102. Enrollment is anticipated to be completed in 2016 with topline data expected in the first half of 2017.

Hyperargininaemia, or excessively high levels of arginine, is the result of a hereditary deficiency of arginase I. Arginase I deficiency is a urea cycle disorder caused by a mutation in the arginase I gene that leads to the inability to degrade arginine, the last step of the urea cycle. AEB1102 is intended to replace the function of arginase I in patients by returning elevated blood arginine levels to the normal physiological range.

AEB1102 for the Treatment of Arginine-Dependent Tumors

A Phase 1 open-label, dose escalation study of AEB1102 in advanced solid tumors, has currently enrolled six cohorts. To date, the maximum tolerated dose (MTD) has not yet been determined. Enrollment, which was initiated in October 2015, is expected to be completed by the end of 2016. Topline data are expected in 2017.

Following the determination of the MTD, additional cohorts of approximately 25 patients each with a specific solid tumor subtype will be enrolled and treated with AEB1102 at the MTD. The solid tumor subtype expansion arms are expected to initiate in 2017.

Additionally, Aeglea has initiated a Phase 1 open-label, dose escalation study of AEB1102 in patients with relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The objectives of the trial will be to determine the MTD and recommended Phase 2 dose as well as to assess the safety profile of AEB1102. Based off of data from the Phase 1 trial of AEB1102 for the treatment of advanced solid tumors, the company has recently amended the trial protocol to increase the starting dose in patients with AML and MDS. Enrollment is expected to be completed in 2017.

Dysregulation of amino acid metabolism has been shown to be a key event in tumor growth and development. Unlike healthy cells, these tumors cells have an abnormally high appetite for certain amino acids and are unable to create their own supply, making them vulnerable to starvation through depletion of that amino acid in the blood. AEB1102 is intended to address an unmet need for these tumor types by degrading arginine in the blood, reducing its level below the normal range to starve the tumor.

"We are pleased to have initiated our Arginase I deficiency and hematological malignancies trials, advancing our programs to bring AEB1102 one step closer to patients," said Sandra Rojas-Caro, M.D., chief medical officer at Aeglea. "There remain significant unmet medical needs for both Arginase I deficiency and cancer. Fulfilling this need and bringing effective treatments to patients are at the center of what drives us at Aeglea."

About AEB1102

AEB1102 is a recombinant human arginase I enzyme designed to degrade the amino acid arginine. Aeglea is developing AEB1102 to treat two extremes of arginine metabolism, including arginine excess in patients with Arginase I deficiency, as well as some cancers which have been shown to have a metabolic dependency on arginine. In patients with Arginase I deficiency, AEB1102 is intended for use as Enzyme Replacement Therapy to restore the function of arginase I in patients and return elevated blood arginine levels to the normal physiological range. Aeglea is currently conducting a Phase 1 clinical trial in solid tumor cancer patients to evaluate the safety and tolerability of AEB1102. Data from this trial demonstrated that AEB1102 has the ability to reduce blood arginine levels, providing initial human proof of mechanism.

On July 18, 2016 MabVax Therapeutics Holdings, Inc. (OTCQB: MBVX), a clinical-stage oncology drug development company, reported the initiation of patient enrollment at Memorial Sloan Kettering Cancer Center (MSK) in a Phase I clinical trial evaluating its new generation diagnostic PET imaging agent, MVT-2163 for patients with locally advanced or metastatic adenocarcinoma of the pancreas (PDAC) or other CA19-9 positive malignancies (Press release, MabVax, JUL 18, 2016, View Source [SID:1234513931]). This study follows another investigational Phase I trial recently initiated at MSK utilizing the Company’s HuMab-5B1 antibody MVT-5873 as a therapeutic product for the treatment of Pancreatic cancer.

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The diagnostic imaging study will administer MVT-2163 as a PET imaging agent for patients with pancreatic cancer. 89Zr-HuMab-5B1 combines a well-established PET imaging radiolabel, Zirconium [Zr-89], with the targeting specificity of the Company’s HuMab-5B1 antibody. This clinical trial will evaluate the safety, pharmacokinetics and biodistribution of MVT-2163 in patients with pancreatic cancer. The trial will also determine the ideal dose and timing for an optimal PET scan image. Preclinical xenograft animal models demonstrated high image resolution of tumors, making MVT-2163 attractive as a potential companion diagnostic agent for use with the MVT-5873 therapeutic product. Some of the preclinical data supporting the development of this new agent was funded by the National Cancer Institute contract (HHSN261201300060C) and previously published in the Journal of Nuclear Medicine, Bioconjugate Chemistry, and the Proceedings of the National Academy of Sciences. This study is under the direction of Dr. Christian Lohrmann as lead investigator who has received a grant from a non-profit foundation to help support this clinical trial.

"We are very excited to begin patient enrollment for this Phase I trial at MSK," said David Hansen, MabVax President and CEO. "We expect to see in the next few weeks the first PET images from this study establishing the level of targeting specificity of the HuMab-5B1 antibody. The results of our study are intended to provide investigators with a better understanding of the cancers afflicting these patients. If the product produces the desired images, it could help improve diagnosis and physician decision making on treatment options for pancreatic cancer and other CA19-9 positive malignancies. We look forward to announcing interim results from this trial during the third quarter of 2016."

About HuMab-5B1:

MabVax’s HuMab-5B1 antibody is fully human and was discovered from the immune response of cancer patients vaccinated with an antigen-specific vaccine during a Phase I trial at Memorial Sloan Kettering Cancer Center. In preclinical research, the 5B1 antibody has demonstrated high specificity and affinity, and has shown potent cancer cell killing capacity and efficacy in animal models of pancreatic, colon and small cell lung cancers. The antigen the antibody targets is expressed on more than 90% of pancreatic cancers making the antibody potentially broadly applicable to most patients suffering from this type of cancer. MabVax’s two lead antibody clinical programs utilize HuMab-5B1 as a naked antibody (MVT-5873) and as an immuno-PET imaging agent (MVT-2163).

On July 18, 2016 Seattle Genetics, Inc. (NASDAQ:SGEN) and Takeda Pharmaceutical Company Limited (TSE:4502) reported the final data of the ADCETRIS (brentuximab vedotin) monotherapy pivotal Phase 2 clinical trial in relapsed or refractory classical Hodgkin lymphoma were published in the journal Blood (Press release, Takeda, JUL 18, 2016, View Source [SID:1234513930]).

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The manuscript, which summarizes the five-year, end-of-study results, highlights that patients who attained a complete response achieved long-term disease control. The manuscript is available online today and will be included in a future print edition of Blood. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a key driver of classical Hodgkin lymphoma tumor pathogenesis. ADCETRIS is being evaluated globally as the foundation of therapy for Hodgkin lymphoma in more than 45 ongoing corporate- and investigator-sponsored clinical trials.

"At the time of trial initiation, historical outcomes for Hodgkin lymphoma patients who relapsed after an autologous stem cell transplant were poor, with median post-progression survival of 1.3 years, and the only long-term disease control option for these patients was considered to be an allogeneic stem cell transplant," said Robert Chen, M.D., City of Hope National Medical Center, Duarte, California, and lead author of the Blood manuscript. "The median survival of the patients on ADCETRIS monotherapy in this pivotal Phase 2 trial exceeds these historic figures, and I am pleased to see the publication of the final data."

"For over a decade, we have demonstrated our commitment to improve treatment outcomes in Hodgkin lymphoma through numerous clinical trials evaluating novel therapeutic approaches. Today’s final publication of the ADCETRIS monotherapy pivotal study in Hodgkin lymphoma patients represents a significant milestone for the trial that supported approval in more than 60 countries globally and established current use as standard-of-care in the relapsed setting," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "The long-term safety and efficacy data from the pivotal trial are supportive of our ongoing development of ADCETRIS for other classical Hodgkin lymphoma settings, including the frontline setting. Our broad clinical program is investigating ADCETRIS as a foundation of care for Hodgkin lymphoma and potentially other CD30-expressing malignancies."

"The positive final results from this trial of ADCETRIS demonstrated that of the patients who had a complete response, 38 percent achieved long-term disease control for the duration of the study," said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. "In addition, the median overall survival of 40.5 months and progression-free survival of 9.3 months observed across the trial further establish the role of ADCETRIS in improving outcomes for patients with relapsed Hodgkin lymphoma."

The pivotal, single-arm trial, which supported the FDA approval in 2011 of ADCETRIS for this indication, was conducted in 102 relapsed or refractory classical Hodgkin lymphoma patients who had previously received an autologous stem cell transplant (ASCT) to assess the efficacy and safety of single-agent ADCETRIS. Enrolled patients had received a median of more than three prior chemotherapy regimens. After a five-year follow-up period, the final results from the pivotal trial include:

The median overall survival and progression-free survival were 40.5 months (95% confidence interval [CI]: 28.7, 61.9) and 9.3 months (95% CI: 7.1, 12.2), respectively. The estimated five-year overall survival and progression-free survival rates were 41 percent and 22 percent.
Of the 102 patients treated, 34 patients (33%) had a complete remission, with the median response duration not reached. For patients who had a complete remission, the estimated five-year overall survival rate was 64 percent (95% CI: 48, 80) and the estimated five-year progression-free survival rate was 52 percent (95% CI: 34, 69).
Thirteen of the 34 patients (38%) who achieved a complete remission continued to be followed and remained in remission for over five years at study closure. Of these patients, four underwent consolidative allogeneic stem cell transplants while in remission, and nine received no further therapy.
The most common adverse events of any grade were peripheral sensory neuropathy, fatigue, nausea, neutropenia and diarrhea. Treatment emergent peripheral neuropathy was experienced by 56 patients (55%). Eighty-eight percent of these patients experienced improvement of their peripheral neuropathy symptoms, including 73 percent with complete resolution.
About ADCETRIS

ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials, including the Phase 3 ALCANZA trial and two additional Phase 3 studies, ECHELON-1 in frontline classical Hodgkin lymphoma and ECHELON-2 in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical Hodgkin lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 60 countries.

In June 2016, the European Commission extended the current conditional approval of ADCETRIS and approved ADCETRIS for the treatment of adult patients with CD30+ Hodgkin lymphoma at increased risk of relapse or progression following ASCT. See important safety information below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

About Seattle Genetics

Seattle Genetics is an innovative biotechnology company that develops and commercializes novel antibody-based therapies for the treatment of cancer. The company’s industry-leading antibody-drug conjugate (ADC) technology harnesses the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. ADCETRIS (brentuximab vedotin), the company’s lead product, in collaboration with Takeda Pharmaceutical Company Limited, is the first in a new class of ADCs approved globally in more than 60 countries for relapsed classical Hodgkin lymphoma (HL) and relapsed systemic anaplastic large cell lymphoma (sALCL). Seattle Genetics is also advancing vadastuximab talirine (SGN-CD33A; 33A), an ADC in a Phase 3 trial for acute myeloid leukemia. Headquartered in Bothell, Washington, Seattle Genetics is also advancing a robust pipeline of innovative therapies for blood-related cancers and solid tumors designed to address significant unmet medical needs and improve treatment outcomes for patients. The company has collaborations for its proprietary ADC technology with a number of companies including AbbVie, Astellas, Bayer, Genentech, GlaxoSmithKline and Pfizer. More information can be found at www.seattlegenetics.com

About Takeda
Takeda Pharmaceutical Company Limited is a global, R&D-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its research efforts on oncology, gastroenterology and central nervous system therapeutic areas. It also has specific development programs in specialty cardiovascular diseases as well as late-stage candidates for vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as its presence in emerging markets, fuel the growth of Takeda. More than 30,000 Takeda employees are committed to improving quality of life for patients, working with our partners in health care in more than 70 countries. For more information, visit View Source

Additional information about Takeda is available through its corporate website, www.takeda.com, and additional information about Takeda Oncology, the brand for the global oncology business unit of Takeda Pharmaceutical Company Limited, is available through its website, www.takedaoncology.com.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Contraindication

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy (PN): ADCETRIS treatment causes a PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.
Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Patients who experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.
Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.
Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.
Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.
Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
Pulmonary toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Gastrointestinal (GI) complications: Fatal and serious GI complications, including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus have been reported in ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
Embryo-fetal toxicity: Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Adverse Reactions

In two uncontrolled single-arm trials of ADCETRIS as monotherapy in 160 patients with relapsed classical HL and sALCL, the most common adverse reactions (≥20%), regardless of causality, were: neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

In a placebo-controlled trial of ADCETRIS in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT, the most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were: neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Drug Interactions

Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations

MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.

Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

For additional Important Safety Information, including Boxed WARNING, please see the full Prescribing Information for ADCETRIS at www.seattlegenetics.com or www.ADCETRIS.com.

ADCETRIS (brentuximab vedotin) Global Important Safety Information

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

INDICATIONS

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL):

1. following autologous stem cell transplant (ASCT) or

2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.

ADCETRIS is indicated for the treatment of adult patients with CD30+ HL at increased risk of relapse or progression following ASCT.

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of ADCETRIS with bleomycin is contraindicated as it causes pulmonary toxicity.

SPECIAL WARNINGS & PRECAUTIONS

Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in PML and death can occur in patients treated with ADCETRIS. PML has been reported in patients who received ADCETRIS after receiving multiple prior chemotherapy regimens.

Patients should be closely monitored for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. ADCETRIS dosing should be held for any suspected case of PML and should be permanently discontinued if a diagnosis of PML is confirmed.

Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Patients should be closely monitored for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. ADCETRIS should be held for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.

Pulmonary Toxicity: Cases of pulmonary toxicity, some with fatal outcomes, have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. New or worsening pulmonary symptoms should be promptly evaluated and treated appropriately.

Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, sepsis/septic shock (including fatal outcomes), and herpes zoster, and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for emergence of possible serious and opportunistic infections.

Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have occurred with ADCETRIS. Patients should be carefully monitored during and after an infusion. If anaphylaxis occurs, administration of ADCETRIS should be immediately and permanently discontinued and appropriate medical therapy should be administered. If an IRR occurs, the infusion should be interrupted and appropriate medical management instituted. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. IRRs are more frequent and more severe in patients with antibodies to ADCETRIS.

Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. These patients should be monitored closely and managed according to best medical practice.

Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically cumulative and reversible in most cases. Patients should be monitored for symptoms of PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay and a dose reduction or discontinuation of ADCETRIS.

Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose.

Febrile neutropenia: Febrile neutropenia has been reported. Patients should be monitored closely for fever and managed according to best medical practice if febrile neutropenia develops.

Stevens-Johnson syndrome (SJS): SJS and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have been reported. If SJS or TEN occurs, treatment with ADCETRIS should be discontinued and appropriate medical therapy should be administered.

Gastrointestinal (GI) Complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorragh, have been reported. New or worsening GI symptoms should be promptly evaluated and treated appropriately.

Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Liver function should be tested prior to treatment initiation and routinely monitored in patients receiving ADCETRIS. Patients experiencing hepatotoxicity may require a delay, dose modification, or discontinuation of ADCETRIS.

Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. However, any patient who experiences an event of hyperglycemia should have their serum glucose closely monitored. Anti-diabetic treatment should be administered as appropriate.

Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations. The recommended starting dose in patients with hepatic impairment or severe renal impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with renal or hepatic impairment should be closely monitored for adverse events.

Sodium content in excipients: This medicinal product contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

INTERACTIONS

Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia and should be closely monitored. Co-administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS but it appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

PREGNANCY: Women of childbearing potential should be using two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. ADCETRIS should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus. If a pregnant woman needs to be treated, she should be clearly advised on the potential risk to the fetus.

LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded. With the potential risk, a decision should be made whether to discontinue breast-feeding or discontinue/abstain from therapy with ADCETRIS.

FERTILITY: In nonclinical studies, ADCETRIS treatment has resulted in testicular toxicity, and may alter male fertility. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.

ADVERSE REACTIONS

Serious adverse drug reactions were: pneumonia, acute respiratory distress syndrome, headache, neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, nausea, pyrexia, peripheral motor neuropathy, peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome.

In the clinical studies of ADCETRIS, adverse reactions defined as very common (≥1/10) were: infection, upper respiratory tract infection, neutropenia, PN (sensory and motor), cough, dyspneoa, diarrhea, nausea, vomiting, constipation, abdominal pain, alopecia, pruritus, myalgia, arthralgia, fatigue, chills, pyrexia, infusion-related reactions and weight decreased. Adverse reactions defined as common (≥1/100 to <1/10) were: Sepsis/septic shock, herpes zoster, pneumonia, herpes simplex, anemia, thrombocytopenia, hyperglycemia, dizziness, demyelinating polyneuropathy, ALT/AST increased, rash, and back pain.

On July 18, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported that its lead Lm immunotherapy candidate, axalimogene filolisbac (AXAL), has been classified as an advanced-therapy medicinal product (ATMP) for the treatment of cervical cancer by the European Medicines Agency’s Committee for Advanced Therapies (CAT) (Press release, Advaxis, JUL 18, 2016, View Source [SID:1234513929]).

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"Classification of AXAL as an ATMP is reflective of a groundbreaking new opportunity for the treatment of HPV-associated cancers," said Robert Ashworth, PhD, Vice President, Regulatory Affairs. "Building upon the approach endorsed at Advaxis’ meetings with National Competent Authorities earlier this year, it allows us to take advantage of a specific EU regulatory framework, akin to fast-track in the United States, designed to facilitate the review, approval, and access of AXAL in the EU market." In the next phase of this regulatory process, CAT assessment of currently available quality and non-clinical data may help resolve some issues prior to the submission of a marketing-authorization application (MAA).

The Committee for Advanced Therapies is the committee at the European Medicines Agency that is responsible for classifying and assessing the quality, safety and efficacy of advanced-therapy medicinal products and following scientific developments in the field. It is a multidisciplinary committee, gathering together some of the best available experts in Europe. The ATMP designation is a classification for certain medicines for human use that are gene-, cell-, or tissue-based. The main responsibility of the CAT is to prepare a draft opinion on each ATMP application submitted to the European Medicines Agency, before the Committee for Medicinal Products for Human Use (CHMP) adopts a final opinion on granting a marketing authorization for the product. During drug development, CAT also reviews and certifies the acceptability of quality and non-clinical data.

Advaxis’ immunotherapies, including AXAL, are designed to capitalize on the body’s ability to recognize and attack bacterial infections. Advaxis’ core technology – Lm Technology – alters a live strain of Listeria monocytogenes bacteria to generate cancer fighting T-cells directed against a cancer antigen and neutralizing factors that protect the tumor microenvironment from immunologic attack and contribute to tumor growth. AXAL has Orphan Drug Designation in Europe for treatment of anal cancer.

About Axalimogene Filolisbac

Axalimogene filolisbac (AXAL) is Advaxis’ lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase 2 study in recurrent/refractory cervical cancer, AXAL showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the Company’s Lm Technology. AXAL has Orphan Drug Designation in the U.S. for the treatment of invasive cervical, head and neck and anal cancers.

On July 18, 2016 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the phase III GOYA study evaluating Gazyva/Gazyvaro (obinutuzumab) plus CHOP chemotherapy (G-CHOP) in people with previously untreated diffuse large B-cell lymphoma (DLBCL) did not meet its primary endpoint of significantly reducing the risk of disease worsening or death (progression-free survival; PFS) compared to MabThera/Rituxan (rituximab) plus CHOP chemotherapy (R-CHOP) (Press release, Hoffmann-La Roche , JUL 18, 2016, View Source [SID:1234513926]). Adverse events with Gazyva/Gazyvaro and MabThera/Rituxan were consistent with those seen in previous clinical trials when each was combined with various chemotherapies. Data from the GOYA study will be presented at an upcoming medical meeting.

“Two previous studies showed Gazyva/Gazyvaro helped people with previously untreated follicular lymphoma or chronic lymphocytic leukaemia live longer without their disease worsening compared to MabThera/Rituxan, when each was combined with chemotherapy. We were hopeful we could show a similar result for people with diffuse large B-cell lymphoma and once again improve on the standard of care,” said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. “We will continue to analyse the GOYA data to better understand the results, and to study other investigational treatments in this disease with the goal of further helping these patients.”

About the GOYA study
GOYA (NCT01287741) is a global phase III open-label, multi-centre, randomised two-arm study examining the efficacy and safety of the combination of Gazyva/Gazyvaro plus CHOP chemotherapy (G-CHOP) compared to MabThera/Rituxan plus CHOP chemotherapy (R-CHOP). GOYA included 1,418 previously untreated patients with CD20-positive DLBCL. The primary endpoint of the study is investigator-assessed PFS, with secondary endpoints including PFS assessed by independent review committee (IRC), response rate (overall response, ORR; and complete response, CR), overall survival (OS), disease free survival (DFS) and safety profile. The GOYA study is being conducted in cooperation with the Fondazione Italiana Linfomi (FIL, Italy).

About Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system.
Gazyva/Gazyvaro is currently approved in more than 70 countries in combination with chlorambucil, for people with previously untreated chronic lymphocytic leukaemia. The approvals were based on the CLL11 study, showing significant improvements with Gazyva/Gazyvaro plus chlorambucil across multiple clinical endpoints, including PFS, overall response rate (ORR), complete response rate (CR), and minimal residual disease (MRD) when compared head-to-head with MabThera/Rituxan plus chlorambucil.
In February 2016, Gazyva was approved by the US Food and Drug Administration in combination with bendamustine followed by Gazyva alone for people with follicular lymphoma who did not respond to a Rituxan-containing regimen, or whose follicular lymphoma returned after such treatment. In June 2016, Gazyvaro was approved by the European Commission in combination with bendamustine followed by Gazyvaro maintenance in people with follicular lymphoma who did not respond or who progressed during or up to six months after treatment with MabThera or a MabThera-containing regimen. Both approvals were based on the phase III GADOLIN study, showing a significant improvement in progression-free survival with Gazyva/Gazyvaro-based therapy compared to bendamustine alone. Gazyva is marketed as Gazyvaro in the EU and Switzerland.

In May 2016, the phase III GALLIUM study in people with previously untreated follicular lymphoma met its primary endpoint early. GALLIUM compared the efficacy and safety of Gazyva/Gazyvaro plus chemotherapy (CHOP, CVP or bendamustine) followed by Gazyva/Gazyvaro alone, head-to-head with MabThera/Rituxan plus chemotherapy followed by MabThera/Rituxan alone. Results from a pre-planned interim analysis showed that Gazyva/Gazyvaro-based treatment resulted in superior progression-free survival compared to MabThera/Rituxan-based treatment. Adverse events with either Gazyva/Gazyvaro or MabThera/Rituxan were consistent with those seen in previous clinical trials when each was combined with various chemotherapies. Data from the GALLIUM study will be presented at an upcoming medical meeting and submitted to health authorities for approval consideration.
Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.

About DLBCL
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for about one in three cases of NHL1. DLBCL is an aggressive (fast-growing) type of NHL, which is generally responsive to treatment in the frontline2. However, as many as 40% of patients will relapse, at which time salvage therapy options are limited and survival is short2. Approximately 123,000 people worldwide are estimated to be diagnosed with DLBCL each year3.